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Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35 Page 7 of 17

tumor, and Mallory bodies were 2.4, 2.0, 1.6 and 1.5 times more likely, respectively, to be found in tumors
[12]
occurring in patients with cirrhosis than those in patients without cirrhosis .

There is conflicting data on the occurrence of prognostic histological indices in non-cirrhotic HCCs.
[12]
Nzeako et al. reported that cirrhotic patients, as compared to non-cirrhotic individuals, have a risk of
harbouring grade 3-4 tumors and venous invasion of 1.7 and 1.6 times respectively. Whereas extrahepatic
[41]
extension was reported to be greater in HCC arising in non-cirrhotic liver (20.5% vs. 6.5%) ; others have
reported comparable tumor differentiation and portal tree invasion between cirrhotic and non-cirrhotic
HCCs [41,57] .

Pathology of background liver
HCC may develop without advanced liver fibrosis or even in normal livers. The non-tumoral liver exhibits
features of chronic hepatitis, varying degrees of fibrosis, steatosis, iron overload or other metabolic
disorders . In actuality, very few cases have an absolutely normal liver. However, in a study, 21/87 HCCs
[58]
occurred in non-cirrhotic livers, and histopathological evaluation showed that nearly a third had no fibrosis
in the liver . Another study of 1,221 patients revealed that 238 (19%) had no cirrhosis yet the grade of
[8]
fibrosis was ≤ F2 in 62% of all non-cirrhotic patients, and F3 in 8%. In another series of surgical resections
[59]
of HCC, a high rate of non-cirrhotic livers was identified (F0-F1 38%, F2-F3 33%, F4 29%) . Other
features such as liver cell dysplasia, more often the large cell type, was found in 27%-40% of cases [60,61] and
these figures decreased to 6%-20% in the subgroup of non-fibrotic livers [62,63] . The presence of NAFLD (12%
[64]
vs. 28%) is more common in patients without cirrhosis than in those with cirrhosis [Figure 4].

Differential diagnosis of HCCs arising in non-cirrhotic livers
There is a plethora of inflammatory, immunologic, neoplastic and infective lesions that occur in a non-
cirrhotic liver background. However, from the point of view of histopathological interpretation, the most
important are preneoplastic and neoplastic conditions, HCC variants and tumor metastasis.

Dysplastic nodules are premalignant lesions, which are well-defined and circumscribed. These lesions
[65]
mostly arise from a background of chronic liver disease and more often, cirrhosis . These are
important for diagnosis as often, they come under the differential diagnosis of well-differentiated HCCs.
Immunohistochemical panels comprising glypican 3, HSP-70, glutamine synthetase, CD34 and CK7, are
[18]
particularly useful in such scenarios [Figure 5].
The differential diagnosis between hepatocellular adenoma (HCA) and well-differentiated HCC arising
in non-cirrhotic livers is another challenging situation, especially the HCA subtype with cytological
or architectural atypia . Clinico-pathological correlation helps to sort this conundrum. Malignant
[66]
transformation is one of the most important complications of HCA and is reported to occur in 4%-10%
of HCA [67-69] . Awareness about the malignant potential and predisposing risk factors such as male gender,
[68]
larger tumor size, and β-catenin activated subtype, is crucial .
Focal nodular hyperplasia (FNH) is another important differential consideration for HCCs occurring in
non-cirrhotic backgrounds. FNH, a benign lesion resulting from the regenerative response to vascular
abnormalities, has a characteristic histomorphology. A central scar with thick-walled vessels and nodular
regeneration of hepatocytes, with marked ductular reaction and inflammatory infiltrate at the junction of
fibrous bands and hepatocyte nodules, distinguishes FNH from HCC. A “map-like,” geographic pattern of
GS staining of FNH is especially useful in diagnostic dilemmas [70-72] .

Awareness of other benign and malignant epithelial, mesenchymal and vascular tumours is crucial.
Cholangiocarcinoma is the second most common primary cancer and accounts for 15% of primary liver