Severe cytological atypia (large cell change) in focal nodular hyperplasia with numerous mallory bodies. A benign (adaptive) change?

Focal nodular hyperplasia (FNH) is a benign hepatocellular lesion composed of hyperplastic appearing hepatocytes arranged in nodules separated by fibrous septa that usually form a central stellate scar. Rare lesions that show unusual cytological or architectural features were reported as variants of focal nodular hyperplasia. We present the morphological features of a case of FNH with severe cytological atypia (so-called large cell change) in a 73-year-old man. In addition to diffuse cytological atypia, Mallory hyaline bodies were found in almost all lesional cells. This rare variant of FNH should be differentiated from other neoplastic lesions, in particular from the fibrolamellar variant of hepatocellular carcinoma.     

Pathologic assessment of liver cell dysplasia and benign liver tumors: differentiation from malignant tumors

Recent developments in the pathologic assessment of several benign hepatic processes are reviewed, with particular emphasis on distinguishing these processes from malignant lesions. Liver cell dysplasia remains a controversial lesion, with mounting evidence to support its preneoplastic nature. Adenomatous hyperplastic nodules are large regenerative nodules in cirrhotic livers, and may also have malignant potential. Distinguishing these nodules from hepatocellular carcinoma by histology may become increasingly important, with the advent of more sensitive imaging techniques. Differentiating features of noncancerous biliary epithelium versus well-differentiated cholangiocarcinoma, sclerosing hemangioma versus epithelioid hemangioendothelioma, and angiomyelolipoma versus the clear cell variant of hepatocellular carcinoma are also presented and discussed.     

ADENOMA WITH MULTIPLE HYPERPLASTIC NODULES IN NONCIRRHOTIC LIVER POSSIBLY RELATED TO LONG-TERM ADMINISTRATION OF A HYPOLIPIDEMIC DRUG

Described here is an autopsy case of a 76-year-old woman with preneoplastic and other adenomatous hepatocellular lesions. Multiple small hyperplastic liver foci with PAS positive reaction and adenomatous nodular lesions were noted in a non-cirrhotic liver. These lesions resembled altered foci or neoplastic nodules which are currently regarded as premalignant changes in experimental animal models. It is suggested that the liver lesions of this woman may be related to long-term administration of hypolipidemic drug cloflbrate for hypercholesteremia and the lesions could be one of the precursor changes of human hepatocellular carcinoma.     

Adenoma with multiple hyperplastic nodules in noncirrhotic liver possibly related to long-term administration of a hypolipidemic drug

Described here is an autopsy case of a 76-year-old woman with preneoplastic and other adenomatous hepatocellular lesions. Multiple small hyperplastic liver foci with PAS positive reaction and adenomatous nodular lesions were noted in a non-cirrhotic liver. These lesions resembled altered foci or neoplastic nodules which are currently regarded as premalignant changes in experimental animal models. It is suggested that the liver lesions of this woman may be related to long-term administration of hypolipidemic drug clofibrate for hypercholesteremia and the lesions could be one of the precursor changes of human hepatocellular carcinoma.     

Histopathological and morphometric analysis of atypical adenomatous hyperplasia of human cirrhotic livers

Atypical adenomatous hyperplasia (AAH) is a hyperplastic parenchymal nodular change in the cirrhotic liver, in which overt hepatocellular carcinoma (HCC) occasionally arises. AAH is defined as a sizable hepatocellular nodule with a variable degree of hepatocellular atypia not regarded as HCC, and is different from ordinary adenomatous hyperplasia in which hepatocellular atypia is absent. In the present study, we attempted to evaluate carcinogenetic processes and to find histological variables which indicate malignant transformation in AAH, using 49 surgically resected or autopsied nodules. AAH frequently showed morphological heterogeneity. Atypical lesions within AAHs were divisible into the following three categories from overall histopathological appearances: malignant (A), equivocal (B), or non-malignant (C) lesions. Analysis of combination of these three lesions, which were frequently intermixed in a given AAH, suggested that B lesions appear subsequent to C lesions, and A lesions finally appear in AAH nodules. Among the 14 histological variables, enlargement, hyperchromasia and irregular contour of nuclei were found to correlate well with A lesions. Increased nuclear density, iron resistance, reduction of reticulin fibres, clear cell change, sinusoidal dilatation and presence of abnormal arteries were suggestive of A or B lesions. Nuclear deviation toward the sinusoids, acinar and compact arrangements, fatty change and Mallory's hyaline alone were not useful indicators of A or B lesions. These results indicate that AAH is a preneoplastic or borderline lesion in which overt HCC is likely to evolve through several steps. Although a needle liver biopsy is a useful tool for diagnosis of benign, equivocal and malignant hepatocellular nodular lesions, the needle biopsy specimen should be carefully evaluated by considering the morphological heterogeneity of the AAH and a variable combination of 14 histological variables.     

Characterization of hyperplastic foci observed in surgical specimens of hepatocellular carcinoma

By reviewing previous surgical specimens of hepatocellular carcinoma, 17 cases with hyperplastic foci (HPF) characterized by discernible increase in nuclear densities, could be histologically selected. Nuclear densities of HPF and control hepatic parenchyma were assessed quantitatively by counting the nuclear number of hepatic cells, and proliferating cell nuclear antigen labeling index was measured. HPF occurred multifocally, confined within a lobular unit, smoothly merging into surrounding hepatic parenchyma. Nuclear densities of HPF were 1.71 times greater than those of control hepatic parenchyma. The hepatocytes of HPF also showed significantly higher proliferative activities than those of control parenchyma. In addition, noticeable structural distortions, such as focal trabecular thickening or microacinar formation of hepatocytes, were sometimes observed in HPF. However, these HPF seemed to be distinguished from minute de novo hepatocellular carcinoma (HCC) or intrahepatic HCC metastasis, because of paucity of distinctive atypical changes, and intimate correlation with neighboring hepatocytes. Several adjacent HPF were aggregated to form a much larger unit of a hyperplastic area with loss of fibrous septa of liver cirrhosis. It was suggested that grossly detectable large regenerative nodules are produced via fusion of several adjacent HPF.     

Diisopropanolnitrosamine (DIPN) induced rat thyroid lesions. III. An immunohistochemical study on their functional aspects

The functional aspects of DIPN induced rat thyroid lesions classified as in our previous studies were analyzed by immunohistochemical detection of Tg, T4, and T3 in serial or semi-serial paraffin sections. The type 1 lesions, i.e., foci of cellular alteration of individual follicles, showed the same pattern of immunostaining as seen in the surrounding hyperplastic follicles and in normal controls. On the other hand, the type 3 lesions, i.e., carcinomas, were mostly negative for T4 and T3 with only partial staining for Tg. The type 2 lesions, i.e. proliferative nodules, which might include a state of nodular hyperplasia as well as benign neoplastic nodules, demonstrated intermediate stainability between the type 1 and type 3 lesions. These results suggest that the histological structures of focal lesions of the thyroid gland may be closely related to their functional activities. Also, the importance of follicular structure formation in thyroid hormone synthesis was demonstrated in each type of focal lesion.     

Classification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds

Over the years, the most appropriate classification scheme for nodular proliferative lesions of the hepatocyte has been heavily debated. In the most recent guidelines there appears to be a consensus for classifying these lesions as hepatocellular adenoma, hepatocellular carcinoma, or regenerative hyperplasia. Also, large foci of cellular alteration may appear somewhat nodular. Some nodular hepatocellular lesions from a group of 7 studies of dioxin and dioxin-like compounds conducted by the National Toxicology Program did not readily fit into these categories. Some of these lesions had morphologic features consistent with hyperplasia. However, there was not sufficient morphological or biological evidence to conclude that the entire response was regenerative. In other instances, these lesions had some features resembling adenoma, but contained a prominent component of biliary epithelium and/or oval cells. This component does not appear to be well described in the literature, and while its presence suggested a nodule to be nonneoplastic, this is inconclusive. This paper describes the morphology of these lesions, as well as the diagnostic approach taken in this series of studies.     

Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion

Large cell change involves the clustering of hepatocytes with hyperchromatism and cellular enlargement without an increase in the nuclear/cytoplasmic ratio. This study investigated whether large cell change in chronic viral hepatitis reflects cellular senescence because of morphological similarities between the 2 conditions. The expression of markers of senescence such as senescence-associated β-galactosidase, senescence-associated heterochromatic foci, and p21, as well as markers of cell kinetics such as Ki-67, was examined in 26 frozen and 82 formalin-fixed liver specimens. Large cell change was frequently detected in chronic hepatitis B cases with advanced histologic staging, particularly those with hepatocellular carcinoma. Senescence-associated β-galactosidase activity, senescence-associated heterochromatic foci, and p21 were frequently detected in areas of large cell change. Hepatocytes with large cell change showed no proliferative or apoptotic activity. The frequent expression of senescent features and the absence of proliferative or apoptotic activity suggest that large cell change represents senescence. The parallel increase in large cell change and hepatocellular carcinoma in chronic hepatitis B raises the possibility that cellular senescence develops as a safeguard against malignant transformation rather than as a precursor of hepatocellular carcinoma.     

Diagnostic criteria for proliferative thyroid lesions in bony fishes

Thyroid proliferative lesions are rather common in bony fishes but disagreement exists in the fish pathology community concerning diagnostic criteria for hyperplastic versus neoplastic lesions. To simplify the diagnosis of proliferative thyroid lesions and to reduce confusion regarding lesion interpretation, we propose specific criteria for distinguishing hyperplastic from neoplastic lesions. Development of these criteria was based on the examination of a large series of proliferative lesions from Japanese medaka (Oryzias latipes), lesions from other small fish species, and a reexamination of the 97 cases of proliferative thyroid lesions from bony fishes deposited in the Registry of Tumors in Lower Animals. Specific diagnostic criteria are provided for all lesion categories including follicular cell hyperplasia (simple, nodular, or ectopic), adenoma (papillary or solid), and carcinoma (well- or poorly differentiated). These criteria should assist fish pathologists in describing and categorizing naturally occurring proliferative lesions from wild fishes, lesions that develop in laboratory fishes due to suboptimal culture practices or water quality, those in fishes used in toxicological assays, and captive aquarium fishes.     

Clinicopathological study of a hilar nodule in the livers of long-term survivors with biliary atresia

With the application of liver transplantation for patients with biliary atresia (BA), we have had the opportunity to review the clinicopathologic features of the native livers from 10 transplanted BA patients. A single large nodule at porta hepatis (hilar nodule) was noted in three of 10 patients, and an ill-defined nodule-like lesion at porta hepatis was present in two other patients. The three BA patients with hilar nodules were long-term survivors, compared to the patients with nodule-like and those without nodules. The hilar nodules measured between 5.0 cm and 8.0 cm and histologically, they were partly surrounded by fibrous septa with relatively well-preserved liver architectures and fewer inflammatory cells at the portal triads when compared to the surrounding cirrhotic lesions. No nuclear or cellular atypia was observed. Proliferating cell nuclear antigen labeling index was higher in the surrounding cirrhotic lesions than the hilar nodules. The nodule-like lesions at porta hepatis also showed similar light microscopic and immunohistochemical features as the hilar nodules. These hilar nodules did not seem to contain any malignant potential. The benign histology with relatively well-preserved liver architecture and the preferential site of occurrence at porta hepatis where bile seemed to flow more smoothly, suggested possible residues of less-affected hepatic tissues.     

Thyroid tumors with a follicular growth pattern: problems in differential diagnosis

Tumors of the thyroid characterized by a follicular growth pattern constitute the most common type of lesion of this organ encountered by pathologists. The vast majority of such lesions do not pose difficulties for histopathologic interpretation. A subset of these tumors, however, can represent a serious challenge for diagnosis. Thyroid tumors with a follicular growth pattern include a broad range of lesions that range from benign, hyperplastic nodules to follicular adenomas to follicular carcinomas. In addition, other types of tumors belonging in separate diagnostic categories can also present histologically with a follicular growth pattern, including the follicular variant of papillary thyroid carcinoma and medullary carcinoma. The histologic features and diagnostic criteria used for distinguishing among these conditions can often be subtle and subjective.     

National Toxicology Program nomenclature for hepatoproliferative lesions of rats

Diagnostic criteria for hepatoproliferative lesions of Fischer 344 rats are presented to permit more complete categorization of the spectrum of lesions observed in two-year chemical carcinogenicity studies. A nomenclature recently adopted by the National Toxicology Program differs from previous classification schemes in that hepatocellular hyperplasia and hepatocellular adenoma are to be used for lesions which were previously combined under the diagnosis of neoplastic nodule. The term hyperplasia is reserved for proliferative lesions that are perceived to be secondary, nonneoplastic responses to degenerative changes in the liver. Foci of cellular alteration, hepatocellular adenoma, and hepatocellular carcinoma are believed to represent a spectrum of changes that comprise the natural history of neoplasia. This change in nomenclature was made subsequent to a peer review of representative hepatoproliferative lesions from two-year carcinogenicity studies. The revised nomenclature is consistent with traditional pathologic diagnoses for proliferative lesions in other epithelial tissues and should facilitate the interpretation of conventional toxicity and carcinogenicity studies in rats. Morphologic features of other selected rat liver lesions are also presented.     

Iron-negative foci in siderotic macroregenerative nodules in human cirrhotic liver. A marker of incipient neoplastic lesions

Resistance to iron accumulation is known as a phenotypic marker of neoplasia and preneoplasia in experimental hepatocarcinogenesis in rodents overloaded by iron. This study was aimed to evaluate whether such iron-free foci are present and valuable for identification of preneoplastic and incipient neoplastic lesions in human cirrhotic livers, especially within macroregenerative nodules in which hepatocellular carcinoma is known to arise. Iron-free foci were found in siderotic macroregenerative nodules in liver cirrhosis. These foci were classic and overt carcinoma or borderline lesions showing an expansive growth pattern. Borderline lesions were composed of hyperplastic or small basophilic hepatocytes with hyperchromasia and distinct nuclear membrane showing pseudoglandular, trabecular, compact, and scirrhous patterns. These data suggest that iron stain is valuable for identification of neoplastic or borderline lesions representing a transition from hyperplastic nodule to carcinoma in human liver cirrhosis.     

Morphometric analysis of hepatocellular nodular lesions in HCV cirrhosis

We generated a computerized morphometric model to evaluate and quantify the morphological features in large regenerative nodules (LRN), high-grade dysplastic nodules (HGDN) and hepatocellular carcinoma (HCC). Sixteen LRN, 10 HGDN and 16 HCC in HCV-cirrhotic livers were stained with H&E, smooth muscle actin, CD34, CD31 and reticulin to evaluate volume and surface fractions. On H&E stains, the most discriminatory features between LRN, HGDN and HCC were volume fraction and the number of hepatocyte nuclei in unit volume and hepatocyte nuclear/cytoplasmic ratio. On immunohistochemistry, volume fractions of capillarised sinusoids, capillary units and isolated arteries were significantly different among all groups and highest in HCC; surface fraction of reticulin was markedly decreased in HCC. Our morphometric model is an objective method for quantification of the morphological changes of the nodular lesions, and it could be applied to studies involving histological evaluation of the spectrum of nodular lesions arising in the cirrhotic liver.     

Unusual hepatocellular lesions in primary biliary cirrhosis resembling but unrelated to hepatocellular neoplasms

Summary Structural, cellular and nuclear abnormalities of hepatocytes are a histological hallmark of well-differentiated, small hepatocellular carcinoma (HCC) or its borderline lesion. This study revealed that several hepatocellular abnormalities found in these hepatocellular neoplasms were also found in non-cirrhotic stages of primary biliary cirrhosis (PBC) in which HCC is unlikely to develop. These changes are small cell changes, consisting of the appearance of small hepatocytes arranged in thin trabecular or compact patterns with increased cellularity and basophilic cytoplasm. This was found in 36%, 71% and 100% in specimens of stages 1, 2 and 3, respectively. Large cell changes occurred and consisted of large hepatocytes with large nuclei and prominent nucleoli, found in 27%, 47% and 22% of the stages, respectively. Finally, liver cell rosettes were seen, showing variable acinar formation and present in 0%, 41% and 33% of the stages, respectively. These lesions were identified microscopically as irregularly shaped areas or vague nodules of hepatocytes without a fibrous rim, in the hepatic lobules. They showed an expansive growth or shaggy border against the surrounding hepatic parenchyma. Follow-up studies, including autopsies, failed to show development of HCC or its borderline lesion in PBC cases. Pathologists must make a diagnosis of HCC and its borderline lesion bearing in mind the occurrence of such unusual hepatocellular lesions probably of a reactive nature.     

‘Atypical adenomatous hyperplasia’ in liver cirrhosis: low-grade hepatocellular carcinoma or borderline lesion?

Adenomatous hyperplasia, defined as a sizable parenchymal nodule in cirrhosis, was examined morphologically. Ninety-seven nodules of adenomatous hyperplasia were obtained from 47 cirrhotic livers and were divided into 'ordinary' (44 nodules) and 'atypical' (53 nodules) types. The former consisted of hepatocytes similar to those of the surrounding liver, and showed regularly distributed portal tracts. The latter type was composed of hepatocytes showing nuclear atypia, relative to the surrounding liver, and showed irregular or sparse portal tracts. Atypical nodules were histologically heterogeneous, possessing areas of normo-trabecular, compact, pseudoglandular and/or scirrhous patterns. Several cytological changes, such as clear cell change, small or large cell change and fatty change, were intermingled variably within a given nodule. Atypical nodules showed expansive and/or replacing growth into the surrounding liver. Atypical hepatocytes also infiltrated into the fibrous septa and portal tracts. Foci of overt hepatocellular carcinoma were found in 11 of the 53 atypical nodules. These findings suggest that ordinary adenomatous hyperplasia may be a large-sized regenerative nodule, while atypical adenomatous hyperplasia may be a hepatocellular neoplasm, a peculiar form of low-grade hepatocellular carcinoma or borderline lesion, in which overt hepatocellular carcinoma is likely to evolve through multiple steps.     

Expression of proliferating cell nuclear antigen in hyperplastic polyps, adenomas and inflammatory cloacogenic polyps of the large intestine.

AIMS--To compare proliferating cell nuclear antigen (PCNA) immunoexpression in hyperplastic polyps, adenomas, and inflammatory cloacogenic polyps of the human colon and rectum using paraffin wax embedded tissue. METHODS--The monoclonal antibody PC10 was used to demonstrate PCNA immunoreactivity in 88 polypoid lesions from 68 patients. Cases in which immunoexpression was completely absent were excluded, leaving 32 hyperplastic polyps, 31 adenomas, and seven inflammatory cloacogenic polyps for analysis. Labelling indices for the upper and lower third of each lesion and for adjacent normal mucosa were calculated. RESULTS--The upper third labelling indices for adenomas were substantially higher than those for hyperplastic polyps or normal mucosa, whereas those for the upper thirds of hyperplastic polyps and normal mucosa did not differ greatly. The differences between the lower third samples were not significant. In 16 (50%) hyperplastic polyps positive cells persisted onto the luminal surface. Some adenomas showed the most intense staining and the highest labelling indices in the upper third, with strong staining of surface cells; this pattern was not seen in the other lesions. The inflammatory cloacogenic polyps did not show a consistent pattern of immunoexpression. CONCLUSIONS--Differences in cell kinetics between adenomas, hyperplastic polyps, and normal mucosa may be shown in formalin fixed, paraffin wax embedded tissue using PC10 as a marker of proliferative activity. PCNA expression also persists into the upper portions of hyperplastic polyps. Assuming that hyperplastic polyps are hypermature lesions with a slower rate of cell migration, this finding suggests that there may be an alteration in PCNA protein metabolism.     

A case of hypervascular hyperplastic nodules in a patient with alcoholic liver cirrhosis

Most hypervascular nodules in a cirrhotic liver are hepatocellular carcinomas (HCCs); however, some are benign hypervascular hyperplastic nodules. We report a case of benign hypervascular hyperplastic nodules in a 41-year-old male patient without hepatitis B or C virus infection, with a history of alcohol abuse, and diagnosed with an aortic aneurysm. The dynamic computerized tomography of the liver demonstrated multiple nodular lesions on both liver lobes with arterial enhancement and delayed washout. The hepatic angiography showed multiple faint nodular staining of both lobes in the early arterial phase. Magnetic resonance imaging revealed numerous nodules showing high signals on T1 weighted images, with some nodules showing a low central signal portion. The clinical impression was HCC. The ultrasonography-guided liver biopsy, which was performed on the largest nodule (2.5 cm in size), revealed hepatocellular nodules with slightly increased cellularity, unpaired arteries, increased sinusoidal capillarization, and focal iron deposition. However, both cellular and cytological atypia were unremarkable. Although the clinical impression was HCC, the pathological diagnosis was hypervascular hyperplastic nodules in alcoholic cirrhosis. Differential diagnosis of hypervascular nodules in cirrhosis and HCC is difficult with imaging studies; thus, histological confirmation is mandatory.     

Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia

 Foci of altered hepatocytes (FAH) represent preneoplastic lesions, as shown in various animal models of hepatocarcinogenesis, but their significance in the human liver has not been established. The cellular composition, size distribution and proliferation kinetics of FAH in 163 explanted and resected human livers with or without hepatocellular carcinoma (HCC) and their possible association with small-cell change of hepatocytes (SCC) were therefore studied. FAH, including glycogen-storing foci (GSF), mixed cell foci (MCF) and basophilic cell foci, were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in cases with (29/32) than in those without HCC (55/79). FAH were observed more frequently in HCC-free cirrhosis associated with hepatitis B or C virus or chronic alcoholic abuse (high-risk group) (37/47) than in that due to other causes (low-risk group) (12/21). MCF, predominant in cirrhotic livers of the high-risk group, were more proliferative, larger and more often involved in formation of nodules of altered hepatocytes (39.3%) than were GSF (8.5%). The results suggest that the FAH are preneoplastic lesions, MCF being more advanced than GSF. Oncocytic and amphophilic cell foci were also observed, but their significance remains to be clarified. Two types of SCC, namely diffuse and intrafocal SCC, were identified, but only intrafocal SCC was found to be related to increased proliferative activity and more frequent nodular transformation of the FAH involved, suggesting a close association with progression from FAH to HCC. Received: 11 March 1997 / Accepted: 2 June 1997