Tumor-associated lymphangiogenesis correlates with prognosis after resection of human hepatocellular carcinoma.
BACKGROUND
Experimental results from animal models as well as studies of human cancers indicate a critical role for tumor-associated lymphangiogenesis in tumor progression. However, its significance in hepatocellular carcinoma (HCC) is not well established.


METHODS
We analyzed tissue specimens from healthy liver (n = 36), cirrhotic liver (n = 24), and HCC (n = 60) by immunohistochemistry, using antibody D2-40 specific for lymphendothelia. We subsequently quantified lymphatic microvessel density (LVD). The LVD was correlated with clinicopathological characteristics of the tumors as well as survival and disease-free survival of the patients.


RESULTS
In contrast to healthy as well as cirrhotic liver, lymphangiogenesis was induced in HCC. Lymphatic vessels were detected in the intratumoral septa as well as within the bulk of tumor cells. Tumors with high LVD (24 of 60) had developed significantly more frequently in cirrhotic livers (P = 0.001) and were more frequently restricted to one liver lobe (P = 0.04). Univariate analysis revealed high LVD as a marker for reduced survival and disease-free survival disadvantage (median >60 vs. 21 months, P = 0.018, and 19 vs. 8 months, P = 0.047, respectively). In multivariate analysis, LVD showed a trend toward association with reduced survival (P = 0.059) and represented an independent prognostic factor for disease-free survival (P = 0.017).


CONCLUSIONS
Tumor-associated lymphangiogenesis is involved in neovascularization of hepatocellular carcinoma. Quantitative analysis of LVD demonstrated a significant influence of lymphangiogenesis on survival and established LVD as an independent predictor of disease-free survival. Quantification of LVD may be helpful in identifying patients with a high risk of tumor recurrence.
Thelen
Armin
A
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Leipzig, Germany. armin.thelen@medizin.uni-leipzig.de
Jonas
Sven
S
Benckert
Christoph
C
Weichert
Wilko
W
Schott
Eckart
E
Bötcher
Christian
C
Dietz
Ekkehart
E
Wiedenmann
Bertram
B
Neuhaus
Peter
P
Scholz
Arne
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D018450:Disease Progression; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000473:pathology*; D008297:Male; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000503:physiopathology*; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult