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Nomenclature of Small Hepatocellular Nodules, Update


Ian R. Wanless
Toronto General Hospital
Toronto, ON, Canada


Advances in imaging have led to the discovery of many small hepatic nodules that test the pathologist's acumen. These lesions are difficult because they tend to be well-differentiated with subtle deviation from normal.

The precursor lesions for hepatocellular carcinoma are widespread low-grade dysplasia followed by high-grade dysplastic nodule (HGDN). HGDN have atypical features that distinguish them from normal or cirrhotic liver but are not sufficient for the diagnosis of carcinoma. Individual HGDN are often heterogeneous and complete sampling often reveals small regions of carcinoma within these otherwise benign lesions.

The International Working Party (IWP) of the World Congresses of Gastroenterology recommended the nomenclature and diagnostic criteria listed in Table 1. However, application of these criteria is often difficult. The International Consensus Group for Hepatic Neoplasia (ICGHN) is currently assessing the reliability of histologic diagnosis of early HCC and dysplastic nodules. This group of two dozen hepatopathologists from 10 countries met in 2002 and 2004. The results of these meetings will be published in detail elsewhere. Early results indicate that refinements of the diagnostic criteria and a teaching aid for general pathologists are needed.

The main difficulties are:

Many histologic criteria require quantitative assessment and cannot be easily summarized as present or absent.
The number of criteria in Table 1 are too numerous to achieve interobserver consensus.
Some criteria are difficult to assess even with the aid of special stains.
There is no consensus on the reliability of new features such as stromal invasion and CD34 positivity of endothelial cells.
Because of sampling error, some criteria are of value only in large resection specimens.
Intralesional variability limits the accuracy of small biopsies.

A new diagnostic approach is being developed, to be known as the Laennec Classification of Hepatocellular Neoplasia (LHN). The proposed LHN system will be defined in detail elsewhere. The system can be applied to premalignant lesions and all grades of hepatocellular carcinoma.

In this system, nuclear atypia, N/C ratio, and architectural atypia are graded 0-4 or 0-6 with the assistance of a standard set of photographs. The scores of these 3 components are summed, giving a possible range of 0-14. When two or more distinct regions are noted, more than one Laennec score is reported along with a comment on the percentage of the lesion occupied by each score. Stromal invasion, mitoses, and arterialization are not considered in this system because they highly dependent on sample size.

The advantages of this system are:
  1. it can be applied to both small and large samples

  2. complexity is reduced

  3. criteria are standardized

  4. the use of a numerical score reinforces the fact that early neoplastic features form a spectrum.
The clinical significance of a given Laennec score is currently being evaluated.

Table 1. IWP histologic criteria to distinguish hepatocellular nodules
Histologic feature Large regenerative nodule Dysplastic nodule, low grade Dysplastic nodule, high grade Well-differentiated HCC Moderately differentiated HCC
Clone-like populations - + + + +
Plates more than 3 cells wide - - - - +
Mitotic figures >5/10 HPF - - - - +
cell density more than twice normala - - - + +
Invasion of stroma or portal tracts - - - + +
Irregular nuclear contour, at least moderate - - - + +
Absence of portal tracts (arterial supply) - - +/- + +
Mitotic figures, occasional (1-5/10 HPF)c - - + + +
Cell density more than 1.3 times normal - - + + +
Nuclear hyperchromasia - - + + +
Irregular nuclear contour, at least mild - - + + +
Pseudogland formation +b - + + +
Cytoplasmic basophilia - - + + +
Cytoplasmic clear cell change - - + + +
Reticulin less than normal - - - - +
Increased or decreased iron accumulation - + + + +

The table is modified from International Working Party, Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983-93.

HCC=hepatocellular carcinoma
HPF=high power field (10x40)
a as a measure of increased nuclear to cytoplasmic ratio
b especially when cholestasis present
c mitoses may occur in any lesion in the presence of cholestasis or recent necrosis