J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

Journal of Clinical , 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 , 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 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 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 the they lack any normal structures. Many examples of other subcategory, the liver is more coarsely scarred, cirrhosis associated with alcoholism, biliary obst- with obvious macronodules surrounded by broad ruction, venous outflow obstruction, haemochro- fibrous septa. These may contain several portal matosis, and Indian childhood cirrhosis fall into the tracts. This pattern has been assumed to result from micronodular category. There is a tendency for the necrosis of large areas of parenchyma ('postcollapse' micronodular pattern ofcirrhosis to be seen relatively or 'postnecrotic' pattern). early in the course of the disease and for larger nodules to develop later, but there are exceptions to (c) Mixedpattern. When micro andmacro nodules are this rule. present in approximately equal proportions the term 'mixed' may be applied. (b) Macronodular pattern (Figs. 2, 4, 5, 7). Many The size of the liver, as seen post mortem, is of nodules are over 3 mm in diameter but the size varies some additional interest. Micronodular cirrhotic considerably and some nodules measure several centi- livers are often normal in size or enlarged, par- metres. They may contain portal structures and ticularly when fatty. Macronodular cirrhotic livers efferent veins, but these are abnormally related to may be normal but are often reduced in size, each other. Two subcategories can be recognised. In especially when coarsely scarred. one, the macronodules are divided by slender, some- times incomplete septa, which link mainly portal Aetiology tracts. The fine, reticulate pattern of fibrosis makes The first of the three categories listed below includes nodularity unapparent to naked-eye examination and established associations between aetiological factors renders histological diagnosis difficult. This seems to and cirrhosis, but the precise nature of the associa- http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Fig. 1 Fig. 2 Fig. 1 Cirrhosis with a micronodular pattern in a middle-aged male alcoholic; nearly all the nodules are less than 3 mm in size (indicated by scale). Fig. 2 Cirrhosis with a macronodular pattern in an elderly man with a history of hepatitis many years before, but tests for hepatitis B antigen negative; many of the nodules are larger than 3 mm in diameter (indicated by scale). J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

398 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, andL. H. Sobin

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Fig. 3 Fig. 4 Fig. 3 Cirrhosis with a micronodular pattern in an alcoholic; the nodules are almost uniform, lack any normal structure, and are roughly lobular or sublobular in size. Reticulin x 24. http://jcp.bmj.com/ Fig. 4 Cirrhosis with a macronodular pattern; no history ofhepatitis, but hepatitis B antigen present on testing; the macronodules are divided by slender, sometimes incomplete septa ('incomplete' or 'posthepatitic' pattern). Reticulin x 24. tions and ofthe pathogenetic mechanisms involved is this fibrosis may be diffuse, extensive, and clinically often far from clear. Aetiological diagnosis is usually important. Whether cirrhosis can also result from on September 26, 2021 by guest. Protected copyright. reached by a combination of epidemiological, schistosomiasis without the intervention of other clinical, biochemical, immunological, and histo- aetiological factors is not proved. logical investigations. The third category includes cirrhosis with a well- In the second category the association between an defined geographical, clinical, or morphological pat- aetiological agent and cirrhosis is debatable or tern but without an established cause. It also controversial. The role of autoimmunity as an includes cirrhosis without a well-defined pattern and initiating cause of cirrhosis remains unproven, inwhichithas not proved possible to identify a cause. although it is likely that immunological mechanisms Such cases have been labelled 'cryptogenic', but this play an important part in the perpetuation ofchronic group presumably includes several different, poten- liver disease due to a variety of causes. It is doubtful tially identifiable aetiologies and should not be if malnutrition by itself is ever a cause of cirrhosis in regarded as a disease entity. man. Protein deficiency, as seen in Kwashiorkor, produces gross fatty change in the liver but it does (a) Cirrhosis with establishedaetiologicalassociations. not lead to chronic liver disease. Mycotoxins, of The following factors are recognised: which aflatoxin is the best known, are a potent cause Viral hepatitis of liver cancer in animals, and can produce cirrhosis Alcoholism in some species. Their exact role in human cirrhosis Metabolic disorders (eg, haemochromatosis, Wilson's is still uncertain. Several parasitic diseases can give disease, alpha-1-antitrypsin deficiency, type IV rise to hepatic fibrosis. In the case of schistosomiasis, glycogenosis, galactosaemia) J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The moIrphology of cirrhosis 399

Fig.UJ,~~~~~~~~~~~5 Cirrhosis with a macronodular pattern, aetiology unknown; the macronodules are separated by broad fibrous septa ('postcollapse' or 'postnecrotic' pattern). Reticulin x 33. 0 L_~ ~ ~ ~ http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Fig. 6 Characteristic fragmentation of a needle biopsy specimen in a case of cirrhosis with a micro- nodular pattern. Such fragments are wholly or partially surrounded by fbrosis, which may be recognised only with the help of reticulin or collagen stains. Reticulin x SO. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

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Biliary disease (intra- and extra-hepatic) recognise with the naked eye. Surgical wedge biopsies http://jcp.bmj.com/ Venous outflow obstruction (veno-occlusive disease, can be misleading since there is sometimes increased Budd-Chiari syndrome) fibrous tissue in the subcapsular area, and the appear- Toxins and therapeutic drugs (eg, pyrrolizidine ances may mimic those of cirrhosis. The problem is alkaloids, methotrexate, oxyphenisatin, alpha usually resolved if the biopsy is sufficiently large, methyldopa) because the changes do not extend into the deeper Intestinal bypass operations for obesity part of the liver except in cirrhosis. The recognition of cirrhosis may be difficult in needle biop.sy speci- on September 26, 2021 by guest. Protected copyright. (b) Debatable aetiological factors. Examples are: mens, especially in those taken with a needle of the Autoimmunity Menghini type. This needle tends to aspirate soft Mycotoxins liver parenchyma preferentially, leaving the tougher Schistosomiasis connective tissue behind. This is a particular prob- Malnutrition lem when nodules are large. Helpful features for the recognition of cirrhosis in a needle biopsy specimen (c) Cirrhosis of unknown aetiology include the following: (i) With well-defined pattern-Indian childhood (a) Presence ofparenchymal nodules separated by cirrhosis fibrous septa. When several well-defined nodules are (ii) Without well-defined pattern 'cryptogenic' seen the diagnosis of cirrhosis is virtually certain, but cirrhosis an occasional rounded area of parenchyma may be seen in any severe fibrotic liver. DIAGNOSIS (b) Differences in liver cell size and appearance Recognition of cirrhosis between one area and another. This may be accom- Recognition is usually easy at necropsy, although the panied by liver cell dysplasia (see below) or by evi- incomplete septal variant of the macronodular pat- dence of active growth (thickened liver cell plates, tern may present some difficulties, especially in the evidence of compression). absence of stains for collagen and reticulin fibres. (c) Fragmentation of the biopsy specimen with or The micronodular pattern is sometimes difficult to without fibrous tissue at the margins of the frag- J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 401

Fig. 8a Swollen, 'ground-glass' hepatocytes showing finely granular, eosinophilic cytoplasm due to the presence ofhepatitis B surface antigen. Haematoxylin and eosin x 640. http://jcp.bmj.com/

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Fig. 8b 'Ground-glass` hepatocytes stainedy-with Shikata's y orcein technique x 400. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

402 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. 1 Scheuer, andL. H. Sobin

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Fig. 9 : Inflamed fibrous septa dissect the liver into nodules; there is also extensive diffuse fibrosis within the parenchyma; liver cells show fatty change. H and E x 100. http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

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Fig. 10 Alcoholic hepatitis; note fibrosis extending from a portal tract (bottom left) to an area once occupied by a central vein which is now obliterated (top right). This change has been referred to as 'centrilobular hyaline sclerosis', as fibrosis is often rather hypocellular and may be quite dense. Masson's trichrome x 160. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 403

ments or partially surrounding them. If the fibrous highlight histological features which may help to tissue is scanty, it may be recognised only with the determine some important causes (Table 2). help of reticulin or collagen stains. (a) Viral hepatitis (Figs 8a, 8b). Demonstration of (d) Fibrous septa traversing the specimen, often the hepatitis B surface antigen in liver cells by with abnormal lobular architecture, for example, empirical stains or immunohistological methods is absence of portal tracts or of normal vascular helpful, but the antigen may also be found in carriers relationships. who have cirrhosis due to other causes. Failure to (e) Altered architecture and vascular relationships demonstrate the antigen does not exclude a viral without septum formation. aetiology. Its presence may be suspected by the The precise point at which pre-cirrhotic changes finding of 'ground-glass' hepatocytes. At present, become established cirrhosis cannot always be tests for other antigens such as core antigen or the determined. 'e' antigen are not yet widely available. (b) Alcoholism (Figs 9, 10, 11). A combination of Morphological pattern fatty change, a micronodular pattern, and areas of This is easier to determine in necropsy material and relatively hypocellular fibrosis should suggest this in wedge biopsies than in needle biopsy specimens, cause. Later in the course of the disease cirrhosis is because of the problem of sampling. It is not possible often macronodular, and fat may be scanty or absent. to deduce the morphological pattern in the whole Features of chronic active hepatitis may be super- liver with confidence from a small specimen. imposed. The most helpful histological feature is the Apparent resolution of cirrhosis after treatment presence of alcoholic hepatitis, characterised by should be interpreted with great care, because the liver cell swelling with or without fatty change, peri- passage of time can lead to increase in nodule size cellular fibrosis, Mallory's hyalin, and focal infiltra- and difficulty in biopsy diagnosis. tion by neutrophils. Hyalin is not always identifiable and is also found in other conditions. Small, PAS- Aetiology negative globules, which represent greatly enlarged This paper does not set out to give a complete mitochondria, may be seen at any stage. Siderosis is description of the characteristics of all forms of common. cirrhosis, but the following guidelines are offered to (c) Haemochromatosis is characterised by increas- http://jcp.bmj.com/ Table 2 Morphological markers and aetiology ofcirrhosis Aetiology Common Fat Choles- Iron Copper Acidophilic Xantho- PAS+ PAS- Mallory's Ground- morphological tasis bodies matous globules globules hyalin glass pattern* change hepatocytes Viral hepatitis Macro or - - - - + - - - - t Micronodular

Alcoholism Microor + i ± - + - - + + on September 26, 2021 by guest. Protected copyright. Macronodular Haemo- Micronodular ± - + ------chromatosis Wilson's Macronodular ± ± - ± + - - - + disease a-l-Anti- Micro or : + - i i - + - ± trypsin Macronodular deficiency Primary Micronodular - i - + - + - - ± - biliary ('Biliary') cirrhosis Secondary Micronodular - + - + - + - - i- biliary ('Biliary') cirrhosis Venous Micronodular - - - - - outflow ('Reversed') obstruction Intestinal Micronodular + - - - i - - - i bypass operation Indian Micronodular - i - ± - - - i + childhood cirrhosis

- usually absent; ± may be present; + usually present. *Progression is generally from micro to macronodular. tMay also be seen in 'healthy' carriers. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

404 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, and L. H. Sobin ing portal fibrosis and septum formation with iron in lobular and vascular relationships and may reveal liver cells, phagocytes, and bile-duct epithelium. efferent veins with subintimal fibrosis, thrombosis, or is usually slight, and, apart from the fibrous obliteration. siderosis, the parenchyma is little altered. (i) Toxins and therapeutic drugs. These can giverise (d) Wilson's disease (Fig. 12a). The morphological to such a large variety of patterns and appearances pattern of cirrhosis varies, but large nodules are that no brief outline can be given here. Drugs should common. Fatty change, nuclear vacuolation, and be suspected as possible aetiological agents in all Mallory's hyalin may be prominent. The cirrhosis cases of cirrhosis. may show considerable activity, with piecemeal (j) Intestinal bypass operations for obesity. Fatty necrosis and inflammatory infiltration. Increased change is common, and hepatic fibrosis may develop. amounts of copper can sometimes be demonstrated, Cirrhosis is rare, and the appearances may be but copper is also found in some other conditions, identical with those seen in the alcoholic. notably primary biliary cirrhosis and other examples (k) Indian childhood cirrhosis. The cirrhosis is of chronic . typically micronodular in pattern, and there is (e) Alpha-l-antitrypsin deficiency (Fig. 12b). In fibrosis around individual cells or small groups. homozygous (Pi ZZ) subjects the liver may be nor- Mallory's hyalin is prominent, widespread, and not mal or abnormal, and a wide variety of disease pat- recognizably centrilobular as it is in alcoholic terns is found, ranging from hepatitis to cirrhosis. hepatitis. Fatty change is usually absent. The latter sometimes resembles the cirrhosis which follows prolonged biliary obstruction. Intracyto- Activity plasmic globules of faintly eosinophilic material, This is measured by the degree of liver cell destruc- which are positive with the PAS stain after diastase tion and inflammatory infiltration, and its assess- digestion, are characteristic. Similar globules have ment is an important part of diagnosis. Piecemeal rarely been found in the absence of liver disease or necrosis at the margins of septa is usually considered emphysema. the most relevant form of necrosis in this respect, but (f) Primary biiary cirrhosis (Fig. 13). Small and other forms (eg, acidophilic bodies, focal necrosis) medium-sized bile ducts are hyperplastic or necrotic should also be taken into account. In cirrhosis due to and are surrounded and infiltrated by plasma cells, alcoholism, for example, activity in the early stages may be largely in the form of alcoholic hepatitis,

lymphocytes, eosinophil leucocytes, and epithelioid http://jcp.bmj.com/ cells. Ill-defined or well-organised granulomas form, while later, perhaps after improved drinking habits, usually near the damaged bile ducts. The lesions are piecemeal necrosis and infiltration by lymphocytes focal and may be missed unless several sections are and plasma cells may become more important. It is examined. Later, the damaged ducts are replaced by customary to grade activity in biopsy specimens as loose lymphoid aggregates, thereis increasingfibrosis, slight, moderate, or severe, but it should be remem- and cholestasis is present at the periphery of the bered that activity may have been modified by treat- lobules. Mallory's hyalin sometimes is prominent ment and that the sample of liver tissue may not be and stains for copper are often positive. Lobular representative. on September 26, 2021 by guest. Protected copyright. architecture remains intact for long periods. When Complications and secondary phenomena cirrhosis is established paucity of bile ducts may sug- (a) Ischaemic necrosis. This may be focal, with gest that it is primary rather than secondary to long- coagulative necrosis of small groups of cells, or standing obstruction. involve whole nodules or centres of nodules. It often, (g) Secondary biiary cirrhosis (Fig. 14). Portal though not invariably, follows gastrointestinal fibrosis and septum formation predominate, and bleeding. parenchymal alterations are often slight. There may (b) Siderosis. Intense liver-cell siderosismaybe seen be morphological cholestasis due to persisting in alcoholic liver disease and it also follows portal obstruction to bile ducts, but this is not invariable or systemic shunt operations. necessary for diagnosis. Lobular architecture sur- (c) Biliary obstruction. This can develop as a result vives for long periods, and groups of adjacent of cholelithiasis or distortion of intrahepatic bile nodules form complex parenchymal islands resemb- ducts. Histologically visible cholestasis may also be ling the pieces of a jig-saw puzzle. due to drug therapy. (h) Venous outflow obstruction (Fig. 15). Helpful (d) Infection. There is an increased risk of viral and diagnostic features include a micronodular pattern bacterial infections in cirrhosis, which may be evi- with predominantly centrilobular fibrosis, which give dent on histology. the appearance of 'reversed lobulation'. Sinusoids around the fibrotic areas are markedly dilated. Col- CIRRHOSIS AND CANCER OF THE LIVER lagen staining is necessary for accurate assessment of Available evidence indicates that cirrhosis is linked J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 405

SP 'T7~~~~~~~~~~~~~~~~~~~~~~~~~ Fig. 11 Alcoholic hepatitis: several hepatocytes contain clumps of Mallory's hyalin in their cytoplasm. Note the presence of neutrophil polymorphs, a characteristic feature. H and E x 640. http://jcp.bmj.com/ with hepatocellular (or liver-cell) carcinoma but not Chronic hepatitis with cholangiocarcinoma (intrahepatic bile duct carcinoma). The increased risk of malignancy may DEFINITION depend on the aetiology and the duration of the cir- Chronic hepatitis has been defined as inflammation rhotic process. of the liver continuing without improvement for at Liver-cell hyperplasia in cirrhosis sometimes pro- least six months. Many examples of chronic hepatitis on September 26, 2021 by guest. Protected copyright. duces distinct, tumour-like nodules made up of follow acute hepatitis, but in others no acute attack double liver-cell plates with increased cytoplasmic can be identified clinically. The transition of chronic basophilia. The term 'adenomatoid hyperplasia' has hepatitis to cirrhosis is often difficult to define. been applied to such appearances. There is no evi- dence that it is associated with an increased risk of CLASSIFICATIONS malignancy. Morphology Malignancy is often associated with, and may be Chronic hepatitis is normally classified according to preceded by, liver cell dysplasia (Fig. 16). The term histopathological features, although a complete refers to cellular enlargement, which affects both diagnosis requires both histological and clinical data. nucleus and cytoplasm, together with nuclear Two main groups are recognised: pleomorphism, multinucleation, and occasional (a) Chronic persistent hepatitis (Fig. 17). This is a mitoses. These changes may involve groups of liver somewhat non-specific picture characterised by por- cells or, less commonly, whole cirrhotic nodules. tal tract expansion and inflammatory cell infiltration. Liver-cell dysplasia is most frequently seen in macro- There is a variable and often slight degree of liver cell nodular cirrhosis, at an earlier age than hepato- damage as shown by focal necrosis and acidophilic cellular carcinoma, and more commonly in males. It bodies. Lobular architecture remains intact, and is also more frequently seen in areas where hepato- piecemeal necrosis and fibrosis are very slight or cellular carcinoma is common, and its presence has absent. When more severe lobular changes of the been associated with the hepatitis B antigen. type seen in acute hepatitis are present, the term J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

406 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, and L. H. Sobin

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Fig. 1 2a Wilson's disease: increased amounts of copper (dark granules) demonstrated by rhodanine. x 640. http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Fig. 12b Alpha-l-antitrypsin deficiency; heavy, intracytoplasmic, PAS-positive deposits in hepatocytes. PAS after diastase digestion x 640. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 407

Fig. 13 Primary biliary cirrhosis; established cirrhosis with lamellar fibrosis surrounding a parenchymal nodule. Note absence of bile ducts and presence of lymphoid aggregates. H and E x 100. http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Fig. 14 Characteristic 'jigsaw' pattern of biliary cirrhosis, primary or secondary, in which outlines of parenchymal nodules appear to fit together as pieces in a puzzle. Masson's trichrome x 40. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

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Fig. 16 Liver cell dysplasia: a group of abnormal liver cells with large, hyperchromatic nuclei stand out in a field of cirrhotic macronodules. H and E x 160. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis A09

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Fig. 17 Chronic persistent hepatitis: expanded portal tract infiltrated by mononuclear inflammatory cells. H and E x 250.

'chronic lobular hepatitis' has been used by some zid) or associated with chronic inflammatory bowel http://jcp.bmj.com/ authors. Chronic persistent hepatitis carries a good disease. In a minority of patients with Wilson's prognosis, and only a minority of patients progress disease and in some alcoholics, the histological pic- to chronic active hepatitis. ture is predominantly that ofchronic active hepatitis. In patients with no known aetiological factors but (b) Chronic active hepatitis (Figs 18, 19). Inflam- with high serum levels of abnormal antibodies (for mation affects portal tracts but is also seen in the example, against smooth muscle) and multisystem lobules. The infiltrate is typically rich in lym- disease, a primary disturbance of immunity has been on September 26, 2021 by guest. Protected copyright. phocytes and plasma cells. There is more fibrosis than postulated ('lupoid hepatitis'). in chronic persistent hepatitis, the lobules are invol- ved, and lobular architecture is often altered. Piece- DIAGNOSIS meal, bridging, and multilobular necrosis may be Certain difficulties should be borne in mind when seen. Chronic active hepatitis has a worse overall needle biopsy specimens are examined: prognosis than chronic persistent hepatitis and tends 1 The histological distinction between acute and to progress to cirrhosis, but the milder forms may chronic hepatitis is often difficult in the first months regress to chronic persistent hepatitis or fibrosis, after an acute attack and tends to become easier with especially after treatment. Chronic hepatitis and liver time. cancer rarely co-exist. 2 The lesions of chronic persistent and chronic active hepatitis may be unevenly distributed through- Aetiology out the liver, and an incorrect diagnosis may be made The lack of specificity of the picture of chronic persis- if the sample is small. tent hepatitis has been referred to above, and similar 3 Treatment, for example with corticosteroids, can appearances can be found in so-called non-specific suppress manifestations of activity and lead to a hepatitis due to a large variety of causes. Chronic falsely optimistic impression. active hepatitis may follow acute viral hepatitis, often 4 It may be difficult to assess whether cirrhosis is identifiable as type B. It may be due to drugs (for present or absent on the basis of a needle biopsy example, oxyphenisatin, alpha methyldopa, isonia- specimen in chronic active hepatitis. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

410 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, and L. H. Sobin

.u *s! -- A Fig. 18 Chronic active hepatitis: liver parenchyma is being destroyed by chronic inflammation and fibrosis, which spread out from portal tracts (bottom right). Liver cells are swollen and some are arranged in gland-like structures or rosettes. H and E x 250. http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Rip Fig. 19 Bridging necrosis linking portal tract (left) with central vein (right) in a case of viral hepatitis B evolving into cirrhosis. H and E x 150. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 411 Hepatic fibrosis superfluous since they correspond closely to classifi- cations of liver disease in general. It is pertinent, DEFINITION however, to state that, in addition to the causes of Fibrosis is defined as the presence of excess collagen cirrhosis already outlined, the following causes of due to new fibre formation. It is to be distinguished hepatic fibrosis can be recognised: from collapse of the pre-existing reticulin framework congenital, eg congenital hepatic fibrosis of the liver. Such collapse, however, may be followed metabolic, eg, mucoviscidosis by active fibroplasia. Used as a nosological term, inflammatory, eg, sarcoidosis, tuberculosis, and other fibrosis excludes the presence of cirrhosis or chronic infectious disease hepatitis. Generally, fibrosis by itself causes little in parasitic, eg, schistosomiasis the way ofclinical symptoms or disturbances ofliver- toxins and drugs, eg, vinyl chloride, Thorotrast, cell function, but portal hypertension can be pro- methotrexate duced byfibrosis alone, as in the case ofschistosomia- vascular, eg, hepatoportal sclerosis, veno-occlusive sis, hepatoportal sclerosis, or congenital hepatic disease, infarcts fibrosis (Fig. 20). physical, eg, radiation HEPATIC FIBROSIS AND CANCER OF THE CLASSIFICATION LIVER Morphology Several agents, notably vinyl chloride, arsenic, and Fibrosis can be classified according to its location Thorotrast, cause fibrosis and tumours of the liver. eg, diffuse, focal, bridging etc. (see Glossary.) The latter have been mainly angiosarcomas, but rare instances ofhepatocellular carcinoma and cholangio- Aetiology carcinoma are also on record. Fibrosis is a component ofmany forms ofliver injury rather than a disease in itself. Aetiological classifica- Glossary tions are, therefore, apt to be lengthy and somewhat acidophilic body, degenerate liver cell with rounded http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.

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*.,:swlbLo7~* * * BL SSUP Fig. 20 Congenital hepaticfibrosis: tortuousfibrous septa, containing many dilated bile ducts, separate nodules ofliver parenchyma that have largely retained their normal lobular organisation. HandE x95. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

412 P. P. Anthonv, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, and L. H. Sobin outline and deeply eosinophilic cytoplasm in which The work was initiated and supported by the World nuclear remnants may be present. Health Organization. We thank the Ciba Founda- ballooning degeneration, swollen liver cell with clear tion, which generously provided meeting facilities in cytoplasm. Nuclear lysis is frequent and the cell may London in March 1976. We are grateful to the many rupture. liver experts and pathologists throughout the world collapse, condensation of the reticulin framework of who provided helpful criticisms and suggestions. the liver following necrosis. The figures are reproduced by permission of the feathery degeneration, see xanthomatous change. World Health Organization. fibrosis, excess collagen due to new fibre formation. Bibliography It may be: A list of efer is give/l of pericellular, fibrosis around individual cells or ences below (as a source Jirtheli reading. This is niecessariily an ar.bitriarvy selection firom the small groups of liver cells. wealth of literature published on chronic liver disease. The difhuse, pericellular fibrosis distributed over most authors aipologise for the inevitable errors oJ omissioni and or whole of the lobule. coflnlissioni. focal, small areas of fibrosis inside lobules or nodules. Anthony, P. P. (1976). The background to liver cell can- zonal, fibrosis consistently localised to a particular cer. In: Liver Cell Cancer, edited by H. M. Cameron, anatomical zone of the lobule. D. A. Linsell and G. P. Warwick, pp. 93-120. Elsevier, periportal, fibrosis around portal tracts. Amsterdam. portal, fibrosis strictly confined to the portal Anthony, P. P., and Farber, E. (1976). Symposium. Early lesions and the development of epithelial cancer. tracts. Session on liver. Cancer Research, 36, 2532-2588. multilobular, fibrosis replacing several contiguous Anthony, P. P., Vogel, C. L., and Barker, L. F. (1973). lobules. Liver cell dysplasia: a premalignant condition. Jolurnnal bridging, fibrosis linking central to central, central of Clinical Pathology, 26, 217-223. to portal, or portal to portal areas. Baggenstoss, A. H. (1975). Morphological features: their periductal, concentric fibrosis around intrahepatic usefulness in the diagnosis, prognosis and management bile ducts. of cirrhosis. Clinics in Gastroenterology, 4, 227-246. 'ground glass' hepatocyte, liver cell with cytoplasm Galambos, J. T. (1972). Natural history of alcoholic which is wholly or partly translucent, lightly eosino- hepatitis. Il1. Histological changes. Gastroenterology, http://jcp.bmj.com/ philic, and finely granular; a halo may be present just 63, 1026-1035. Galambos, J. T. (1975). Classification of cirrhosis. inside the cell membrane. American Journal of Gastroenterology, 64, 437-451. Mallory's hyalin, clumped, intertwined, deeply Gall, E. A. (1960a). Posthepatitic, postnecrotic, and eosinophilic or amphophilic material in the cyto- nutritional cirrhosis: a pathologic analysis. American plasm of intact or necrotic liver cells, often sur- Journal ofPathology, 36, 241-271. rounded by neutrophil leucocytes. Gall, E. A. (1960b). Primary and metastatic carcinoma of necrosis the liver: relationship to hepatic cirrhosis. Archives of on September 26, 2021 by guest. Protected copyright. focal, necrosis of individual or few liver cells. Pathology, 70, 226-232. zonal, necrosis consistently localised to a particular Gastroenterology (1956). Report of the Board for anatomical zone of the lobule. Classification and Nomenclature of Cirrhosis of the of areas of necrosis. Liver. Fifth Pan-American Congress of Gastro- confluent, merging adjacent enterology, La Habana, Cuba. Gastroenterology, 31, piecemeal, focal necrosis at the junction of portal 213-216. tracts or fibrous septa with parenchyma. Gedigk, P., Muller, R., and Bechtelsheimer, H. (1975). bridging, necrosis linking central to central or Morphology of liver damage among polyvinyl chloride central to portal or portal to portal area. production workers. A report on 51 cases. Annals ofthe reverse lobulation, appearance of well-defined areas New York Academy of Sciences, 246, 278-285. of liver parenchyma with portal tracts at their centres. Goldstein, G. B., Lam, K. C., and Mistilis, S. P. (1973). rosette, a group of liver cells often surrounded by fine Drug-induced active chronic hepatitis. American fibrous tissue and arranged around a bile canaliculus. Journal of Digestive Diseases, 18, 177-184. septum, a wall of fibrous tissue, usually seen as a Gudat, F., Bianchi, L., Sonnabend, W., Thiel, G., Aenishaenslin, W., and Stalder, G. A. (1975). Pattern band separating parenchymal nodules. of core and surface expression in liver tissue reflects siderosis, stainable iron in the liver. state of specific immune response in hepatitis B. xanthomatous or pseudoxanthomatous change, swol- Laboratory Investigation, 32, 1-9. len liver cell or Kupifer cell, showing small pyknotic Hartroft, W. S. (1973). The liver-nutritional guardian of nucleus and finely vacuolated and reticulated cyto- the body. In The Liver, edited by E. A. Gall and F. K. plasm. Bile pigment may be present. Mostofi, pp. 131-149. Williams and Wilkins, Baltimore. J Clin Pathol: first published as 10.1136/jcp.31.5.395 on 1 May 1978. Downloaded from

The morphology of cirrhosis 413 Higginson, J. (1969). The geographical pathology of liver Popper, H. (1977b). Pathologic aspects of cirrhosis: a disease in man. Gastroenterology, 57, 587-598. review. American Journal of Pathology, 87, 228-264. Hodgson, H. J. F., Davies, D. R., and Thompson, R. P. H. Popper, H., and Kent, G. (1975). Fibrosis in chronic liver (1976). Congenital hepatic fibrosis. Journal of Clinical disease. Clinics in Gastroenterology, 4, 315-332. Pathology, 29, 11-16. Popper, H., and Schaffner, F. (1976). Chronic hepatitis: Horvath, E., Kovacs, K., and Ross, R. C. (1973). Sub- taxonomic, etiologic and therapeutic problems. In cellular features of alcoholic liver lesion: alcoholic Progress in Liver Diseases, Volume V, edited by H. hyalin. Journal ofPathology, 110, 245-250. Popper and F. Schaffner, pp. 531-558. Grune and Ishak, K. G. (1976). Light microscopic morphology of Stratton, New York. viral hepatitis. Amer-ican Journal of Clinical Pathology, Popper, H., and Udenfriend, S. (1970). Hepatic fibrosis. 65, 787-827. Correlation of biochemical and morphologic investiga- Kent, G., Gay, S., Inouye, T., Bahu, R., Minick, 0. T., tions. American Journal ofMedicine, 49, 707-721. and Popper, H. (1976). Vitamin A-containing lipocytes Poulsen, H., and Christoffersen, P. (1972). Abnormal bile and formation of type III collagen in liver injury. duct epithelium in chronic aggressive hepatitis and Proceedings of the National Academy of Sciences cirrhosis: a review of morphology and clinical, bio- (Washington), 73, 3719-3722. chemical, and immunologic features. Human Pathology, Kent, G., and Schneider, K. A. (1974). Cirrhosis and iron 3, 217-225. overload. In The Liver and its Diseases, edited by F. Powell, L. W., and Kerr, J. F. R. (1975). The pathology of Schaffner, S. Sherlock, and C. M. Leevy, pp. 314-327. the liver in hemachromatosis. Pathobiology Annual, 5, Intercontinental Medical Book Corporation, New 317-337. York. Ramalingaswami, V., and Nayak, N. C. (1970). Liver Klatskin, G. (1974). Drug-induced hepatic injury. In The disease in India. In Progress in Liver Diseases, Volume Liver and its Diseases, edited by F. Schaffner, S. III, edited by H. Popper and F. Schaffner, pp. 222-235. Sherlock, and C. M. Leevy, pp. 163-178. Inter- Grune and Stratton, New York. continental Medical Book Corporation, New York. Rojkind, M., and Kershenobich, D. (1976). Hepatic Lancet (1977). Occasional Survey: Acute and Chronic fibrosis. In Progress in Liver Diseases, Volume V, Hepatitis Revisited. Review by an International Group. edited by H. Popper and F. Schaffner, pp. 294-310. Lancet, 2, 914-919. Grune and Stratton, New York. Lee, F. I. (1966). Cirrhosis and hepatoma in alcoholics. Rubin, E. (1973). The spectrum of alcoholic liver injury. Gut, 7, 77-85. In The Liver, edited by E. A. Gall and F. K. Mostofi, Leevy, C. M., Popper, H., and Sherlock, S. (1976). pp. 199-217. Williams and Wilkins, Baltimore. Diseases of the Liver and Biliary Tract: Standardisation Rubin, E., Krus, S., and Popper, H. (1962). Pathogenesis

of Nomenclature, Diagnostic Criteria and Diagnostic of postnecrotic cirrhosis in alcoholics. Archives of http://jcp.bmj.com/ Methodology. Fogarty International Centre Proceed- Pathology, 73, 288-299. ings, No. 22, DHEW Publication No (NIH) 76-725, Rubin, E., and Lieber, C. S. (1975). Relation of alcoholic US Government Printing Office, Washington, DC. liver injury to cirrhosis. Clinics in Gastroenterology, 4, Mackay, I. R. (1976). The concept of autoimmune liver 247-272. disease. Bulletin ofthe New York Academy ofMedicine, Rubin, E., and Popper, H. (1967). The evolution ofhuman 52, 453-465. cirrhosis deduced from observations in experimental MacSween, R. N. M., and Scott, A. R. (1973). Hepatic animals. Medicine, 46, 163-183.

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414 P. P. Anthony, K. G. Ishak, N. C. Nayak, H. E. Poulsen, P. J. Scheuer, and L. H. Sobin Smetana, H. F. (1972). Cirrhosis of the liver: principles drome) to angiosarcomas. New England Jour.nal of of classification, histogenesis, and pathogenesis. Medicine, 292, 17-22. Pathology Annual, 7, 107-144. Van Waes, L., and Lieber, C. S. (1977). Early peri- Sternlieb, I. (1972). Evolution of the hepatic lesion in venular sclerosis in alcoholic fatty liver: an index of Wilson's disease (hepatolenticular degeneration). In progressive liver injury. Gastr-oenterology, 73, 646-650. Progress in Liver Diseases, Volume IV, edited by H. Popper and F. Schaffner, pp. 511-526. Grune and Stratton, New York. Requests for reprints to Dr L. H. Sobin, Cancer Unit, Sternlieb, I. (1975). The development of cirrhosis in WHO, 1211 Geneva, 27 Switzerland. Colour trans- Wilson's disease. Clinics in Gastroenterology, 4, 367- parencies, prints, and microfiche are available from: Dr 379. James R. McArthur, Associate Professor of Medicine, Thomas, L. B., Popper, H., Berk, P. D., Selikoff, I., and Assistant Director, Health Sciences Learning Resources Falk, H. (1975). Vinyl-chloride-induced liver disease. Center, T-252 Health Sciences, University of Washington, From idiopathic portal hypertension. (Banti's syn- Seattle, Wa 98105, USA. http://jcp.bmj.com/ on September 26, 2021 by guest. Protected copyright.