Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma.
OBJECTIVE
Little is known about the function of tumor-associated neovascularization in the progression of intrahepatic cholangiocarcinoma (IHC). This study was conducted to evaluate the influence of tumor-associated angiogenesis and lymphangiogenesis on progression of IHC.


METHODS
We analyzed tissue specimens of IHC (N=114) by immunohistochemistry using the endothelial-specific antibody CD31 and the lymphendothelial-specific antibody D2-40 and subsequently quantified microvessel density (MVD) and lymphatic microvessel density (LVD). To analyze the influence of tumor-associated angiogenesis and lymphangiogenesis on tumor progression, tumors were allocated according to mean MVD and LVD, respectively, into groups of "high" and "low" MVD and LVD, respectively, and various clinicopathological characteristics as well as recurrence and survival data were analyzed.


RESULTS
IHC revealed an induction of tumor-associated angiogenesis and lymphangiogenesis. Tumors of "high" MVD displayed more frequently advanced primary tumor stages and multiple tumor nodes. Furthermore, patients with tumors of "high" MVD had an inferior curative resection rate and suffered more frequently from recurrence. A "high" LVD was correlated with increased nodal spread, and patients with "high" LVD tumors more frequently developed recurrence. In the univariate analysis, MVD and LVD revealed significant influence on survival, and MVD was identified as an independent prognostic factor for survival in the multivariate analysis. The 5-year survival of patients with "low" MVD tumors was 42.1%, compared with 2.2% in patients with "high" MVD tumors (P<0.001).


CONCLUSIONS
This study suggests a critical function of tumor-associated angiogenesis and lymphangiogenesis for progression of IHC. Therefore, antiangiogenic and antilymphangiogenic approaches may have therapeutic potency in this tumor entity.
Thelen
Armin
A
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Leipzig, Germany. armin.thelen@medizin.uni-leipzig.de
Scholz
Arne
A
Weichert
Wilko
W
Wiedenmann
Bertram
B
Neuhaus
Peter
P
Gessner
Reinhard
R
Benckert
Christoph
C
Jonas
Sven
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001650:Bile Duct Neoplasms / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D001653:Bile Ducts, Intrahepatic; D001707:Biopsy, Needle; D018281:Cholangiocarcinoma / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D042583:Lymphangiogenesis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D015996:Survival Rate