Intratumoral Lymphatics and Lymphatic Invasion Are Associated with Tumor Aggressiveness and Poor Prognosis in Renal Cell Carcinoma

Objectives: Because lymphangiogenesis and lymphatic invasion are key steps to nodal involvement in various types of cancer, we examined the clinicopathologic significance of lymphangiogenesis and lymphatic invasion in renal cell carcinoma. Methods: Peritumoral lymphatics and intratumoral lymphatics (ITLs) from 106 patients with clear cell renal cell carcinoma specimens were immunostained with D2-40 antibody, which specifically recognizes the lymphatic-specific marker podoplanin. The clinicopathologic significance of the densities and presence of lymphatic vessels and lymphatic invasion (LVI) was evaluated, and the staining pattern of D2-40 was compared with that of CD34. Results: Peritumoral lymphatics were present in 100 patients (94.3%), and ITLs were present in only 20 (18.9%). LVI was present in 6 patients (5.7%), of whom 5 had concomitant microvascular invasion. Some lymphatic vessels were positive not only for D2-40, but also for CD34. The presence of ITLs and LVI were significantly associated with pathologic T stage (P <0.0001 and P = 0.0136, respectively), regional lymph node involvement (P = 0.0312 and P = 0.0067, respectively), distant metastasis (P = 0.0046 and P = 0.0294, respectively), and microvascular invasion (P = 0.0105 and P = 0.0312, respectively). Univariate analysis showed that patients with ITLs had significantly shorter cancer-specific survival than those without ITLs (P = 0.0025) but multivariate analysis did not (P = 0.0527). Conclusions: The results of our study have shown that ITLs and LVI are associated with tumor aggressiveness, and patients with ITL have poor prognosis in renal cell carcinoma. One should be aware that some of the intratumoral microvessels are lymphatics and patients with microvascular invasion evident on the routine histologic examination often also have LVI.