**Primary and Metastatic Tumours of the Liver: Expanding Scope of Morphological and Immunohistochemical Details in the Biopsy**

Ilze Strumfa, Janis Vilmanis, Andrejs Vanags, Ervins Vasko, Dzeina Sulte, Zane Simtniece, Arnis Abolins and Janis Gardovskis

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52838

**1. Introduction**

[30] Nousbaum JB, Cadranel JF, Bonnemaison G, Bourliere M, Chiche L, Chor H, et al. [Clinical practice guidelines on the use of liver biopsy]. Gastroenterologie clinique et

[31] Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a pro‐ spective nationwide survey. For the Group of Epidemiology of the French Associa‐

[32] West J, Card TR. Reduced mortality rates following elective percutaneous liver biop‐

tion for the Study of the Liver (AFEF). Hepatology. 2000; 32(3):477-81.

biologique. 2002; 26(10):848-78.

114 Liver Biopsy - Indications, Procedures, Results

sies. Gastroenterology. 2010; 139(4):1230-7.

Evaluation of liver biopsy for tumour diagnostics is a highly practical task with major clini‐ cal influence. The liver is frequently affected by wide spectrum of neoplasms including be‐ nign tumours as well as primary malignancies [1-3]. In addition, due to the rich dual blood flow to liver, secondary malignant tumours also often develop here. In order to ensure the optimal management of the patient, a correct diagnosis is necessary. At present, biopsy is the gold standard in oncology [4-5].

The scope of liver neoplasms can be following. The benign tumours include hepatic adeno‐ ma, bile duct adenoma, cavernous haemangioma and angiomyolipoma, among others. The primary liver malignancies embrace hepatocellular carcinoma [6,7], cholangiocarcinoma [3] and hepatoblastoma [8]. The diagnostics of hepatocellular carcinoma (HCC) is especially ur‐ gent topic due to high incidence in Asia and rising – in Europe and USA, possibly because of high prevalence of chronic hepatitis C [4,9]. Also, prognostic data should be reported in‐ cluding the features of early vs. progressed HCC, presence of stem cell immunophenotype, multicentric growth or metastatic spread [7]. Among mesenchymal malignant tumours, epi‐ thelioid haemangioendothelioma and angiosarcoma [10,11] are notable. Metastatic tumours represent the bulk of malignancies in Western countries [2]. Cystic liver tumours include biliary cystadenoma and biliary cystadenocarcinoma [12-14].

Most of the above mentioned neoplastic processes can be diagnosed in core biopsy. The key aspects include the following. First, the biopsy must be representative regarding the biologi‐

© 2012 Strumfa et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cal process and radiologically detected changes [15]. Further, the obtained tissue must be subjected to adequate technological process. Innovations here allow shortening the turnover time significantly. Next, the evaluation of morphology must be done searching for the char‐ acteristic traits of the above noticed tumours. However, due to the limited tissue amount in the biopsy, the tumour architecture sometimes is difficult to identify embarrassing the dis‐ tinction between nodular hyperplastic process, benign tumour or low-grade malignancy. In contrast, high-grade malignancies can show significant cytological atypia by few signs of differentiation embarrassing the detection of histogenesis [6] and the distinction between primary and metastatic tumour.

**2.1. Liver cell adenoma and its differential diagnosis with focal nodular hyperplasia**

present, up to 4 molecular types are identified:

**2.** inflammatory hepatic adenoma;

**1.** hepatic adenoma with *TCF1* gene inactivation;

**3.** beta-catenin-mutated non-inflammatory hepatic adenoma;

**4.** hepatic adenoma not displaying any before described feature or unsuitable for analysis [29]. The hepatic adenomas with *TCF1* gene mutation comprise 35-40% of liver cell adenomas. The patients are female. The tumour loses the expression and functions of hepatocyte nu‐ clear factor 1 (HNF1) encoded by *TCF1* gene. Inactivation of the gene can be caused by mutation in both alleles or by combination of a mutation and 12q deletion leading to loss of heterozygosity in the corresponding region [33]. Germ-line mutation of *HNF1* gene man‐

Liver cell adenoma or hepatic adenoma is defined as benign tumour arising from hepato‐ cytes. The epidemiology is characterised by female predominance (90%) and strong associa‐ tion with oral contraceptive use [26-27] as 85% of affected persons have such history. Liver cell adenoma was rare before the era of oral contraceptives [27]. At present, the incidence has increased but is still low: 3-4 /100 000 per year in long-term users of oral contraception [27-29]. The patients mostly are 20-39 years old. The other risk factors of hepatic adenoma include androgen burden. The tumours can also arise spontaneously or occasionally can be related toglycogen storage diseases or diabetes mellitus. Clinically, the patients mostly are symptomatic. Abdominal fullness can be attributed to the presence of mass lesion; pain can be caused by necrosis [27]. Rupture and bleeding (40%) represent dangerous complications [27,29-31]; the risk of these events is increased in pregnant ladies affected by liver cell adeno‐ ma due to prior use of hormonal contraceptives. Risk of malignant transformation also is recognised [29,32]. By literature analysis, Farges and Dokmak concluded that 5% of resected hepatic adenomas bear HCC foci [32]. The risk of malignant transformation is higher in ade‐ nomas exceeding the size of 5 cm irrespectively of the number of adenomas as well as in males. Grossly, liver cell adenomas are mostly unifocal (80%) and subcapsular. The tumours can be quite large (5-20 cm). In most cases (75%) adenomas are encapsulated [27]. However, the capsule can be thin or absent [10]. In contrast to HCC, adenomas usually are not associ‐ ated with cirrhosis [31]. Otherwise, radiological similarities exist between adenoma and HCC as both can be large, have rich vascularity and can undergo necrosis [31]. Microscopi‐ cally, the tumour is composed by hepatocytes lacking anaplasia and arranged in thin (1-2 cells) trabeculae [27,29]. Cellular atypia and macrotrabeculae must be absent. Single arterio‐ les, a pair of arteriole and venule or isolated biliary ducts are scattered throughout the le‐ sion. However, well-formed triads enveloped in connective tissue are absent within the lesion. The tumour can be distinguished from normal liver by larger size of neoplastic cells, presence of capsule and lack of triad-containing portal tracts. Steatosis, hydropic degenera‐ tion or Mallory hyaline can be observed. Fibrous tissue, haemosiderin and calcifications can develop in the consequence of haemorrhage. The immunophenotype is characterised by ex‐ pression of Hep Par 1 and other antigens that confirms the hepatic origin and by lower pro‐ liferation than in HCC. Molecular typing is emerging for liver cell adenoma as well. At

Primary and Metastatic Tumours of the Liver: Expanding Scope of Morphological and Immunohistochemical Details...

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Immunohistochemical markers as glypican-3 [1], Hep Par 1 [3,6], CD10 [3], alpha-fetopro‐ tein [6] and TTF-1 [16] are useful in the HCC diagnostics. Alterations of CD31 and CD34 positive endothelial cell network reflect vascular remodelling during hepatic carcinogenesis [7]. Cytokeratin (CK) 19 and 7 are characteristic for cholangiocellular carcinoma [3]. In meta‐ stases, organospecific markers including CDX2, mammaglobin, nuclear expression of TTF-1 or presence of neuroendocrine markers can confirm extra-hepatic origin [17]. As colorectal, breast, lung and neuroendocrine cancers are frequent cause of metastatic liver damage [2] high diagnostic value of immunohistochemistry (IHC) can be expected. However, the exact detec‐ tion of histogenesis can be difficult with metastatic pancreatic or gastric tumours and highgrade malignancies. IHC is mandatory for the diagnostics of haematological neoplasms and epithelioid haemangioendothelioma. Assessment of tumour biological potential can be done by IHC, evaluating Ki-67, Cyclin D1, FOXJ1, stem cell markers, matrix metalloproteinases and other markers [7-8,18-22]. Novel markers appear continuously as heat-shock protein 70 [23].

Nowadays, pathology is not any more purely descriptive but it is becoming more functional and clinically relevant. The classic morphologic characteristics must be combined with inte‐ grated evaluation of neoplastic process in the liver, including histogenesis, grading, clonal changes, type and extent of vascularisation, immunophenotype, heterogeneity, prediction of treatment sensitivity and the clinical behaviour [7]. New technologies as proteomic profiling and genomic marker analysis should be applied in the evaluation of liver tumours [4]. Mi‐ croRNA studies can lead to new findings in cancer pathogenesis and prediction of treatment efficacy [24,25].

The aim of the following chapter is to describe morphological and immunohistochemical characteristics of primary and secondary liver tumours in order to develop logistic basis for differential diagnosis of these processes in biopsy materials. Short discussion about the gen‐ esis and clinical course of each tumour will be included as well.
