Australian Society of Cytology

Case of the Month

March 2005 - Answer and Discussion

Hepatocellular carcinoma

Answer

Cytology:

Microscopy
Highly cellular smears
Very bloody background
Numerous single atypical epithelial cells, bare stripped nuclei and loosely cohesive groups. (fig 1)
Some groups have a trabecular architecture. (fig 2)
Cells are polygonal hepatocyte-like cells, with a high n/c ratio and central round nuclei with prominent large nucleoli.
Binucleated, multinucleated and isolated giant cells are seen.
Cytoplasm is granular giving the cells an oncocytic appearance due to increased numbers of mitochondria. Some vacuolation is noted.
Cytoplasmic hyaline globules are present in some tumour cells. (figs 3 - 6)

Summary
Malignant - Hepatocellular carcinoma (HCC)

The cytology showed the classic cytomorphological features of HCC, and the patient was referred for surgical resection of the liver mass. The patient was deemed a good candidate for surgery.

Histology:

Macroscopic
Liver resection - 19x9x4.5cm wedge of liver.
Sectioning revealed a 3.6x2.6cm rounded tumour with irregular margins and an adjacent 0.9cm satellite tumour nodule 2.5cm from the larger lesion.
2x hepatic lymph nodes removed.

Microscopy
Epithelioid tumour with a mainly trabecular and in some areas pseudoglandular architecture. A thin fibrous capsule surrounds the tumour. (figs 7 - 9)
The trabecular plates are lined by endothelial cells, diagnostic of HCC. (fig 10)
The tumour is moderate to well differentiated.
In well differentiated areas the tumour cells resemble hepatocytes and are oncocytic in appearance. (figs 11, 12)
Some tumour cells are producing bile and a few have cytoplasmic hyaline globules.
A few nuclei have intranuclear cytoplasmic inclusions.
Vascular invasion by the tumour is seen. (figs 13 - 16)
Adjacent liver tissue is normal with no evidence of cirrhosis.
The tumour nodules are clear of the resection margins and there is no evidence of tumour within the portahepatis lymph nodes.


Fig 7	Fig 8	Fig 9

Fig 10	Fig 11	Fig 12

Fig 13	Fig 14	Fig 15

	Fig 16

Immunocytochemistry


Fig 17	Fig 18

MNF116	pCEA	CD10	CK7	CK20
+	+	+	-	-

MNF 116 (fig 17) establishes the epithelial nature of the tumour,and the unique bile canallicular staining of polyclonal CEA (fig 18) and CD10 confirms its hepatocytic differentiation. Negative results for CK7 and CK20 are as expected for a diagnosis of HCC.

This immuno-profile combined with the histological morphology of the tumour is consistent with a moderate to well differentiated Hepatocellular carcinoma – grade 2-3, Steiner and Edmonstone classification.

Discussion

Hepatocellular carcinoma is the most common primary malignancy of the liver. It is also one of the commonest malignant tumours worldwide, accounting for up to 40% of cancer related deaths in regions of high incidence. The highest rates of incidence are seen in South East Asia and Southern Africa where patients are predominantly Hepatitis B positive individuals. Hepatitis B virus infection is thought to be responsible for the majority of the world’s HCC cases. Europe, America and Australia are considered low incidence areas for HCC. In 2001, HCC was responsible for 2.6% of all cancer related deaths in Australia. Alcohol induced cirrhosis is considered the most frequent cause of HCC in the western world. The disease has been shown to be up to 8 times more common in (elderly) men than in women.

This brief overview of epidemiology/ aetiology serves to highlight some unusual aspects of this case’s clinical picture. In the Australian/ Western context, the sex and age of the patient place her outside of the most typical clinical presentation and the tumour presented in a non-cirrhotic liver. 90% of patients with HCC will have an underlying cirrhosis induced by Hepatitis B/ C infection or alcoholism. Patients with non-cirrhotic livers and smaller tumours are seen as the best candidates for surgical resection and subsequent treatment, and account for only 5% of HCC cases in western countries.

By contrast, other clinical and morphological features of this case could be considered textbook for HCC. It is this disparity which makes the case worthy of examination.

Prior to resection the patients alpha-fetoprotein (AFP) level was 12µg/L. In the presence of the liver mass this is suggestive of HCC although raised levels have been seen in patients with metastatic germ cell tumours. Elevated AFP levels are seen in up to 90% of cases, but only 20 - 40% of these cases will have levels raised significantly ( >20µg/L). Lower AFP levels such as this will often be seen in well differentiated tumours, smaller (<4cm) diameter lesions and tumours arising in non-cirrhotic livers.

Follow-up

Surgical resection is regarded as the most effective treatment for this disease and the best hope of long term survival (5-10 years) for the patient.

However, up to 70% of these tumours will recur within 3 years of surgical resection, making this high recurrence rate the biggest hindrance to the patient’s survival.

The patient’s post resection AFP levels (fig 19) suggest the possibility of a poorer prognosis than other clinical features may have indicated.

Fig 19

The expected decrease in the level of oncoprotein after surgery did not occur and a steady and marked increase was noted concluding in the most recent 77µg/L AFP result.

This could suggest an increased and earlier risk of tumour recurrence or the presence of a hitherto undetected metastatic deposit from the primary HCC lesion. (Note the presence of the daughter tumour nodule in the gross specimen and vascular invasion seen in the histology – both evidence of early local metastasis.)

Follow up on this patient is on-going.

References:

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