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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 51  |  Issue : 5  |  Page : 192-197

Small cell carcinoma of upper urinary tract: A pooled analysis of survival


1 Department of Urology, An-Nan Hospital; Department of Urology, School of Medicine, China Medical University, Taichung, Taiwan
2 Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Date of Submission24-Nov-2017
Date of Decision27-Feb-2018
Date of Acceptance19-Apr-2018
Date of Web Publication17-Oct-2018

Correspondence Address:
Prof. Tzong-Shin Tzai
Department of Urology, An-Nan Hospital, China Medical University, Tainan
Taiwan
Dr. Yuh-Shyan Tsai
Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan, 70403
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_170_17

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  Abstract 

Introduction: Small cell carcinoma (SCC) of upper urinary tract is not common and often associated with poor prognosis. We aimed to analyze the prognostic factors based on the pooled cases published in the literature.
Patients and Methods: In addition to 10 cases treated at our hospital since 1990, 52 additional published cases with SCC of renal pelvis and ureter were enrolled into this study. We investigated the following risk factors associated with clinical outcome: age at diagnosis, gender, tumor location, histology, tumor stage, and treatment modality using univariate log-rank test and multivariate Cox analyses.
Results: A total of 62 cases were enrolled into the study, including ten added by us. There were 30 cases from renal pelvis, 26 from the ureter, and 6 both sites. The mean age is 65.8 ± 13.0 years, and the median survival is 12 months. Patients with SCC of renal pelvis were significantly younger than did those of the ureter (P = 0.004), as well as higher stage (P = 0.043). Univariate analysis showed that both tumor stage and the presence of radiotherapy were significant predictors of disease-specific overall survival (P = 0.015 and 0.029, respectively), as well as the overall survival (P = 0.035 and 0.036, respectively). Cox's multivariate analysis showed tumor stage is an independent prognostic factor for disease-specific overall survival (hazard ratio, 2.11; 95% confidence interval, 1.08–4.13; P = 0.029).
Conclusions: In the current study, tumor stage is significantly associated with disease-specific overall survival. This finding warns us the importance of early diagnosis of SCC.

Keywords: Renal pelvis, small cell carcinoma, survival, ureter, urothelial neoplasm


How to cite this article:
Tzai TS, Tsai YS. Small cell carcinoma of upper urinary tract: A pooled analysis of survival. Formos J Surg 2018;51:192-7

How to cite this URL:
Tzai TS, Tsai YS. Small cell carcinoma of upper urinary tract: A pooled analysis of survival. Formos J Surg [serial online] 2018 [cited 2018 Nov 17];51:192-7. Available from: http://www.e-fjs.org/text.asp?2018/51/5/192/243582


  Introduction Top


Upper urinary tract tumors mean those tumors of renal pelvis or ureter. The majority of them are upper tract urothelial carcinoma (UTUC). In contrast, nonurothelial carcinoma is uncommon such as squamous cell carcinoma, adenocarcinoma, small cell carcinoma (SCC), etc.[1] There was an unusual higher incidence of UTUC in Taiwan, particularly in the resident of the southwest coast,[2] and recent research also pointed that aristolochic acid-related Chinese herb nephropathy is responsible for this phenomenon.[3] Several environmental factors may contribute to the formation of UTUC including exposure to tobacco or aromatic amines, consumptions of phenacetin or aristolochic acid-containing food or Chinese herbs.[3],[4],[5] Some are more specific for UTUC whereas others are similar to those associated with bladder cancer. In contrast, the incidence of upper tract SCC (UTSCC) of the renal pelvis, and ureter is rare and only case report or small case series were reported. Like those derived from the urinary bladder and prostate, the exact etiology of the UTSCCs is not known, in which the tumor cell may grow de novo from the multipotential undifferentiated stem cells of the urothelium or through transition from urothelial carcinoma.[6] Such molecular mechanism was postulated through the epigenetic changes rather than genetic damage.[7] Since UTUCs and bladder cancer are disparate twins,[8] it still requires more evidence to understand the real characteristics of UTSCCs at the clinical and molecular levels.

Nephroureterectomy with bladder cuff resection is the standard treatment for localized UTUC, and neoadjuvant or adjuvant, systemic chemotherapy with or without radiotherapy were for advanced or metastatic diseases. However, it is difficult for this rare UTSCC, to develop the treatment consensus without more clinical information. Therefore, we analyzed the prognostic factors based on the pooled cases published in the literature, together with our cases.


  Patients and Methods Top


Studied subjects

After obtaining the approval from Institute Ethical Committee's of National Cheng Kung University Hospital, patients with small cell carcinoma or neuroendocrine tumor of renal pelvis and ureter were enrolled in the study. The patient characteristics were retrieved from the chart record including age at diagnosis, resident area (black foot disease [BFD]-endemic area or not], gender, medical history, presenting symptoms, clinical or pathological staging, treatment modalities, histological patterns, and outcome.

We did a systematic review of original articles published or recorded in the PubMed, Google Scholar, and Embase® (updated to September 2017). A total of 40 articles (58 patients) were identified using the keywords “SCC,” “neuroendocrine tumor,” “renal pelvis neoplasm,” “ureter neoplasms” and “upper urinary tract neoplasm.” The number of patients was reduced to 52 due to the lack of survival data. Those identified in the same study or duplicate data by reviewing each paper were excluded from the current analysis. The patients' characteristics were retrieved including age at diagnosis, gender, medical history, presenting symptoms, clinical or pathological staging, treatment modalities, histological patterns, and outcome [Supplementary Table 1].



Statistical analysis

For comparisons, the difference of the clinical or pathological characteristics between patients from BFD-endemic and non-BFD-endemic area patients, or between renal pelvis and ureteral tumors, Chi-square or Fisher's exact test was used. Disease-specific overall survival and overall survival were calculated from the time of definite treatment (surgery, radiotherapy, chemotherapy or observation) to the patient's death according to the death cause using univariate log-rank test and multivariate Cox analysis.


  Results Top


Upper tract small cell carcinoma at National Cheng Kung University Hospital

From 1992 to 2015 December, a total of 10 UTSCCs were diagnosed and treated at our hospital [Table 1]. Five patients are residents of BFD-endemic area, where people with chronic arsenism were prevalent due to arsenic-containing drinking water before 1960. There were two tumors from renal pelvis tumor alone, and the other eight from ureter with or without other urinary tracts. The mean age is 76.7 ± 5.98 years, and the median survival is 13 months. Those patients from BFD-endemic area were female (P = 0.048). In contrast, 4 of five patients from non-BFD-endemic are male. In addition, the former is borderline older than the latter (P = 0.058). Except for age and gender, there was no difference between two groups.
Table 1: Patients' Characteristics of 10 small cell carcinoma of the upper urinary tract at National Cheng Kung University Hospital

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All the studies subjects

A total of 62 cases were enrolled into the study, including ten added by us. There were 30 cases from renal pelvis alone, 26 from the ureter, and 6 from both sites. The mean age is 65.8 ± 13.0 years, and the median survival is 12 months. There were 34 males, 27 females, and 1 unknown. The majority of the patients presented either with gross hematuria, flank pain or both and were diagnosed at advanced staging. Fifty-two of 62 patients (83.8%) received nephrectomy or nephroureterectomy with or without chemotherapy or radiotherapy. After nephroureterectomy, there were 13 patients receiving chemotherapy, 3 receiving radiotherapy, and 4 receiving chemoradiation. Three patients did not receive any treatment, and two of them died of metastatic disease 1 month after diagnosis. The other one died of myocardial infarction 4 months later. In addition to 6 unknown staging, there were 7 (11.3%) patients Stage I or II, 19 (30.6%) Stage III, and 30 (48.4%) Stage IV. Among the 62 cases, six patients exhibited distant metastases in addition to the primary tumor in the upper urinary tract. All of the enrolled SCC cases were reported as urinary tract origin. About 34 of 62 (54.8%) patients were diagnosed as pure SCC in histology, and the others are composed of urothelial carcinoma or other variants. Among these seven patients with localized tumors, four patients received radical nephrectomy alone, and none of localized disease died of disease. Until reported, 32 (51.6%) patients died of disease, 7 (11.3%) died of unrelated disease, 8 (12.9%) alive with disease, and 9 (14.5%) alive and free of disease. Patients with SCC of renal pelvis were significantly younger than did those of the ureter (P = 0.004), as well as higher stage (P = 0.043). There were no other significant differences between renal pelvis and ureteral tumors [Table 2].
Table 2: Patients' Characteristics of 62 small cell/neuroendocrine carcinoma of the upper urinary tract

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Regarding disease-specific overall survival, univariate analysis showed tumor stage is a significant prognostic factor (hazard ratio [HR], 3.44; 95% confidence interval [CI], 1.23–9.67; P = 0.015), as well as the presence of radiotherapy (HR, 0.34; 95% CI, 0.20–0.89; P = 0.029). Cox's multivariate analysis showed only tumor stage is an independent prognostic factor for disease-specific overall survival (HR, 2.11; 95% CI, 1.08–4.13; P = 0.029). Regarding overall survival, univariate analysis showed tumor stage is a significant prognostic factor (HR, 2.71; 95% CI, 1.03–7.15; P = 0.035), as well as the presence of radiotherapy (HR, 0.43; 95% CI, 0.23–0.90; P = 0.036). Cox's multivariate analysis showed only tumor stage is a borderline significant prognostic factor for overall survival (HR, 1.71; 95% CI, 0.97–2.99; P = 0.062) [Table 3] and [Figure 1].
Table 3: Univariate and multivariate analyses of variables associated with survival in 62 small cell carcinoma of upper urinary tract

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Figure 1: Effect of tumor stage and radiotherapy on patients' outcome. Proportion of disease-specific overall survival according to tumor stage (a) or the presence of radiotherapy or not (c). Proportion of overall survival according to tumor stage (b) or the presence of radiotherapy or not (d). RT: Radiotherapy

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  Discussion Top


In the current study, we demonstrated that patients with SCCs of renal pelvis had significantly younger age and higher tumor staging than did those of the ureter. Patients living in BFD-endemic area exhibited borderline older age than did those living in non-BFD-endemic area. In addition, there is gender difference of the patients between these two areas. In general, tumor staging is an independent prognostic factor for disease-specific overall survival in patients with UTSCCs. Until recently, there is no report regarding the survival analysis in this rare disease. Our study warns the importance of early diagnosis in patients with UTSCCs and the urgent need of understanding the etiology.

Conventionally, extrapulmonary SCCs detected outside the lungs, including the bladder, prostate, and colon was suggested to be treated as metastatic disease, even if there is no evidence of disease in other sites.[9] Owing to the characteristics of chemosensitivity and the potential of metastasis, bladder preservation therapy with multimodal therapy was the most used for localized or locally advanced urinary bladder SCCs based on the American National Cancer Database. Despite this, those receiving neoadjuvant chemotherapy followed by radical cystectomy exhibited the best survival,[9] which highlights the importance of regional control. Unlike the urinary bladder SCCs, UTSCCs may not easily be differentially diagnosed from urothelial carcinoma before nephrectomy owing to a tiny specimen obtained from ureterorenoscopic biopsy or percutaneous needle biopsy. For operable disease, radical nephrectomy or nephroureterectomy will be done first, rather than neoadjuvant chemotherapy. Although SCC is chemosensitive,[10] subsequent relapse is frequent despite of either adjuvant systemic chemotherapy or systemic chemotherapy alone in the current study. Our survival analysis did not support systemic chemotherapy as a favorable prognostic factor. In contrast, our data demonstrated the utility of radiotherapy might be a favorable prognostic factor since the statistical significance was found in univariate analysis rather than in multivariate analysis. The possible reason is that radiotherapy might provide loco-regional control of disease and improve the survival.[11] Therefore, further investigation is still required for this rare disease.

Our data showed that there is a significant difference regarding age and initial staging at diagnosis between renal pelvis and ureteral SCCs. Only few patients had a durable disease-free status of more than one decade, and some of them received surgery alone. Although the exact etiology is not known, the majority of SCCs detected from each site were at advanced stage with a short survival. UTSCC patients with a history of chronic arsenic exposure were female; in contrast, four of five without arsenic exposure were male. The former was older. Moreover, patients with ureteral tumors usually older than those with renal pelvis tumors. This evidence hint their etiology might be varied. Actually, tumor cells may undergo evolution following environmental stimuli, or as a result of selection pressure of any forms of therapies.[12] The progress of genomic sequencing provide an insight regarding the molecular pathogenesis of neuroendocrine tumors, including de novo formation or a lineage plasticity in response to environmental pressure.[7],[13] Regarding prostate cancer, only a few patients were neuroendocrine carcinoma at initial diagnosis, the majority of prostate neuroendocrine or SCC developed and was detected at advanced diseases after androgen privation therapy, in which the epigenetic modulation is responsible for such evolution.

Conventionally, theories regarding the SCC origin included cells derived from a Kultschitzky-type cell or from cells that do not normally exist in the urinary bladder mucosa.[14] Evidence from molecular genetic analysis showed that there is a common clonal origin of coexisting SCC and UC components of the urinary bladder, suggesting that the cell origin was an undifferentiated, multipotential cell, or stem cell.[6] Besides, there were high frequencies of loss of heterozygosity in p16 (9p21), VHL (3p25–26), DBC1 (9q32–33), and TP53 (17p13)[6],[15] and a high incidence of promotor region methylation of RASSSF1, MLH1, DAPK1, TERT, and MGMT tumor suppressor genes.[16] On the other hand, positive GATA3 immunostaining was detected immunohistochemically in 32% of tumors, which is lower than in UC.[17] Owing to the rarity, it is lack of molecular genetic data of UTTSCCs. Despite this, our data showed that about half of the tumors were mixed SCCs in histology, which has no impact on the survival.

There were several limitations in the current study. First, this is a retrospective study that collected from the published case series or reports. It would reduce the consistency of data due to a great heterogeneity regarding diagnosis and treatment. For example, all of the reported and our own cases were diagnosed according to the microscopic characteristics with various and inconsistent immunohistochemical evidence, such as CD56, chromogranin, or synaptophysin. The majority of the case reports or series did not describe how to confirm the origin of SCC. They were presumed from renal pelvis instead of renal parenchyma probably based on the theory that SCC may de novo derive or transdifferentiate, from the urothelium. Second, owing to the small number of patients, it is difficult to make strong conclusion. Despite this, about half of cases died of disease based on publication, there were three parameters that could be used for multivariate analysis. Third, we did not enroll some promising markers for analysis due to the inconsistency or different methodology. It may lose some useful information. Fourth, it is difficult to see any difference between BFD series and non-BFD series based on the limited patients. In addition, it is currently difficult to investigate molecular difference using the limited paraffin-embedded archived tissues. Further genomic studies will be required after collecting enough samples.


  Conclusions Top


In the current study, tumor staging is significantly associated with disease-specific over survival in patients with UTTSCCs. This finding warns us the importance of early diagnosis. Owing to the rarity, it still requires more studies investigating the molecular pathogenesis and treatment outcome.

Acknowledgment

This project was supported by grants of An-Nan hospital, Tainan, Taiwan (ANHRF106-01).

Financial support and sponsorship

This project was supported by grants of An-Nan hospital, Tainan, Taiwan (ANHRF106-01).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester R, Burger M, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013;63:1059-71.  Back to cited text no. 1
    
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Chou YH, Huang CH. Unusual clinical presentation of upper urothelial carcinoma in Taiwan. Cancer 1999;85:1342-4.  Back to cited text no. 2
    
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Lai MN, Wang SM, Chen PC, Chen YY, Wang JD. Population-based case-control study of Chinese herbal products containing aristolochic acid and urinary tract cancer risk. J Natl Cancer Inst 2010;102:179-86.  Back to cited text no. 3
    
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Colin P, Koenig P, Ouzzane A, Berthon N, Villers A, Biserte J, et al. Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary tract. BJU Int 2009;104:1436-40.  Back to cited text no. 4
    
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Hoang ML, Chen CH, Sidorenko VS, He J, Dickman KG, Yun BH, et al. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med 2013;5:197ra102.  Back to cited text no. 5
    
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Cheng L, Jones TD, McCarthy RP, Eble JN, Wang M, MacLennan GT, et al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol 2005;166:1533-9.  Back to cited text no. 6
    
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Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016;22:298-305.  Back to cited text no. 7
    
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Green DA, Rink M, Xylinas E, Matin SF, Stenzl A, Roupret M, et al. Urothelial carcinoma of the bladder and the upper tract: Disparate twins. J Urol 2013;189:1214-21.  Back to cited text no. 8
    
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Thota S, Kistangari G, Daw H, Spiro T. A clinical review of small-cell carcinoma of the urinary bladder. Clin Genitourin Cancer 2013;11:73-7.  Back to cited text no. 9
    
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Quek ML, Nichols PW, Yamzon J, Daneshmand S, Miranda G, Cai J, et al. Radical cystectomy for primary neuroendocrine tumors of the bladder: The university of Southern California experience. J Urol 2005;174:93-6.  Back to cited text no. 10
    
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Koay EJ, Teh BS, Paulino AC, Butler EB. Treatment trends and outcomes of small-cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 2012;83:64-70.  Back to cited text no. 11
    
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Nowell PC. The clonal evolution of tumor cell populations. Science 1976;194:23-8.  Back to cited text no. 12
    
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Rickman DS, Beltran H, Demichelis F, Rubin MA. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat Med 2017;23:1-0.  Back to cited text no. 13
    
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Cramer SF, Aikawa M, Cebelin M. Neurosecretory granules in small cell invasive carcinoma of the urinary bladder. Cancer 1981;47:724-30.  Back to cited text no. 14
    
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Pan CX, Zhang H, Lara PN Jr., Cheng L. Small-cell carcinoma of the urinary bladder: Diagnosis and management. Expert Rev Anticancer Ther 2006;6:1707-13.  Back to cited text no. 15
    
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Abbosh PH, Wang M, Eble JN, Lopez-Beltran A, Maclennan GT, Montironi R, et al. Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder. Mod Pathol 2008;21:355-62.  Back to cited text no. 16
    
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Wang X, MacLennan GT, Lopez-Beltran A, Cheng L. Small cell carcinoma of the urinary bladder – Histogenesis, genetics, diagnosis, biomarkers, treatment, and prognosis. Appl Immunohistochem Mol Morphol 2007;15:8-18.  Back to cited text no. 17
    


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