Case 5 -
Well Differentiated Hepatocellular Carcinoma with Persistent Portal Blood Supply
University of Chicago
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This 57-year-old male was diagnosed with chronic HBV hepatitis in 1991. Laboratory evaluation
at that time revealed a positive serum HBsAg test but a negative HBeAg test. A liver biopsy in 1994
documented the presence of cirrhosis. An abdominal ultrasound examination and CT scan performed in 1998
revealed two nodules that were more than 4 cm in greatest dimension, as well as several smaller lesions.
None of the lesions was regarded as radiographically diagnostic of hepatocellular carcinoma. The serum
AFP at that time was 30 ng/ml. A percutaneous needle biopsy of the largest nodule was read as atypical
macroregenerative nodule (borderline lesion). The patient was treated with Lamivudine and followed with
serial MRI examinations and serum AFP levels. The two large lesions remained essentially unchanged and
the serum AFP level remained stable.
On 4/3/01 the patient underwent orthotopic liver transplantation. Examination of the explanted native
liver revealed cirrhosis with six distinct nodules, including 6.0 cm and 5.0 cm masses. Sections
revealed that two of the smaller lesions (3.5 and 3 cm) were well-differentiated hepatocellular
carcinomas. There were also two macroregenerative nodules. Sections of the two largest lesions were
more difficult to precisely classify. A section from the largest mass is submitted for your review. The
patient has had no evidence of recurrent hepatocellular carcinoma in the post-transplant period, with
last follow-up on 3/6/05.
The radiographic diagnosis of hepatocellular carcinoma takes advantage of the hypervascular arterial
supply of these tumors. In the arterial phase of the examination the contrast agent injected into the
arterial blood brightly delineates the tumor. During the venous phase of the examination the tumor
appears dark compared to the surrounding cirrhotic parenchyma, which now is highlighted by the contrast
agent. This distinctive radiographic appearance is regarded as diagnostic of hepatocellular carcinoma
and obviates the need for biopsy confirmation if the lesion is greater than 2 cm in diameter
Four MRI examinations were performed in the patient under discussion between 1998 and 2001. They
revealed two large lesions that grew very slowly, if at all. Neither was clearly evident in the arterial
phase images; instead they were best seen in the subsequent venous phase portions of the examinations.
In the last MRI study two new smaller lesions were identified that were hypervascular, being seen best in
the arterial phase images. Soon afterward the patient underwent liver transplantation.
Gross examination of the explanted native liver revealed established cirrhosis. Sections exposed six
distinct nodules, including 6 and 5 cm masses that corresponded to the hypovascular lesions seen in the
MRI studies. These two lesions were grossly distinctive in that they were quite homogenous, and were
demarcated by unusually thin capsules given their large sizes. In contrast, the smaller hypervascular
lesions were grossly typical hepatocellular carcinomas, with variegated cut surfaces and thick capsules.
Sections of the large lesions revealed that they were composed of cytologically bland and monotonous
hepatocytes with minimal architectural atypia. The reticulin stains reveal no thickening of the
trabecular cords and no loss of reticulin. There is no evidence of stromal or vascular invasion. There
are, however, scattered foci of small cell change and pseudo-acinar change. Steatosis and clear cell
change were not evident. Interestingly, unpaired arteries are notably sparse. In contrast, sections of
the smaller tumors reveal significant cytologic and architectural distortion, with loss of reticulin,
thickening of trabecular cords, and numerous unpaired arteries.
It is now well established that hepatocellular carcinomas in the setting of cirrhosis arise from
pre-existing dysplastic nodules with characteristic histologic features. These features well elucidated
in careful morphologic studies performed by Japanese investigators of small nodules detected by
radiographic studies performed as part of surveillance programs of high risk patient populations. In the
early studies the histologic findings thought to indicate future malignant potential included: increased
cell density, microacinar formation, cytoplasmic basophilia, clear cell change, and steatosis
The malignant potential of these lesions were confirmed in studies of explanted cirrhotic livers
Standardized criteria and nomenclature to describe these borderline nodules were proposed in a 1993
article that brought the subject to the attention of Western surgical pathologists .
Subsequent improvements in the radiographic identification of hepatocellular carcinomas centered upon
distinction from benign and premalignant lesions based on the vascular supply to the nodule . This
in turn led to the histologic evaluation of the number and type of vessels within these nodules. The
arterial supply to dysplastic nodules was indeed increased when compared to ordinary cirrhotic nodules
and macroregenerative nodules, in the form of unpaired ("isolated"} arterioles
arterioles were incorporated as a diagnostic feature in an international consensus classification scheme
of hepatocellular nodules in cirrhotic livers . This system remains in wide use, but the authors are
currently at work on a revised system that is more useful in the diagnosis of needle biopsies .
Alteration in the phenotype of sinusoidal endothelial cells was also identified during hepatic
carcinogenesis, a process termed "capillarization". The endothelial cell fenestrae are lost and basement
membrane is deposited, producing an appearance similar to the endothelial cells lining systemic arteries
. The altered phenotype can be easily documented by use of the CD34 immunostain. Normal
sinusoidal endothelial cells are negative with this antibody, while an increasing number of cells become
reactive in the sequence from cirrhosis to macroregenerative nodule, to low and high grade dysplastic
nodule, and finally hepatocellular carcinoma
Vascular alterations that occur during the process of hepatic carcinogenesis are among the diagnostic
markers helpful in the distinction of dysplastic nodules from hepatocellular carcinoma
accumulating evidence suggests that neoangiogenesis may also actually be an important driver of the
neoplastic process. A number of studies using molecular profiling methods have demonstrated that as a
group, angiogenic molecules are among the most commonly differentially expressed during the process of
. A number of endothelial cell antigens expressed in hepatocellular
carcinomas are known to influence members of the cell cycle cascade, formation of tumor stroma, and
The mechanisms responsible for neoangiogenesis during hepatic carcinogenesis have yet to be fully
elucidated. A recent study has demonstrated macrophages are increased in number in dysplastic nodules
and early hepatocellular carcinomas when compared to the surrounding cirrhotic parenchyma . A
follow-up study showed that proteins secreted by malignant hepatocytes stimulate the migration of these
macrophages. Moreover, macrophages activated by co-culture with hepatocellular carcinoma cells
stimulated angiogenesis . There are several reports in the literature that suggest that macrophage
migration inhibitory factor may be responsible in part both for the migration of macrophages into
hepatocellular carcinoma and for the stimulation of angiogenesis
A recent study reported the rare occurrence of neoplastic hepatic nodules in which, for
unknown reasons, the conversion to an arterial supply doesn't develop . These large nodules grow
very slowly and do not develop thick capsules. Morphologically they are remarkably bland and
homogeneous, without well-developed features of overt hepatocellular carcinoma. The incidence of such
nodules in a surveillance program of patients with chronic HCV and HBV related cirrhosis was 2.6%. The
large nodules present in the patient under discussion appear to be examples of this new entity, which was
termed "atypical large well-differentiated hepatocellular carcinoma with benign nature" by the author of
the study . In the study no nodule developed into a traditional arterially supplied hepatocellular
carcinoma. The existence of nodules of this type, however they are classified, provides additional
evidence for the central role of the switch to an arterial blood supply in the process of hepatic
carcinogenesis. Further study of the mechanisms of angiogenesis in the spectrum of hepatocellular
lesions will contribute to the understanding of tumorigenesis.
Well differentiated Hepatocellular Carcinoma with Persistent Portal Blood Supply
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