ANTICANCER RESEARCH 31: 3503-3506 (2011)

Review The Prognostic Role of Lymphovascular in Urothelial- Cell of Upper and Lower Urinary Tract

EUGENIO BRUNOCILLA, REMIGIO PERNETTI and GIUSEPPE MARTORANA

Department of Urology, University of Bologna, Bologna, Italy

Abstract. Background: Carcinoma of the bladder represents tumors (stages Ta, T1 or tumors in situ [Tis]), but as many the fourth most common in men and the eighth most as 50-70% of these superficial tumors will recur and roughly common in women in Europe and the United 10-20% will progress to muscolaris propria invasive disease States. Prognostic factors for recurrence and survival are (T2-4) (2). The standard of care for invading tumor stage and dimension, tumor grade and the presence of the muscolaris propria is radical cystoprostatectomy for men, . We assess the impact and the role of and anterior exenteration including the bladder, uretra, uterus lymphovascular invasion (LVI) on the prognosis of patients and ventral vaginal wall for women. treated for lower and upper tract urothelial carcinoma by Nowadays, the standard prognostic discrimination in reviewing the literature curentable. Materials and Methods: urothelial cancer of the bladder is based on classic pathologic We performed a detailed review of the literature to assess the oncologic factors such as tumor grade, stage and histologic prognostic role of LVI assessed in histological specimens of subtypes; The presence of lymph node metastases are urothelial cell carcinoma of the upper and lower urinary correlated with a poorer outcome following radical cystectomy, tract. Results: We presented the definition of lymphovascular predicting reduced recurrence-free and overall survival. invasion in histological specimens of urothelial carcinoma. Lymphovascular invasion (defined as the presence of LVI in histological specimens was correlated significantly tumor cells within an endothelium-lined space) may with increasing tumor stage and grade. Moreover, LVI is represent a parameter for tailoring appropriate treatment in significantly correlated with earlier disease recurrence and a patient with bladder cancer; in fact, it could help to stratify lower cancer-specific survival, and seems to be an patients after radical cystectomy and improve management independent predictor of recurrence-free survival on of bladder cancer, which is currently based on imaging, multivariate Cox analysis. Conclusion: LVI in histological endoscopic and histological findings. The purpose of this specimens seems to have an important prognostic value for study was to review the prognostic value of LVI in patients with urothelial cell carcinoma of the upper and lower transitional-cell carcinoma of the upper and lower urinary urinary tract, and could be a useful tool for the urologist in tract. choosing the best and most appropriate management during disease treatment and follow-up. Materials and Methods

Carcinoma of the bladder represents the fourth most common A systematic literature review was carried out. The electronic cancer in men and the eighth most common malignancy in databases Pubmed/Medline, Cochrane, and Embase were searched women in the United States (1). The incidence increases with using the following key words: bladder cancer, radical cystectomy, lymphovascular invasion and prognosis. From Medline/Pubmed, 450 age, peaking between 50 and 70 years and is three times references were obtained; 20 references were obtained from more common in men than in women. At the initial diagnosis Cochrane; and 500 references were obtained from Embase. Twenty- of bladder cancer, about 70% of cases present as superficial four articles were then selected based on content, abstract, and study format. Randomized trials with high levels of evidence were selected primarily.

Correspondence to: Dr. Remigio Pernetti, Augusto Murri 63, 40137, Analysis of Evidence Bologna, Italy. Tel: +39 3392699532, e-mail: [email protected]

Key Words: Bladder cancer, transitional carcinoma, lymphovascular Definition of LVI. In the series regarding the prognostic role invasion, upper tract transitional carcinoma, prognostic role, review. of LVI in urothelial-cell cancer, there is a lack of

0250-7005/2011 $2.00+.40 3503 ANTICANCER RESEARCH 31: 3503-3506 (2011) standardization regarding the definition of LVI. Many grade and also with the incidence of lymph node metastasis authors define LVI as “the unequivocal presence of tumor (8, 22). In the article by Streeper (15), 163 patients with cells within an endothelium-lined space with no underlying urothelial-cell carcinoma of the bladder who underwent muscular walls” but in other cases, the criteria employed are transurethral resection bladder tumor (TURBT) or radical not specified at all, only applying the statements of the cystectomy with the finding of LVI in their pathological pathologist’s report (3) and with no reference to the specimens, were compared to a control group (without LVI) immunohistochemical demonstration of the vessels. to assess whether the patients of the first group (with LVI) In order, to determine whether LVI has any clinical would have a worse prognosis than those of the latter and a application, it is important to have morphological criteria that higher likelihood of clinical understaging. The presence of may guide the diagnosis. Algaba (4) reviewed the series LVI at the time of TURBT varied with clinical stage investigating the prognostic significance of LVI in urothelial- (p=0.049) and this finding was significantly related to a cell carcinoma and stated the histological/morphological poorer disease-specific survival (33.6% at 5 years vs. 62.9% features in favor and against the diagnosis of LVI, based on for LVI-negative patients, p=0.027). Moreover, patients with the usual method (hematoxylin-eosin); the invasion of the the finding of LVI at TURBT and clinical stage T1-T2 had a space near to an arteriole, the unequivocal involvement of the lower survival rate than those without LVI, whereas LVI did endothelial lining (with at least two cells per space), isolated not affect the survival for those with clinical stage T3-T4. vascular invasion, and the presence of a complete free Thus for patients with T1-T2 stage with LVI histological thrombus made of tightly cohesive cells with a smooth findings, could an improvement of clinical outcome and border represent typical aspects demostrating LVI. In very disease-free survival be achieved with a target therapy doubtful cases, an immunohistochemical study is (performing an early cystectomy, for example)? recommended (4, 5). The studies conducted in patients who underwent radical cystectomy (3, 9, 11-14, 21-24) showed a 25-50% incidence LVI as a prognostic factor for urothelial-cell carcinoma. of LVI; the recurrence-free, cancer-specific and overall Nowadays, many features have been identified as variables survival were lower in patients with LVI-positive disease for recognizing risk groups among patients with urothelial when compared with patients without LVI in their bladder cancer and to determine the risk of recurrence and pathological specimens, with statistical significance (p<0.05). survival after radical cystectomy, such as pathological stage, In a multi-institutional study conducted on a cohort of tumor size (>3 cm), presence of lymph node metastases (for 1099 patients who underwent radical cystectomy and pelvic recurrence) and pathological stage/lymph node metastasis lymph node dissection for bladder carcinoma (14), LVI was (for survival). LVI in primary tumor has been related to detected in 295 (26.8%) patients; the presence of LVI lymph node metastasis in bladder cancer (6). Could LVI correlated significantly with increasing tumor stage (29.4% represent a histological marker useful for determining the in T1 stage, 31.5% in T2 stage, 31.8% in T3 stage and 38.1% appropriate management for urothelial-cell cancer? The in T4 stage, p=0.002) and grade (11.2% in G1, 30.6% in G2, literature regarding the prognostic role of LVI remains 28.8% in G3, p<0.001). At univariate analysis, the 5- and 10- controversial. year cancer-specific survival of all patients was 73.2% and The spreading of neoplastic cells through the local 68.8% respectively, and the respective overall survival rates lymphovascular network is the first step in their were 59.2% and 42.4%. LVI was significantly correlated dissemination to distant organs, although this process is also with earlier disease recurrence (5-year recurrence-free influenced by other factors (biology of the tumor, evolution survival of 66.6% in patients with LVI-positive and 73.9% time and the patient’s immunological state). For example, in in these with LVI-negative disease, p=0.008) and a lower the classification of germ cell testicular tumor, vascular cancer-specific survival (69.5% at 5 years vs. 74.5% for invasion has been included in the T category of the TNM patients with LVI-negative disease). LVI, moreover, was an classification system and a local tumor with LVI is independent predictor of recurrence-free survival considered pT2 (7). The hypothesis of a correlation between (p<0.0001), along with age and tumor stage at multivariate LVI and a poorer outcome for cancer patients with urothelial- Cox analysis. cell has stimulated many authors to demonstrate a possible Lotan (8) also reported their results on 750 patients from prognostic value of the microscopic findings of a multi-institutional radical cystectomy database and lymphovascular invasion. demonstrated that LVI was statistically significant in terms As regards the implications of LVI on the clinical outcome of local and distant recurrence, overall survival, disease- for urothelial-cell cancer patients, several studies on both the specific survival and recurrence-free survival, especially in lower (3, 8-17) and upper urinary tract have been published lymph node negative cases. (18-20). These series (8-10, 12, 14, 15, 19, 21, 22) show a In the study by Quek (3), in the largest single-institution significant correlation of LVI with higher tumor stage and series and one of the most complete studies investigating the

3504 Brunocilla et al: Lymphovascular Invasion in Urothelial-Cell Carcinoma of Upper and Lower Urinary Tract (Review) role of LVI, the presence of LVI affected the recurrence free- (p≤T2/LVI-negative, vs. p≤T2/LVI-positive, vs. pT3/LVI- survival (at 10 years, 74% in patients without LVI compared negative, vs. pT3/LVI-positive), the authors demonstrated with 42% in those with LVI, p<0.0001). They subdivided that the frequency of disease-specific death in pT3/LVI- patients with LVI into three pathological subgroups: organ- positive cases (41%) was significantly higher than in p≤T2 confined/lymph node-negative, extravescical/lymph node- /LVI-negative (5.5%), p≤T2/LVI-positive (11.1%), and negative, lymph node positive disease; overall survival and pT3/LVI-negative cases (8.7%) (p<0.001). Recurrence-free recurrence free survival were significantly lower in organ- and disease-specific survival rates in pT3/LVI-positive cases confined/lymph node-negative and lymph node-positive were significantly worse than in the other three groups subgroups (p=0.001 and p=0.027, respectively); although (p<0.001), but there was no difference in recurrence-free or this was not the case for the extravescical/lymph node- disease-specific survival rates among the other three groups. negative subgroup (p=0.19). At multivariate analysis, LVI Five-year recurrence-free and disease-specific survival rates status (p=0.0004) with pathological subgroups was in patients with pT3/positive LVI were 56.9% and 53.0%, confirmed as an independent and significant prognostic respectively. features for recurrence-free survival. Similar results were obtained by How-Huang (20). Of 106 Others have reported similar results. Canter (12) noted patients, who underwent nephroureterectomy for upper tract LVI as an independent prognostic factor for overall and urothelial carcinoma, LVI was present in 32 (30.2%) disease specific survival, but not for recurrence free survival patients. LVI was significantly associated with higher in lymph node negative patients. Herrman (13) demonstrated pathological stage (13.6%, 29.4%, 63.3% of pT1, pT2, pT3 that the presence of LVI was associated with impaired disease respectively, p<0.001) and high histological grade survival (p=0.0001) in a cohort of 614 patients treated with (p<0.012). At univariate analysis, the 5-year recurrence-free RC and bilateral PLND; at multivariate analysis, pathological survival rates were 91.9% in the LVI-negative group and stage, lymph node status and LVI were independent 65.3% in the LVI-positive group (p<0.002); dividing patients prognostic factors: even in the ≤pT2 subgroup, LVI was a into six groups (pT1/LVI-negative, pT1/LVI-positive, predictive of survival, although it did not correlate with pT2/LVI-negative, pT2/LVI-positive, pT3/LVI-negative, lymph node metastasis. pT3/LVI-positive), the five-year recurrence-free survival rates In some series, invasion was subdivided into lymphatic were, respectively, 100%, 75%, 72.7%, 66.7%, 76.9% and and vascular and considered separately. In two of these 58.8%. At Cox multivariate analysis, moreover, LVI was studies (9, 11), only blood vessel invasion had statistical found to be an independent risk factor for poor prognosis and significance. Leissner (9) found that the vascular invasion high recurrence of cancer. status was correlated with pathological stage and that the presence of blood vessel invasion in 37 out of the 283 Conclusion patients was independently significant at multivariate analysis. Several factors have been identified in the literature as being Similar results were found when considering LVI in possible predictors of recurrence and survival, such as histological specimens of the upper urinary tract carcinoma. pathological stage (pT), the presence of lymph-node Saito (19) explored the prognostic impact of LVI in patients metastases (N+), and tumor size >3 cm for recurrence. The with localized upper urinary tract urothelial carcinoma (pTa- presence of LVI in the primary tumor has been proven to pT3, N0, M0). In a total of 135 patients who underwent have prognostic significance for regional lymph node nephroureterectomy, LVI was found in 57 (42.2%) patients; recurrence and a higher recurrence rate in patients with in the LVI-positive group, pT and grade (G) were higher than various solid tumors, including bladder and upper urinary in the LVI-negative group (p<0.001). Of the 135 patients tracturothelial carcinoma. Several studies have demonstrated studied, 5-year and 10-year overall survival rates were 70.8% the prognostic value of LVI, in terms of disease-free, and 55.8%, respectively. Five and 10-year recurrence-free recurrence-free and overall survival. In fact, most of the survival rates were 77.2% and 75.6%, respectively. Five-year studies reported in this review showed a lower 5-year and 10-year disease specific survival rates were 82.5% and disease-free, disease-specific and overall survival in patients 78.2%, respectively. Disease recurrence in patients with pT3 with LVI. Patients with LVI positivity had a greater chance stage was significantly more frequent than in patients with of having high-stage disease. LVI-positive status and high- pTa-2 stage. The frequency of disease recurrence in patients stage disease led to a higher risk of recurrence and, in turn, with positive LVI was significantly higher than that in recurrence led to a higher mortality rate. Moreover, in patients without LVI (33.3% vs. 10.3%, p<0.001). The patients with bladder urothelial carcinoma with lymph node recurrence-free survival rate in the 57 patients with LVI- involvement, LVI seems to have no predictive impact on positive disease was significantly worse than in the 78 LVI- recurrence or survival, while LVI might predict recurrence negative cases (p<0.001). Dividing patients into four groups and survival in those without lymph node involvement. LVI

3505 ANTICANCER RESEARCH 31: 3503-3506 (2011) in histological specimens seems to have an important 14 Bolenz C, Herrmann E, Bastian PJ, Michel MS, Wülfing C, prognostic value in patients with urothelial cell carcinoma of Tiemann A, Buchner A, Stief CG, Fritsche H-M, Burger M, the upper and lower urinary tract, and could be an useful tool Wieland WF, Höfner T, Haferkamp A, Hohenfellner M, Müller for the urologist in choosing the best and the most SC, Ströbel P and Trojan L: Lymphovascular invasion is an independent predictor of oncological outcomes in patients with appropriate management during disease treatment (surgical lymph node-negative urothelial bladder cancer treated by radical and systemic) and follow-up. cystectomy: a multicentre validation trial. BJU Int 106: 493-499, 2010. 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J Urol 180: 879-885, 2008. specific survival and local and distant recurrence in patients with 21 Harada K, Sakai I, Hara I, Eto H and Miyake H: Prognostic negative lymph nodes at radical cystectomy. J Clin Oncol 23: significance of vascular invasion in patients with bladder cancer 6533-6539, 2005. who underwent radical cystectomy. Int J Urol 12: 250-255, 2005. 9 Leissner J, Koeppen C and Wolf HK: Prognostic significance of 22 Manoharan M, Katkoori D, Kishore TA, Jorda M, Luongo T and vascular and in urothelial bladder cancer Soloway MS: Lymphovascular invasion in radical cystectomy treated with radical cystectomy. J Urol 169: 955-960, 2003. specimen: is it an independent prognostic factor in patients 10 Lopez JI and Angulo JC: The prognostic significance of vascular without lymph node metastases? World J Urol 28: 233-237, invasion in stage T1 bladder cancer. Histopathology 27: 27-33, 2010. 1995. 23 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, 11 Hong SK, Kwak C, Jeon HG, Lee E and Lee SE: Do vascular, Pappagallo G and Pagano F: Prognostic factors of outcome after lymphatic, and perineural invasion have prognostic implications radical cystectomy for bladder cancer: a retrospective study of a for bladder cancer after radical cystectomy? Urology 64: 697- homogeneous patient cohort. J Urol 161: 1494-1497, 1999. 702, 2005. 24 Hara S, Miyake H, Fujisawa M, Okada H, Arakawa S, 12 Canter D, Guzzo T, Resnick M, Magerfleisch L, Sonnad S, Kamidono S and Hara I: Prognostic variables in patients who Bergey M, Tomazewski J, Vaughn D, Van Arsdalen K and have undergone radical cystectomy for transitional cell Malkowicz B: The presence of lymphovascular invasion in carcinoma of the bladder. Jpn J Clin Oncol 31: 399-402, 2001. radical cystectomy specimens from patients with urothelial carcinoma portends a poor clinical prognosis. BJU Int 102: 952- 957, 2008. 13 Herrmann E, Stöter E, van Ophoven A, Bierer S, Bolenz C, Hertle L and Wülfing C: The prognostic impact of pelvic lymph Received May 17, 2011 node metastasis and lymphovascular invasion on bladder cancer. Revised August 10, 2011 Int J Urol 15: 607-611, 2008. Accepted August 11, 2011

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