Until 1995, a number of redundant nomenclatures and conflicting descriptions of the morphological characteristics for dysplastic lesions were responsible for frequent difficulties in diagnoses of these lesions. A correct diagnosis is crucial because each lesion requires a different clinical approach. It has already been suggested that in LGDN the best approach is to perform a biopsy when the lesion's appearance changes with imaging methods. However, in HGDN the management varies in different centers. Some perform a surgical resection when the diagnosis is associated with HCC. Ethanol injection or thermoablation can also be a therapeutic option.
Based on IWP classification, we analyzed 107 nodular lesions from explanted cirrhotic livers. This has been done before by other authors [10, 12–14], but not in our Latin American setting. In our study, 17 nodular lesions were classified as LRN, 38 LGDN, 28 HGDN and 24 HCC. With regard to the IWP criteria that consider dysplastic nodules larger than 0.1 cm, the smallest dysplastic nodule identified in our study measured 0.18 cm. When smaller than 0.1 cm, the nodules are called dysplastic foci. Maybe such small lesions are not capable of compromise in patient prognosis, but we should evaluate if these patients should have a closer follow-up. Theise et al. also considered that these lesions should be described as dysplastic since nodule size is merely reflection of how clonal expansion has been occurring.
The IWP  considers morphological variables in order to achieve the microscopic characterization of these nodular lesions. In our study, the most relevant variable was cellularity, which was smaller in LRN and LGDN and larger in those of HGDN and HCC. Trabeculae thickness also increased as the lesions advanced through the different steps of hepatocarcinogenesis. Regarding cytoplasm tintorial affinity, those defined as HGDN and HCC showed a greater basophilic aspect when compared to LRN and LGDN. Hypercromasia and nuclear atypia were also observed in HGDN and HCC.
All variables described above with the exception of cytoplasmic basophilia were considered as major criteria in the IWP diagnosis of nodular liver lesions, as observed in this study. Some other characteristics also important in their differential diagnosis were pseudoacinar pattern, which was more frequent in HGDN and HCC, and mitosis, observed almost exclusively in HCC lesions. Although these findings were considered as secondary in the IWP, they were helpful in the diagnosis of the different nodules when analyzed with the other characteristics.
Amongst all the morphological characteristics observed for the diagnostic definition, the clear-cut increase in cellularity helped in the discrimination of the different lesions, even using a subjective method for definition. In previous studies the counting of hepatocytes/mm2 had been performed and the final results were similar to ours [15, 16]. Perhaps, in the near future, studies using image automatization systems will provide better results . However, we believe that this criterion should not be considered apart from the others in the differential diagnosis of these nodules.
Although the IWP consensus is known and largely adopted by many authors [10, 12, 18], studies that test its reproducibility and its prospective validation are lacking. Some proposed microscopic criteria are very subjective and lead to great difficulty in differential diagnosis between lesions. Le Bail et al. also suggest that the differential diagnosis of benign, atypical or malignant nodular hepatic lesions may even be difficult for highly qualified pathologists. Thus, we believe that the time has come for a critical analysis of the IWP proposal, with an accompanying redefinition of some criteria, once international use by expert hepatopathologists over several years bears enough evidence to support these changes. However, we should consider the possibility that some lesions will not have their biological behavior defined on the basis of microscopic criteria alone, similar to the situation observed in HGDN and HCC. Molecular and immunohistochemical methods may offer collaborative evidence and have been shown as an important contribution to diagnosis .
Some studies have suggested that cirrhosis progression from dysplastic nodules to HCC is accompanied by an abnormal vascularization process [12–14]. The number of isolated arteries has also disclosed some abnormalities in a semi-quantitative evaluation in preneoplastic lesions and in HCC [20, 21]. Terada et al. demonstrated that these arteries are lacking in the normal liver parenchyma and are scarce in chronic hepatitis as well as in LRN. This observation led us to suggest that perhaps these lesions are not dysplastic lesions, and are different from the borderline nodules that contained many arterial elements. In our study, we observed isolated arteries with the HE technique in the different types of nodule, but they were more prominent in those classified as HGDN and HCC. The immunohistochemical study with the use of anti-smooth muscle antibodies may facilitate the identification of arteries in these nodules, allowing a semi-quantitative evaluation that could provide a more objective approach in the differential diagnosis of these types of lesions . A more prevalent artery supply also facilities the angiographic diagnosis of HCC and differentiated non-neoplastic and preneoplastic conditions.