Liver Carcinoma

1. GROSS DESCRIPTION

Specimen

— fine needle aspirate/core biopsy/wedge excision/segmentectomy/ partial hepatectomy/R/L lobectomy.

Hepatic resection in malignant disease is potentially considered for

• primary liver tumour involving a single lobe with no invasion of portal vein or inferior vena cava and no significant background cirrhosis.

• isolated metastases (e.g. carcinoid, colorectal carcinoma) localized to a single lobe with no metastatic spread elsewhere and adequate excision of the primary lesion.

Depending on the anatomical extent of disease as determined by MRI/CT/ultrasound scans the resection can be major (partial hepatec-tomy, lobectomy) or segmental, the latter excised with its supplying lym-phovascular pedicle. Note that the surgical definition of lobes and their constituent segments differs from the classical anatomical lobes. Small subcapsular metastases can be removed by wedge resection or erroneously diagnosed as such at frozen section when a bile duct adenoma or Von Meyenberg complex is submitted. Where metastases or a primary hepatocellular carcinoma are potentially resectable or transplant is considered there is a reluctance to carry out FNA/needle biopsy for fear of upstaging the tumour, e.g. needle tract implantation. However, in the absence of a significantly elevated serum alpha-fetoprotein (AFP) or other obvious primary site, needle biopsy (percutaneous or transjugular) may be needed for a firm tissue diagnosis and to exclude other treatable tumours, e.g. malignant lymphoma. Presentation of hepatic malignancy may be with jaundice, weight loss, anaemia and anorexia. There can be a palpable mass and investigations include serum AFP and CA19-9, liver function tests and imaging studies. Metastatic colorectal and pancreatic cancers may have high serum CEA and CA19-9 levels. Needle biopsy yields either a positive diagnosis or the changes adjacent to a mass lesion, i.e. liver plate atrophy, prominent sinusoids and focal inflammation. Transjugular cores are very fine and require careful handling in the laboratory. However, they can produce useful morphological and immunohistochemical results if the tumour is in a suitably accessible location. Some of the potential upstaging risks are also obviated if a percutaneous route is avoided.

Tumour

Site

— subcapsular/parenchymal/ductocentric/vasculocentric/lobe/multi-focal (particularly when cirrhosis is present).

Size

— length x width x depth (cm) or maximum dimension (cm).

— in a cirrhotic liver a lesion >5 cm is probably a hepatocellular carcinoma.

Appearance

— hepatocellular carcinoma: solitary/diffuse/multifocal (particularly in cirrhosis)/bile stained/venous spread/pedunculated/encapsulated/ background cirrhosis/haemochromatosis.

— cholangiocarcinoma: papillary/nodular/stenotic/scirrhous/ductocen-tric/multifocal.

— metastatic carcinoma: single/multiple/necrotic/umbilicated/calcifica-tion/diffuse/mucoid/subcapsular.

Edge

— circumscribed/irregular. 2. HISTOLOGICAL TYPE

Hepatocellular carcinoma

— trabecular, plate-like or sinusoidal.

— pseudoglandular (acinar).

— these are the usual types comprising hepatoid cells, bile cytoplasmic staining and canalicular plugging, eosinophilic intranuclear pseudoinclusions, and a sinusoidal vascular pattern with a CD34 positive endothelial lining (capillarization).

— solid (compact): inconspicuous sinusoids.

— scirrhous: fibrotic. Distinguish from cholangiocarcinoma and post-chemo-/radiotherapy changes.

— rarely pleomorphic, clear cell, spindle cell or osteoclast-like.

— variants with good prognosis: fibrolamellar carcinoma (90% <25 years old); pedunculated carcinoma; minute, small or encapsulated carcinoma (see below).

Cholangiocarcinoma (intrahepatic)

— nodular/scirrhous (infiltrative)/intraductal (rare), and, single or multifocal.

The dividing plane is between the gall bladder bed and inferior vena cava

The regional lymph nodes are the hilar, hepatic (along the proper hepatic artery), periportal (along the portal vein) nodes and those along the abdominal inferior vena cava above the renal vein (except the inferior phrenic nodes).

Figure 10.1. Liver and regional lymph nodes. |W

— ductulo-acinar pattern of heterogeneous cuboidal to columnar mucin-secreting cells in a fibrous stroma. Sometimes papillary.

— portal expansion/periportal sleeve-like and parenchymal sinusoidal distributions.

— few survive longer than 2-3 years due to late presentation and limited resectability.

— rarely: mucinous; signet ring cell; adenosquamous; clear cell; pleomorphic; osteoclast-like; spindle cell (sarcomatoid). These are prognostically adverse variants.

Mixed liver cell/bile duct carcinoma

Hepatoblastoma

— 50-60% of childhood liver cancers, 90% <5 years of age.

— usually a large solitary mass and raised serum AFP. Epithelial component of two cell types (fetal/embryonal hepatocytes or small cell anaplastic) and fibrous mesenchyme (25% of cases: osteoid or undif-ferentiated spindle cells). Treatment is surgery and chemotherapy with a 50-70% long-term survival. Age <1 year, large size and a significant small cell component are adverse factors.

Metastatic carcinoma

— in order of frequency: carcinoma, malignant lymphoma and sarcoma.

— direct spread: stomach, large intestine, pancreas, gall bladder and biliary tree.

— distant spread: stomach, oesophagus, colorectum, lung, breast, malignant melanoma, kidney, urinary bladder, ovary, teratoma.

The tumour distribution may reflect its origin, e.g.

— colorectum: multiple, large nodules with central necrosis and um-bilication, ±mucin, ±calcification. As in renal cell carcinoma can be solitary and massive.

— gall bladder: bulk of disease centred on the gall bladder bed.

— lung: medium-sized nodules and fleshy appearance (small cell carcinoma).

— breast, stomach: medium-sized nodules or diffuse cirrhotic-like pattern.

— malignant melanoma: pigmented.

— angiosarcoma, choriocarcinoma, leiomyosarcoma, renal/thyroid carcinoma: haemorrhagic.

NB: carcinoma rarely metastasizes to a cirrhotic liver, i.e. the tumour is more likely to be primary. Histologically there can be considerable difficulty distinguishing hepatocellular carcinoma and its variants from other metastases, e.g. renal cell carcinoma, adrenal cortical carcinoma and malignant melanoma. Similarly, cholangiocarcinoma from gastrointestinal secondaries. Morphology allied to a panel of antibodies should be used, including:

liver—Hep Par 1, AFP, canalicular polyclonal CEA/CD10.

adrenal—inhibin, melan-A, vimentin, synaptophysin.

renal—EMA, vimentin, RCCab, CD10.

colorectal—CK20, CDX-2.

Resection of some hepatic metastases is done to good effect, e.g. carcinoid tumour, colorectal carcinoma.

3. DIFFERENTIATION/GRADE

Well/moderate/poor, or, Grade I/II/III(/IV).

Based on the degree of resemblance to hepatic tissue. Well to moderately differentiated lesions show trabecular (plate-like) or pseudoglan-dular patterns seen in tumours <2-3 cm diameter. Larger lesions (>3 cm) usually only have a well differentiated periphery with a less differentiated centre characterized by greater cytoarchitectural atypia and no discernable sinusoids. This nodule within nodule appearance is diagnostically useful and highlights the heterogeneity and active evolution of hepatocellular carcinoma. Bile secretion varies.

For cholangiocarcinoma based on the percentage tumour gland formation: well/G1 > 95%; moderate/G2 50-95%; poor/G3 < 50%; undiffer-entiated/G4 no glands.

4. EXTENT OF LOCAL TUMOUR SPREAD

Border: pushing/infiltrative. Lymphocytic reaction: prominent/sparse.

The TNM classification applies to hepatocellular carcinoma and intra-hepatic cholangiocarcinoma.

pT1 solitary tumour with no vascular invasion pT2 solitary tumour with vascular invasion or multiple tumours, none >5cm pT3 multiple tumours >5 cm or tumour involving a major branch of the portal or hepatic vein(s)

Figure 10.4. Liver carcinoma.

Multiple tumours more than 5 cm or tumour involving a major branch of the portal or hepatic vein(s)

Figure 10.4. Liver carcinoma.

Major branch of the portal or hepatic vein(s) Figure 10.5. Liver carcinoma. I

Stomach

Tumour(s) with direct invasion of other organs other than gallbladder or with perforation of visceral peritoneum

Stomach

Tumour(s) with direct invasion of other organs other than gallbladder or with perforation of visceral peritoneum

Perforated visceral peritoneum pT4 tumour with direct invasion of adjacent organs other than the gall bladder or with perforation of visceral peritoneum.

Vascular invasion is diagnosed by clinical imaging. The pathological classification includes gross and histological involvement.

Multiple tumours includes multiple independent primaries or intrahepatic metastases from a single hepatic carcinoma. Multicentricity is associated with poor prognosis.

5. LYMPHOVASCULAR INVASION

Present/absent. Intra-/ extratumoral.

Note the particular propensity for hepatocellular carcinoma to involve portal tract veins, major branches of portal and hepatic veins and inferior vena cava, ultimately with metastases to lung, adrenal gland and bone. Cholangiocarcinoma typically shows lymphovascular and perineural invasion with spread to regional lymph nodes, lungs, bone, adrenal gland, kidney, pancreas and peritoneum.

6. LYMPH NODES

Site/number/size/number involved/limit node/extracapsular spread. Regional nodes: hilar (hepatoduodenal ligament), hepatic (along the hepatic artery), periportal (along portal vein) and those along the inferior vena cava above the renal veins.

pN0 no regional lymph node metastasis pN1 metastasis in regional lymph node(s).

7. EXCISION MARGINS

Distances (mm) to the serosa and limits of excision of parenchyma, bile ducts and veins.

Mucosal dysplasia at the bile duct excision limits.

8. OTHER PATHOLOGY

Budd-Chiari syndrome secondary to venous invasion Hepatocellular carcinoma

Risk factors: hepatitis B, C (50-70%, 20-30% of cases respectively, worldwide). Cirrhosis is present in 60-80% of cases in the West secondary to viral hepatitis, alcohol, congenital bile duct atresia, alpha-1-antitrypsin deficiency or haemochromatosis. Small/large cell liver cell dysplasia— there is a strong association between large cell dysplasia and hepatitis B surface antigen. Small cell dysplasia (enlarged nucleus, decreased volume of cytoplasm) is regarded as being a premalignant change and a more important risk factor for development of carcinoma. Adenomatous hyperplastic nodules or macroregenerative nodules in a background of cirrhosis—range from 1 mm diameter to 2-3 cm, ±a fibrous rim, ±cytoar-chitectural atypia (plates 3 cells thick, irregular edges, loss of reticulin,

±cellular dysplasia). They show a spectrum of changes towards hepatocellular carcinoma with type 2 (high-grade dysplastic) nodules particularly significant. Increasingly sophisticated imaging is leading to greater detection of these premalignant dysplastic nodules and small, early hepa-tocellular carcinomas.

Immunophenotype: Hep Par 1, AFP (25%: high specificity but low sensitivity) and polyclonal CEA/CD10 in bile canaliculi. Also CAM5.2 (but not AE1/AE3), cytokeratin 8, 18 (but not 7, 19), ER/PR. PAS-positive cytoplasmic glycogen, intracellular PAS-positive globular inclusions, loss of pericellular reticulin. EMA, Ber EP4 negative.

Cholangiocarcinoma

Risk factors: primary sclerosing cholangitis/ulcerative colitis/liver fluke/biliary tree anomaly. Treatment is surgical (partial/total hepatic resection ± liver transplantation) but prognosis is poor with overall mean survival <2 years.

Immunophenotype: cytokeratins (7, 19), EMA, CEA, CA19-9, mucin positive. Also CAM5.2 (low molecular weight cytokeratins, as for hepato-cellular carcinoma) and AE1/AE3 (including high molecular weight cytokeratins, negative in hepatocellular carcinoma).

Differential diagnosis of hepatic mass lesions

Focal nodular hyperplasia: young to middle-aged women, usually solitary and asymptomatic. Radiological and gross central scar with thick-walled vessels, marginal ductular proliferation, plates 2 or 3 cells thick, cirrhosis-like nodule with adjacent normal parenchyma. A vascular anomaly.

Hepatocellular adenoma: middle-aged women with acute abdominal presentation and history of oral contraception. No portal tracts or central veins, liver cell plates >2 cells thick with retention of reticulin pattern and sinusoidal Kupffer cells (CD68 positive).

Hepatocellular carcinoma: evidence of risk factors, e.g. cirrhosis. Plates > 2 cells thick, loss of reticulin pattern and Kupffer cells with sinusoid capillarization (CD34), atypia, look for vascular invasion. Serum AFP markedly elevated in 40-75% of cases: CT/MRI scan shows the location of the lesion, its extent of invasion and multicentricity.

Poorly differentiated metastatic carcinoma: specific histological appearance (e.g. small cell carcinoma lung), immunogenicity (e.g. PSA positive) or histochemical feature (e.g. mucin positive—this cannot distinguish secondary adenocarcinoma from primary cholangiocarcinoma).

Sometimes the distinction between a regenerative nodule, adenoma and well-differentiated hepatocellular carcinoma is not possible and the subsequent clinical course establishes the diagnosis. FNA cytology of hepatic mass lesions is useful for simple cysts, abscesses and some metastatic cancers (e.g. small cell lung carcinoma). Secondary adenocar-

cinoma cannot always be distinguished from cholangiocarcinoma and previous history is important, e.g. resection for colorectal carcinoma. Differential cytokeratin expression may help: colorectal cancer (CK20+/ CK7-), cholangiocarcinoma (CK7, 19+/CK20±). FNA is reasonably robust for moderately differentiated hepatocellular carcinoma but may need to be supplemented by core/open biopsy in poorly differentiated carcinomas (to exclude metastatic cancers) and well-differentiated lesions (to exclude adenoma, focal nodular hyperplasia, cirrhosis). Useful diagnostic features for hepatocellular carcinoma are: hepatoid cells (polygonal with central nucleus), nuclear/nucleolar enlargement, a trabecular pattern with sinusoidal capillarization, nuclear pseudoinclusions, bile secretion and an absence of bile duct epithelial and inflammatory cells. Immunostaining may also be helpful, e.g. AFP positive.

Prognosis

Treatment of hepatocellular carcinoma depends on surgical resection ± liver transplantation. Chemotherapy is used for recurrent or inoperable tumours. Prognosis relates to tumour size (>5cm), cell type or differentiation, encapsulation, multifocality, high serum AFP levels, vascular invasion and the presence or absence of a background cirrhosis (an adverse indicator). Five-year survival is at most 10-15% and more usually about 3%. The majority die within several months of presentation with liver failure, haemorrhage and infection. Small tumours (<3-5 cm) and variants such as fibrolamellar and pedunculated carcinoma are potentially curable. Hepatic arterial chemoembolization, percutaneous alcohol injection and radiofrequency ablation also have roles to play with potential survival benefit. These modalities can also be applicable to metastatic deposits in the liver, e.g. colorectal carcinoma.

Fibrolamellar carcinoma

— large eosinophilic cells in a fibrous stroma, potentially resectable.

— serum AFP not raised, no cirrhosis. May also have areas of usual liver cell carcinoma and cholangiocarcinoma.

Pedunculated carcinoma

— inferoanterior aspect right lobe, up to 1 kg weight.

Minute, small encapsulated carcinoma

— 2-5 cm, encapsulated by fibrous tissue.

— 90-100% 5-year survival if no angio-invasion.

9. OTHER MALIGNANCY

Lymphoma/leukaemia

— secondary involvement by Hodgkin's/non-Hodgkin's lymphoma (50-60% of cases) or leukaemia [80% of chronic lymphocytic leukaemia (CLL)]. Lymphoma is mainly portal and leukaemia sinusoidal but mixed patterns of distribution are common.

— primary lymphoma is rare but of more favourable prognosis—solitary/multiple masses or diffuse and high-grade large B cell in type.

Angiosarcoma

— cirrhosis, PVC (polyvinyl chloride), thorotrast exposure, commonest sarcoma of liver.

— exclude peliosis (well-differentiated angiosarcoma) and primary and secondary carcinoma (poorly differentiated angiosarcoma).

— growth is typically along vascular structures (sinusoids, vessels) and the liver cell plates. The endothelial cells are atypical and CD31/34 positive.

Epithelioid hemangioendothelioma

— multinodular fibrous masses with a zoned periphery of cords and tube-like structures of spindle and epithelioid cells in myxoid stroma and a central hyalinized scar. Cytoplasmic vacuoles, CD31 positive.

— of low to intermediate-grade malignancy: also seen in skin, lung and bone.

Kaposi's sarcoma

Embryonal sarcoma

— 15% 5-year survival in patients of 6-10 years of age.

— spindle/stellate/pleomorphic/rounded cells.

Embryonal rhabdomyosarcoma

— <5 years of age, poor prognosis, desmin/myo D1/myogenin positive small cells.

— arises from major bile ducts near the porta hepatis.

Leiomyosarcoma, fibrosarcoma

— exclude sarcomatoid liver carcinoma and more commonly secondary sarcoma, e.g. gastrointestinal stromal tumour.

Carcinoid tumour

— usually represents metastases from gastrointestinal tract. Associated with carcinoid syndrome. Detect by octreotide scan.

Mimics of malignancy

— abscess, sclerosed haemangioma, inflammatory myofibroblastic or pseudotumour (spindle cells in a storiform pattern, plasma cells), angiomyolipoma (fat, vessels, HMB 45 positive spindle cells), solitary fibrous tumour (storiform spindle cells, CD34 positive).

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