Primary Liver Cancers-Part 1: Histopathology, Differential Diagnoses, and Risk Stratification

Abstract

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the 2 most common primary malignant liver tumors, with hepatocellular and bile ductular differentiation, respectively. This article reviews the key histopathological findings of these 2 primary liver cancers and includes a review of the role of ancillary testing for differential diagnosis, risk stratification according to the American Joint Committee on Cancer (AJCC) staging recommendation, and a review of precancerous lesions. A literature review was conducted to identify articles with information relevant to precancerous precursors, current histopathological classification, ancillary testing, and risk stratification of primary malignant liver tumors. The histomorphology of normal liver, preinvasive precursors, primary malignancies, and morphological variants, and the utilization of ancillary tests for the pathological diagnosis are described. Dysplastic nodules are the preinvasive precursors of HCC, and intraductal papillary neoplasms of bile ducts and biliary intraepithelial neoplasia are the preinvasive precursors of CC. Benign liver nodules including focal nodular hyperplasia and adenomas are included in this review, since some forms of adenomas progress to HCC and often they have to be differentiated from well-differentiated HCC. A number of morphological variants of HCC have been described in the literature, and it is necessary to be aware of them in order to render the correct diagnosis. Risk stratification is still dependent on the AJCC staging system. The diagnosis of primary liver carcinomas is usually straightforward. Application of the appropriate ancillary studies aids in the differential diagnosis of difficult cases. The understanding of the carcinogenesis of these malignancies has improved with the standardization of the pathological classification of preinvasive precursors and studies of the molecular pathogenesis. Risk stratification still depends on pathological staging.

Keywords: biliary intraepithelial neoplasia; cholangiocarcinoma; dysplastic nodule; focal nodular hyperplasia; hepatic adenoma; hepatocellular carcinoma; intraductal papillary neoplasm.

Figure 1.

Normal liver. Photomicrograph (original magnification, ×40; hematoxylin–eosin [H&E] stain) of benign hepatic parenchyma obtained by excisional biopsy (A), and needle core biopsy (B). Both show the presence of portal tracts (arrow) and 1- to 2-cell thick hepatic plates. No large vessels, cytologic atypia, mitoses, or necrosis are seen. (C) Portal tract showing bile duct, vein branch, arteriole, nerve, and lymphatic. (D) Liver showing central vein. (E) Photomicrograph of reticulin special stain in benign liver tissue, which highlights 1- to 2-cell thick plates and unremarkable portal tract (arrow). (F) Photomicrograph of CD34 immunostain in benign liver tissue, which demonstrates a restricted pattern of periportal labeling (arrow). (G) Periodic acid-Schiff (PAS)-diastase highlights portal tract and bile duct (arrow). (H) Photomicrograph of glutamine synthetase immunostain in benign liver, with pericentral labeling (arrow); peripheral lobular areas are not labeled.

Figure 2.

Dysplastic foci and nodule. (A) and (B) Small cell change with a high N/C, and small, hyperchromatic nuclei. H&E, ×20 and ×40. (C) High-grade dysplastic nodule showing retained reticulin framework. Reticulin, 20. (D) Immunohistochemistry for glypican 3 is negative. 20. N/C indicates nuclear to cytoplasmic ratio.

Figure 3.

Biliary intraepithelial neoplasia (BilIN). A, Nonneoplastic bile duct lined by columnar epithelium, with basally located nuclei (H&E, ×20). B, BilIN 1. Bile duct lined by pseudostratified columnar cells. The nuclei are slightly enlarged and elongated (H&E, ×20). C, BilIN 3. The cells demonstrate loss of polarity, and extend to the luminal surface. The nuclei are enlarged, with vesicular nuclei and nuclear membrane irregularity (H&E, ×20).

Figure 4.

Intraductal papillary neoplasm of the bile duct (IPNB) with moderate dysplasia. This case was adjacent to an invasive carcinoma (not shown here). A, The lumen of the bile duct is completely replaced by a papillary epithelial proliferation (H&E ×4). B. The neoplasm exhibits finger-like, papillary projections (H&E, ×10). C. The papillary fronds are lined by columnar, mucin-containing cells (H&E, ×20). D, The nuclei are enlarged, elongated, and pseudostratified (H&E, ×40).

Figure 5.

Photomicrograph (H&E stain) of hepatocellular carcinoma. A, Absence of portal tracts and thickened hepatic plates in HCC, ×40. B, Solid and nodular growth pattern, ×100. C, Endothelial wrapping and lining in sinusoidal space in HCC, ×200. D, Unaccompanied vessels. H&E, ×200. E, HCC with a tubular and pseudoglandular pattern, ×100. F, HCC with large nuclei with prominent nucleoli, and steatotic clear change, ×200. HCC indicates hepatocellular carcinoma.

Figure 6.

Variants of HCC. A, HCC, clear cell variant. H&E, ×40. B, Scirrhous variant of HCC, ×100. C, Small cell variant HCC. H&E, ×40. HCC indicates hepatocellular carcinoma.

Figure 7.

Histomorphology of FL-HCC. (A) and (B) FL-HCC with thick fibrous collagen bands that encircle and surround neoplastic hepatocytes (H&E, ×40 and ×100). (C) and (D) Polygonal FL-HCC cells with abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli (×200 and ×400; arrow: pale/hyaline body). (E) and (F) Polygonal cells with hyaline bodies, some of which cause nuclear indentation and nuclear pseudo-inclusion (arrows, ×600). FL-HCC indicates fibrolamellar hepatocellular carcinoma.

Figure 8.

Photomicrograph (special stains and immunostains) of HCC. A, Thickened hepatic plates shown by reticulin, ×40. B, Absence of iron deposition, Prussian blue, ×100. C and D, Diffuse sinusoidal CD34 labeling in HCC, ×100. E, P-CEA labeling with a prominent canalicular pattern, ×100. F, Diffuse glutamine synthetase labeling in HCC, ×100. G, Focal, patchy labeling of heppar 1, ×100. H, glypican 3 immunostain, ×100. HCC indicates hepatocellular carcinoma.

Figure 9.

Histopathological features of FNH. (A) and (B) Photomicrograph (×20 and ×40; H&E stain) shows the multinodular contoured lesion with adjacent normal liver with portal tracts (arrow heads, A) and focal inflammatory fibrous bands (arrow, B). (C) and (D) Photomicrograph (H&E stain, ×100) shows a septum (arrow) dividing 2 neighboring nodules (C). The septum contains connective tissue and thick-walled vessels (arrow heads in C and D). (E) and (F), At the interface of the FNH nodule and septa, reactive biliary ductular proliferation is enriched (arrows). (G) and (H), Glutamine synthetase showing a maplkie-pattern. Peroxidase, ×200. FNH indicates focal nodular hyperplasia.

Figure 10.

(A) to (D) Type 1 to 4 hepatocellular adenoma: (1) HNF-alpha mutated; (2) inflammatory type; (3) Beta-catenin-mutated; and lastly; (4) nonclassifiable HA. HA indciates hepatic adenoma; HNF, hepatocyte nuclear factor.

Figure 11.

A new nosology of hepatic adenomas. Reprinted from Gastroenterology, 152(4), Nault JC, Couchy G, Balabaud C, et al. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation, 880–894, 2017, with permission from Elsevier.

Figure 12.

Histopathological features of intrahepatic cholangiocarcinoma (ICC). (A) and (B), Photomicrograph (×20 and ×40; H&E stain) shows an ICC with cystic glandular structures and adjacent benign liver. (C) Photomicrograph (H&E stain, ×40) shows a solid, nodular pattern of ICC. (D) Photomicrograph (H&E stain, ×40) shows mucinous adenocarcinoma morphology of ICC. (E) Photomicrograph (H&E stain, ×40) shows a well-differentiated IHCC. (F) Photomicrograph (H&E stain, ×100) shows a moderately to poorly differentiated ICC.

Figure 13.

Highly invasive behavior and immunohistochemistry of intrahepatic cholangiocarcinoma (IHCC). A, Photomicrograph (×100; H&E stain) shows IHCC gland invading into benign liver, with adjacent reactive bile ducts (arrows for benign ducts). B, IHCC with intraneural and perineural invasion; arrow: nerve tract (×100, H&E stain). (C) Photomicrograph (H&E stain, ×40) shows a vascular space containing tumor embolus. (D) CK-7 immunostain, (×100) shows uniform strong labeling in IHCC tumor cells, in contrast to entirely negative CK-20 (E, ×100). (F) Photomicrograph (×100) shows occasional nuclear labeling by Caudal Type Homeobox 2, a nuclear transcription factor in intestinal type epithelium (CDX-2). CK indicates cytokeratin.