Hepatocellular carcinoma: a clinical and pathological overview

Abstract

HCC incidence rates have been rising in the past 3 decades and by 2025 > 1 million individuals will be affected annually. High-throughput sequencing technologies led to the identification of several molecular HCC subclasses that can be broadly grouped into 2 major subgroups, each characterized by specific morphological and phenotypical features. It is likely that this increasing knowledge and a more appropriate characterization of HCC at the pathological level will impact HCC patient management.

Keywords: angiogenesis; diagnosis; hepatocellular carcinoma; prognosis; tumor microenvironment.

Figure 1.

Classification of HCC. This scheme illustrates the correlations existing among molecular classes of HCC ^,, and genetic, morphological and clinical features.

Figure 2.

Pathology of HCC. This figure illustrates some of the most typical pathological features of HCC subtypes. (A, B) CTNNB1-mutated. In this fresh specimen, HCC presents as a mass made by several cluster of small and confluent green nodules (cd. “Multinodular confluent HCC”) with some satellites (A); at histology the lesion is characterized by the presence of several pseudo-glandular structure filled by green material consistent with cholestasis (B). (C, D) Macrotrabecular Massive. In this fixed specimen the multiple confluent HCC nodules bulge over the surrounding flat fibrous strands (C); at microscopic level the lesion is characterized by a macrotrabecular pattern of growth (D).

Figure 2.

Pathology of HCC. (E) Scirrhous. This HCC is characterized by abundant stroma separating neoplastic trabeculae. (F) In this HCC, neoplastic cells are characterized by diffuse steatosis and occasional cell ballooning; the tumor shows scattered inflammatory infiltrates. (G) Lymphocyte-rich. A rich intratumoral infiltrate of lymphocytes denotes this HCC. (H) A clear cell variant of HCC.

Figure 3.

Vascularization of HCC. (A, B, C) The images illustrate an HCC (lower right corner, A) with a rich vascular support as highlighted by a CD34 staining (B); at higher magnification CD34+ vessels show a capillary distribution; (C). (D, E, F) also this HCC (right part, D) shows a rich vascular network when stained with CD34 (E); in this cases however, CD34+ vessels encapsulate clusters of neoplastic cells (F) featuring a peculiar phenotype described as VETC ^,.

Figure 4.

Diagnostic of well differentiated hepatocellular lesions in healthy liver: Focal Nodular Hyperplasia. (A) This liver biopsy illustrates an area characterized by the presence of fibrous septa: a feature which might raise the suspect of a not adequate specimen; (B) in such cases the expression of CD34 by the endothelium of sinusoids can be of great help: indeed, a diffuse increase is in keeping with lesional sampling; (C) CK7 highlights that the lesion is characterized by the presence of portal tracts; (D) GS immunostaing proves a pathognomonic strong, map-like, staining for GS. The mopho-phenoptypical findings are conclusive for an FNH.

Figure 5.

Diagnosis of well differentiated hepatocellular lesions in healthy liver: Steatotic Hepatocellular Adenoma. (A) This liver biopsy documents a well differentiated lesion which, at H/E, is barely detectable (right part); (B) at higher magnification lesional hepatocytes are characterized by clear nuclei; (C) CD34 staining highlights the lesion; (D) lesional hepatocytes, as compared to the surrounding, do not stain for LFABP. The morpho-phenotypical findings are conclusive for a steatotic HA.

Figure 6.

Diagnosis of well differentiated hepatocellular lesions in healthy liver: teleangiectatic/inflammatory Hepatocellular Adenoma. (A) This liver biopsy illustrates a well differentiated hepatocellular lesion characterized, at higher magnification, by teleangiectatic vessels; (B) CK7 highlights that the lesion is characterized by the presence of scattered pseudo-portal tracts; (C and D) the lesion is immunoreactive for SAA and PCR. The morpho-phenotypical findings are conclusive for telenagiectatic HA.

Figure 7.

Diagnosis of well differentiated hepatocellular lesions in healthy liver: Atypical Hepatocellular Adenoma. (A) These biopsies document a well differentiated hepatocellular lesion (*) and the surrounding parenchyma; (B) the lesion, which is barely seen on H/E at scanning magnification, is highlighted and clearly outlined by CD34; and shows (C) strong and diffuse immunoreactivity for GS; (D) at higher magnification, the lesion is characterized by a mild degree of architectural disarrangement and cytological atypia (pseudo-glands and increased N/C ratio), (E) reticulin framework is conserved and (F) few neoplastic cells showing nuclear immunoreactivity for HSP70. The morpho-phenotypical findings are conclusive for an atypical HA.

Figure 8.

Diagnosis of well differentiated hepatocellular lesions in hepatitis/cirrhotic liver. (A) This biopsy document, in the setting of a chronic steatohepatitic background, the presence of a well differentiated lesion (*); (B) at higher magnification the lesion is characterized by unpaired arteries and pseudo-glandular arrangement of hepatocytes; (C) the nodule showed an diffuse and intense immunoreactivity for GS (non neoplastic parenchyma showed a laminar staining); (D) neoplastic cells are also immunoreactive for CHC. The morpho-phenotypical findings are conclusive for an eHCC.