ANTICANCER RESEARCH 31: 3503-3506 (2011) Review The Prognostic Role of Lymphovascular Invasion in Urothelial- Cell Carcinoma 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 cancer in men and the eighth most as 50-70% of these superficial tumors will recur and roughly common malignancy 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 bladder cancer invading tumor stage and dimension, tumor grade and the presence of the muscolaris propria is radical cystoprostatectomy for men, lymph node metastasis. 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