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Fig. 8.36 Intrahepatic cholangiocarcinoma. A Clear cell type. B Mucinous type. C Pleomorphic type. D Spindle cell type.

Fig. 8.36 Intrahepatic cholangiocarcinoma. A Clear cell type. B Mucinous type. C Pleomorphic type. D Spindle cell type.

tic hepatocytes or bile ductules containing bile. It is always seen at the periphery of the tumour. Bile production by tumour cells is never found.

Carcinoma cell nests with small tubular or cord-like patterns extend by compressing the hepatocytes or infiltrating along the sinusoids. Occasionally, carcinoma cells abut directly on to hepato-cytes. As a result, the portal tracts are incorporated within the tumour and appear as tracts of elastic fibre-rich connective tissue. Fibrous encapsulation is not seen.

ICC frequently infiltrates portal tracts, and invades portal vessels (lymphatics, portal venules); there is also perineural invasion, particularly in the large portal tracts. Infiltrating, well-differentiated tubular carcinoma must be differentiated from the non-neoplastic pre-existing small bile ducts. The carcinoma cells infiltrate around nerve fibres and have variably-sized cancerous lumens.

Adenosquamous and squamous carcinoma. The former is an adenocarcinoma containing significant amounts of unequivocal squamous carcinomatous elements, i.e. keratin and/or intercellular bridges. The latter is entirely composed of squamous cell carcinoma. They are occasionally seen at advanced stages of ICC. Cholangiolocellular carcinoma. The carcinoma cells are arranged as small, regular, narrow tubular structures resembling ductules or canals of Hering {1828}. The cells are larger than the usual ICC. Mucinous carcinoma. A predominant component of extracellular mucus (mucus lakes), usually visible to the naked eye, is present in the stroma. Carcinoma cells distended with mucus are seen floating in the mucus lakes. The histology is similar to that seen in other organs. These tumours show rapid progression clinically {1671}. Signet-ring cell carcinoma. A malignant tumour in which there is a predominance of discrete cells distended with mucus. ICC composed only of signet ring cells is extremely rare.

Sarcomatous ICC. A cholangiocarcino-ma with spindle cell areas resembling spindle cell sarcoma or fibrosarcoma or with features of malignant fibrous histiocytoma. This variant may have a more aggressive behaviour. Carcinomatous foci, including squamous cell carcinoma, are scattered focally.

Lymphoepithelioma-like carcinoma. Two cases of undifferentiated lymphoepithe-liomatous lesions with adenocarcinoma have been reported {757, 2025}. In these cases, EBV-coded nuclear RNAs were demonstrable.

Clear cell variant. This lesion is characterized by distinct overgrowth of clear cells in an acinar or tubular pattern. The tumour cells are PAS reactive and diastase resistant, indicating the presence of mucin.

Mucoepidermoid carcinoma. This variant resembles the tumour arising in salivary glands.

Differential diagnosis

Hepatocellular carcinoma. Some ICCs grow in a cord-like pattern reminiscent of the trabeculae of HCC. The cords are always separated by a connective tissue stroma rather than by sinusoids; canali-culi and bile are also absent. Almost all

Fig. 8.37 Intrahepatic cholangiocarcinoma. In situ hybridisation for human telomerase mRNA shows signal in carcinoma cells (left). Non-neoplastic bile duct is negative (right).
Fig. 8.38 Intrahepatic cholangiocarcinoma, in a patient with heterozygous alpha-1 antitrypsin deficiency of the Piz type. A Tubular adenocarcinoma. B Cytokeratin 7 immunohistochemistry demonstrates tumour cells spreading along bile ducts and infiltrating liver tissue.

ICCs are diffusely positive for cytokeratin 7 and 19, whereas only a few cases of HCC are positive. The hepatocyte antigen (Dako) is expressed by HCC but not by ICC.

Metastatic carcinoma. ICC cannot be distinguished histologically from metastatic adenocarcinoma of biliary tract or pancreatic origin. Occasionally, dysplas-tic changes in neighbouring bile ducts suggest intrahepatic origin. In addition, diffuse expression of cytokeratin 20 favours metastatic adenocarcinoma, particularly from colon {1141}. While cyto-keratin 7 is common in ICC, it is not so common in metastatic carcinoma. Sclerosing cholangitis. Periductal spread of ICC may be difficult to distinguish from sclerosing cholangitis, particularly when only biopsy material is available. The most important criteria for the diagnosis of malignancy are severe cytological atypia, random and diffuse infiltration of the duct wall by the neoplastic cells, and perineural invasion.

Fig. 8.39 Immunoexpression of atz11 demonstrates alpha-1 antitrypsin deficiency of piz type.

Grading

ICCs can be graded into well, moderately, and poorly differentiated adenocarcinoma according to their morphology. In the case of the common type of adeno-carcinoma, well-differentiated lesions form relatively uniform tubular or papillary structures, moderately differentiated tumours show moderately distorted tubular patterns with cribriform formations and/or a cord-like pattern, while the poorly differentiated show severely distorted tubular structures with marked cellular pleomorphism.

Precursor and benign lesions

Biliary intraepithelial neoplasia (dysplasia)

This is characterized by abnormal epithelial cells with multilayering of nuclei and micropapillary projections into the duct lumen {2078, 1322}. The abnormal cells have an increased nuclear/cyto-plasmic ratio, a partial loss of nuclear polarity, and nuclear hyperchromasia. They are divisible into low-grade and high-grade lesions. Some peribiliary glands may also be dysplastic. Cell kinetic studies have disclosed proliferative activity of intraepithelial neoplasia between that of hyperplasia and ICC, and telomerase activity is demonstrable in both intraepithelial and invasive carcinoma {1915, 1440}. Carcinoembryonic antigen (CEA) is focally detectable in biliary intraepithelial neoplasia and more so in carcinoma {1322}. These findings support the concept of a hyperplasia-dys-plasia-carcinoma sequence in the biliary tree {1989}.

In liver fluke infestations, the bile ducts first show desquamation of the epithelial lining with subsequent hyperplasia, periductal fibrosis, inflammation and goblet cell metaplasia {2008, 913}. The neoplastic transformation from hyperpla-sia in bile ducts to ICC through dysplas-tic changes is demonstrable in opisthor-chiasis. In hepatolithiasis, the findings are those of cholangitis, with proliferation of the biliary epithelial lining and peri-biliary glandular cells, and multiple foci of biliary intraepithelial neoplasia {1323}. Hyperplasia and intraepithelial neoplasia of the duct epithelium in livers with Thorotrast-deposition and congenital biliary anomalies may be also related to the development of ICC {1626, 2165}. It has been reported in patients with PSC that biliary intraepithelial neoplasia could evolve from papillary hyperplasia {2078, 1107}. However, recent experience at orthotopic liver transplantation of PSC has detected hardly any in situ or invasive neoplastic foci.

Biliary papillomatosis

Dilated intrahepatic and extrahepatic bile ducts are filled with papillary or villous excrescences, which microscopically are papillary or villous adenomas with delicate fibrovascular stalks covered with a columnar or glandular epithelium {806, 351}. They are soft and white, red or tan. In some cases, there are variable degrees of cellular atypia and multilayering of nuclei. Occasionally, foci of in situ or invasive carcinoma are encountered {1340}.

Von Meyenburg complex (biliary micro-hamartoma)

The lesions are small, up to several mm in diameter. They are usually multiple and

Fig. 8.40 Bile duct adenoma. A Frozen section. B Cytokeratin immunostain showing characteristic branching pattern of bile ducts.

are adjacent to a portal area. Within a fibrous or hyalinized stroma, they present as irregular or round ductal structures that appear somewhat dilated and have a flattened or cuboidal epithelium. The lumina contain proteinaceous or bile-stained secretion. These lesions carry little or no malignant potential {736, 673}.

Bile duct adenoma (BDA)

BDA is usually single and subcapsular, and is white and well circumscribed but non-encapsulated. BDA is usually less than 1 cm in size, and is composed of a proliferation of small, normal appearing ducts with cuboidal cells that have regular nuclei and lack dysplasia {44}. These ducts have no or little lumen and can elaborate mucin. Their fibrous stroma shows varying degrees of chronic inflammation and collagenization. Enclosed in the lesion are normally spaced portal tracts. They are considered to be a focal reaction to injury.

BDA and peribiliary glands share common antigens, suggesting a common line of differentiation {136}. Occasionally, BDA contains periductular endocrine cell clusters {1384}.

In addition, there are several atypical BDA with a neoplastic nature. Biliary adenofibroma is characterized by a complex tubulocystic biliary epithelium without mucin production, together with abundant fibroblastic stromal components {1972}. Its expansive growth, and foci of epithelial tufting, cellular atypia and mitoses favor a neoplastic process.

Intrahepatic peribiliary cysts

In chronic advanced liver disease and biliary anomalies, and also in normal livers, multiple cysts may be seen around the intrahepatic large bile ducts {1319, 1320}. They are visible by ultrasound or CT. These cysts are derived from peribil-iary glands and should be differentiated from ICC clinically and histologically.

Diffuse and multifocal hyperplasia of peri-biliary glands

Diffuse, severe, macroscopically recognizable dilatation and hyperplasia of the peribiliary glands of intrahepatic and extrahepatic bile ducts is a rare condition {1319, 437}. Some ducts may be cysti-cally dilated. Lack of familiarity with this lesion could lead to an erroneous diag nosis of a well-differentiated cholangio-carcinoma. It occurs in apparently normal livers and also in acquired liver diseases.

Molecular genetics and genetic susceptibility

Mutations of the RAS and TP53 genes are the most common genetic abnormalities identified in ICC. The incidence of KRAS mutations ranges from 100% and 60% among British {1054} and Japanese patients respectively {1878, 1402}, to 4% among Thai patients {1510}. Taiwanese and Korean patients show an intermediate frequency {1037, 887}. The most frequently mutated position in the KRAS

Fig. 8.41 Bile duct adenoma. Small, normal appearing proliferating bile ducts associated with a small connective tissue component and lymphocytic infiltration.

gene is codon 12 involving GGT (glycine) to GAT (aspartic acid). Less frequent mutations have been identified in codon 13, involving GGT (glycine) to GAT (aspartic acid) and codon 61, involving CAA (glutamine) to CAC (histidine) {1402, 1969, 1511}.

TP53 mutations occur between exons 5 to 8, the most common change being G to A transitions {887, 1511, 907, 1848}. The mutations are random with no specific hot spot, being mostly missense mutations and less frequently nonsense mutations {887}. p53 protein is immuno-histochemically detectable in carcinoma cells in more that 70% of ICC cases. KRAS and TP53 mutations correlate with the gross morphology of ICC {1969, 1401}; a higher prevalence of KRAS gene alterations is found in the periduc-tal and spicular forming infiltrating subtype compared to the slower growing, non-invasive mass-forming type. TP53 mutations are prominent in the mass-forming type of ICC.

The variable incidence of KRAS mutations in different populations of ICC may reflect different aetiologies. O. viverrini infection and increased consumption of nitrates and nitrites are contributing factors in Thailand where the incidence of KRAS abnormalities is low {2025, 1446}. Overexpression of c-erbB-2 occurs in one fourth to about two thirds of carcinoma of the biliary tract, and may be used as a phenotypic marker for neoplastic transformation {1912}. Membranous expression of E-cadherin, alpha-catenin, and beta-catenin is reduced in a majority of ICC and this down-regulation correlates with ICC at high-grade {91}. Overexpession of MET, the receptor for hepatocytes growth factor, occurs in ICC and correlates with tumour differentiation, being poorly expressed in poorly differentiated tumours {1912}. It also correlates with the markedly increased proliferation indices seen in precancerous glands and cholangiocarcinoma. Biliary epithelial cells are continuously exposed to genotoxic insults such as chronic inflammation and hydrophobic bile acids, predisposing to oncogenic mutations. Progression to malignancy may be due, in part, to failure in activating apop-tosis and deleting cells with genetic damages {263}. The anti-apoptotic protein bcl-2, is overexpressed in ICC {281} and telomerase activity is detectable in carcinoma cells of almost all ICC cases.

Prognosis and predictive factors

Early detection of ICC is difficult, and the overall prognosis after resection is poor compared with that of HCC. Lymph node spread, vascular invasion, positive margins and bilobar distribution are associated with a high recurrence rate and a poor prognosis. One study found the 5-year survival rate was 39% in patients with mass-forming tumours and 69% for intraductal tumours while no patients with mass-forming plus periductal-infiltrating tumours survived > 5 years {2161}.

Histologically, squamous cell or sarcomatous elements and mucinous variants confer a poor prognosis {1312, 1313}. Patients with well differentiated ICC seem to survive longer than those with moderately or poorly differentiated ones. A few cases of well differentiated ICC with bland features resembling bile duct adenoma show a good prognosis {522}. MUC 2 protein expression is relatively frequent in well differentiated ICC, suggesting a somewhat more favourable prognosis {1915}.

Lymph node metastasis is a significant prognostic factor {2160}. The 5-year survival rate in patients with lymph node metastases is significantly lower than that in patients without lymph node metastasis (51%).

In liver fluke-associated ICC, survival after right hepatectomy is better than after left hepatectomy, and is not associated with tumour size {1990}. In addition, multiple tumour masses have a poor prognosis. Concomitant hepatolithiasis prevents precise diagnosis preoperative-ly, and precipitates biliary sepsis. Long-term post-surgical survival of patients with stone-containing ICC compared to ICC alone is controversial {291, 1849}. ICC found in non-biliary cirrhosis is usually detectable as a small nodule during follow-up of hepatitis virus-related cirrhosis, and is treatable with hepatectomy {2159}.

Combined hepatocellular and cholangiocarcinoma

C. Wittekind H.P. Fischer T. Ponchon

Definition

A rare tumour containing unequivocal elements of both hepatocellular and cholangiocarcinoma that are intimately admixed.

This tumour should be distinguished from separate hepatocellular carcinoma and cholangiocarcinoma arising in the same liver {605}. Such tumours may be widely separated or close to each other ('collision tumour').

Fig. 8.42 Combined hepatocellular carcinoma and cholangiocarcinoma arising in non-cirrhotic liver tissue in a patient with heterozygous Piz type alpha-1 antitrypsin deficiency. A Pale, homogeneous cut surface. B Microscopic, showing glandular areas.

Epidemiology

This tumour type comprises less than 1% of all liver carcinomas. There are similar geographical distribution differences as for hepatocellular carcinoma and a similar age and sex distribution.

Tumour spread and staging

Some studies have found a higher frequency of lymph node metastasis compared with HCC.

Macroscopy

Gross inspection does not show significantly different morphology compared to hepatocellular carcinoma. In tumours with a major cholangiocarcinomatous component with fibrous stroma, the cut surface is firm.

Histopathology

Combined hepatocellular and cholangio-carcinoma is the term preferred for a tumour containing both hepatocellular and distinct or separate cholangiocarci-noma. The presence of both bile and mucus should be sought in the combined tumour. This category should not be used for tumours in which either form of growth is insufficiently differentiated for positive identification. Hepatocytes preferentially express cytok-eratins 8 and 18 and, like duct epithelial cells, cytokeratins 7 and 19. However, the different patterns of expression are not as clear-cut in these tumours. For practical purposes, demonstration of bile canalicull by polyclonal CEA (mixed biliary glycoproteins) combined with Hep Par immu-

noexpression is sufficient for the diagnosis of a hepatocellular carcinomatous component, and that of neutral epithelial mucin by the PAS-diastase reaction for the diagnosis of a cholangiocarcinoma-tous component {1046, 1456, 667}.

Prognostic factors

Some authors have reported patients with combined hepatocellular and cholangiocarcinoma having a worse prognosis as compared with patients with HCC.

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