8Advanced precancerous lesions in the liver
Section snippets
General concepts of hepatocarcinogensis and nomenclature: dysplastic nodules and early HCC
It is recognized that the vast majority of HCC (90%) develops in the background of chronic hepatitis/cirrhosis usually following a multistep sequence; de novo development of HCC may also occur as the end result of sequential events which can not be traced back for the destructive overgrowth of the progressed tumour. Precancerous lesions include dysplastic foci (DF) and nodules (DN) while small cancerous lesions (up to 2 cm) are early (eHCC) and progressed (pHCC) HCC. DF are microscopic
The early diagnosis of HCC and the detection of non-malignant/dysplastic nodules during screening and surveillance programs of cirrhotic patients
Worldwide the majority of patients with HCC are identified with an advanced cancer, that almost invariably prevents the application of potentially curative treatments. The hope of cure only relies on the early diagnosis of tumours less than 2 cm (small HCC) through the surveillance of patients at risk. HCC takes place in the context of well known and readily identifiable environmental risk factors, mostly occurring in patients with chronic liver disease, including cirrhosis caused by chronic
The radiological diagnosis of DN and HCC
The pathologic basis of the diagnostic role of imaging in HCC rests on the portal to neo-arterial shift of the tumour vascular supply during hepatocarcinogenesis. According to American and European international practice guidelines ∗[7], ∗[8] it is recommended to consider as HCC any lesion >1 cm displaying a typical vascular pattern and to consider as indeterminate any nodule displaying an atypical vascular pattern. Nodules ≤1 cm should be strictly monitored by imaging. DN are usually detected
The nodule pathology
A DN is defined as a nodule macroscopically distinct from surroundings due to its size, colour and bulging cut surface (Fig. 4A). DN mostly measure 1–1.5 cm, may be single or multiple and are classified as LG or HG depending on the degree of cellular and architectural atypias. Both types of nodules are usually hypercellular and can exhibit features suggestive of clonal cell origin (HG-DN in particular) such as hepatocytes groups showing cytoplasms with clear/fatty/eosinophilic modifications,
Early HCC (Fig. 5) and progressed HCC
Small HCC is arbitrarily defined as carcinoma measuring less than 2 cm. There are two types of small HCC: the eHCC and the pHCC. eHCC is a low-grade, early stage and slowly growing tumour of vaguely nodular appearance at macroscopical level. This macroscopical appearance is due to the deceptive growth of tumour cells progressively replacing, without destroying, the pre-existing cirrhotic parenchyma. This tumour is hard to be recognized also at microscopical level. Histologically eHCC is always
The diagnostic role of tissue markers
Several hepatocyte and vascular tissue markers have been evaluated in DN and HCC with the aim to find useful adjuvant tools for diagnosis such as AFP, DCP, CD34, p53, PCNA, GPC3, HSP70, GS, agrin, EZ2H. Some of these are HCC serum biomarkers (AFP and DCP) but without sufficient sensitivity for eHCC detection [19]. CD34 is a commonly used vascular marker, usually unreactive in the liver sinusoids. Sinusoidal capillarization may occur in relation to increased blood flow pressure in different
The liver biopsy
As previously mentioned biopsy is recommended for de novo 1–2 cm nodules lacking a conclusive malignant behaviour at dynamic imaging. These lesions include DN and eHCC and WD-HCC with an atypical vascular pattern (usually hypovascular HCC). A correct biopsy procedure should include intra- and extra-lesional sampling by a cutting needle of 20/21 gauge under US guidance. Liver tissue should be fixed in formalin and sent to the pathology department for processing. An integrated
Diagnostic criteria in the liver biopsy (Table 2) and the pathology report (Table 3)
After H&E assessment a consistent number of cases show up as clearly non-malignant (likely LG-DN) or malignant (likely pHCC) and as such should be reported (Table 3), with the remaining cases uncertain in the window HG-DN vs. e/WD-HCC. In these cases it is mandatory to investigate the vascular features (CD34 immunostaing) and those with the most discriminatory value (reticulin framework, stromal invasion and markers) (Table 3 and Fig. 8). The distinction between stromal invasion vs.
Expert or non-expert setting for the liver biopsy?
The search for tissue markers is mostly useful to confirm a suspicious e/WD-HCC or to help detecting HCC when the material is fragmentary or scarce. This is particularly valuable in a non-expert setting [28] to make pathologists more familiar and confident with features of WD-HCC. However AASLD and EASL-EORT guidelines suggested the liver biopsy to be evaluated by expert pathologists but in the clinical practice this is hardly the case; the search of tissue markers in a relatively simple
The natural history of DN
Although DN have been described since 1995, their natural history has not been fully clarified. Series collected in pre-dynamic imaging era suggested that pathologically-proven HG-DN carried the highest risk of transformation, hazard ratio 2.4 and 16.9, during a mean follow up of 33 and 38 months, respectively ∗[30], [31], although it was hard to predict the elapsing time from US-detection to HCC occurrence. In fact, some HG-DN remained stable over a long time period, often exceeding two years
DN: the issue of treatment
The early treatment of precancerous lesions, particularly HG-DN, which might theoretically improve survival, is controversial. Unlike other human models of gastrointestinal carcinogenesis (colo-rectal and gastroesophageal cancer) where treatment of precancerous lesions is recommended, hepatocellular carcinogenesis lacks data supporting this policy. The longer and unpredictable natural history of precancerous lesions of the liver seems to discourage their systematic treatment and, accordingly,
Summary
HG-DN are the most advanced HCC precursors in a sequence of events ranging from chronic hepatitis/cirrhosis to LG-DN, HG-DN to eHCC to pHCC. Following international guidelines recommending the surveillance of cirrhotic patients, a growing number of 1–2 cm hepatocellular nodules, including eHCC and DN, are recognized. The use of radiological techniques permits the diagnosis of malignancy in a minority of them (30–40%) while the majority needs to be biopsied for characterization. The histological
Conflict of interest statement
None declared.
Acknowledgement
This paper was partly supported by AIRC (Associazione Italiana Ricerca Cancro), Grant n.10247 to Massimo Roncalli (2010).
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Massimo Roncalli MD PhD and Fabio Farinati MD are senior authors equally contributing to the work.
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