On the Epidemiology, Diagnosis and Treatment of Upper Tract Urothelial Carcinoma
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Aims: The overall aim of this thesis was to increase our knowledge about the epidemiology, diagnostics and treatment of upper tract urothelial carcinoma (UTUC). For paper 1, the aim was to obtain contemporary knowledge about UTUC incidence, UTUC tumour and patient characteristics, and possible changes over time using national, population based data. For paper 2 and 3, the aim was to evaluate current standard diagnostics before radical nephroureterectomy (RNU), and see if our findings could be used for selecting patients for intensified treatment. Further, we aimed to evaluate a previously published diagnostic model through an external validation. For paper 4, we aimed to evaluate the outcomes of endoscopic treatment for UTUC given at our hospital with particular emphasis on tumour grade. Materials and methods: For paper 1, the study population included all patients registered with an International Classification of Diseases tenth version (ICD-10) diagnosis code C65 (cancer of the renal pelvis) and C66 (cancer of the ureter) at the Norwegian Cancer Registry (NCR) during 1999-2018. After an inclusion/exclusion process, 3096 cases of verified UTUC in 2818 patients were included in the study. For purpose of comparisons with other urothelial cancers and renal cell carcinoma (RCC), 24467 cases of bladder cancer (BC), 287 cases of urethral cancer, and 13619 cases of RCC were drawn from the same main database during the same time period. Statistical analyses were performed to calculate UTUC age standardized rates (ASR), UTUC incidence rates compared to other urothelial cancers and RCC, and to look for possible changes over time regarding incidence rates, epidemiological variables and survival. For paper 2 and 3, all patients treated with a RNU for UTUC at Haukeland University Hospital and Vestfold Hospital Trust during 2005-2017 were evaluated. After an inclusion/exclusion process, 179 patients were included in the study. For paper 2, all available preoperative features regarding the patients, the CT scan and the ureteroscopy (URS) were analysed regarding their abilities to predict tumour stage and survival. Further analyses were performed to evaluate if our findings could be used to select patients for intensified treatment. For paper 3, 162 of the 179 patients had complete dataset needed for external validation of the published Margulis nomogram and were included in the study. An external validation assessing both model calibration and discrimination was performed. For paper 4, 43 patients treated endoscopically with curative intent at Haukeland University Hospital 2001-2012 were included. Statistical analyses were performed regarding survival, kidney protections rates and recurrence both for the whole cohort and stratified by indication for treatment and tumour grade. Results: Paper 1. The ASR according to the European standard population was 3.88 for the whole period, increasing significantly from 3.21 to 4.70 from the first to last five-year period, corresponding to an estimated annual increase of 2.5%. The proportion of UTUC compared to all urothelial cancers and RCC significantly increased. UTUC constituted 12.6% of all urothelial cancers in Norway during 2014-2018. Mean age at diagnosis increased from 71.8 to 73.9 years during the study period. The 5-year overall survival (OS) increased moderately over time from 44.3% to 51.7% comparing last decade with the first. In paper 2, we found that local invasion and the presence of pathological lymph nodes at CT predicted both tumour stage at final pathology and survival in uni-and multivariate regression analyses. These variables can be used when selecting patients for intensified treatment. Diagnostic URS has a limited role in preoperative tumour staging. In paper 3, we found an overall high concordance between predicted risk of non-organ confined disease using the Margulis nomogram, and the observed risk in our cohort. The accuracies of both the predicted and observed risks were 0.83 to indicate adequate model discrimination. The calibration was assessed in a scatter plot where the overall concordance was high, quantified with a Cronbach Alpha of 0.96. There seems to be a mis-calibration at the low-risk levels. In paper 4 we found that the five –year disease specific survival (DSS) of patients treated endoscopically with an elective indication or for a low grade tumour (according to the World Health organization (WHO) classification from 2004) was high (DSS 94% and 96% respectively). The survival of patients treated with an imperative indication or for a high-grade tumour were significantly lower (DSS 41% and 39% respectively). 25 of 43 patients were assessed as tumour free at one point during follow-up, and the five-year recurrence free survival among these patients were 76%. The five-year kidney protection rate (KPR) for patients with low-grade tumours was 60%. The KPR for patients tumour free at first follow-up (14 of 43), was 90%. Conclusions: The incidence of UTUC in Norway was higher than expected, and increasing. Patient age at diagnosis is increasing. Local invasion and pathological lymph nodes at CT can predict tumour stage and survival after RNU, and can be used when selecting patients for intensified treatment. The Margulis nomogram is considered validated for clinical use. Tumour grade according to the WHO classification from 2004 is a strong predictor of outcomes after endoscopic treatment for UTUC, and should be considered when selecting patients for this treatment modality.
Has partsPaper I: Almås B, Halvorsen OJ, Johannesen TB, Beisland C. Higher than expected and significantly increasing incidence of upper tract urothelial carcinoma. A population based study. World journal of urology 2021. The article is available at: https://hdl.handle.net/11250/2767114
Paper II: Almås B, Øverby S, Halvorsen OJ, Reisæter LAR, Carlsen B, Beisland C. Preoperative predictors of pathological tumour stage and prognosis may be used when selecting candidates for intensified treatment in upper tract urothelial carcinoma. Scandinavian journal of urology 2021; 55(2):100-107. The article is available at: https://hdl.handle.net/11250/2767020
Paper III: Almås B, Øverby S, Halvorsen OJ et al. Tumour architecture, grade and location remain predictors of non-organ-confined upper tract urothelial carcinoma at time of radical nephroureterectomy: results from a multicenter Norwegian external validation study. World journal of urology 2020; 38:717-23. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1007/s00345-019-02813-8
Paper IV: Almås B, Halvorsen OJ, Gjengstø P, Ulvik Ø, Beisland C. Grading of urothelial carcinoma of the upper urinary tract according to the World Health Organization/International Society of Urological Pathology classification from 2004 is a valuable tool when considering whether a patient is suitable for endoscopic treatment. Scandinavian journal of urology 2016; 50:298-304. The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.3109/21681805.2016.1144220