East–West pathology agreement on precancerous liver lesions and early hepatocellular carcinoma

The notion of cancer development as a multistep process, recognized in experimental liver carcinogenesis in rats,1 also applies to human hepatocellular carcinoma (HCC). This implies the occurrence of recognizable precancerous lesions before the development of overt malignancy. Years ago, studies of small nodular liver lesions resulted in a confusing plethora of terms, such that at the World Congresses of Gastroenterology in Los Angeles in 1994, an ad hoc International Working Party (IWP) agreed upon a standardized classification of nodular liver lesions with rationalized nomenclature.2 The precancerous lesions proposed by the IWP comprised microscopic and macroscopic alterations. Microscopic changes of less than 1 mm in diameter are referred to as dysplastic foci with either large or small cell change. Large cell change (previously large cell dysplasia) is associated with malignancy but does not represent true precursor populations of cancer cells. In contrast, small cell change (previously small cell dysplasia) is composed of parenchymal cells of smaller size and larger nuclei (causing nuclear crowding), often containing hepatic progenitor cells and intermediate hepatocytes (transitional forms between progenitor and mature epithelial liver cells). Small cell change foci are considered direct precursors of HCC.3 Macroscopic precancerous lesions are represented by nodules measuring more than 1 mm in diameter, termed dysplastic nodules (DNs), characterized by dysplasia but without definite criteria for malignancy. Many DNs reveal themselves as indistinctly or distinctly nodular lesions ranging from 5 to 10 mm in diameter. They are subclassified into low-grade DNs (LGDNs) and high-grade DNs (HGDNs). LGDNs show only mild dysplasia, and might be confused with large regenerative nodules, corresponding to nodules of 5 mm in diameter, larger than surrounding cirrhotic nodules, without atypia, and with no link to neoplasia. In contrast, HGDNs carry a worse prognosis with a four-fold risk of HCC development. They are characterized by clearly higher cell density than that of surrounding tissue, a higher degree of dysplasia, and represent borderline lesions to be differentiated from, but closely resembling well-differentiated HCCs.4 The next step is malignancy, comprising a continuum from in situ HCC and microinvasive HCC to more progressed stages of HCC through ill-defined borderlines in between.3 The transition of HGDN into early malignancy may occur by development of module-in-module (term and concept from Popper5) in which the subnodule often is less differentiated than the original lesion, representing a further step along the pathway of progressing malignancy. Over the years, the entities proposed by the 1995 IWP became more precisely defined by research efforts in different centers. Presently, the diagnosis is based not only on the accurate search of a set of cyto-architectural features (such as cell atypia, cell crowding, trabecular thickness, microacini) but also on a supplement of histochemical (Gomori’s silver stain for reticulin fibers) and immunocytochemical stains, including immunostaining of keratins 7 and 19 for evaluating stromal invasion, CD34 immunostaining for visualizing capillarization of sinusoids, and staining for alpha-smooth muscle actin to highlight unpaired arteries that otherwise are difficult to discern. The latter term refers to arteries not accompanied by bile ducts as in portal tracts of normal liver. They reflect neoangiogenesis, increase in number from early to fully malignant nodular lesions, and represent the microscopic counterpart of hypervascularity with washout in the portal/venous phase in contrast-enhanced liver imaging. Of particular importance are histochemical markers of malignant transformation, including heat shock protein 70, glutamine synthetase, and glypican3.3,4,6 Regarding the evaluation of borderline cases, there has been a discrepancy in interpretation between Japanese and Western pathologists. DNs with a vaguely nodular contour, diagnosed as HGDN by Western pathologists, often corresponded to what is recognized as early welldifferentiated HCC (eWDHCC) in Japan.7 Abbreviations: DN, dysplastic nodule; eWDHCC, early well-differentiated hepatocellular carcinoma; HCC, hepatocellular carcinoma; HGDN, high-grade dysplastic nodule; ICGHN, International Consensus Group for Hepatocellular Neoplasia; IWP, International Working Party; LGDN, low-grade dysplastic nodule. Address reprint requests to: Valeer J. Desmet, Laboratory of Morphology and Molecular Pathology, University Hospital St. Rafael, Leuven, Belgium. E-mail: v.desmet@pandora.be; fax: (38) 16 33 65 48; 32 16 33 66 40. Copyright © 2008 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.22681 Potential conflict of interest: Nothing to report.