Terminology of nodular hepatocellular lesions

Special Article Terminology of Nodular Hepatocellular Lesions INTERNATIONAL

WORKING

The discipline of hepatology has advanced rapidly through the efforts of investigators in many countries. Inevitably, this advance has been accompanied by the c r e a t i o n o f a l a r g e v o c a b u l a r y t h a t is a m i x t u r e o f c u r r e n t a n d o b s o l e t e t e r m s . I n a n a t t e m p t to s t a n d a r d i z e t h e t e r m i n o l o g y a p p l i e d to d i s e a s e s o f t h e l i v e r , t h e organizers of the World Congresses of Gastroenterology 1994 s p o n s o r e d a n I n t e r n a t i o n a l W o r k i n g P a r t y c o m posed of four panels, each with experience in a selected area of hepatology. This document, prepared by one of these four panels, considers all mass lesions composed ofhepatocytes in humans, with the exception ofmesenc h y m a l h a m a r t o m a a n d h e p a t o b l a s t o m a . I t is h o p e d that the suggested terms, definitions, and codes will assist clinicians and laboratory physicians in the care of patients and in the retrieval of information (Tables 1 a n d 2).

Abbreviations: DNH, diffuse nodular hyperplasia; NRH, nodular regenerative hyperplasia; FNH, focal nodular hyperplasia; CNS, central nervous systern; HCC, hepatocellular carcinoma. From the 1Universityof Toronto, Toronto, Canada; 2Universita Degli Studi Di Brescia, Brescia, Italy; 3St. Jude Medical Center, Fulterton, CA; 4Brigham and Women'sHospital, Boston, MA; 5Universitaire Ziekenhuizen, Leuven, Belglum; 6Universityof California, San Francisco, CA; 7TexasChildrens Hospital, Houston, TX; SCedars-SinaiMedical Center~Los Angeles, CA; 9Tulane University Schoolof Medicine, New Orleans, LA; 1°ArmedForces Institute of Pathology, Washington, DC; 11Kurume University School of Medicine, Kurume-shi, Japan; 12ChibaUniversity SchoolofMedicine,Chiba, Japan; 18CollegeofPhysicians and Surgeons of Columbia University, New York, NY; 14MayoClinic, Rochester, MN; 15WesternInfirmary, Glasgow,Scotland; ~6KanazawaUniversity Schoolof Medicine,Kanazawa, Japan; ~TKin~sCollege,London, England; ~SRoyalFree Hospital, London, England; 19NewYork University, New York, NY; and the 2°Mount Sinai Schoolof Medicine, New York, NY. Members of Panel: Ian R. Wanless (chair),~ Francesco Callea,2 John R. Craig,3 James M. Crawford,4Valeer J. Desmet,5 Emmanuel Farber, 1Linda D. Ferrell,~ Milton J. Finegold,~ Stephen A. Geller,s Michael A. Gerber,9 Kamal G. Ishak, I° Masamichi Kojiro,11Fukuo Kondo,12YoichiroKondo,~ Jay H. Lefkowitch,1~Jurgen Ludwig,I4RoderickN. M. MacSween,1~Masayuki Nakano,12 Yasuni Nakanuma, 16 Kunio Okuda,~2 Bernard C. Portmann, ~7 Peter J. Scheuer,~sTadashi Terada, I6 Neil D. Theise,~9and Swan N. Thung.2° This document was prepared by a panel of an International Working Party on the Terminology of Chronic Hepatitis, Hepatic Allograft Rejection, and Nodular Lesions of the Liver. The working party was organized and funded by the World Congresses of Gastroenterology, Los Angeles, 1994 (Program chair: Douglas B. McGill;Chair of Working Party: Jurgen Ludwig). The material was presented in part at that meeting, October 3, 1994. Received April 25, 1994; accepted January 9, 1995. Address reprint requests to: Ian R. Wanless, MD, Department of Pathology, The Toronto Hospital, 200 Elizabeth St, Toronto, Canada, M5G 2C4. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2203-004053.00/0

PARTY

RECOMMENDATIONS OF THE PANEL ON THE TERMINOLOGY OF N O D ~ LESIONS OF THE LIVER: GENERAL P R I N C I P L E S F o r a n o m e n c l a t u r e to h a v e c l i n i c a l u t i l i t y , i t m u s t b e based on pathogenesis or etiology and reflect prognosis. Because pathogenetic and etiological concepts evolve, incorporation of these concepts increases the opportun i t y for o b s o l e s c e n c e . To m i n i m i z e t h i s effect, t h e t e r m s h a v e b e e n k e p t a s d e s c r i p t i v e a s p o s s i b l e ( T a b l e 1). This classification uses qualitative rather than quantitative histologic criteria whenever possible. However, w e r e c o g n i z e t h a t c l a s s i f i c a t i o n b a s e d o n s i z e is u s e f u l to s e l e c t l e s i o n s f o r r e s e a r c h a n d to n a m e l e s i o n s t h a t are incompletely studied, such as mass lesions seen by imaging techniques, gross inspection, or needle biopsy. S y n o n y m s a r e o f f e r e d for s u c h p u r p o s e s . Application of this nomenclature may at times be difficult because many anatomic criteria are either nonspecific or are found only in large samples of tissue. Recognizing that a definite diagnosis will sometimes be impossible, some less specific alternate terms have been suggested. T h e n o m e n c l a t u r e p r e s e n t e d h e r e is d e r i v e d f r o m m a n y s o u r c e s . T h o s e c i t e d i n r e f e r e n c e s 1 t h r o u g h 11 will serve as an entry into the literature. Lesions are c a t e g o r i z e d u s i n g t w o m a i n s e t s o f c r i t e r i a ; (1) w h e t h e r t h e c e l l s a r e r e g e n e r a t i v e o r d y s p l a s t i c , a n d (2) a n a tomic characteristics of the adjacent hepatic stroma. Regenerative nodules are the result of localized prol i f e r a t i o n o f h e p a t o c y t e s a n d t h e i r s u p p o r t i n g s t r o m a . 1° This regenerative response usually occurs in a setting of decreased functional liver mass, when levels of growth factors are presumably elevated. Because reg e n e r a t i v e n o d u l e s a r e a f u n d a m e n t a l r e s p o n s e to almost any significant liver injury, there are anatomic similarities among these nodules. The differences that permit recognition of subcategories are determined by t h e c o n d i t i o n o f t h e s t r o m a , w h i c h is d e t e r m i n e d b y t h e character of the initiating injury. Most regenerative n o d u l e s a r e a s s o c i a t e d w i t h o b l i t e r a t i o n o f v e i n s , so t h a t i s c h e m i a , w i t h o r w i t h o u t c o n g e s t i o n , is i m p o r t a n t . 12~4 I n f o c a l n o d u l a r h y p e r p l a s i a , t h e s u r r o u n d i n g l i v e r is h i s t o l o g i c a l l y n o r m a l so t h a t t h e s t i m u l u s to d e v e l o p m e n t o f t h e n o d u l e i s p r o b a b l y n o t a decrease in functional liver mass. In these lesions the s t i m u l u s m a y b e a c o n g e n i t a l o r a c q u i r e d a n o m a l y of t h e a r t e r i a l s u p p l y l e a d i n g to f o c a l h y p e r p e r f u s i o n o f

983

984 INTERNATIONALWORKING PARTY TABLE 1. Classification of Hepatocellular Nodules

1 Regenerativelesions 1.1 Monoacinarregenerative nodule 1.1.1 Diffusenodular hyperplasia without fibrous septa (nodular regenerative hyperplasia) 1.1.2 Diffusenodular hyperplasia with fibrous septa or in cirrhosis 1.2 Multiacinar regenerative nodule 1.3 Lobar or segmental hyperplasia 1.4 Cirrhotic nodule 1.4.1 Monoacinarcirrhotic nodule 1.4.2 Multiacinar cirrhotic nodule 1.5 Focal nodular hyperplasia 1.5.1 Focal nodular hyperplasia, solid type 1.5.2 Focal nodular hyperplasia, telangiectatic type 2 Dysplasticor neoplastic lesions 2.1 Hepatocellularadenoma 2.2 Dysplasticfocus 2.3 Dysplasticnodule 2.3.1 Dysplasticnodule, low-grade 2.3.2 Dysplasticnodule, high-grade 2.4 Hepatocellularcarcinoma

the parenchyma. 15 However, growth factors and hormones m a y also be important. In this report, the terms dysplasia and dysplastic are used to refer to populations of cells t h a t display either (1) histological characteristics of abnormal growth caused by presumed genetic alteration, or (2) proof of genetic alteration. Although genetic criteria are not yet generally available, dysplastic lesions are currently defined histologically by the presence of cytoplasmic or nuclear variations and the topographic clustering of such variations to form recognizable subpopulations of cells, as described in the following sections. 1~-22 REGENERATIVE LESIONS

1.1 Monoacinar Regenerative Nodule Definition. A regenerative nodule is a well~defined region of parenchyma t h a t has enlarged in response to necrosis, altered circulation, or other stimuli. Monoacinar regenerative nodule is a regenerative nodule containing no more t h a n one portal tract. Monoacinar nodules are usually multiple and involve most of the liver as diffuse nodular hyperplasia (DNH)93 When DNH occurs in the absence of fibrous septa, it is also known as nodular regenerative hyperplasia (NRH) (subtype 1.1.1). 12'2<2~ Diffuse nodular hyperplasia may also be superimposed on a previously cirrhotic liver (subtype 1.1.2). 28

Subtypes 1.1.1 Diffuse nodular hyperplasia with no or few fibrous septa (nodular regenerative hyperplasia) 1.1.2 Diffuse nodular hyperplasia with fibrous septa or in cirrhosis Synonyms and Related Terms Note: The terms mil-

iary hepatocellular adenomatosis, nodular transformation, micronodular transformation, macronodular transformation, multiple nodular hyperplasia, and

HEPATOLOGYSeptember 1995

noncirrhotic nodulation should be discontinued. Multiple hepatocellular adenomatosis should not be used for this condition. It is acceptable to name the condition based on the primary vascular lesion when this is known, for example: obliterative portal venopathy, for intrahepatic small portal vein obliteration; extrahepatic portal vein block, for extrahepatic obstruction; or portal vein thrombosis, when the mechanism of the block is established as being thrombotic in origin. Thus, a descriptive diagnosis may take the form: obliterative portal venopathy with diffuse nodular hyperplasia. Diffuse nodular hyperplasia is usually a response to portal vein obstruction t h a t m a y occur in noncirrhotic or cirrhotic livers. Monoacinar regenerative nodules also occur in other states with disturbed circulation, as with primary lesions of the hepatic veins or sinusoids, but, compared with the classical description of NRH, the nodules are less uniformly distributed or are accompanied by more congestion and fibrous septation. In such cases, or when the tissue sample is not sufficient to demonstrate a diffuse lesion, the term nodular hy~ perplasia can be used, with appropriate qualifiers. Diagnostic Criteria Clinical: Although most examples of NRH are incidental findings at autopsy, symptomatic patients usually have features of portal hypertension. The patients often have an underlying disease t h a t caused the portal venous obliteration, especially polycythemia vera, agnogenic myeloid metaplasia, and rheumatoid arthritis. There m a y be pancytopenia from hypersplenism. Mild to moderate elevation of alkaline phosphatase is often present. Gross appearance: The liver in diffuse nodular hyperplasia without cirrhosis (NRH) is normal in size unless there is coexistent myeloproliferative disease. The capsular surface is finely granular, with the nodules paler t h a n the internodular tissue. The cut surface demonstrates nodules 1 m m in diameter, occasionally with clusters of nodules up to 10 m m in diameter t h a t are centered on a large portal tract. Rarely, monoacinar nodules form confluent masses m a n y centimeters in diameter t h a t are located mostly in the perihilar region. This variant, formerly known as partial nodular transformation, is usually associated with high-grade obstruction of the medium-sized or large portal veins. Microscopic appearance: Diffuse nodular hyperplasia in cirrhosis is identical to DNH without cirrhosis (NRH) except for the presence of fibrous septa and obliteration of small hepatic veins in the former. Within cirrhotic nodules there may be one or more monoacinar regenerative nodules with parenchymal atrophy between the regenerative nodules. Obliteration of small portal veins (<0.05 ram) is widespread. The nodules are supplied with portal tracts t h a t m a y or may not contain portal veins (Fig. 1). When the cause of DNH is portal vein thrombosis, there is postthrombotic intimal fibrosis in medium and large portal veins. The presence of regenerative nodules may be suspected in a small biopsy specimen by the presence of two populations of hepatocytes t h a t differ in cell size. In the nod-

INTERNATIONAL WORKING PARTY

HEPATOLOGYVol. 22, No. 3, 1995

985

TABLE 2. S N O M E D C o d e s for H e p a t o c e l l u l a r N o d u l e s Suggested Term

Available Name With Abbreviated SNOMED Codes

Monoacinar regenerative nodule

Micronodular regeneration T62-M79942

Multiacinar regenerative nodule

Macronodular regeneration T62-M79944

Lobar or segmental hyperplasia

Compensatory lobar hyperplasia T62-M7202

Monoacinar cirrhotic nodule

Micronodular regeneration associated with cirrhosis T62-M79942-GC002-D5806

Multiacinar cirrhotic nodule

Macronodular regeneration associated with cirrhosis T62-M79944-GC002-D5806

Focal nodular hyperplasia

Nodular hyperplasia, focal T62-GA351-M7203

Hepatocellular adenoma

Hepatocellular adenoma T62-M817

Dysplastic focus

Focal hepatocellular dysplasia T6226-GA351-M74

Dysplastic nodule, NOS

Nodular regeneration, NOS, with dysplasia, NOS T62-M74, 7994

Hepatocellular carcinoma

Hepatoceltular carcinoma, NOS T62-M81703

SNOMED Codes (Complete codes with explanation)

T-62000 M-79942 T-62000 M-79944 T~62000 M-72020 T-62000 M-79942 G-C002 D5-80600 T-62000 M-79944 G-C002 D5-80600 T-62000 G-A351 M-72030 T-62000 M-81700 T-62260 G-A351 M-74000 T-62000 M-79940 M-74000 T-62000 M-81703

Liver Micronodular regeneration Liver Macronodular regeneration Liver Compensatory lobar hyperplasia Liver Micronodular regeneration Associated with Cirrhosis of liver, NOS Liver Macronodular regeneration Associated with Cirrhosis of liver, NOS Liver Focal Nodular hyperplasia Liver Hepatocellular adenoma Hepatocyte Focal Dysplasia, NOS Liver Nodular regeneration, NOS Dysplasia, NOS Liver Hepatocellular carcinoma, NOS

NOTE. The lesions in this document are listed in an order that does not imply progression of one lesion to another. The SNOMED codes are based on SNOMED INTERNATIONAL (1993), which differs considerably from SNOMED II (1979), although the general principles are the same. For convenience, the abbreviated coding format familiar to users of SNOMED II was used here also. Thus, dashes between field symbols are omitted, fields are separated by dashes, trailing zeros are omitted, and codes within one field are separated by a comma.

ules, plates are one or two cells wide, and the sinusoids are narrow. In the internodular regions the plates are one cell wide, hepatocytes m a y be atrophic, and sinusoids are usually dilated. Nuclei are uniform without features of dysplasia such as nuclear atypia and mitotic figures. Differential diagnosis: N R H may resemble micronodular cirrhosis grossly, but the nodules are less well defined and the parenchyma is softer than in cirrhosis. If the capsular surface is sharply indented, then cirrhosis is likely to be present. A small biopsy specimen m a y allow recognition of regenerative nodules but m a y not allow a complete diagnosis. Monoacinar regenerative nodules m a y be difficult to distinguish from dysplastic foci. Rounded margins, centrally located portal tract, lack of cellular atypia, and atrophy of surrounding tissue will usually allow a diagnosis of regenerative nodule to be made.

FIG. 1. Monoacinar regenerative nodule. The portal tract at upper left is at the center of the nodule. The margin of the nodule is poorly demarcated because the transition is gradual and the hepatocytes inside and outside the nodule differ only in their size and plate arrangement. (Hematoxylin-phloxine-saffron, original magnification x150.)

1.2 Multiaeinar Regenerative Nodule Definition. A regenerative nodule containing more than one portal tract, located in a liver that is otherwise abnormal, either with cirrhosis or with severe disease of portal veins, hepatic veins, or sinusoids. These nodules are usually multiple. When surrounded by fibrous septa, the nodules are synonymous with cirrhotic nod-

986

INTERNATIONAL WORKING PARTY

HEPATOLOGY September 1995

focal nodular hyperplasia. Dysplastic nodules are more expansile and less firm than regenerative nodules and are associated with dysplastic foci in the surrounding parenchyma. Adenoma and focal nodular hyperplasia (FNH) have normal or nearly normal surrounding tissue.

1.3 Lobar or Segmental Hyperplasia Definition. Enlargement of a lobe or large portion of a lobe. This is usually accompanied by atrophy, necrosis, or fibrosis, of other lobes. Synonyms and Related Terms. The phenomenon of hyperplasia associated with atrophy of other parts of the liver has also been referred to as the atrophy-hyper-

trophy complex. 2s

FIG. 2. Multiacinar regenerative nodule. Measuring 15 m m in diameter, this is also a large regenerative nodule. It contains m a n y monoacinar nodules, each approximately 1 m m in diameter. Shown here are two portal tracts each situated at the center e r a monoacinar nodule. (Elastic trichrome, original magnification ×50.)

ules. When multiacinar regenerative nodules are distinctly larger than most cirrhotic nodules of the same liver, generally at least 5 mm in diameter, they may be called large regenerative nodules or macroregenerative

nodules. 2.9,~6,27 Synonyms and Related Terms. Macroregenerative nodule, large regenerative nodule. Note: The terms macroregenerative nodule types I and II, partial nodular transformation, adenomatous hyperplasia, adenomatoid hyperplasia, and cirrhotic pseudotumor should be discontinued. Diagnostic Criteria. Clinical: Portal hypertension is usually present because of portal vein obstruction. Large regenerative nodules m a y be identified by ultrasonography. Anatomic findings: The capsular surface may be deformed by large nodules. Multiacinar regenerative nodules usually measure at least 2 mm in diameter. Large regenerative nodules usually measure 5 to 15 mm in diameter, b u t rarely m a y be 5 cm or more in diameter. Large regenerative nodules are often adjacent to large portal systems. Color and texture are usually similar to surrounding liver, although the nodules m a y be paler or more bile stained. Multiacinar regenerative nodules contain portal tracts that m a y be normal or scarred, often with ductular proliferation and obliteration of portal veins (Fig. 2). Rarely, ducts m a y be absent. Plates are one or two cells wide, and the cells are histologically the same as those in adjacent parenchyma. During regeneration from massive necrosis, nodules show residual necroinflammatory changes and mitotic activity; otherwise, mitotic activity is absent. Differential diagnosis: Large regenerative nodules m a y be mistaken for dysplastic nodule, adenoma, or

Diagnostic Criteria. Anatomic findings: When hyperplasia arises in Budd-Chiari syndrome or primary sclerosing cholangitis, there m a y be some involvement of the hepatic veins or bile ducts in both the hyperplastic and atrophic or fibrotic portions. Regions with the best blood flow become hyperplastic; thus, in Budd-Chiari syndrome the caudate lobe is often hyperplastic because of drainage independent of the main hepatic veins. 29 Differential diagnosis: Lobar and segmental hyperplasia is histologically normal or relatively normal, extends to the capsule, and measures at least several centimeters in average dimension. Thus, gross examination is required to make the diagnosis. Large regenerative nodules this size are roughly spherical, are usually separated from the capsule by severely altered parenchyma, and usually contain prominently enlarged arteries.

1.4 Cirrhotic Nodule Definition. A regenerative nodule composed of hepatocytes that is largely or completely surrounded by fibrous septa. Monoacinar cirrhotic nodules contain no more than one terminal portal tract, and multiacinar cirrhotic nodules contain more than one portal tract.

Subtypes 1.4.1 Monoacinar cirrhotic nodule 1.4.2 Multiacinar cirrhotic nodule Synonyms and Related Terms. The terms micronodule and macronodule are not strictly comparable to the subtypes defined here. 1 Micronodules and macronodules in cirrhosis have been defined by size, with a division point usually at 3 mm diameter. These terms are often preferable for routine use and when histology is not available. Monoacinar and multiacinar are especially useful for certain anatomic and functional studies. Diagnostic Criteria. Monoacinar and multiacinar regenerative nodules are terms that can be applied to nodules in cirrhotic or noncirrhotic liver. When a regenerative nodule is surrounded by fibrous septa and comprises the whole region bounded by those septa, it is also a cirrhotic nodule. If the nodule comprises only a portion of a cirrhotic nodule, it is a regenerative nodule within a cirrhotic nodule.

HEPATOLOGY Vol. 22, No. 3, 1 9 9 5

1.5 Focal Nodular Hyperplasia

Definition. A nodule composed of benign-appearing hepatocytes occurring in a liver that is otherwise histologically normal or nearly normal. The lesion is supplied by large arteries accompanied by fibrous stroma containing ductules. The stroma is usually prominent, forming a stellate "scar." Anatomic subtypes 1.5.1 Focal nodular hyperplasia, solid type 1.5.2 Focal nodular hyperplasia, telangiectatic type

Clinical subtypes Solitary focal nodular hyperplasia Multiple focal nodular hyperplasia syndrome Synonyms and Related Terms Note: The terms fo-

cal cirrhosis, pseudo-cirrhosis, mixed hamartoma, hamartomatous cholangiohepatoma, solitary hyperplastic nodule, nodular transformation type 2, and mixed adenoma should be discontinued. The variable appearance of focal nodular hyperplasia is sufficiently broad to include the criteria used for mixed hamartoma. Diagnostic Criteria Clinical: FNH is usually asymptomatic, being discovered during imaging studies, at surgery for other indications, or at autopsy. It is found at all ages, with a marked female predominance, even in childhood. There is no clear association with hormone ingestion. Large lesions may present rarely with infarction, rupture, or hemorrhage. Imaging studies often show a central stellate region differing from the remainder of the lesion and evidence of increased vascularity with filling of sinusoids from the center outwards. Imaging studies are frequently unable to reliably distinguish FNH from other hepatocellular nodules. Lesions are solitary in two thirds of livers with FNH. Multiple focal nodular hyperplasia syndrome is present if at least two FNH lesions and one or more other lesions are present, including hepatic hemangioma, arterial structural defects (so-called dysplasia), central nervous system (CNS) vascular malformation, menin-gioma, and astrocytoma. 3° If any of the associated lesions are found in the presence of solitary FNH, the syndrome is probably present with incomplete expression. The FNH lesions may be solid or telangiectatic in type; often both types are present in the same liver, s° Anatomic findings: The solid type of FNH is the most common type. The lesions are usually solitary but are multiple in a third of cases. Grossly, the lesion may have an irregular puckered capsular surface. Some lesions are pedunculated. On the cut section, most lesions have a central fibrous stalk region; this is often absent or inconspicuous in lesions smaller than 1 cm in diameter. The stalk region contains an artery that is larger than expected for the locale in the liver and for the accompanying ducts. Microscopically, the lesion has a uniform internal substructure with the afferent arteries branching into a hierarchy of vessels. The smallest arteries supply monoacinar nodules approximately 1 mm in diameter. Ducts are usually small or absent. Ductules are usually present at the interface

INTERNATIONAL

WORKING

PARTY

987

with the parenchymal plates. Portal veins are usually absent. The parenchymal plates are one or two cells in width with nuclei that may show mild regenerative changes. Degenerative changes are frequent in larger lesions, including postthrombotic arterial fibrosis and cholestasis manifested by feathery degeneration, bile plugs, copper-associated protein, and Mallory bodies. The surrounding liver is normal. The telangiectatic type of FNH has multiple dilated blood spaces near the center of the lesion. The lesions may grossly resemble hemangioma or peliosis. The arteries in the central region are small and numerous compared with those in solid FNH. These lesions usually occur in the multiple FNH syndrome. Differential diagnosis: The differential diagnosis of FNH includes large regenerative nodule, adenoma, hepatocellular carcinoma (HCC), and cirrhosis. Large regenerative nodules are surrounded by abnormal liver parenchyma. The difference between FNH and adenoma may be very subtle, explaining much confusion in the literature. The presence of ductular proliferation almost excludes adenoma, but it is important to recognize that normal portal tracts may be trapped within FNH, adenoma, and HCC. FNH lesions are usually static in size, so that enlargement or recurrence requires exclusion of neoplastic disease. Adenomas have a homogeneous appearance; the arteries are evenly spaced and accompanied by scanty stroma. Adenomas (and HCC) may have pseudoglandular differentiation that can be mistaken for ductular proliferation.* Regenerative nodules in Budd-Chiari syndrome and in Osler-Weber-Rendu disease are similar to FNH. 31 However, because the surrounding liver is not normal, these nodules should not be called FNH. Nodules similar to FNH have been reported adjacent to hemangiomas32; such composite lesions may be seen in the multiple FNH syndrome, s DYSPLASTIC OR N E O P L A S T I C L E S I O N S

2.1 Hepatocellular Adenoma Definition. A benign neoplasm composed of hepatocytes occurring in a liver that is otherwise histologically normal or nearly normal. Synonyms and Related Terms Note: Benign hepatoma and minimal deviation hepatoma should be discontinued. The terms multiple adenomas, 33 multiple hepatocellular adenomatosis, 2 and adenomatosis 34 have been applied to patients having many nodules histologically indistinguishable from adenoma. From the natural history and associated features of these few cases, it appears that some of these cases can be reclassified as other lesions, such as multiple focal nodular hyperplasia syndrome, nodular regenerative hy-

* The terms acinar or pseudo-acinar have been applied to rosettes or glandlike structures because they have l u m i n a similar to those of acini in g l a n d u l a r organs. These terms should not be used in reference to the liver because of confusion with normal hepatic acini, which do not have glandular lumina.

988 INTERNATIONALWORKING PARTY perplasia, regenerative nodules, or well-differentiated HCC; therefore, more experience is necessary to define the lesions in these patients. Diagnostic Criteria. Clinical: Large examples give an irregular contour to the liver. The lesion is vascular on angiogram, and sulphur-colloid scans show decreased uptake of radionuclide. Serum alpha-fetoprotein is normal or minimally elevated. The clinical setting is critical for the diagnosis of adenoma. Almost all examples of adenoma occur in a setting of hepatocellular stimulation, usually with oral contraceptive, anabolic steroids, or abnormal carbohydrate metabolism as in familial diabetes mellitus, glycogen storage disease type la, and galactosemia. If none of these conditions is present, the diagnosis is doubtful, and other diagnoses such as dysplastic nodule, well-differentiated HCC, or focal nodular hyperplasia should be considered. Adenomas may regress after withdrawal of the stimulus. Malignant progression has been reported, b u t it is rare. Gross appearance: Adenomas are characteristically large, soft, and well demarcated, usually without a fibrous capsule. Most adenomas are solitary, b u t several lesions are present in 10% to 20% of patients. Adenoma almost always occurs within parenchyma that is normal (minimal abnormalities, peliosis, or hemorrhage excepted). Adenoma in a cirrhotic liver is extremely rare; this diagnosis should be made only if it can be supported by the presence of one of the accepted risk factors for adenoma or by evidence of regression after removal of the stimulus. Microscopic appearance: The liver cell plates are one to two cells in width, usually with an irregular and nonlinear arrangement and compressed sinusoids, giving a uniform pavement appearance. Sinusoidal dilatation or peliosis m a y be present in tumor or adjacent liver. Portal tracts, ducts, and ductu]ar differentiation are usually not seen. However, these elements may be seen if preexisting portal tracts are trapped in the periphery of the tumor. The hepatocytes are usually very uniform in nuclear and cytoplasmic detail with normal nuclear-cytoplasmic ratio. Occasional large hyperchromatic nuclei or multiple nuclei are seen. Nucleoli are inconspicuous, and mitotic figures are very rare. The cytoplasm may be normal, hydropic, clear (glycogen-rich), or fatty. Lipofuscin m a y be normal, decreased, or occasionally increased. Mallory bodies are rare. Regions of infarction and hematoma m a y rupture or heal, leaving gelatinous fibrosis and hemosiderin-laden macrophages. Kupffer cells may be seen in adenomas, although in smaller numbers than normal. A normal reticulin pattern is usually present. Differential diagnosis: The histological differential diagnosis includes normal liver, FNH, regenerative nodule, dysplastic nodule, and well-differentiated HCC. Ductular proliferation in regenerative nodules and F N H m a y be scan~¢ and hard to find. Features favoring HCC are mitoses, moderate to severe nuclear atypia, plates or trabeculae more than two or three

HEPATOLOGYSeptember 1995 cells wide, loss of reticulin fibers, pseudoglandular growth pattern, infiltrative growth or invasion of veins, and regional cellular variation suggesting multiple clones of cells in the tumor or adjacent parenchyma. Adenomas associated with anabolic steroids are more likely to have a prominent pseudoglandular pattern or nuclear atypia than other adenomas. These tumors are also more likely to be multiple and associated with peliosis inside or outside the adenomas. Adenomas with central fibrosis may have a gross appearance resembling FNH. 2.2 Dysplastie Focus Definition. A cluster of hepatocytes less than 1 mm in diameter with dysplasia b u t without definite histologic criteria of malignancy. Dysplasia is defined in the section General Principles. Synonyms and Related Terms. Dysplasia. Note: Use of the terms adenomatous regeneration and adenomatoid hyperplasia should be discontinued. Large cell change and small cell change have often been described, especially in cirrhotic livers. These cellular changes are often found within dysplastic loci. Diagnostic Criteria Clinical: Dysplastic foci are frequently present in cirrhosis of any cause and are infrequent in noncirrhotic livers. 16-22 Diseases with high prevalence of dysplastic foci include al-antitrypsin deficiency, tyrosinemia, and chronic viral hepatitis B and C. Serum alpha-fetoprotein is normal or minimally abnormal except in tyrosinemia, where high levels m a y be present before nodules are grossly visible. Anatomic findings: The cells of a dysplastic focus are usually uniform and differ from those of adjacent hepatocytes with respect to cytoplasmic staining, nuclear size, or degree of nuclear atypia. Nuclei may be normal in size or large and hyperchromatic. There is a spectrum of nuclear atypia from minimal to severe. The cytoplasmic contents of fat or glycogen m a y be more or less than the surrounding liver. The margin is distinct b u t irregular, usually without a rounded or pushing margin. When portal tracts are present, they tend to be at the margin rather than at the center of the focus, in contrast to the arrangement in monoacinar regenerative nodules. Differential diagnosis: Monoacinar regenerative nodule contains a portal tract, and the nodule margins are rounded and may be defined by the presence of atrophy in the adjacent tissue. 2.3 Dysplastic Nodule Definition. A nodular region of hepatocytes at least 1 mm in diameter with dysplasia but without definite histologic criteria of malignancy. 35-43 Dysplasia is defined in the section General Principles. These nodules are usually, but not always, found in cirrhotic livers.

Subtypes 2.3.1 Dysplastic nodule, low-grade: nodule in which atypia is mild.

HEPATOLOGYVol. 22, No. 3, 1995

INTERNATIONAL WORKING PARTY 989 the various types of nodules. Serum alpha-fetoprotein is normal or within the range seen with chronic hepatitis. Gross findings: Dysplastic nodules m a y be any size within the grossly visible range. Studies depending on gross identification and routine histology have often set a lower limit of 5 to 10 mm, but special studies detecting clonality allow recognition of smaller lesions. As size of lesion increases, there is a greater likelihood t h a t high-grade or malignant lesions are present; benign lesions are seldom greater t h a n 20 mm in diameter. Lesions often have a soft texture and bulge above the cut surface. Lesions m a y be either more bile stained or paler t h a n surrounding liver. Necrosis and hemorrhage are not seen. The liver is usually cirrhotic but m a y show mild scarring. Microscopic findings: Low-grade and high-grade

FIG. 3. Junction of two dysplastic foci situated within a 6-mm low-grade dysplastic nodule. There is a sharp transition between the two fociwith differencesin the granularity and staining color of the cytoplasm. There is minimal nuclear atypia. (H&E, original magnification ×200.) 2.3.2 Dysplastic nodule, high-grade: nodule in which atypia is at least moderate but insufficient for the diagnosis of malignancy.

Synonyms and Related Terms. Adenomatous hyperplasia. Borderline lesion has been used in a manner similar to high-grade dysplastic nodule. 4 Note: The term adenomatous hyperplasia is discouraged. The terms macroregenerative nodule, hyperplastic nodule, atypical macroregenerative nodule, regenerative nodule, and nodular hyperplasia should not be used for dysplastic nodules. The terms adenomatoid hyperplasia, ordinary adenomatous hyperplasia, atypical adenomatous hyperplasia, adenomatous regeneration, normotrabecular hepatocellular carcinoma, early hepato-cellular carcinoma, and hepatocellular pseudotumor should be discontinued. Note that hepatic pseudotumor is not a hepatocellular lesion. Terms m a y be modified from the basic vocabulary above. When insufficient criteria are present to arrive at a diagnosis, a t e r m such as hepatocellular nodule of uncertain type or hepatocellular nodule of uncertain malignant potential m a y be used. Some observers m a y prefer to diagnose dysplastic nodules without applying a grade (e.g., dysplastic nodule, NOS). These modifications m a y be especially appropriate when the entire lesion is not available for study. Diagnostic Criteria. Separation of large regenerative nodules from low-grade dysplastic nodules and high-grade dysplastic nodules from carcinoma is often impossible. These difficulties are related to (1) the limited published experience with these lesions, and (2) adequacy of sampling. Clinical: Dysplastic nodules m a y protrude, giving an irregular contour to the liver. Small dysplastic nodules are commonly detected by u l t r a s o u n d examination. Imaging techniques do not reliably differentiate

FIG. 4. Two low-grade dysplastic nodules that measured 4 (A) and 13 mm (B) in diameter. These nodules were immediately adjacent, separated by a fibrous septum. Both nodules have uniform, round, and small nuclei. The smaller nodule (A) has a slightly higher N/C ratio and less cytoplasmiceosinophilia. (Bothphotos H&E, original magnification ×200.)

990

INTERNATIONAL WORKING PARTY

HEPATOLOGYSeptember 1995

FIG. 5. This patient had cirrhosis with a 24-mm diameter irregular mass composed of multiple dysplastic nodules, each with a different architectural pattern and cellular phenotype. (A) This 4-mm dysplastic nodule was outside the main mass and is similar in size to the other cirrhotic nodules. It is composed of hepatocytes showing moderate nuclear enlargement and pleomorphism but with normal N/C ratio and no mitotic figures. The plates are one to two cells wide. (B) Most of the main mass was composed of confluent high-grade dysplastic nodules similar to this one (5-mm diameter) with moderate nuclear pleomorphism and moderately increased N/C ratio. (C) Another high-grade dysplastic nodule (4 mm) in the main mass has a higher N/C ratio and plates that are two to three cells in width, with nuclei deviated toward the sinusoids. Mitotic figures were not seen, and there was no evidence of invasion. This nodule contained portal tracts and no unaccompanied arteries. (All three photos H&E, original magnification ×200.)

d y s p l a s t i c n o d u l e s r e p r e s e n t p a r t s of a s p e c t r u m t h a t is a r b i t r a r i l y divided for t h e p u r p o s e s of clinical u t i l i t y (Figs. 3, 4, a n d 5) (Table 3). 44 L o w - g r a d e d y s p l a s t i c n o d u l e s a r e c o m p o s e d of h e p a t o c y t e s t h a t a r e m i n i m a l l y a b n o r m a l . T h e n u c l e a r - c y t o p l a s m i c r a t i o is norm a l or slightly i n c r e a s e d . N u c l e a r a t y p i a is m i n i m a l , a n d m i t o t i c f i g u r e s a r e a b s e n t . C y t o p l a s m m a y be eosinophilic or c o n t a i n fat. M a l l o r y bodies m a y be seen, u s u a l l y a c c o m p a n i e d b y cholestasis. T h e liver cell p l a t e s a r e one to two cells wide b u t focally m a y a p p e a r w i d e r b e c a u s e of t a n g e n t i a l cuts. T h e r e m a y be n u c l e a r d e v i a t i o n t o w a r d t h e sinusoids. P o r t a l t r a c t s a r e p r e s ent. T h e d y s p l a s t i c nodules, as well as t h e s u r r o u n d i n g liver, u s u a l l y c o n t a i n d y s p l a s t i c foci, often w i t h l a r g e or s m a l l cell change. T h e m a r g i n s of d y s p l a s t i c n o d u l e s a n d t h e m a r g i n s of c o n t a i n e d d y s p l a s t i c foci m a y be r o u n d e d b u t do not s h o w c o m p r e s s i o n of a d j a c e n t tissue. H i g h - g r a d e lesions m a y h a v e a n y of t h e f e a t u r e s of l o w - g r a d e n o d u l e s b u t in a d d i t i o n h a v e one or m o r e of

t h e following: h i g h n u c l e a r - c y t o p l a s m i c ratio, n u c l e a r h y p e r c h r o m a s i a , i r r e g u l a r n u c l e a r contour, r a r e mitotic figures, p l a t e s m o r e t h a n two cells wide, pseud o g l a n d f o r m a t i o n , c y t o p l a s m i c b a s o p h i l i a , a n d resist a n c e to iron a c c u m u l a t i o n . 45 I n v a s i o n of s t r o m a or p o r t a l t r a c t s is a b s e n t . T h e s e f e a t u r e s of h i g h - g r a d e d y s p l a s t i c n o d u l e s m a y be confined to one or m o r e dysp l a s t i c foci w i t h i n t h e nodule, giving t h e a p p e a r a n c e of multiple subpopulations (subcomponents). Differential diagnosis: T h e m o s t certain w a y to distinguish dysplastic nodules f r o m r e g e n e r a t i v e nodules is application of molecular genetic techniques, 4~4s a prospect for the future. More exact histologic criteria m a y be established after studies using such techniques. Dysplastic nodule should be diagnosed if t h e r e are f e a t u r e s suggestive of a neoplastic process, b u t these features do not m e e t the criteria for malignancy. High-grade dysplastic nodule should be diagnosed if the neoplastic f e a t u r e s approach those seen with malignancy. Regenerative nodules and dysplastic nodules are

HEPATOLOGYVol. 22, No. 3, 1995

INTERNATIONAL WORKING PARTY 991

TABLE 3. Histological Criteria to Distinguish Hepatocellular Nodules Large

Dysplastic

Dysplastic

Nodule,

Nodule,

Regenerative Histological

Feature

Primary group Mitotic figures, at least moderate (>5/ 10 HPF) Cell density more than twice normal* Nuclear hyperchromasia Irregular nuclear contour, at least moderate Clonelike populations Plates more than 3 cells wide Secondary group Cell density more than 1.3 times normal Irregular nuclear contour, at least mild Pseudogland formation Cytoplasmic basophilia Cytoplasmic clear cell change Reticulin less than normal Resistance to iron accumulation Mitotic figures, occasional (1-5/10 HPF)$ Invasion of stroma or portal tracts

Nodule

Low

Grade

High

Grade

Moderately Well-Differentiated HCC

Differentiated HCC

_

_

+

--

+

÷

+

÷

+

--

--

-b

+

+

+

+

+

_

_

_

÷

_

_

+

÷

÷

_

_

÷

+

+

+t

-

+

+

+

_

_

÷

+

÷

_

_

+

+

+

--

?

+

+

+

+

÷

÷

--

÷

÷

NOTE. The presence of any one feature in the primary group is highly suggestive of one of the lesions with a '+' sign in that row. Features in the secondary group have differential value but are individually less significant. If a lesion lacks a feature listed with a '+' sign, this does not exclude the diagnosis. Invasion is tentatively placed in the secondary group until there is more published experience with this feature. Abbreviations: HCC, hepatocellular carcinoma; HPF, high power field (10 × 40). * As a measure of increased nuclear to cytoplasmic ratio. t Especially when cholestasis present. Mitoses may occur in any lesion in the presence of cholestasis or recent necrosis.

u s u a l l y s u p p l i e d b y p o r t a l t r a c t s . As d y s p l a s t i c n o d u l e s enlarge, n e w v e s s e l s c o m p o s e d of n o n t r i a d a l a r t e r i e s b e c o m e d o m i n a n t . A n o d u l e - i n - n o d u l e p a t t e r n m a y be s e e n in cirrhotic n o d u l e s w h e n e i t h e r m o n o a c i n a r reg e n e r a t i v e n o d u l e s or s m a l l d y s p l a s t i c n o d u l e s a r e p r e s e n t w i t h i n t h e cirrhotic nodule. T h e c r i t e r i a u s e d to d i s t i n g u i s h h i g h - g r a d e d y s p l a s tic n o d u l e s f r o m c a r c i n o m a a r e a r b i t r a r y , b a s e d on h o w m u c h t h e nodule r e s e m b l e s definite h e p a t o c e l l u l a r carc i n o m a (Table 3). 44 C r i t e r i a in f a v o r of m a l i g n a n c y include p r o m i n e n t n u c l e a r a t y p i a , h i g h n u c l e a r - c y t o p l a s m i c r a t i o w i t h n u c l e a r d e n s i t y g r e a t e r t h a n twice n o r m a l , p l a t e s t h r e e or m o r e cells thick, u n a t t a c h e d "floating" cross-sections of t r a b e c u l a , a b s e n c e of p o r t a l t r a c t s , n u m e r o u s u n a c c o m p a n i e d a r t e r i e s , r e d u c t i o n of r e t i c u l i n fibers, a n d m i t o s e s in m o d e r a t e n u m b e r s . P o r t a l t r a c t s w i t h i n t h e lesion do n o t exclude malignancy. I n v a s i o n of s t r o m a or p o r t a l t r a c t s is h i g h l y sugg e s t i v e of m a l i g n a n c y , 49's° a l t h o u g h i n v a s i o n m a y be difficult to d i a g n o s e w i t h c e r t a i n t y . I t is k n o w n t h a t s o m e lesions c o m p o s e d of v e r y w e l l - d i f f e r e n t i a t e d h e p a tocytes w i t h m i l d d y s p l a s i a m a y s h o w invasion. I n addition, foci of c a r c i n o m a a r e p r e s e n t in a t h i r d of otherwise b e n i g n d y s p l a s t i c nodules. 44 T h u s a diagnosis of c a r c i n o m a c a n n o t be excluded in a n y d y s p l a s t i c lesion t h a t is s a m p l e d only w i t h a biopsy.

2.4 Hepatocellular Carcinoma Definition. A m a l i g n a n t n e o p l a s m c o m p o s e d of cells w i t h h e p a t o c e l t u l a r differentiation. S m a l l h e p a t o c e l l u l a r c a r c i n o m a is defined as m e a s u r i n g less t h a n 2 c m in d i a m e t e r . Synonyms and Related Terms Note: U s e of t h e t e r m s early hepatocellular carcinoma, hepatoma, malignant hepatoma, a n d hepatocarcinoma should be discontinued. Diagnostic Criteria Clinical: S m a l l H C C s a r e being f o u n d i n c r e a s i n g l y w i t h u l t r a s o u n d a n d c o m p u t e d t o m o g r a p h y e x a m i n a t i o n . Lesions less t h a n 1.5 cm in d i a m e t e r do not u s u a l l y show a t u m o r s t a i n w i t h angio g r a p h y . Lesions m a y be m o r e or less echogenic t h a n t h e s u r r o u n d i n g liver. M a n y p a t i e n t s h a v e f e a t u r e s of chronic h e p a t i t i s or cirrhosis. A l p h a - f e t o p r o t e i n is u s u ally n o r m a l or m i n i m a l l y e l e v a t e d b u t is e l e v a t e d above 400 n g / m L in 20% of p a t i e n t s w i t h s m a l l H C C . Gross appearance: S m a l l foci of H C C m a y be invisible g r o s s l y a n d r e c o g n i z e d microscopically, often arising w i t h i n d y s p l a s t i c nodules. A fibrous c a p s u l e is comm o n l y p r e s e n t in lesions g r e a t e r t h a n 1.5 cm in d i a m e t e r . S m a l l c a r c i n o m a s u s u a l l y do not h a v e evidence of necrosis. T h e b a c k g r o u n d liver is cirrhotic in m o s t cases.

992

INTERNATIONAL WORKING PARTY

Microscopic appearance: Small HCC are usually well differentiated. In well-differentiated HCC cell size is usually decreased, and the nuclear-cytoplasmic ratio is increased with a nuclear density at least twice normal. 39 Nuclei have definite atypia with anisonucleosis, irregular nuclear outline, prominent nucleoli, and occasionally mitotic figures. 51 Plates or trabeculae are irregular and usually have regions two or more cells wide. Pseudoglandular structures m a y be seen. Reticulin is occasionally less than normal in amount, but this is usually a feature of moderately differentiated HCC. Variegation with distinctive subpopulations within the lesion m a y be seen. These subpopulations are recognizable because of a different cellular appearance or growth pattern; cytoplasmic variations include size, color, texture, quantity of glycogen or fat, Mallory bodies, and eosinophilic inclusions. Hepatitis B viral antigens may be found in the tumor or in surrounding tissue. Small HCC m a y contain nontriadal arteries as well as portal tracts. Invasion of stroma or portal tracts is usually present if a large sample of the lesion is available for examination. 49'5° Apparent stromal invasion by cells having minimal nuclear and cytoplasmic atypia m a y be a feature of some lesions. Such lesions have been called very well-differentiated HCC by some authorities, although the clinical significance of these lesions remains to be proven. Necrosis is a feature of moderately or poorly differentiated HCC. Differential diagnosis: The differential diagnosis includes dysplastic nodule, adenoma, and large regenerative nodule. Most small HCC cannot be distinguished grossly from dysplastic nodules. Suggestive criteria are marked pallor (steatosis), hemorrhage, necrosis, thick fibrous capsule, and satellite formation. Histological criteria are discussed under dysplastic nodules and summarized in Table 3. REFERENCES

1. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morpholog57 of cirrhosis: recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978;31:395-414. 2. Craig JR, Peters RL, Edmondson HA. Tumors of the liver and intrahepatic bile ducts. (Fascicle 26, 2nd series). Washington, DC: Armed Forces Institute of Pathology, 1989. 3. Crawford JM. Pathologic assessment of liver cell dysplasia and benign liver tumors: differentiation from malignant tumors. Semin Diagn Pathol 1990;7:115-128. 4. Ferrell LD, Crawford JM, Dhillon AP, Scheuer PJ, Nakanuma Y. Proposal for standardized criteria for the diagnosis of benign, borderline, and malignant hepatocellular lesions arising in chronic advanced liver disease. Am J Surg Pathol 1993; 17:11131123. 5. Ishak KG, Anthony PP, Sobin LH. Histological typing of turnouts of the liver. Ed 2. Berlin, Springer-Verlag, 1994. 6. Nakanuma Y, Terada T, Ueda K, Terasaki S, Nonomura A, Matsui O. Adenomatous hyperplasia of the liver as a precancerous lesion. Liver 1993; 13:1-9. 7. Okuda K, Ishak KG. Neoplasms of the liver. Tokyo: SpringerVerlag, 1987. 8. Cot~ RA, Rothwell DJ, Palotay JL, et al, eds. SNOMED International [Systematized Nomenclature of Human and Veterinary Medicine]. Ed 3, Vols I and II, Numeric indices; Vol III and IV,

HEPATOLOGYSeptember 1995

9. 10. 11. 12.

13.

14.

15. 16. 17. 18. 19. 20. 21. 22.

23. 24. 25. 26. 27. 28. 29.

30.

31. 32.

Alphabetic indices. Chicago: College of American Pathologists, 1993. Wada K, Kondo F, Kondo Y. Large regenerative nodules and dysplastic nodules in cirrhotic livers: a histopathologic study. HEPATOLOGY1988;8:1684-1688. Wanless IR. Vascular disorders. In: MacSween RNM et al, eds. Pathology of the liver. Ed 3. Edinburgh: Churchill Livingstone, 1994:535-562. Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol 1983; 14:512-537. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2500 autopsies and a new classification of benign hepatocellular nodules. HEPATOLOGY1990; 11:787-797. Castellano G, Canga F, Solis-Herruzo JA, Colina F, MartinezMontiel MP, Morillas JD. Budd-Chiari syndrome associated with nodular regenerative hyperplasia of the liver. J Clin Gastroenterol 1989;11:698-702. de Sousa JMM, Portmann B, Williams R. Nodular regenerative hyperplasia of the liver and the Budd-Chiari syndrome: case report, review of the literature and reappraisal of pathogenesis. J Hepatol 1991;12:28-35. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. HEPATOLOGY1985; 5:1194-1200. Anthony PP, Vogel CL, Barker LF. Liver cell dysplasia: a premalignant condition. J Clin Pathol 1973;26:217-223. Anthony PP. Liver cell dysplasia: what is its significance? HEPATOLOGY 1987;7:394-395. Watanabe S, Okita K, Harada T, Kodama T, Numa Y, Takemoto T, Takahashi T. Morphologic studies of the liver cell dysplasia. Cancer 1983;51:2197-2205. Cohen C, Berson SD. Liver cell dysplasia in normal, cirrhotic and hepatocellular carcinoma patients. Cancer 1986;57:1535-1538. Lefkowitch J, Apfelbaum TF. Liver cell dysplasia and hepatocellular carcinoma in non-A, non-B hepatitis. Arch Pathol Lab Med 1987; 111:170-173. Roncalli M, Borzio M, Tombesi MV, Ferrari A, Servida E. A morphometric study of liver cell dysplasia. Hum Pathol 1988; 19:471-474. Nakanuma Y, Kanel GC, Moishita K, Ohta G, Peters RL. Risk lesions in cirrhosis and development of hepatocel|ular carcinoma: an autopsy study. Biomed Pharmacother 1989;43:127133. Weinbren K, Mutum SS. Pathological aspects of diffuse nodular hyperplasia of the liver. J Pathol 1984; 143:81-92. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol 1959;35:943-953. Stromeyer FW, Ishak KG. Nodular transformation (nodular "regenerative" hyperplasia) of the liver. Hum Pathol 1981; 12:6071. Wanless IR. Portal vein thrombosis is associated with large regenerative nodules and diffuse nodular hyperplasia in cirrhotic livers. HEPATOLOGY1994;20:412A. Eguchi A, Nakashima O, Okudaira S, Sugihara S, Kojiro M. Adenomatous hyperplasia in the vicinity of small hepatocellular carcinoma. HEPATOLOGY1992; 15:843-848. Hadjis NS, Blumgart LH. Clinical aspects of liver atrophy. J Clin Gastroenterol 1989; 11:3-7. Tavill AS, Wood EJ, Creel L, Jones EA, Gregory M, Sherlock S. The Budd-Chiari syndrome: correlation between hepatic scintigraphy and the clinical, radiological and pathological findings in 19 cases of hepatic venous outflow obstruction. Gastroenterology 1975;68:509-518. Wanless IR, Albrecht S, Bilbao J, Frei JV, Heathcote EJ, Roberts EA, Chiasson D. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 1989;2:456462. Wanless IR, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia. Arch Pathol Lab Med 1986; 110:331-335. Ndimbie OK, Goodman ZD, Chase RL, Ma CK, Lee MW. Hemangiomas with localized nodular proliferation of the liver: a sugges-

HEPATOLOGYVol. 22, No. 3, 1995

33. 34. 35.

36.

37.

38. 39.

40. 41.

42.

tion on the pathogenesis of focal nodular hyperplasia. Am J Surg Pathol 1990; 14:142-150. Lui AFK, Hiratzka LF, Hirose FM. Multiple adenomas of the liver. Cancer 1980;45:1001-1004. Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, Benhamou JP. Liver adenomatosis: an entity distinct from liver adenoma? Gastroenterology 1985;89:1132-1138. Arakawa M, Kage M, Sugihara S, Nakashima T, Suenaga M, Okuda K. Emergence of malignant lesions within an adenomatous hyperplastic nodule in a cirrhotic liver: observations in 5 cases. Gastroenterology 1986;91:198-208. Ferrell L, Wright T, Lake J, Roberts J, Ascher N. Incidence and diagnostic features of macroregenerative nodules vs. small hepatocellu]ar carcinoma in cirrhotic livers. HEPATOLOGY 1992; 16:1372-1381. Furuya K, Nakamura M, Yamamoto Y, Togei K, Otsuka H. Macroregenerative nodule of the liver: a clinicopathologic study of 345 autopsy cases of chronic liver disease. Cancer 1988;61:99105. Terada T, Terasaki S, Nakanuma Y. A clinicopathologic study of adenomatous hyperplasia of the liver in 209 consecutive cirrhotic livers examined by autopsy. Cancer 1993;72:1551~1556. Nagato Y, Kondo F, Kondo Y, Ebara M, Ohto M. Histological and morphometrical indicators for a biopsy diagnosis of welldifferentiated hepatocellular carcinoma. HEPATOLOGY 1991; 14:473-478. Sakamoto M, Hirohashi S, Shimosato Y. Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 1991;22:172q78. Sugihara S, Nakashima O, Kojiro M, Majima Y, Tanaka M, Tanikawa K. The morphologic transition in hepatocellular carcinoma: a comparison of the individual histologic features disclosed by ultrasound-guided fine-needle biopsy with those of autopsy. Cancer 1992;70:1488-1492. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Okazaki N, Takayasu K, Kosuge T, et al. Malignant transformation of

INTERNATIONAL WORKING PARTY 993

43.

44. 45.

46. 47.

48.

49.

50.

51.

adenomatous hyperplasia to hepatocellular carcinoma. Lancet 1990; 336:1150-1153. Theise ND, Schwartz M, Miller C, Thung SN. Macroregenerative nodules and hepatocellular carcinoma in forty-four sequential adult liver explants with cirrhosis. HEPATOLOGY1992;16:949955. Terada T, Ueda K, Nakanuma Y. Histopathological and morphometric analysis of atypical adenomatous hyperplasia of human cirrhotic livers. Virchows Arch A Pathol Anat 1993; 422:381-388. Deugnier YM, Charalambous P, Le Quilleuc D, Turlin B, Searle J, Brissot P, Powell LW, et al. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. HEPATOLOGY1993; 18:1363-1369. Hsu HC, Chiou TJ, Chen JY, Lee CS, Lee PH, Peng SY. Clonality and clonal evolution of hepatocellular carcinoma with multiple nodules. HEPATOLOGY1991;13:923-928. Tsuda H, Hirohashi S, Shimosato Y, Terada M, Hasegawa H. Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma. Gastroenterology 1988;95:1664-1666. Zhang X, Huang D, Qui D-K, Chiu J. The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. Oncogene 1990;5:909914. Kondo F, Kondo Y, Nagato Y, Tomizawa M, Wada K. Interstitial tumor cell invasion in small hepatocellular carcinoma: evaluation in microscopic and low magnification views. J Gastroenterol Hepatol 1994;9:604-612. Nakano M, Saito A, Takasaki K, Obata H, Kobayashi S. A histopathologic study of early hepatocellular carcinoma: Portal tract invasion and progression to advanced hepatocellular carcinoma. Acta Hepatol Japan 1990;31:754-762. Nagao T, Kondo F, Sato T, Nagato Y, Kondo Y. Immunohistochemical detection of aberrant p53 expression in hepatocellular carcinoma: correlation with cell proliferative activity indices including mitotic index and MIB-1 immunostaining. Hum Pathol 1995; 26:326-333.