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Page 2 of 16 Borzio et al. Hepatoma Res 2019;5:15 I http://dx.doi.org/10.20517/2394-5079.2019.11

INTRODUCTION
It has long been known that, like in others human carginogenetic models as colo-rectal cancer, in
hepatocellular multistep carcinogenesis precancerous lesions both micro- and macroscopic precede the
[1,2]
development of hepatocellular carcinoma (HCC) . Chronic hepatitis and cirrhosis represent the natural
background in which precancerous lesions grow through stepwise sequence. These lesions have been
described many years ago and include microscopic dysplastic foci (DF) and sizable dysplastic nodules (DN).
The latter are further categorized as low-grade (LG-DN) and high-grade dysplastic nodules (HG-DN) with
[3]
specific and distinctive morphologic characteristics and different carcinogenetic propensity . Representation
of multistep hepatic carcinogenesis is schematized in [Figure 1]. Given the low attitude to perform liver
biopsy in cirrhotic patients, microscopic preneoplastic lesions have been losing interest in clinical practice.
Hence, the present review will focus specifically on preneoplastic nodules which can be routinely detected
by radiologic techniques and monitored over time for their potential neoplastic transition. Histologic
classification, histopatologic features, radiologic diagnostic criteria, natural history and treatment of these
lesion will be discussed.

In cirrhosis, application of regular ultrasound surveillance resulted in the discovery of an increasing
number of small nodules [< 2 cm according to the definition of small lesion by International Working Party
[4]
(IWP)] . Small nodules usually include definite hepatocellular carcinoma (HCC), either early hepatocellular
carcinoma (eHCC) and very-early hepatocellular carcinoma (veHCC) or progressed hepatocellular
[5-9]
carcinoma (pHCC) and the large majority of pre-neoplastic nodules . Other small lesions as metastases or
mesenchymal neoplasms are much less frequently detected during surveillance.

Distinction of pre-neoplastic nodules from well-established HCC is mandatory for decision making process,
particularly in transplant or surgical setting. To decide whether a given nodule is malignant, premalignant
or benign is therefore of paramount importance demanding a great radiologic, morphologic and clinical
expertise. The following key points should help clinicians to get oriented in the management of such small
nodules:
1. Precancerous nodules have a maximum diameter seldom exceeding 2 cm and are typically detected in
cirrhosis/chronic hepatitis.
2. Their prevalence is relevant ranging from 60% to 70% among nodules < 1 cm and from 20% to 30% among
nodules > 1 < 2 cm.
3. They can be intercepted as single or multiple lesions and often concomitant with already established HCC.
4. HG-DN account for 30 % of all precancerous nodules and are considered true precancerous lesions
whereas LG-DN have a trivial neoplastic risk comparable to that of large regenerative nodules.
5. Transforming risk of HG-DN is largely unpredictable at baseline.

HISTOPATOLOGICAL CLASSIFICATION AND FEATURES OF DYSPLASTIC NODULES
Nomenclature
Definition and nomenclature of precancerous nodules was firstly proposed by the International Working
[10]
[4]
Party in 1995 and further updated in an east-western consensus of pathologists in 2008 .
Non-malignant hepatocellular nodules include large regenerative nodules (LRN) and DN. The latter are
subclassified as LG-DN and HG-DN. However, LG-DN share a number of features to non-neoplastic LRN
and therefore, the distinction between these two lesions is particularly difficult and unpractical. Hence, the
panel of experts recommended not to separate LG-DN from LRN and classify as LG-DN any nodule that
[4]
cannot be classified as HG-DN . Their size ranges from few millimetres to 2 cm rarely exceeding 3 cm.
Histologic differential diagnosis
Histologic differentiation of LG-DN, HG-DN and eHCC is challenging, particularly when pathologists have
to deal with small samples obtained by fine needle biopsy. It has been repeatedly stressed that histology is