Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract Manel Mellouli1*, Slim Charfi1, Walid Smaoui2, Rim Kallel1, Abdelmajid Khabir1, Mehdi Bouacida2, Mohamed Nabil Mhiri2, Tahya Sellami Boudawara1 Purpose: To evaluate the impact of lymphovascular invasion on the prognosis of patients treated for upper urinary tract urothelial carcinomas. Materials and methods: Clinical records of 49 patients treated surgically at our institute for upper urinary tract urothelial carcinomas were reviewed retrospectively. LVI was defined as the presence of cancer cells within an en- dotheluim-lined space without underlying muscular walls. Actuarial survival curves were analysed by Kaplan-Mei- er method. Multivariate analysis was performed using Cox’s proportional hazard model. Results: Median follow-up was 32 months. Lymphovascular invasion was present in 26 (53%) patients. Lym- phovascular invasion was associated with higher pathological tumor stage (pT) and higher tumor grade. The dis- ease-free and overall survival rates of the patients with lymphovascular invasion were significantly worse than those of the patients without lymphovascular invasion (p < 0.001 and p = 0.027 respectively). Multivariate analysis revealed that lymphovascular invasion as well as tumor grade and pathological tumor stage were significant prog- nostic factors for disease-free and overall survival. Conclusion: The presence of lymphovascular invasion was a strong predictor of a poor outcome for UTUC. This finding could help identify patients at greater risk for disease recurrence who would benefit from close follow-up and early adjuvant therapy. Keywords: transitional cell carcinoma; urinary tract; lymphovascular invasion; prognosis. INTRODUCTION Upper urinary tract urothelial carcinomas (UTUC) are rare tumors representing only 5% of all urothe- lial carcinomas.(1) The estimated incidence of UTUC in Europe is 1 to 4 cases per 100,000 individuals per year. (1) In Tunisia, according to the register of the southern Tunisian cancers (2007 edition), the estimated inci- dence of UTUC is 0.21 cases per 100,000 individuals in women and 0.67 cases per 100,000 individuals in men (Sellami A, 2007, unpublished data). To date, radical nephroureterectomy (RNU) remains the gold standard treatment for non-metastatic UTUC.(2) Despite surgery, UTUC remains a malignancy with a high potential for local and distant relapse, especially in patients with ad- vanced disease.(3) Numerous criteria, such as age, mul- tifocality, tumor stage, grade and architecture, and lym- phovascular invasion (LVI) have been established as determinant prognostic factors in UTUC.(1) In UTUC, LVI is detected in 15 to 20% of cases and is associat- ed with high stage and grade.(3-8) However, the prog- nostic role of LVI has not still been routinely assessed, checked and described in pathological reports. The aim of the current study was to further delineate the prog- nostic significance of LVI by analyzing survival out- come for patients with UTUC treated by surgery. MATERIALS AND METHODS We retrospectively analyzed 49 patients who underwent surgery for UTUC between 1992 and 2013 in the CHU Habib Bourguiba of Sfax. Surgical procedures were performed in one center by various surgeons. All gross- ly involved lymph nodes were removed during surgery. Clinical features Clinical data were collected via medical file review. They included age, gender, history of bladder carcino- ma or synchronous bladder carcinoma and outcomes. Pathological Evaluation All surgical specimens (partial ureterectomy, Nephrec- tomy or RNU) were processed according to standard pathologic procedures and all slides were re-reviewed by two pathologists. All specimens were evaluated for tumor location, tumor multifocality, tumor size, tumor architecture, pathological stage, histological grade, presence of LVI, tumor necrosis, concomitant carci- noma in situ (CIS), surgical margin status and lymph node status. Tumors were staged according to the 2009 American Joint Committee on Cancer–International Union against Cancer (AJCC/UICC) TNM staging sys- tem.(9) Tumor grade was assessed according to the 2004 World Health Organization grading system.(10) Multi- focality was defined by the presence of two or more synchronous tumors. Tumor architecture was defined as 1Department of pathology, Habib Bourguiba Hospital, 3029 Sfax, Tunisia. 2Department of urology, Habib Bourguiba Hospital, 3029 Sfax, Tunisia. *Correspondence: Department of pathology, Habib Bourguiba Hospital, 3029 Sfax, Tunisia. Tel : 00216 21 027 852. Fax : 00216 74 243 427. Email : mellouli.manel@yahoo.fr. Received August 2016 & Accepted May 2017 UROLOGICAL ONCOLOGY Urological Oncology 5008 papillary or sessile. LVI was defined, on H&E stained slides, as the presence of tumor cells within an endothe- lium-lined space without underlying muscular wall. No immunohistochemistry techniques were used to deter- mine the presence of LVI. The extent of lymph node dissection was not stand- ardized and thus was not available for analysis. Nodal status was determined by pathological assessment of retrieved lymph nodes at time of surgery. Follow-up regimen Patients were followed every 3-4 months for the first year following surgery, every 6 months from the second through the fifth years, and annually thereafter. They underwent physical examination, cystoscopy, urine cy- tology and abdominal-pelvic CT at each visit. Recurrence was defined as the disease occurring in the bladder or in the contralateral upper urinary tract. Statistical analysis Clinicopathologic features of patients were evaluat- ed. In the analysis, age was reclassified into 2 groups: younger than 60 versus 60 or older. Tumor size was re- classified into 2 groups: less than 4 cm or more than 4 cm. Tumour stage was classified into 2 groups: pTa, pT1 and pT2 versus pT3 and pT4. In multifocal tumors, clinicopathologic factors were defined according to the site with the highest stage. Qualitative variables were compared by the chi-square test and quantitative vari- ables by the student t-test. Patient disease free-surviv- al (DFS) was computed from the day of surgery until Lymphovascular invasion in UTUC-Mellouli et al. Table 1. Characteristics of 49 patients with UTUC. Total, n=49 (%) LVI negative, n=23 LVI positive, n=26 P-value Age (years) 0.357 <60 18 (36.8) 10 8 >60 31 (63.2) 13 18 Sex 0.174 Men 41 (83.6) 21 20 Women 8 (16.3) 2 6 History of bladder carcinoma 0.319 Yes 14 (28.6) 5 9 No 35 (71.4) 18 17 Tumor location 0.622 Renal pelvis 39 (79.5) 19 20 Ureter 10 (20.4) 4 6 Tumor size (cm) 0.786 <4 14 (28.5) 7 7 >4 35 (71.5) 16 19 Multifocality 0.012 Unifocal 34 (69.3) 20 14 Multifocal 15 (30.6) 3 12 Tumor architecture 0.062 Papillary 42 (85.7) 22 20 Sessile 7 (14.3) 1 6 Pathologic stage 0.117