Impact of urothelial carcinoma with divergent differentiation on tumor stage

E-mail: sanatchalise@hotmail.com, sanat_chalise@yahoo.com Background: Urinary bladder cancer is classiied as urothelial or non-urothelial. Ninenty percent of bladder cancer are urothelial and has propensity for divergent differentiation. Squamous differentiation is associated with unfavourable prognostic features. The aim of this study is to determine the signiicance of urothelial carcinoma with divergent differentiation in relation to tumor stage and lymphovascular as well as perineural invasion in radical cystectomy and partial cystectomy specimen.

worldwide, with an estimated 260000 new cases occurring each year in men and 76000 in women. 1 The prevalence of these tumor is higher in developed countries as compared to developing countries.In the United States alone, an estimated 70980 new cases were diagnosed with an estimated 14330 deaths in 2009. 2 The most common type is urothelial carcinoma derived from urothelium which constitute more than 90% of bladder cancer in America, France and Italy. 1 Urothelial carcinoma is known to show variant histological features, otherwise known as divergent differentiation, with an estimate ranging from 7% to 81% in a series speciically reporting the differentiation patterns of urothelial cancer. 3e recognization of histological variants in urothelial neoplasm is important because some type may be associated with different clinical outcomes, some may have different therapeutic approach and awareness of unusual pattern may be critical in avoiding diagnostic misinterpretation. 4uamous differentiation is the most important histological variant of urothelial carcinoma followed by glandular differentiation. 5Upto 60% of tumor exhibit squamous differentiation and approximately 10% of urothelial carcinoma contains foci of glandular differentiation. 4adical cystectomy with bilateral pelvic lymphnode dissection is currently the gold standard treatment for muscle invasive urinary bladder carcinoma.Unfortunately, 40% of patient with organ conined disease at the time of cystectomy urinary bladder subsequently suffer recurrence. 6 a large study done by Wasco and colleague, it was found that urothelial carcinoma with divergent differentiation were most likely to be invasive (p<0.001). 3The aim of the present study is to evaluate the urothelial carcinoma and its differentiation in radical cystectomy and partial cystectomy specimens and correlate the divergent differentiation with tumor stage as well as lymphovascular and perineural invasions.

MATERIALS AND METHODS
This is a prospective study done in the Department of Pathology, Bhaktapur Cancer Hospital.A total of 51 patients who underwent radical cystectomy and partial cystectomy with bilateral pelvic lymphnode dissection during the period of 1st August 2013 to 31st December 2015 were included in the study.Prior to study permission from ethical review committee has been obtained.
The received specimens were grossed and processed using standard technique.Tumor type, differentiation, depth of invasion, lymphovascular invasion and perineural invasion were assessed.Tumor staging and grading were done according to American joint committee of cancer (AJCC).Statistical analysis was done using Pearson chi-square test and statistically signiicant value was set at p<0.05.

RESULTS
The study comprises of 51 patient of which 41 (80.4%) were male and 10 (9.6%) were female, treated with radical cystectomy (n=43) and partial cystectomy (n=8) with pelvic lymphnode dissection.The age of the patient ranged from 45-85 years with mean age of 66.1 years.
Urothelial carcinoma with divergent differentiation were staged as pT3a in 25.4% of cases or even higher stage (Table 2 and 3).Using pearson chi-square test, statistical signiicant correlation was obtained between UC with divergent differentiation and tumor stage (p=0.012)which signiies that divergent differentiation is associated with higher stage (Table 4).
Lymphovascular and perineural invasion were present in 64.7% of cases.Most of the cases with divergent differentiation were positive for lymphovascular and perineural invasion (Table 5 and 6).Statistical signiicant correlation was also obtained between UC with divergent differentiation and lymphovascular as well as perineural invasion (Table 7 and 8)

DISCUSSION
Urothelial carcinoma are the commonest urothelial neoplasm and have a great capacity for divergent differentiation.Squamous differentiation is the commonest divergent differentiation. 7Pathological stage and lymphnode status are the common primary prognostic factors after radical cystectomy as they are the strong predictors for the survival. 8he clinical signiicance of squamous differentiation remains uncertain, but seems to be an unfavourable prognostic features predicting local recurrence after cystectomy. 7 this study, the mean age was found to be 66.1 of which 41 (80.4%) were male and 10 (19.6%) were female.Among 51 cases, 27 (52.9%)had a iniltrating carcinoma with divergent differentiation, the commonest being squamous differentiation (39.2%) followed by glandular differentiation

CONCLUSION
Squamous differentiation is the commonest divergent differentiation.Patient with divergent differentiation is associated with higher stage as well as lymphovascular and perineural invasion.Thus extensive search for the divergent differentiation should be done by the pathologist as these   Chalise S et al.

Table 4 : Correlation between urothelial carcinoma with divergent differentiation and tumor stage Urothelial carcinoma with divergent differentiation and tumor stage Pearson Chi-Square
11, they also found signiicant correlation (p<0.01) between histological UC variants and tumor stage.In concordance to the present study, Lopez-Beltran A et al7in their study concluded higher tumor stage and grade in the urinary bladder tumor with squamous differentiation. Silar to our study, Autunes AA et al11

Table 8 : Correlation between urothelial carcinoma with divergent differentiation and perineural invasion Urothelial carcinoma with divergent differentiation and perineural invasion Pearson Chi-Square
the current study which was similar to the study done by Brunocilla E 13, Lee YJ et al5, Kim SP et al9 and Antunes AA et al11 in their study also found signiicant statistical correlation between Urothelial carcinoma with divergent differentiation and lymphovascular as well as perineural invasion.In contrast to our study, Kucuk U et al6 does not found signiicant correlation between divergent and lymphovascular invasion.
also found squamous differentiation as a commonest tumor and signiicant correlation was obtained between UC with squamous differentiation and tumor stage (p=0.031).