Prognostic factors and treatment impact on overall survival in patients with renal neuroendocrine tumour

Abstract Background Renal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates. Objective The objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN. Design, setting and participants We identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival. Results and limitations Of 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p < 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03–1.06; p < 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96–5.1; p < 0.001), NEC‐NOS histology (HR, 2.82; 95% CI, 1.64–4.86; p < 0.001), LC‐NEC histology (HR, 2.73; 95% CI, 1.04–7.17; p = 0.041) and SC‐NEC histology (HR, 5.17; 95% CI, 2.95–9.05; p < 0.001) were all positive predictors of worsening overall survival. The main limitation of the study is its retrospective design. Conclusion R‐NEN is an aggressive tumour characterized by high mortality rates. Surgery continues to be the mainstay of treatment and has shown to provide a survival benefit for most patients. Patient Summary R‐NEN is composed of several tumour histologies that differ based on their aggressiveness with NEC‐NOS and SC‐NEC being the most lethal. Surgery, predominantly through minimally invasive approaches, is the mainstay of treatment and has a clear survival benefit.


| INTRODUCTION
Neuroendocrine neoplasms (NEN) are rare tumours with reported age-adjusted incidence of 7 out of 100 000 individuals in the United States. 1,2NENs are composed of tumours linked by histological markers that can arise in any organ, including those that do not harbour neuroendocrine cells. 3The most common primary sites for NENs are the gastrointestinal tract, lungs and the pancreas. 4,5These tumours have been difficult to characterize due to their varying biologic behaviour, histology and treatment response. 3,6][9][10] They can be broadly classified as either well-differentiated neuroendocrine tumours (NET) or poorly differentiated neuroendocrine carcinomas (NEC). 11Renal NEC can further be subdivided into large cell neuroendocrine carcinomas (LC-NEC) or small cell neuroendocrine carcinomas (SC-NEC). 3,6ere is a paucity of data on primary R-NEN with most of the current literature composed of small case series or individual case reports. 9,12Thus, there is a need for population-based data to understand treatment trends and overall survival for patients with R-NEN in hopes of better characterizing which patients may benefit from specific treatments based on their underline histology.We present the largest population-based study of patients with primary R-NEN, characterize treatment options and provide predictors of worsening overall survival.

| Study population
The National Cancer Database (NCDB) was queried from 2004 to 2019 to identify adult patients with R-NENs.The clinical oncology database consists of data collected from over 1500 accredited hospitals across the United States and reports approximately 72% of newly diagnosed cases in the country.Primary site code C64.9 (Kidney, NOS) was used to identify 668 400 cases of renal cancer.

| Variables studied
The following variables were extracted and analysed: • Baseline characteristics: age at diagnosis, sex, race, Hispanic ethnicity, insurance status, rural or urban classification, treatment facility type and Charlson-Deyo score.
• Tumour characteristics: histological classification, tumour size, laterality and AJCC clinical stage at diagnosis, sites of metastasis.
• Treatment details: surgical intervention, treatment with chemotherapy, radiation or immunotherapy, type of surgery, timing of surgery, surgical approach and time from diagnosis to surgery.

| Statistical analysis
Baseline characteristics were tabulated for all R-NEN patients.A median and an interquartile range were calculated for continuous variables, while absolute numbers and proportions were reported for categorical variables.Kaplan-Meier analysis was used to estimate 1-, 3-, 5-

| DISCUSSION
Studies have shown an increased incidence and prevalence of NEN in the last decade, yet primary R-NEN remains a poorly understood subset due to its rarity. 1 This study represents the largest populationbased investigation of this rare tumour.Our study shows that a The origin of R-NEN is still unclear, as there are no known neuroendocrine cells within the renal parenchyma. 3Studies suggest that R-NEN precursor cells arise from renal stem cells that develop towards neuroendocrine differentiation. 12Previous studies suggest that metastasis is common at the time of diagnosis, typically to the liver or regional lymph nodes, even in patients with well-differentiated tumours. 4,84][15] R-NENs often share features found in others NENs including immunohistochemical expression of chromogranin A and synaptophysin.Yet studies have shown that they have highly variable mutational profiles and their oncologic potential can be quite heterogenous, making it difficult to predict outcomes based on histology alone. 11Overall, studies have confirmed that well-differentiated R-NENs tend to have better outcomes than those with poorly differentiated features, but information on survival outcomes based on histological subtype is still lacking. 3ere have been no clinical trials establishing treatment guidelines for R-NENs.Current treatment options are extrapolated from renal cancers and neuroendocrine cancers alike.First-line treatment for localized R-NEN is often nephrectomy with lymph node dissection. 16For those with metastatic R-NENs, systemic treatments used for other neuroendocrine tumours such as peptide-receptor radio

and 10 -
year OS estimates for R-NEN patients along with mean and median OS.Survival times represented the months elapsed from diagnosis to death.Additional Kaplan-Meier survival curves were generated to compare survival outcomes based on overall AJCC stage at diagnosis, AJCC T stage at diagnosis, histologic subtype and the presence of surgical intervention.Log-rank tests were used to detect significant differences in survival between groups.Case-control matching was used to compare overall mortality between patients diagnosed with R-NEN and clear cell renal cell carcinoma (ccRCC).Patients with ccRCC were identified in the NCDB database using the histological code 8310/3.R-NEN and ccRCC cohorts were matched on age, sex, AJCC T stage, and Charlson-Deyo score.Predictors of OS were evaluated via a univariate and multivariate Cox proportional hazard model.SPSS Statistics Version 28 (IBM Corp., Armonk, N.Y., United States) was used for all analyses, with a two-tailed alpha of 0.05 indicating significance.

F I G U R E 1
Kaplan Meier curve on overall survival in patients with R-NEN.Notches on lines indicate censored cases.F I G U R E 2 Kaplan Meier curve on overall survival in patients with R-NEN separated by histologic subtype: NET versus NEC.NET was defined as Grade 1 or 2 neuroendocrine tumours; NEC was defined as large cell, small cell or NOS neuroendocrine carcinoma.Notches on lines indicate censored cases.majority of these tumours are treated in academic centres or comprehensive community cancer programmes.Most of these tumours are treated with surgery though 30% of patients underwent chemotherapy, and 13% had radiation.The median overall survival for patients in our series with R-NEN was 44 months.There was a significant difference in overall survival between patients who underwent surgery and those who pursued more conservative treatments (136.61months vs. 7.89 months).Increased age, higher stage, NEC-NOS histology, LC-histology and SC-NEC histology were all predictors of worsening overall survival.

F I G U R E 3
Kaplan Meier curve showing probability of overall mortality in patients with R-NEN versus clear cell RCC after matching.Cases matched on age, sex, AJCC T stage and Charlson-Deyo score.Notches on lines indicate censored cases.F I G U R E 4 Kaplan Meier curve on overall survival for patients based on surgical intervention.Hazard ratio (HR) is for overall mortality.Notches on line indicate censored data.