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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 51  |  Issue : 3  |  Page : 323-328
Angiogenesis in liver cirrhosis and hepatocellular carcinoma


1 Department of Pathology, BYL Nair Charitable Hospital and TN Medical College, Mumbai, Maharashtra, India
2 Department of Pathology, Postgraduate Institute of Medical Sciences, Chandigarh, India

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   Abstract 

Background: Angiogenesis has been well documented in hepatocellular carcinoma (HCC). As liver cirrhosis is considered preneoplastic condition, the aim of this study was to evaluate the process of angiogenesis using CD 34 as an endothelial cell marker in normal liver, cirrhosis and HCC. Materials and Methods: A total of 111 cases were included in this study, which consisted of 30 cases each of normal liver and cirrhosis that were all autopsy cases. Twenty-one cases of HCC included 10 autopsy specimens, nine surgically resected specimens and two liver biopsies. Remaining were 30 cases of metastasis to the liver, which included 20 autopsy specimens, one surgically resected specimen and nine liver biopsies. The patients were between the age range from 17 to 80 years with 70 males and 11 females. Paraffin-embedded liver sections of all these cases were stained routinely by hematoxylin-eosin stain, while immunohistochemistry for CD 34 was performed for expression of endothelial cells. The positivity of CD 34 staining was evaluated by counting in 10 high-power field, grading was done from 0 to 4 and compared between normal liver, cirrhosis and HCC and metastasis. Results: CD 34 was positive in 16/30 (53.3%) cases of cirrhosis, 18/21 (85%) cases of HCC and 26 (86.6%) of metastasis to the liver. None of the normal liver showed any positivity. Grade 3 to 4 positivity was seen in 4/16 (25%) and 13/18 (72%) cases of cirrhosis and HCC, respectively. Amongst these, 10 were moderately differentiated, one well differentiated and rest two were fibrolamellar and sarcomatoid variants of HCC. Conclusion: Over expression of endothelial cell marker CD 34 with gradual progression was found from normal liver to cirrhosis to HCC and metastasis. Understanding of this process of angiogenesis might help in the design of efficient and safe antiangiogenic therapy for these liver disorders.

Keywords: Liver, angiogenesis, Cirrhosis, hepatocellular carcinoma, CD 34

How to cite this article:
Amarapurkar AD, Vibhav, Kim V. Angiogenesis in liver cirrhosis and hepatocellular carcinoma. Indian J Pathol Microbiol 2008;51:323-8

How to cite this URL:
Amarapurkar AD, Vibhav, Kim V. Angiogenesis in liver cirrhosis and hepatocellular carcinoma. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 Dec 7];51:323-8. Available from: http://www.ijpmonline.org/text.asp?2008/51/3/323/42504



   Introduction Top


Liver cirrhosis is an important risk factor for hepatocellular carcinoma (HCC) with more than 80% cases of HCC arising in the background of cirrhosis. The process of angiogenesis includes formation of new vasculature from pre-existing capillaries. It is seen in various inflammatory and neoplastic conditions. [1],[2],[3],[4] Although traditionally associated with tumerogenic process, hepatic angiogenesis has also been observed in context of various inflammatory and fibrotic conditions of the liver. [5],[6],[7]

Hepatic angiogenesis is characterized by capillarization of the sinusoids. The sinusoids are normally bordered by liver-specific endothelial cells, characterized by intercellular openings or fenestrate. In liver, resting endothelial cells rarely proliferate under physiological conditions. When they undergo a process called "sinusoidal capillarization," these endothelial cells form tight junctions along with deposition of extracellular matrix followed by a new vessel formation. [8] The importance of neovascularization in the progression of HCC has been highlighted recently, suggesting that micro vessels increase gradually from cirrhotic nodules through low-grade and high-grade dysplastic nodules, with the greatest numbers recorded in HCC. [9] The liver is one of the most common sites of distant metastasis. The unique vascular architecture of the liver enables a tumor to acquire adequate nutrients and oxygen through various mechanisms, such as vessel co-option, modification of the existing sinusoidal network and eventually, traditional angiogenesis. [10]

CD34 is a 110-kDa transmembrane glycoprotein present on leukaemic cells, endothelial cells and stem cells. QBEND/10 is a monoclonal CD34 Ig G 1 antibody directed against endothelium. [11] Because CD34 is considered as one of the marker for neovascularization, the expression of CD34 positive endothelial cells may play an important role in understanding the process of angiogenesis in cirrhosis, HCC and metastasis. Several studies recently have emphasized on controlling the growth of tumor by suppressing their blood supply (angiogenesis). For this kind of therapy to be beneficial, it is paramount to understand the process of angiogenesis in liver cirrhosis and HCC. Hence, the aim of this study is to evaluate the process of angiogenesis using CD 34 as an endothelial cell marker in normal liver, cirrhosis, HCC and liver metastasis.


   Materials and Methods Top


We assessed paraffin blocks of thin core biopsies, surgically resected specimens and autopsy specimens of liver referred to the Department of Pathology over a period of 5 years. A total of 111 cases were included in this study, which consisted of 30 cases each of normal liver and cirrhosis that were all autopsy cases. Twenty-one cases of HCC included 10 autopsy specimens, nine surgically resected specimens and two liver biopsies. Remaining were 30 cases of metastasis to the liver, which included 20 autopsy specimens, one surgically resected specimen and nine liver biopsies. The 30 cases that were taken as controls did not show evidence of liver disease, clinically as well as at autopsy (gross and microscopy). Clinical details were obtained from the hospital records. All paraffin blocks were processed and cut into 4-µm-thick sections. The sections were stained with routine hematoxylin and eosin and were studied to ascertain the morphology of the lesion (cirrhosis, HCC and metastasis). Immunohistochemistry was performed using monoclonal mouse anti-human CD34 Class II, Clone QBEnd-10 (DAKO) antibody at 1:50 dilution for the expression of endothelial cells. Immunohistochemical staining was performed using standard routine avidin-biotin-peroxidase method. A section of angiosarcoma was used as a positive control and phosphate-buffered saline was used as a negative control in place of primary antibody.

CD34 positive staining was taken as any cell that stained brown with a dotty, linear, semicircular, or circular pattern and was clearly separate from an adjacent one. Large vessels with thick muscular walls were excluded from the study. Semi-quantitative assessment was performed. [12] The counting was carried out in 10 high-power fields and average was taken which was then graded as follows: grade 0 (no staining), grade 1 (<25% staining of endothelial cells), grade 2 (25-50% staining of endothelial cells), grade 3 (50-75% staining of endothelial cells) and grade 4 (>75% staining of endothelial cells). Statistical analysis was done using chi-squared test to evaluate the results to look for significant difference in the expression of CD34 in different study groups.


   Results Top


The demographic profile of our cases showed an age range from 17 to 80 years. The patients with normal liver histology, cirrhosis and the tumor (HCC and metastasis) were in the age ranges 20-40 years, 20-60 years and 41-80 years, respectively. The cases included were 70 males and 11 females.

Amongst 30 cases of cirrhosis, alcohol was found to be the commonest etiological factor; present in 20 (60%) cases. Alcohol in conjunction with HBV infection was seen in three cases and with HCV and HIV infections in one case each. Out of remaining 10 cases, HBV infection alone was seen in three cases, HCV infection alone in two cases and no etiological risk factor for cirrhosis could be identified in the other five cases which were grouped together as cryptogenic cirrhosis.

Evaluation of CD34 expression

In this study, none of the cases of normal liver showed any sinusoidal positivity [Figure 1]. Amongst cirrhosis, 14 (46.7%) cases were negative, 12 (40%) cases showed grades 1 and 2 positivity and only 4 (13.3%) cases showed grade 3 positivity for CD34. In contrast to this, HCC showed grades 3 and 4 positivity in 13 (62%) cases with grades 1 and 2 positivity in another 5 (23.7%) cases. Only 3 (14.3%) cases of HCC were CD34 negative. From metastasis, 15 (50%) and 11 (36.6%) cases showed grades 1 and 2 and grades 3 and 4 positivity, respectively. Statistical analysis using Chi-squared test showed a significant difference ( P < 0.05) in the grades 3 and 4 expression of CD34 in cases of HCC and metastasis as compared to cirrhosis and normal liver [Table 1].

Out of 30 cirrhosis cases, macronodular, micronodular and mixed varieties constituted 9 (30%), 8 (26.7%) and 13 (43.3%) cases, respectively. The sinusoidal positivity was seen in six out of nine cases of macronodular cirrhosis. The micronodular variety showed positivity in two out of eight cases, whereas 13 cases of mixed nodular cirrhosis showed positive staining in eight cases [Figure 2].

In cases of HCC, CD 34 positivity was observed more within the tumor as compared to surrounding tissues [Figure 3]. Out of five cases of well-differentiated HCC, one case showed grade 3 positivity, two were grades 1 and 2 positivity and two cases showed negative staining for CD34. On other hand, out of 14 cases of moderately differentiated HCC, 10 cases showed grade 4 positivity, three were grade 2 positivity and only one case showed negative staining. There was not a single case of poorly differentiated HCC in our study. The fibrolamellar and sarcomatoid variants also showed strong CD 34 positivity within the tumor cells. Statistical analysis showed a significant difference ( P < 0.05) in the expression of CD34 between the well-differentiated and moderately differentiated HCCs [Table 2].

The cases of metastases to liver were a heterogeneous group comprising tumors from many parts of the body. It included three cases of colonic adenocarcinoma, of which two showed grades 3 and 4 positivity and the remaining one showed grades 1 and 2 positivity. Out of four cases of gall bladder adenocarcinoma, two cases each showed grades 1 and 2 and grades 3 and 4 positivity, respectively. From the two cases of pancreatic adenocarcinoma, one case each showed grade 1/2 and grade 3/4 positivity. All the three cases of periampullary carcinoma showed grades 1 and 2 positivity. There was only one case of cholangiocarcinoma showing grade 3/4 positivity. From five cases of stomach adenocarcinoma, one case showed grades 3 and 4 positivity, three cases showed grades 1 and 2 positivity and one case showed negative staining. We also had two cases of neuroendocrine tumors, both showing grades 1 and 2 positivity. Out of three cases of pulmonary metastases, which included two cases of small cell carcinoma and one case of adenocarcinoma, only a case of small cell carcinoma showed grades 1 and 2 positivity and the other two being negative. We had one case each of renal cell carcinoma and bladder transitional cell carcinoma metastasizing to liver and all showed grades 3 and 4 positivity. One case was of infiltrating duct carcinoma from breast which showed grades 1 and 2 positivity. The metastasis from cervical adenosquamous carcinoma showed grade 4 positivity. A single case of choriocarcinoma metastasizing to liver showed grades 1 and 2 positivity. Besides above tumors where the primaries were known, there were two cases of occult primary metastasizing to liver. In them, CD34 was grades 3 and 4 positivity in one case while being negative in the other [Table 3].

Considering surrounding liver in HCC, out of 21 cases of HCC, the surrounding liver was cirrhotic in 15 (71.5%) cases, noncirrhotic in 4 (19%) cases and adjacent liver tissue was not sufficient to opine in 2 (8.5%) cases. CD 34 staining was also observed in adjacent liver in cases of HCC. Amongst these, three cases (all cirrhotic) showed grade 3 positivity and other seven cases showed grade 1 positivity (6 cirrhotic and 1 normal). The remaining nine cases showed negative staining, while adjacent liver was insufficient to opine in two cases as these were biopsy material, hence inadequate to evaluate.

In case of metastasis, the adjacent liver tissue was sufficient to opine in 27 cases. Out of this, grades 3 and 4 positivity was seen in two cases, grades 1 and 2 positivity in nine cases and negativity in 16 cases. With reference to adjacent liver tissue, the hepatocytes which were in very close proximity to the tumor margin (abutting tumor), only those showed sinusoidal CD 34 positivity, while those away from tumor were negative for CD 34.


   Discussion Top


The role of angiogenesis in liver has been studied extensively in relation to HCC. In this study, we evaluated progression of angiogenesis with the help of CD 34 expression in normal liver, cirrhosis, HCC and metastasis.

None of our cases of normal liver showed any sinusoidal positivity for CD 34. This is in concordance with the other studies in literature, which have also shown absence of positive staining for sinusoidal endothelial cells in normal liver. [13],[14] This can be attributed to the fact that in a normal liver, endothelial cells rarely proliferate under physiological conditions and hence do not express CD 34, unless they are stimulated.

Amongst 30 cirrhosis, grades 1 and 2 positivity was seen in 12 cases of alcoholic cirrhosis Remaining 4 (13.3%) cases of cirrhosis showed grade 3 positivity, Two of them had HBV infection with one having associated alcohol as a risk factor, one had HCV infection associated with alcohol and remaining were two cases of alcoholic cirrhosis.

It was difficult to compare CD 34 in different etiologies of cirrhosis in this study, since majority of our cases were alcoholic cirrhosis. There have been few reports in the literature suggesting increased angiogenesis in alcoholic liver disease and HCV infection as compared to other etiologies for chronic liver disease. [15],[16] It is stated that macronodular cirrhosis is much more prone to progress to HCC as compared to micronodular cirrhosis as regenerative activity going in the former is more. It is obvious to state that macronodular cirrhosis will show more angiogenic activity as compared to micronodular cirrhosis. In our study, out of nine cases of macronodular cirrhosis, six showed positive expression of CD34 out of which three were grade 3 positivity. In contrast, only two out of eight cases of micronodular cirrhosis showed positivity, which is consistent with study carried out by Vertemati et al . [17]

Park et al . [9] in their study found that there was a gradual increase in CD34 expression from cirrhotic nodules to dysplastic nodules to HCC, with all the cases of HCC showing diffuse strong CD34 positivity. Semela and Dufour [18] have also documented angiogenesis in HCC and have mentioned that antiangiogenic therapy might be of help in treating HCC. De Boer et al . [19] studied CD34 expression in 40 cases of HCC and found that 33 (82.5%) cases showed diffuse positivity for CD34 with another 6 (15%) cases showing weak positivity and 1 (2.5%) case showing negative staining. When compared, our study showed grades 3 and 4 expression in 13 (61.9%) cases of HCC, grades 1 and 2 in 5 (23%) cases and negative in 3 (14.3%) cases. Cui et al . [20] have shown moderate to diffuse positivity for CD 34 in majority of well-differentiated HCC. In contrast to this, Park et al . [9] studied CD34 expression in HCC and found that 14 out of 21 cases of moderate to poorly differentiated HCC showed strong positivity while it was seen in three out of 11 cases of well-differentiated HCC. Maeda et al . [21] have also reported negative staining in substantial number of well-differentiated HCC This is similar to our study where we found grades 3 and 4 positivity in 10 out of 14 cases of moderately differentiated HCC as compared to only one out of five cases of well-differentiated HCC. Therefore, we suggest that angiogenesis as assessed by CD34 expression probably correlates well with the dedifferentiation and growth of the tumor and may play an important role in multistep carcinogenesis process in HCC. As against this, Kimura et al . [22] did not find any significant difference in CD 34 among all clinical stages and histological grades of HCC.

Successful metastasis depends on the microenvironment of each organ and the essential step in the metastatic cascade is angiogenesis. [10] Angiogenesis of liver metastases progresses stepwise as the metastases enlarge and capillarization of the sinusoidal endothelium around the liver metastases occurs. [23] In our study, we had heterogeneous group of tumors metastasizing to liver. Out of 30 cases, 11 (36.7%) cases showed grades 3 and 4 positivity, 15 (50%) cases showed grades 1 and 2 positivity while 4 (13.3%) cases were negative. The 11 tumors showing strong expression included two cases of gall bladder adenocarcinomas, one case each of cervical adenosquamous carcinoma, pancreatic adenocarcinomas, cholangiocarcinoma, stomach adenocarcinoma, bladder transitional cell carcinoma and renal cell carcinoma and one case of occult primary. We could not derive any statistical differences in the angiogenesis of different tumors metastasizing to liver because of less number of individual cases. Vermeulun et al . [24] studied different patterns of liver metastases from colorectal adenocarcinomas and observed that the sinusoidal type of angiogenesis was seen in "replacement" pattern while portal type of angiogenesis was associated with "desmoplastic" pattern of metastasis. We have also observed angiogenesis in periportal areas along with sinusoidal CD 34 expression in some of the cases. Hillen et al . [25] studied angiogenesis in unknown primary tumors metastasizing to liver and compared it to those where the primary was known. They did not find any significant difference in CD34 expression in these two groups. In our study, out of two cases with occult primary, one showed strong diffuse positivity, while the other one was negative. Peeters et al . [26] observed that the degree of angiogenesis as expressed by CD34 was lower in metastases as compared to their primary tumors. Overall in our study, both HCC and metastatic tumors in liver showed increased expression of CD34, as compared to liver cirrhosis. Considering CD 34 positivity in surrounding liver, although there are conflicting results in literature, we have not found any difference in CD 34 expression between HCC and metastasis. [27] As our sample size was small, we could not derive any conclusion regarding CD 34 positivity in normal (control) liver and normal liver adjacent to the tumor. Further study is required with large sample size for expression of CD 34 in normal liver and the liver tissue adjacent to tumor.


   Acknowledgments Top


The authors are thankful to the Nair Golden jubilee research foundation for the financial support to carry out immunohistochemistry and also to Mr Ajit Kadam for the technical support to carry out immunostaining.

 
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Anjali D Amarapurkar
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DOI: 10.4103/0377-4929.42504

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