Recent Advances:Hepatocellular Nodules

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Text of Recent Advances:Hepatocellular Nodules

  • Dr.Niharika Singh Gandhi Medical College Bhopal

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  • There is observation of hepatic progenitor cell features in hepatocellular neoplasms at an early stage (dysplastic nodules) or advanced tumours with mixed hepatocellular and cholangiocellular phenotypes.


  • The 4th edition of the WHO classification of tumours of the digestive system

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  • Regenerative hepatocellular nodules

    Boundaries consist usually of fibrous septa, collapsed reticulin strands, multilobular areas of parenchymal collapse, atrophic hepatic plates, other nodules or a combination of the above.


  • Acetaminophen Toxicity

    This gross photograph of the liver from this patient demonstrates the pale areas of necrosis (arrows).*

  • 29 days Serial biopsies from native liver during its recovery phase following auxiliary transplantation Acute necrosis with sparing of periportal hepatocytes results in an initial phase of hepatocellular proliferation, acute inflammation and reticulin collapse with parenchymal nodular transformation.


  • Acute liver failure due to acetaminophen overdose146 days


  • 350 daysResolution of inflammation, matrix reabsorption and hepatic plates remodelling and growth lead eventually to full reconstitution of the liver mass, involution of the graft and withdrawal of immunosuppression.


  • Regenerative nodule in nodular regenerative hyperplasia. The nodular area is flanked by atrophic plates with condensation of reticulin fibres but no bridging fibrosis.


  • Regenerative nodule in advanced stage chronic hepatitis C. The nodular area is surrounded by bridging fibrous septa..In chronic hepatitis C, the nodules are of small size due to porto-portal and porto-central bridging with loss of the vascular anatomical relationships .Two cell- thick hepatic plates are often present, and there may be deposition of granules of copper-binding protein at the interface with the fibrous septa which is an indirect sign of advanced fibrosis may be helpful in the interpretation of core needle biopsy specimens, in which nodule formation is not readily apparent due to the small size of the sample or the large size of the nodules or both.

    Grade 1tumor cells resemble non-neoplastic hepatocytes, with small round nuclei and little/no atypia.Grade 2tumor cells have conspicuous nucleoli, hyperchromatism, and irregular nuclear membranes.Grades 3 & 4tumor cells display increasing nuclear pleomorphism, which may result in anaplasia and giant tumor cells (a bad prognostic sign)*

  • Primary biliary cirrhosis.Bridging fibrosis linking up portal tracts generate a jigsaw puzzle pattern rather than round nodules.


  • Primary sclerosing cholangitis. Marked segmental hypertrophy and lateral atrophy lead to severe distortion of the lobar anatomy.


  • Benign hyperplastic regenerative proces secondary to a local abnormality of blood flow due to a vascular malformation such as: BuddChiari syndrome, hereditary haemorrhagic telangiectasia,portal vein thrombosis/ atresia, congenital portosystemic shunt.

    Polyclonality, increased ANGPT1/ANGPT2 ratio.Usually solitary, but multiple vascular malformations and coexist with intracranial tumour. Develops in noncirrhotic livers of women 3040 years FNH is usually the easiest to differentiate, due to its architecture and bland appearance of lesional hepatocytes.

  • Macroscopically, FNH can range in size from a few mm to several cm. It usually shows a pale, micronodular and firm parenchymal surface, with or without a central scar.There is usually no capsule, the periphery of the lesion merging with the adjacent liver .

    Fresh specimen: note the multinodularity and central stellate scar (arrow).*

  • Microscopically, it consists of nodules of benign-looking hepatocytes separated by fibrous septa containing a ductular reaction, a lymphoid infiltrate and aberrant vascular structures.

    Focal nodular hyperplasia. Fibrous septa separate hepatocellular nodules of different sizes that resemble cirrhosis (Masson trichrome)*

  • A 32-year-old woman transplanted for glycogen storage disease type 1. A 10-mm hepatocellular adenoma showed diffuse staining for glutamine synthetase. No nuclear or cytoplasmic staining for -catenin was identified. Please note background liver on the right hand side showing normal glutamine synthetase expression by perivenular hepatocytes.52-year-old woman. Liver resection for focal nodular hyperplasia. The pattern of glutamine synthetase is typically map like.

    Glycogen storage disease (GSD) type I is also known as von Gierke disease .In 1952, Cori and Coridemonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I. *

  • An important practical point is the identification of a regenerative nodule in a core needle biopsy specimen, as the changes can be very subtle and easily overlooked.Signs representing that the needle has hit a regenerative area:

    Two-cell-thick hepatic plates in biopsy cores from adult patients.Thin hepatic plates sometimes in a parallel configuration.Sinusoidal dilatation without other accompanying features of venous outflow blockage.Few focal deposits of copper binding protein on the orcein/ Victoria blue stain without other signs of biliary pathology.

    *A full clinical history, close correlation with imaging findings and ideally an adequate sample of lesional tissue along with a separate sample of non-lesional tissue to assess the status of background liver should be the basis for the histological interpretation of liver nodules.

  • DYSPLASTIC NODULESNodules of relatively small size, up to about 1015 mm,identified in cirrhotic livers, and showing atypical histological features without fulfilling the criteria of HCC. These nodules are thought to be HCC precursors, based mainly on the following observations: Their occurrence in livers affected elsewhere by overt HCC. The identification of small nodular lesions with atypical features and containing foci of overt HCC (nodule-in-nodule pattern). Similarities at molecular level with HCC.Clinicopathological studies based on biopsy and clinical follow-up suggesting their transformation into HCC. Change in their vascular supply. Histologically,associated with the presence of unpaired arteries and sinusoidal capillarisation marked by the CD34 immunohistochemical marker.

    This latter point is particularly important. Progression from cirrhosis to HCC ischaracterised by a switch from a dual portalarterial to a predominantly arterial supply,due to neoangiogenesis.*

  • Additional stains, which can be of help in identifying the porto-lobular relationship, are immunohistochemistry for cytokeratins (e.g. Ker 7) glutamine synthetase

    *To highlight portal regions and centrilobular venules, respectively.Degree of sinusoidal capillarisation by CD34 immunostaining.

    CD34 helps discerning where the lesion is located in the fragment*

  • Arterialisation is exploited radiologically by demonstrating contrast uptake in arterial phase and rapid washout in the venous phase to the point that demonstration of arterialisation by one or two imaging modalities is considered to be sufficient for the diagnosis of HCC without the need of histological confirmation. The use of liver biopsy is therefore confined to lesions with atypical features on imaging. According to a recent consensus paper, dysplastic nodules are further subdivided into Low-grade lesions: may be indistinguishable from large regenerative nodules, differing only by the focal presence of some of the dysplastic changes. High-grade lesions:nodules may be indistinguishable from early HCC probably because they represent part of a continuum.

  • Macroscopically, dysplastic

    nodules are distinct from the background liver in terms of their size, appearance, colour, texture and/or bulging cut surface.Dysplastic nodule in cirrhotic liver showing a nodule- in nodule pattern.

    The line of triangles marks the boundary of the nodule against the background liver. The arrow indicates an area of increased cell density.


  • Changes in Nodule in Nodule pattern include

    SiderosisCopper/copper-binding protein deposits SteatosisClear cell changeMalloryDenk bodiesIncreased trabecular thicknessPseudoglandular structuresNuclear hyperchromasia or irregularity of the nuclear contour,Cytoplasmic basophilia Increased proliferative rate within areas of a nodule or compared with background liver and loss of the reticulin stroma.

    Micrographshowing aMallory bodywith the characteristictwisted-ropeappearance (centre of image - within aballooning hepatocyte).*

  • 11)Large cell change, originally called liver cell dysplasia :Present in association with chronic liver disease Hepatocytes show large atypical nuclei with preserved nuclear cytopla