Previous studies reported the vital role of smoking in urothelial carcinogenesis 5; however, other factor may also contribute to it because not all smokers have urothelial malignancies. Accordingly, the present study clarified the relationship between UTUC recurrence and clinicopathological parameters in NMIBC patients according to a smoking history. In all patients, a history of BCG therapy was identified as a significant predictor of UTUC recurrence, while in those with a positive smoking history, a lower urinary pH and concomitant CIS increased the risk of UTUC recurrence. These results suggest that BCG therapy may prevent UTUC in NMIBC patients. Meanwhile, acidic urine and concomitant CIS appeared to increase the risk of UTUC recurrence in patients with a smoking history.
The multifocality and frequent recurrences are well-known characteristics of urothelial cancer. There are currently the two main concepts which have been proposed to explain this phenomenon14. The first hypothesis is intraluminal seeding theory, in which the multifocality or recurrence of urothelial carcinoma occurs due to the release of tumor cells from the primary lesion and the implantation of tumor cells at different sites of the urothelium. Several clinical outcomes suggest the dissemination theory. The risk of UTUC after transurethral resection of bladder tumor (TURBT) was previously reported to be 0.5-6%, which is markedly lower than the risk of bladder cancer after nephroureterectomy for UTUC (30–40%) 1–4, 7,8,15. However, the risk of UTUC has been shown to increase by 15- to 22-fold if patients have VUR 16,17. Therefore, local control, including intravesical treatments, plays an important role in preventing dissemination from the bladder. Regarding UTUC development in NMIBC patients, previous studies identified several risk factors, including the occurrence of intravesical recurrence, the presence of VUR, and failed intravesical chemotherapy 1,7,8. The present study showed that BCG instillation was an independent factor for UTUC in all patients, which was supported by the first hypothesis described above, i.e. the mechanism of dissemination.
The second hypothesis postulates that multiple cells become initiated or partially transformed as a result of carcinogenic insults and acquire independent genetic alternations. Therefore, the detection and exclusion of carcinogens, such as aromatic amines, are essential for preventing the development of urothelial carcinoma. In in vitro studies, aromatic amines were found to be affected by urinary pH 18. Specifically, the rapid hydrolyzation of the N-glucuronide of N-acetyl-benzidine and further metabolism to bind to DNA were observed under acidic conditions 19,20. Furthermore, the half-life of 4-aminobiphenyl (ABP) N-glucuronide conjugates before being hydrolyzed was 11 minutes at pH 5.5 and 3 hours at pH 7.4 21. Bois et al. also reported that urinary pH was a strong contributor to interindividual variations in the DNA binding of ABP in the bladder 22. Clinically, previous studies reported that a consistent acidic urinary pH increased the risk of bladder cancer 13 as well as bladder recurrence in UTUC 23. Collectively, these findings indicate that acidic urine is a key factor for urothelial carcinogenesis and recurrence through the activation of aromatic amines derived from cigarettes. The subgroup analysis of smokers in the present study revealed a significant difference in the incidence of UTUC between the higher and lower urinary pH groups in patients with a larger smoking intensity or longer duration of smoking, but no significant differences between these groups in the counterparts. Moreover, after reducing the bias of multiplicity using propensity score matching, similar results were obtained. Taken together, urine pH appears to be important for UTUC recurrence in NMIBC patients with a smoking history.
NMIBC patients with CIS were previously reported to have a higher incidence of UTUC recurrence than those without it (21.2% vs 2.3%, P < 0.001) 24. Schwartz et al. showed that the UTUC recurrence rate was 13% in NMIBC patients with CIS, which was significantly higher than that in those without CIS (3.1%) 25. A recent study demonstrated that the smoke load (over 20 pack-year) increased the risk of recurrence and progression (HR = 1.019 and 1.034, p = 0.00004 and 0.00002, respectively) in NMIBC patients treated with BCG, suggesting that the smoke load reduces the efficacy of BCG therapy 26. These findings appear to support our results showing that concomitant CIS, but not a history of BCG, is an independent predictor of UTUC recurrence in NMIBC patients with a positive smoking history.
Although the incidence of UTUC is relatively low 1,2,7,8,15, most urologists perform UTUC surveillance for all NMIBC patients. Based on the present results, NMIBC patients may be divided into several risk groups based on smoking history. BCG may prevent UTUC recurrence in all NMIBC patients, while BCG and the inhibition of transcription factors induced in an acidic environment may effectively prevent UTUC recurrence in those with a smoking history. A recent study demonstrated that an acidic environment promoted tumor progression through the activation of sterol regulatory element-binding protein 2 (SREBP2) 27, which was reported to function with p53 28. A p53 mutation was detected in more cases of bladder cancer patients with a smoking history than in those without it 29. Accordingly, further studies to investigate pH-regulated effectors of p53 in bladder cancer, such as SREBP2, might be needed to predict and prevent UTUC recurrence.
The present study has several limitations. Since it was performed in a retrospective manner, unknown sources of bias may exist. Accordingly, we performed a comparative analysis of the risk of UTUC in lower and higher pH NMIBC patients with a smoking history using propensity scoring to control for selection bias 30. As aforementioned, there are several factors that alter urinary pH 31, and patients with diseases or taking medication that affect urinary pH were excluded. The smoking status was self-reported, which may cause a recall bias. Regarding urinary pH measurements, the accuracy of the dipstick test is also a study limitation. The gold standard measurement of urinary pH is with an electrochemical pH meter. However, it is not clinically used due to its complexity and cost.
In conclusion, the results of the present study suggest that BCG instillation prevented UTUC recurrence in NMIBC patients. Acidic urine and concomitant CIS increase the risk of UTUC recurrence in NMIBC patients with a smoking history. Therefore, monitoring urine pH and modifications to pH for urine alkalization may benefit NMIBC patients with a positive smoking history.