Squamous Cell Malignancies of the Upper Urinary Tract : A Survival Study and a Systematic Review of the Literature

Neoplasms of the upper urogenital tracts involving the renal pelvis and ureter are defined as any neoplastic growth involving the lining of the urinary tract from the renal calyces to the ureterovesical junction [1]. These tumors are rare representing less than one percent of genitourinary malignancies [2,3]. The incidence of neoplasms of the upper urinary tract in the United States has increased slightly over the last 20 years from an annual incidence of 0.69 to 0.73/1000,000 person years from 1973 to 1996 [4]. The paucity of cases makes it difficult to establish a standard of care for these malignancies and the prognosis remains poor. Squamous cell histology represents only a small fraction of the total number of malignancies of the upper urinary tract (UUT). Most of our knowledge about these rare malignancies originates from anecdotal evidence and squamous cell histology, has been associated with a poor prognosis in early reports [5-10]. Several studies have challenged this assumption. We present one of the largest registry studies and systematic literature reviews of UUT malignancies to date and investigate the impact of squamous cell histology on overall and cancer specific survival.


Introduction
Neoplasms of the upper urogenital tracts involving the renal pelvis and ureter are defined as any neoplastic growth involving the lining of the urinary tract from the renal calyces to the ureterovesical junction [1]. These tumors are rare representing less than one percent of genitourinary malignancies [2,3]. The incidence of neoplasms of the upper urinary tract in the United States has increased slightly over the last 20 years from an annual incidence of 0.69 to 0.73/1000,000 person years from 1973 to 1996 [4]. The paucity of cases makes it difficult to establish a standard of care for these malignancies and the prognosis remains poor. Squamous cell histology represents only a small fraction of the total number of malignancies of the upper urinary tract (UUT). Most of our knowledge about these rare malignancies originates from anecdotal evidence and squamous cell histology, has been associated with a poor prognosis in early reports [5][6][7][8][9][10]. Several studies have challenged this assumption. We present one of the largest registry studies and systematic literature reviews of UUT malignancies to date and investigate the impact of squamous cell histology on overall and cancer specific survival. around the country. Trained abstractors collect data on patient age, sex, site, histological findings, tumor grade, and stage from hospital records, outpatient clinics, radiation centers, private laboratories and physician offices. For coding purposes the ICD-O-3 classification was used [12].

Patients
Patients were eligible if they presented between 1973 and 2004 with a malignancy of the renal pelvis or ureter (site coding C65.9 and C66.9). Only patients with a clearly malignant coded phenotype were included. The primary exposure of interest was the underlying histology. Histologies were subdivided into squamous cell (SC), transitional cell (TC), (including the papillary subtype) and other histologies (OT) (mainly small cell, sarcomatoid and undifferentiated carcinomas). The primary outcome of interest was cancer specific survival. We also examined overall survival and performed sensitivity analyses, excluding and right censoring patients who died from causes other than UUT malignancies. Since survival prognosticators in UUT malignancies are poorly delineated, we examined race, prior surgery and radiotherapy, decade of diagnosis, age at diagnosis, gender, preceding malignancies and stage as potential predictors of the primary outcome and cancer specific survival. Race was coded as Caucasian, Black, Hispanic or Asian/other. The other category included mainly smaller Asian subpopulations and the indigenous population of the Western hemisphere. Decade of diagnosis was coded into the 70s, 80s, 90s and 2000s, while the age group was subdivided into 49 or younger, 50 to 75, and older than 75 years of age at diagnosis. Prior therapies were classified as having been received or not. Secondary to coding issues, we utilized the traditional American Joint Committee on Cancer (AJCC) staging classification, which entails the following stages: in situ, local, regional and distant. The regional stage included patients with extension beyond the ureter or renal pelvis and patients with documented lymph node involvement.

Statistical methods
We examined descriptive statistics to describe demographic composition of the study population and distribution of the other relevant predictors of the outcome. Univariate Kaplan Meier survival analysis was performed to investigate which variables were of predictive relevance. In our cancer specific survival analysis, the patients who died from a cause other than a malignancy of the upper urinary tract were right censored. Differences along the strata of predictors of interest were evaluated using a log rank test. If the log rank test was statistically significant, the covariates were retained in the final model. In the final model ,we performed Cox proportional hazards regression to determine hazard ratios [13]. Post-estimation diagnostics were performed to analyze if the proportional hazard assumptions were violated, using graphical and computational methods [14]. All analyses were performed using STATA 9.0 (College Station, TX).

Systematic literature review
We identified 41 studies that met the pre-specified criteria for further review. Only five of them provided information to compare the features of squamous cell carcinoma of the upper urinary tract (SCC-UUT) with other histologies in the same location. One of them compared the outcome of SCC-UUT with other rare histologies [5] and one did not provide sufficient information to compare survival as an outcome measure [15]. The remaining three studies included two single institution retrospective reviews and one high quality registry study comparing the survival of SCC-UUT and transitional cell carcinomas of the upper urinary tract (TCC-UUT) [16][17][18].
The reported results were mixed. The study from Virginia reported a disease specific mortality rate for patients with SCC-UUT of 77% versus only 46%17 for patients with TCC-UUT. The study from Scandinavia reported even less encouraging results for patients with SCC-UUT. The five year overall survival and 1 year post nephrectomy death rate for patients with SCC-UUT were 7% and 67%, respectively, against 56% and 22% for TCC-UUT [18]. In contrast, a large scale, high quality registry study from Sweden which included 743 patients with transitional cell and 65 with squamous cell histology, revealed comparable outcome results for patients with SCC-UUT and TCC-UUT, when equal stages were compared. The particular strength of this study was a central pathology review process of the majority of the specimens and the availability of clinical details from review of hospital records [16]. Table 1 depicts the patient characteristics and outcome results of selected studies, included into our review.

Patients
We identified 13,213 patients with malignancies of the UUT in our registry study. One hundred and ninety nine patients had squamous cell malignancies of the UUT and 12,395 had transitional or papillary histology. Baseline characteristics by histology are displayed in Table  1. Transitional carcinomas and other histologies demonstrated a male gender predominance, while the gender distribution for squamous cell carcinomas was equally balanced. Appropriate lymph node sampling in surgically resected cases was consistently reported in less than twenty percent, an observation that has persisted into the 21st century. Patients with squamous cell malignancies were more likely to present with regional (p<0.01) and distant (p<0.01) disease, while TCC had a higher likelihood to present at a local (p<0.01) or in situ stage (p<0.01). Patients with squamous cell histology were less likely to undergo radiation therapy (p<0.01) and surgery (p<0.01) ( Table 2).

Survival
At the time of our analysis approximately 56% of patients with squamous cell malignancies of the upper urothelial tract had died from their underlying malignancies. The death rate from bladder tumors was consistently less than or equal to 1% (2 in the squamous cell group and 93 in the TCC group). The overall survival for patients who presented with UUT squamous cell cancer was significantly worse than for TCC (see Kaplan Meier graph A in graph 1). We examined race, prior surgery and radiotherapy, decade of diagnosis, age at diagnosis, gender, preceding malignancies and stage as other potential predictors of outcome and retained them in our final Cox proportional hazard (Cox PH) model if they had a significant impact on survival on univariate, non parametric analysis. We retained race, prior surgery and/or radiotherapy, decade of diagnosis, age at diagnosis, gender and stage in our final model. Of note is that the covariate stage was introduced as described above, utilizing the above described staging classification, which collapses extension beyond the organ (renal pelvis or ureter) and local lymph node involvement into regional disease. We performed Cox proportional hazard modeling for cancer specific survival, adjusting for race, prior surgery and radiotherapy, decade of diagnosis, age at diagnosis, gender, preceding malignancies and stage. We then examined the survival difference for regional and metastatic disease across the three different histologies. As graphically illustrated in Kaplan Meier graph C, no significant difference in survival was established for patients presenting with metastatic disease. The major difference in survival is most notable in the patient group presenting with regional stage disease (graph B). *The percentage figure refers to the total amount of cases in the regional disease category. The table above displays the distribution of clinically relevant disease characteristics for patients with UUT malignancies across the different histologies, i.e. transitional cell, squamous cell and others( mainly small cell, sarcomatoid and undifferentiated carcinomas).  As outlined in table 1 of the 4,499 patients with regional disease only 1,316 patients obtained appropriate lymph node sampling (26 with squamous, 2,232 with transitional cell and 58 with other histological subtype). In the group of patients with regional TCC, survival was significantly decreased in patients with positive lymph nodes (p<0.01) (graph D). In the small group of patients with SCC only a trend but no statistically significant survival difference could be observed in the patients with positive or absent lymph node involvement ( p=0.63) (graph E) ( Table 3) (Figure 1).

Discussion
Malignancies of the upper urinary tract are rare malignancies. The carcinomas of the renal pelvis has first been described by Rayer in 1841 and Hedenius published in 1878 the first specific case of squamous cell carcinoma of the upper urinary tract(UUT) [1]. Grace recommended almost half a century ago a radical uteronephrectomy with a thorough sampling of the loco-regional lymph nodes as most appropriate treatment for carcinomas for UUT [19].
One of our previous analyses suggested a relevance of the locoregional lymph node status for the outcome of patients with carcinomas of the UUT [20]. Hence, we present the largest registry based study of squamous cell malignancies of the upper urothelial tract to date and contextualize the results with findings in the literature with a specific focus on the data on loco-regional lymph node status.
Most previously published reports regarding the outcome of patients with SCC of the UUT are case reports or small series [5][6][7][8]10]. Two retrospective single institution studies compared the outcome of patients with SCC-UUT and TCC-UUT. Unfortunately none of these studies provided detailed information about the loco-regional extent and lymph node involvement [17,18]. The largest study published to date is a retrospective registry study from Sweden [16]. This Swedish study included 743 patients with transitional cell and 65 with squamous cell histology included a central review process of the majority of the resected specimens and reviewed clinical details from hospital records [16].
Our study reveals several interesting findings. First, SCC of the UUT present on average with more advanced stages when compared to TCCs. This can probably be explained by a more aggressive biology and a lower incidence of clinical warning signs, such as hematuria, in patients with SCC. Second, the overall survival for patients diagnosed in the US with SCC of the UUT is dismal and overall inferior to patients with TCC. Third, stage for stage the survival difference between squamous and transitional histologies is less pronounced. This is in accordance to the prior Swedish study by Holmang et al. [16], which demonstrated an equally poor prognosis for both tumor types when only advanced stages were considered. Holmang et al. [16] observed a trend towards a decreased survival in patients with pT3 with SCC that did not reach statistical significance (p=0.099). In our study the survival difference at six and twelve months after diagnosis did reach statistical significance. This is largely due to the greater number of observed events thus resulting in a higher statistical power in our study. Fourth, our study demonstrates that patients with TCC involving the regional lymph nodes fare significantly worse than patients with disease extending beyond the organ. Interestingly, this survival difference is less pronounced in patients with SCC and regional disease. Unfortunately, the paucity of data on patients in our registry with SCC and regional disease of the UUT and the large fraction of patients with inadequate lymph node sampling does not allow for a firm conclusion regarding the prognostic relevance of local lymph node status in patients with SCC of the UUT.
Our study has several shortcomings. First, the SEER registry obtains information from medical charts and, therefore, the registry data can only be as accurate as the medical record from which it is obtained. Second, clinical history and comorbidities cannot be obtained from the SEER registry. This might have introduced a bias of differential attrition across the different histological subtypes into our study. In addition, the SEER registry provides insufficient information about the extent of post-operative therapy. Several studies have suggested some benefit from adjuvant chemotherapy [21][22][23][24][25][26][27] and no information about this modality is available in the SEER registry. Although information about post-operative radiotherapy is provided, this modality has never demonstrated a benefit to patient survival in UUT malignancies [22,28]. Lastly, the stage coding on patients with UUT malignancies was largely done in the old AJCC Staging system. This classification collapses local lymph node involvement and tumors exceeding the confinement of the involved organ into the regional stage category. As demonstrated above this leads to inaccurate prognostication, at least in TCCs. Hence, our reported hazard ratio has to be considered with caution. Despite these shortcomings, the size of this study and the quality of the performed  The panel above graphically illustrates the survival of patients with UUT malignancies. Graph A demonstrates the survival by histology. All stages are considered. Graph B considers only the patients presenting with regional disease, i.e. patients with malignancies beyond the confinement of the renal pelvis or ureter or positive lymph node involvement. Graph C displays the survival of patients with metastatic disease, by histology. Graph D illustrates the survival of patients with locoregional disease and known lymph node status. All histologies are included. Graph E demonstrates the superior survival of patients with absent lymph node involvement in patients with transitional cell histology and regional disease status. Graph F demonstrates the absence of a significant difference by lymph node status in patients with regional disease status and squamous cell histology. Early outcome reports of patients with UTT carcinomas reported a wide spectrum of 5 year overall survival fractions. Whilst a survival of 82% of all patients with low grade lesions was reported [29], only 0-19% of all patients were alive after five years, if locoregional lymph node metastasis was detected on initial examination [30][31][32]. Patients with carcinomas of the UUT and loco-regional lymph node involvement have a prognosis comparable to metastatic disease. This is reflected in the current TNM staging classification [33], which considers regional lymph node involvement as stage IV disease. Regardless, inadequate lymph node sampling has been described in many of the more recent therapeutic studies on upper urinary tract malignancies [21][22][23][24][25][26][27]. In a single armed phase II Hellenic Cooperative Oncology Group study, investigating the adjuvant use of carboplatin and paclitaxel in patients with advanced carcinoma of the upper urinary tract, only 61% of all patients had a known status of the loco-regional lymph nodes [21]. In retrospective Canadian and Mayo clinic reports about the use of adjuvant systemic chemotherapy in high-risk UTT patients, only 80% and 61% of all patients had a known status of the loco-regional lymph nodes [25,26]. The shortcoming of unknown lymph node status in many of the recent studies on this disease entity complicates their interpretability.

Conclusion
Squamous cell cancers of the upper urinary tract are associated with a poor prognosis. Overall, patients with SCC present with more advanced disease and have lower survival rates when compared to their transitional cell counterparts. Lymph node dissection has not been a standard part of the surgical management of UUT. However, the lymph node status in patients with UUT provides further information to help give patients more accurate prognoses and potentially to guide further therapy. To improve this prognosis the rigorous future study of effective systemic chemotherapy for palliative and adjuvant treatment, especially in patients with advanced disease, is needed.