Page 66 - Read Online

studies have shown that VEGF-C/D blockade suppresses by univariate analysis. Nevertheless, high LVD was
lymphangiogenesis and lymphatic metastasis, enhancing signifi cantly associated with tumor aggressiveness. These
UBC chemosensitivity. [46,47] Therefore, there is no doubt results have been corroborated by others. [58,59] Moreover,
that both blood and lymphatic vessels participate in we observed that intratumoral lymphatic vessels seemed
the metastatic process. Lymphovascular invasion (LI) to cooperate actively in malignant dissemination by the
has been identifi ed as an independent prognostic factor presence of single-malignant cells in well-preserved
for recurrence and OS. [48,49] A recent meta-analysis vessels [Figure 1b]. Although these vessels have been
demonstrated that LI is an important selection criterion described as collapsed and non-functional by others, [60,61]
for early cystectomy in high-grade stage T1 UBC. in our series, there was a signifi cant proportion of cases
[50]
Also demonstrated is that the LI status helps to stratify where vessels with visible lumina were seen; edema
N0 UBC patients at increased risk of UBC recurrence was not observed, which would support a more effi cient
[51]
and death. Regardless of these important associations, lymphatic fl ow. Accordingly, the presence of intratumoral
LI occurrence is not included as a standard parameter in lymphatic vessels was correlated with parameters of
[62]
many pathology reports, mostly due to the lack of strict UBC aggressiveness in one study, and was identifi ed
diagnostic criteria. [52,53] as a predictive factor of pelvic lymph node metastasis in
another. [59]
In our research, in 83 UBC tissue sections, we used
immunohistochemistry (IHC) (CD31 and D2-40 Another result of our study was the validation of the
antibodies) to assess BVD and blood vessel invasion use of IHC markers to separate blood and lymphatic
(BVI), and lymphatic vessel invasion (LVI), respectively vessels. Its usefulness was particularly important in the
[Table 1]. Regarding angiogenesis occurrence, detection of isolated malignant cells invading lymphatic
[54]
although we observed an association between BVD and capillaries [Figure 1b]. These cells, intravased in a
parameters of UBC aggressiveness and progression, we milieu that fl ows slowly and has a composition similar to
did not fi nd a signifi cant infl uence on prognosis. In fact, interstitial fl uid, have a higher survival probability when
confl icting results exist, [38,55,56] and it has been advocated compared to the typical rigors of the blood. LVI by
[63]
that additional factors are necessary to determine the isolated malignant cells was signifi cantly correlated with
real impact of angiogenesis in UBC progression and a poor prognosis. The same association was observed
dissemination. In accordance, BVI occurred more when considering BVI, but only when malignant emboli
[57]
frequently in cases with high BVD and was identifi ed were intravased [Figure 1a]. Thus, these parameters
as an independent prognostic factor for OS. The same represent potential biomarkers of progression that can
correlation was observed between LVD and LVI, guide therapeutic regimes, and their routine evaluation
although LVI was identifi ed as a prognostic factor only is recommended by us and others. [53,54] We additionally

Table 1: Major fi ndings of selected immunohistochemical studies on urothelial bladder cancer biomarkers
Reference Cohort n Markers Cut-off Impact on clinicopathological parameters and survival
[54] RC 83 BVD ≥ 17.6 vessels Quantifi cation of vessel density and identifi cation of lymphovascular
LVD ≥ 8.8 vessels invasion signifi cantly improved when using blood (CD31) and
lymphatic (D2-40) vessel markers. High LVD associated with tumor
BVI Malignant emboli aggressiveness. BVI and LVI signifi cantly lowered DFS and OS.
LVI Isolated tumor cells BVI remained an independent prognostic factor for OS.

[75] RC 76 p-mTOR ≥ 10% positive cells p-mTOR expression decreased with increasing stage and was lost
from non-tumor to tumor urothelium. T3/T4 positive cases (n = 49)
had signifi cant worse DFS rate.
[85] RC 81 RKIP ≥ 10% positive cells RKIP expression associated with favorable clinicopathological
profi le. Loss of RKIP expression associated with LVI occurrence,
signifi cantly lowered DFS and OS, remaining independent
prognostic factor for DFS.
[100] RC and 114 MCT1 Percentage of immunoreactive MCT1, MCT4, CD147 expressions signifi cantly associated with
†
TUR MCT4 cells*+intensity of staining unfavorable clinicopathological parameters and poor prognosis. In
CD147 (positive score ≥ 4) selected platinum treated-patients, OS was signifi cantly lower for
those with MCT1+CD147-positive tumors.
[101] RC 77 Scoring ≥ 3 positive parameters Model stronger in predicting prognosis than individual parameters,
model ‡ remaining independent prognostic factor for DFS and OS. CD147
expression added signifi cant prognostic information to the model.
*0: 0% of positive cells; 1: < 5% of positive cells; 2: 5-50% positive cells; 3: > 50% of positive cells; 0: negative; 1: weak; 2: intermediate; 3:
†
strong; scoring model: includes stage, grade, BVI, LVI, CD147 overexpression. BVD: Blood vessel density; BVI: Blood vessel invasion; DFS:
‡
Disease-free survival; LVD: Lymphatic vessel density; LVI: Lymphatic vessel invasion; MCT: Monocarboxylate transporter; OS: Overall survival;
p-mTOR: Phospho-mammalian target of rapamycin; RC: Radical cystectomy; RKIP: Raf kinase inhibitor protein; TUR: Transurethral resection
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 2 ¦ July 15, 2015 ¦ 59