Evaluation of histological variants of upper tract urothelial carcinoma as prognostic factor after radical nephroureterectomy

Purpose To evaluate the impact of variant histology on patients with upper tract urothelial carcinoma (UTUC) survival outcomes. Materials and methods A total of 519 patients underwent radical nephroureterectomy without neoadjuvant therapy for UTUC at a single institution between May 2003 and December 2019. Multivariate Cox regression analysis evaluated the impact of variant histology on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results Among 84 patients (16.2%) with variant histology, the most frequent variant type was squamous cell differentiation (64.3%), followed by glandular differentiation (25.0%) and sarcomatoid variant (2.4%). They showed pathologically advanced T stage (for ≥ T3, 59.5% vs 33.3%, p < 0.001), higher tumor grade (96.4% vs 85.7%, p = 0.025), and higher rates of lymph node metastasis (17.9% vs 7.8%, p = 0.015), angiolymphatic invasion (41.7% vs 25.7%, p = 0.003), tumor necrosis (57.1% vs 29.0%, p < 0.001) and positive surgical margin (13.1% vs 5.7%, p = 0.015). On multivariate Cox regression analyses, variant histology was significantly associated with worse PFS (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.55–3.21; p < 0.001), CSS (HR 2.67; 95% CI 1.35–5.30; p = 0.005) and OS (HR 2.22; 95% CI 1.27–3.88; p = 0.005). In subgroup analysis, no significant survival gains of adjuvant chemotherapy occurred in patients with variant histology. Conclusions Variant histology was associated with adverse pathologic features and poor survival outcomes. Our results suggest that patients with variant histology may require a close follow-up schedule and novel adjuvant therapy other than chemotherapy postoperatively. Supplementary Information The online version contains supplementary material available at 10.1007/s00345-024-04878-6.


Introduction
Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare genitourinary malignancy, occupying 5-10% of all urothelial carcinoma [1,2] while showing poor survival outcomes.Approximately one-third of patients with localized UTUC are reported to experience disease recurrence and cancer-related mortality [3,4] after radical nephroureterectomy (RNU) with ipsilateral bladder cuff excision, which is the gold standard treatment option for high-risk localized UTUC [5].Therefore, establishing potential or significant prognostic factors of UTUC is necessary for evidencebased decision-making or patient counseling.However, considering the rarity of UTUC, the potential prognostic factors might be extrapolated from those of bladder cancer.
In general, variant histology has been recognized as an adverse risk factor in patients with urothelial carcinoma of the bladder, achieving a consensus that variant histology presents a poor prognosis, especially in non-muscle invasive T1 bladder cancer [6].Therefore, it could be reasonable to suggest that variant histology might be associated with worse survival outcomes in patients with UTUC, which is histologically like bladder cancer [7].
However, the clinical importance of variant histology in patients with UTUC has not been well established compared with those with bladder cancer, partially due to the rarity of UTUC [1].The previous studies showed controversial results on the impact of concurrent variant histology on the prognosis of UTUC [8][9][10][11][12].Therefore, our study aims to evaluate the effect of variant histology on survival outcomes of UTUC after RNU.

Patients
A total of 519 patients who underwent RNU for UTUC between May 2003 and December 2019 were enrolled in our retrospective single-institution study.Exclusion criteria were patients with a history of muscle-invasive bladder cancer (MIBC), neoadjuvant therapy, distant metastasis before surgery, or incomplete medical records.In the final cohort, there were no patients with history of dialysis, solitary kidney, or conservative treatment for UTUC before RNU.The surgical method (open, laparoscopic, or robotic) was decided based on each patient's and surgeon's preference.Regional lymphadenectomy was performed in patients with suspicious lesions identified in preoperative imaging or those with enlarged lymph nodes intraoperative examination, while the surgeon's discretion determined the extent of lymphadenectomy.

Clinicopathologic data and survival outcomes
All surgical specimens after RNU were assessed in detail by a single genitourinary pathologist according to standard pathologic procedures.Pathologic stage and grade for UTUC were evaluated according to the 2002 American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) TNM classification and 1998 World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) consensus classification, respectively, as previously reported [13].Variant histology was evaluated according to the standardized diagnostic criteria described in the WHO classification of tumors [14].Clinicopathologic data included the patient's age at RNU, gender, body mass index (BMI), co-morbidity, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status scale, the previous history of gross hematuria, the presence of preoperative hydronephrosis, the laterality and location of the primary tumor, tumor stage, tumor grade, and the presence of angiolympathic invasion, concurrent carcinoma in situ (CIS), tumor necrosis and positive surgical margin.
The primary outcomes of this study included disease progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS), while the secondary outcomes were urothelial recurrence-free survival (URFS).Disease progression was defined as tumor recurrence in the surgical region, regional lymph nodes, and/or distant metastases.Distant metastasis was defined as recurrent disease detected by imaging outside the bladder or the contralateral upper urinary tract.Recurrence in the bladder or the contralateral upper urinary tract was defined as urothelial recurrence.OS and CSS were defined as the time from RNU to death from any cause and specifically from UTUC, respectively.PFS and URFS were defined as the time from treatment initiation to disease progression and urothelial recurrence, respectively.

Follow-up protocol
Patients who underwent RNU were followed up every 3 months for the first year, every 6 months from the second to fifth year, and annually after that.Follow-up examinations included history taking, physical examination, laboratory evaluation, urinary cytology, cystoscopy, and chest and abdomen/pelvic computed tomography (CT) scan based radiographic evaluations.Additional radiographic evaluations such as bone scintigraphy or MRI were performed when clinically indicated.Disease recurrence was identified based on radiography, endoscopy, or biopsy results.

Statistical analyses
All statistical analyses were performed using IBM SPSS version 27.0 (IBM Corp., Armonk, NY, USA).The test for normality was performed with the Shapiro-Wilk test.Continuous variables were expressed as median (interquartile range).Categorical variables are presented as percentages.Continuous variables were compared among groups using the Mann-Whitney U test, while categorical variables were compared using the Chi-square test or Fisher's exact test.The Kaplan-Meier method was used to analyze the effects of CT-based features on OS, CSS, PFS and URFS with a log-rank test.Univariate and multivariate Cox regression analyses were utilized to evaluate independent predictors for overall death, cancer-specific death, progression, and urothelial recurrence.Statistical significance was set at a two-tailed p-value < 0.05.

Results
The median age of all patients was 69 years, with a median follow-up duration of 46.0 months.Among 519 patients in our cohort, variant histology was present in 84 (16.2%) patients.The baseline clinical characteristics of pure UC and variant histology groups are shown in Table 1.The variant histology group showed a higher rate of hypertension (63.1% vs 50.1%, p = 0.029) and hydronephrosis (72.3% vs 60.0%, p = 0.035) preoperatively.However, other clinical features had no significant differences according to variant histology status.
To compare the efficacy of adjuvant chemotherapy in patients with variant histology, we initially compared baseline clinicopathologic features according to the performance of adjuvant chemotherapy, which showed no significant differences in general (all p > 0.05; Supplementary Table 2).There were no statistically significant differences in PFS (p = 0.775), URFS (p = 0.433), OS (p = 0.724) and CSS Fig. 1 Kaplan-Meier curves comparing disease progression-free survival (A), overall survival (B), and cancer-specific survival (C) after radical nephroureterectomy for upper tract urothelial carcinoma between the pure urothelial carcinoma group and variant histology group (p = 0.626) according to adjuvant chemotherapy among patients with variant histology (Supplementary Fig. 2).

Discussion
In the present study, 519 patients who underwent RNU for UTUC were enrolled to evaluate retrospectively the impact of variant histology on survival outcomes.Our result showed that the prevalence of variant histology was 16.2% among the patients who underwent RNU, similar to previous studies with a wide range from 7.5 to 40% [8,9,[15][16][17].The most frequent subtype of variant histology was squamous differentiation, followed by glandular differentiation and other variants congruent with results of previous studies [17].
In general, variant histology has been acknowledged to be associated with adverse features.According to our results, patients with variant histology showed significantly higher rates of hydronephroses preoperatively, which has been reported to be related to the aggressiveness of UTUC [18].For pathologic outcomes, patients with variant histology presented advanced T stage, higher tumor grade, and higher rates of lymph node metastasis, angiolymphatic invasion, tumor necrosis, and positive surgical margin, which have been well-recognized as adverse pathologic features [5].The previous meta-analysis study supports our data, showing that UC with variant histology is usually associated with advanced-stage necrosis and angiolymphatic invasion [2].These results suggest that variant histology might be related to other adverse pathologic features.
Recently, several studies have reported the effect of variant histology on prognostic outcomes in patients who underwent RNU for UTUC.However, the results of previous studies were somewhat controversial.Furthermore, several studies [8][9][10] advocated that variant histology was correlated with poor prognosis, while others [10,11] failed to show a significant association.Nogueira et al. reported that UTUC with variant histology was associated with advanced stage and poor survival.However, after adjusting for the pathologic T stage, variant histology was not significantly associated with CSS [16].
In our study, patients with variant histology were likely to show higher rate of disease progression, cancer-specific and overall mortality, but not urothelial recurrence and MIBC recurrence.After adjusting the other adverse pathologic features on multivariate Cox regression analyses, variant histology was identified as an independent risk factor for disease progression, cancer-specific mortality, and overall mortality after RNU, while was not associated with urothelial recurrence.Our results were consistent with those of the previous meta-analyses [2].Therefore, it would be reasonable to consider additional therapeutic options for patients with variant histology after RNU.There are several studies on adjuvant chemotherapy in UTUC patients with variant histology.However, those studies provided conflicting results.Chung et al. showed that the significant differences in OS, CSS, and recurrencefree survival between patients with pure UC vs variant histology disappeared after adjuvant chemotherapy, concluding that adjuvant chemotherapy improved survival outcomes in patients with UTUC with variant histology [9].Lo et al. [19] also reported that adjuvant chemotherapy provided significant survival benefits in CSS and disease-free survival for patients diagnosed with UTUC with variant histology.On the contrary, Rink and colleagues reported no significant differences in survival outcomes between pure UC and variant histology groups, despite variant histology correlated with adverse features [20].Kim et al. [8] also demonstrated that patients with variant histology still showed worse survival outcomes than those with pure UC after adjusting for other confounding features.In our cohort, there were generally no significant differences in baseline clinicopathologic features according to adjuvant chemotherapy status among patients with variant histology.However, adjuvant chemotherapy failed to show significant benefits in PFS, URFS, OS, and CSS among patients with variant histology.Our results suggest that novel adjuvant treatments other than chemotherapy might have to be considered for patients with variant histology.These results should be verified with a longer follow-up period and a larger population volume.
Our study had limitations, mainly due to the nature of the retrospective design.Considering that the present study was single institution based, the radiologic and pathologic evaluation protocol and surgical technique could be homogenous; however, the risk of selection bias could not be excluded.In addition, the comparison among subgroups of variant histology was not available due to the small number of cases.Further study involving a larger population is required.
Moreover, we could not assess the efficacy of the other adjuvant therapy besides adjuvant chemotherapy, such as radiotherapy or novel immunotherapy.Furthermore, the current study also could not include the results of ureteroscopic biopsy before RNU because most patients omitted preoperative ureteroscopic evaluation or biopsy.Therefore, we could not evaluate the diagnostic accuracy of ureteroscopic biopsy for variant histology, although it might be inferior in comparison with definitive pathologic results after RNU.

Conclusion
In our cohort, variant histology accounted for 16.2% of all UTUC patients who underwent RNU.Variant histology was associated with adverse pathologic features and poorer survival outcomes, such as overall survival, cancer-specific survival, and progression-free survival after adjusting other clinicopathologic factors.Adjuvant chemotherapy after RNU failed to provide significant survival gains for UTUC patients with variant histology.These results suggest that UTUC patients with variant histology may be recommended a close follow-up schedule and adjuvant therapy other than chemotherapy after RNU.

Table 1
BMI body mass index, DM diabetes mellitus, HTN hypertension, NMIBC Nonmuscle-invasive bladder cancer, ECOG PS Eastern Cooperative Oncology Group Performance status, UTUC upper tract urothelial carcinoma a Mann-Whitney U test b chi-square test c Fisher's exact test, Data presented are median (interquartile range) or number (%)

Table 2
UC urothelial carcinoma, CIS carcinoma in situ, MIBC muscle-invasive bladder cancer a Mann-Whitney U test b chi-square test c Fisher's exact test, Data presented are median (interquartile range) or number (%)

Table 3
CI confidence interval, BMI body mass index, DM diabetes mellitus, HTN hypertension, NMIBC Non-muscle-invasive bladder cancer, CIS carcinoma in situ

Table 4
Univariable and multivariable Cox regression analyses of factors associated with cancer-specific mortality in 519 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma OR odds ratio, CI confidence interval, BMI body mass index, DM diabetes mellitus, HTN hypertension, ECOG PS Eastern Cooperative Oncology Group Performance status, NMIBC Non-muscle-invasive bladder cancer, CIS carcinoma in situ

Table 5
CI confidence interval, BMI body mass index, DM diabetes mellitus, HTN hypertension, ECOG PS Eastern Cooperative Oncology Group Performance status, NMIBC Non-muscle-invasive bladder cancer, CIS carcinoma in situ