Histopathology

Liver biopsy samples can be obtained by percutaneous or transjugular routes with or without imaging techniques for guidance, as a wedge during laparotomy, or a fine needle can be used to aspirate material for cytology. Each of these methods has advantages and drawbacks but a guided percutaneous needle biopsy producing a core of liver for histology is the one most frequently used. It produces a tissue sample that is usually adequate for all purposes, including the use of special stains, immunohistochem-istry and molecular biological techniques. Touch preparations for cytology can also be prepared from needle cores before fixation and may provide an instant diagnosis {1523}.

Differential diagnosis

Hepatocellular carcinoma can usually be distinguished from metastatic tumours by its trabecular structure, sinusoids, lack of stroma, bile production, absence of mucin secretion, and the demonstration of bile canaliculi by polyclonal CEA antisera, which is specific for a liver cell origin. Other useful immunophenotypic features in this differentiation are the presence of liver export proteins (albumin, fibrinogen, alpha-1-antitrypsin), the cyto-keratin pattern, and the expression of Hep Par 1 antigen {1046}. Metastatic tumours that often mimic hepatocellular carcinoma are adrenal cortical and renal cell carcinomas. Amelanotic melanoma may also cause difficulties but it is easily identified by positive immunostaining for S100 protein and HMB45 . The distinction between primary cholan-giocarcinoma and metastatic adenocar-

Fig. 8.80 Typical histological changes adjacent to space occupying liver lesions: sinusoidal dilatation, leukocyte infiltration, and bile-ductular proliferation.

cinomas is much more difficult and may be impossible {351}. Cholangiocarcino-ma may take on any of the histological patterns of an adenocarcinoma; it is usually tubular but may be mucinous, signetring, papillary, cystic, or undifferentiated. Mucin secretion and production of CEA are nearly always demonstrable in both primary and secondary adenocarcino-mas. Metastases from many sites form similar patterns. However, small tubular or tubulo-papillary glands frequently derive from the stomach, gallbladder and extrahepatic biliary tree, and a signet-ring cell appearance suggests a gastric primary. Perhaps the easiest pattern to recognize as metastatic in origin is that exhibited by adenocarcinomas of the colon and rectum, which nearly always show glands of variable size and shape that are lined by tall columnar cells and contain debris within the lumina. Metastases from the colorectum frequently have well defined edges whereas those from other glandular sites tend to be more diffuse. Colorectal metastases are also frequently necrotic and may show calcification {653}. The presence of carcinoma-in-situ in intrahepatic bile ducts in the vicinity of an adenocarcinoma is evidence that it is a cholangiocarcinoma. However, this may be mimicked by intrabiliary ductal growth of metastatic colonic adenocarcinoma {1593}. Analysis of cytokeratin expression may be useful in the distinction of primary and metastatic gastrointestinal adenocarcinomas. The former express cytokeratins 7 and 19 but not 20, whereas the latter are negative for 7 and positive for 20 {1141}.

Carcinoma of the breast often produces a diffuse sinusoidal infiltrate that on imaging studies may mimic cirrhosis and, indeed, may be associated with splenomegaly, ascites and oesophageal varices {174}; sclerosis following systemic chemotherapy may exaggerate this effect. Metastases from the breast may be identified by the combined use of zinc-a2-glycoprotein, gross cystic disease fluid protein 15 and oestrogen receptor {283}. However, occult breast carcinoma presenting with metastases is rare and most patients with liver involvement have a past history of a primary tumour.

Most hepatic metastases from the lung in clinical practice are undifferentiated small cell carcinomas, characteristically producing an enlarged liver due to diffuse or miliary spread. The primary tumour may still be small, asymptomatic and undetected. Squamous cell and adenocarcinomas will metastasize to the liver but their existence is usually known already. The same applies to squamous cell carcinomas of the oesophagus and cervix. Squamous cell carcinomas of the head and neck seldom involve the liver. Neuroendocrine/islet cell/carcinoid tumours are easily identified by their organoid nesting pattern, uniform cytology and vascularity, and positive immunostaining for chromogranin, syn-aptophysin and neuron specific enolase; islet cell tumours also produce specific hormones such as insulin, glucagon, gastrin, vasoactive intestinal peptide and somatostatin, which either give rise to clinical syndromes or can be demonstrated in the blood or tumour tissue. Most sarcomas that metastasize to the liver are gastrointestinal stromal tumours that are positive for CD34 and c-kit, or leiomyosarcomas of the uterus that may be positive for desmin or muscle-specific actin. Some carcinomas, notably of the kidney, may be sarcomatoid in their morphology.

Many haematological malignancies, e.g. leukaemias, myeloproliferative disorders and both Hodgkin and non-Hodgkin lymphomas, involve the liver. Leukaemias tend to produce diffuse sinusoidal infiltrates. Hodgkin and high-grade non-Hodgkin lymphomas produce tumourlike masses, while low-grade non-Hodgkin lymphomas produce diffuse portal infiltrates.

Rare secondary tumours include those from the thyroid, prostate, and gonads. The diagnosis can be confirmed by the immunohistochemical demonstration of thyroglobulin, prostate specific antigen and AFP and |3HCG, respectively. A triad of histological features, namely proliferating bile ducts, leukocytes and focal sinusoidal dilatation, is found in the liver adjacent to space-occupying lesions. Their presence in a core biopsy suggests the possibility of a metastatic deposit missed by the biopsy needle. Three lesions, bile duct adenoma, scle-rosed haemangioma, and larval granuloma may resemble metastatic tumours at laparotomy.

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