In a recent survey, the prevalence of urinary tract ur-othelial carcinoma (UTUC) was 1-2 per 100,000 in the United States, and 4.8 per 100,000 in the Republic of Korea.^1,2 UTUC is a highly aggressive malignancy, and rad-ical nephroureterectomy (RNUx) is the current standard treatment for patients with the disease.³ The 5-year re-currence-free survival (RFS) estimate was 70% in patients with UTUC treated with radical RNUx.⁴

Tumor stage, lymph node metastasis, chronic urinary tract infection, hydronephrosis, and smoking are closely related to recurrence of UTUC.^5-9 Hypertension (HTN) and obesity, which are metabolic factors, have been studied regarding cancer. Many studies have reported regarding a relationship between HTN and body mass index (BMI) and renal cell carcinoma, bladder cancer, prostate cancer, breast cancer, and lung cancer.^10-17 However, there are few studies about the relationship between HTN, BMI, and UTUC in patients with RNUx. One study reported that patients with low-BMI (<18.5 kg/m²) had a worse prognosis, regarding RFS and cancer-specific survival (CSS), than patients with normal BMI (18.5-25 kg/m²) or obesity (BMI ≥25 kg/m²).¹⁸ Another study reported that diabetes mellitus was related to post-operative bladder cancer recurrence in China.¹⁹ Therefore, we investigated the influence of HTN and BMI on onco-logic outcomes in patients with UTUC treated with RNUx.

Among a total of 453 patients, 233 (51.4%) had a history of HTN (Table 1). There were no significant differences between the HTN and no-HTN groups, except for the rate of diabetes mellitus (27.5% vs. 10.0%, p<0.001).

Median BMI was 24.06 kg/m² (interquartile range, 21.78-26.08 kg/m²) in the 453 patients, among whom 222 (49.0%) had high-BMI (≥24 kg/m²). High-BMI patients had a high-er rate of HTN than the low-BMI group (56.8% vs. 46.3%, p=0.026) and a lower rate of transfusions (14.0% vs, 24.7%, p=0.046). Other perioperative parameters, including surgical methods, operation time, were similar between the 2 groups.

Clinical and pathologic profiles for the 453 patients were stratified by HTN, and BMI (Table 1). In HTN versus no-HTN patients, significant differences were evident in tu-mor location (p=0.012), tumor laterality (p=0.054), and the presence of preoperative diabetes mellitus (p<0.001), and hydronephrosis (p=0.054). In low-BMI versus high-BMI patients, a significant difference was evident in the presence of preoperative HTN (p=0.026).

Table 2 shows pathologic outcomes according to each group. Overall, 168 patients had pathologic pT3-4 (37.1%). Pathologic stage, grade, and lymph node invasion were similar between the groups. The positive surgical margin was greater in the low-BMI than high-BMI group (9.1% vs. 4.1%, p=0.031). During 42.0-month follow-up, cancer re-currence was observed in 274 patients (60.5%). The most frequent sites of recurrence were the bladder (153 of 453 patients, 33.8%), lymph nodes (119 of 453, 26.3%), lung (68 of 453, 15.0%), and bone (44 of 453, 9.7%). Adjuvant chemotherapy rate was no significantly difference between HTN and no-HTN patients (29.6% vs. 30.0%, p=0.880), al-so no significantly difference between low-BMI and high- BMI group (29.0% vs. 30.6%, p=0.683). Cancer recurrence was more frequent in the HTN than no-HTN group (65.2% vs. 55.5%, p=0.033). Five-year RFS rates were 76.2% in the HTN group and 79.9% in the no-HTN group (log-rank, p=0.002) (Fig. 1), and those were 77.3% in the low-BMI group and 79.0% in the high-BMI group (log-rank, p=0.007) (Fig. 2). Five-year intravesical RFS rates were no significant difference in the HTN group and in the no-HTN group (66.4% vs. 65.7%, log-rank p=0.120), also no difference in low-BMI group and in the high-BMI group (67.4% vs. 64.7% log-rank p=0.438).

Multivariate Cox proportional hazard analysis showed the significance of BMI and HTN in relation to cancer recurrence after adjusting for other factors (Table 3). That is, BMI (hazard ratio [HR], 0.740; 95% confidence interval [CI], 0.551-0.995; p=0.046) and HTN (HR, 1.687; 95% CI, 1.174-2.426; p=0.005) were significant predictors of cancer recurrence. That is, BMI (hazard ratio [HR], 0.740; 95% confidence interval [CI], 0.551-0.995; p=0.046) and HTN (HR, 1.687; 95% CI, 1.174-2.426; p=0.005) were sig-nificant predictors of cancer recurrence.

Five-year OS rates were no significant difference in the HTN group and in the no-HTN group (89.3% vs, 90.5%, log-rank p=0.661), also no difference in low-BMI group and in the high-BMI group (86.6% vs, 93.2% log-rank p=0.143). Five-year CSS rates were no significant difference in the HTN group and in the no-HTN group (91.8% vs. 94.1%, log-rank p=0.802), also no difference in low-BMI group and in the high-BMI group (91.8% vs. 94.1% log-rank p=0.300) (Table 2). Multivariate Cox proportional hazard analysis showed that BMI and HTN are not significantly related to OS and CSS after adjusting for other factors (Tables 4, 5).

Although UTUC is not a common cancer, it has a high recurrence rate. In particular, smoking status, tumor stage, and lymph node metastases are associated with UTUC recurrence. This study assessed how obesity and HTN, which continue to increase in incidence, might be linked to UTUC. Thus, in 453 RNUx-operated UTUC patients, we found that RFS in patients with high-BMI, without HTN, was good. Several papers exist about the relationship between renal cell carcinoma and HTN and BMI, but few studies have been published about the relationship between UTUC and HTN and BMI.

In one study, when 236 UTUC patients underwent RNUx in China, higher BMI was associated with better RFS and CSS.¹⁸ In another paper, low-BMI was an independent pre-dictor of worse CSS on multivariate analysis in 103 obese patients (HR, 2.210; p=0.047).²¹ In patients with high-BMI, increased fat between the kidney and Gerota's fascia may suggest that the higher the BMI, the better will be survival, as UTUC has difficulty in transitioning and invading beyond the fascia.¹⁸ Furthermore, Obesity is associated with hyperinsulinemia, which may increase the secretion of pep-tide hormones such as leptin and adiponectin. These peptide hormones promote the proliferation and activation of natural killer cells, resulting in antitumor effects.²²

Recently, a large-scale prospective study of 226,505 patients with UTUC reported that HTN was related to UTUC by using univariate analysis. HTN are components of meta-bolic syndrome, which is involved in cancer development. HTN affects apoptosis, which regulates cell turnover in oth-er solid cancers. HTN also has a metabolic pathway asso-ciated with oxidative stress, another cancer-causing factor.²³

In this study, the patient with HTN and low-BMI showed higher recurrence rate than the patient with high-BMI and without HTN (67.6% vs. 47.4% p=0.013). Although, BMI and HTN is generally positively correlated, those factors can affect in a contradictory manner. A study showed that obese patients had lower mortality by cardiovascular and is-chemic heart disease than non-obese patients in hyper-tensive patients.²⁴ Like this research, BMI and HTN can act as independent variables and even obesity showed pro-tective effects in some studies regarding UTUC patients. But it is difficult to clearly describe underlying pathophysi-ology of this contradictorily looking phenomenon. This is considered to be a limitation, and further investigation would be needed.

Our study has several limitations. First, as a retrospective study, each patient had a different follow-up period, and various biases were generated, such as inability to adjust the treatment method for UTUC. Second, BMI and HTN were assessed just before surgery, but all patients who underwent surgery were not being treated for HTN, so it was unclear how well HTN was being treated and controlled. Third, the effect of HTN and BMI on OS and CSS in UTUC patients was investigated, but there was no statistically significant difference in this study. Despite these limitations, our paper suggests that HTN and BMI tend to relapse in UTUC. Therefore, further prospective studies are needed to inves-tigate the relationship between HTN, BMI, and UTUC.

Among UTUC patients who underwent RNUx, HTN ver-sus no-HTN was associated with worse RFS. Further, low-BMI (<24 kg/m²) was associated with worse RFS than high-BMI. Future prospective studies are required to vali-date our results, and basic or translational research should be conducted to determine potential mechanisms for the re-lationships between HTN, BMI, and UTUC.