Squamous cell carcinoma of the upper urinary tract in patients with urolithiasis: a systematic review

Search strategy

A comprehensive bibliographic search was conducted in December 2024 using the MEDLINE, Scopus, Web of Science, and Cochrane Library databases to identify studies investigating the current evidence on SCC of the upper urinary tract in patients with urolithiasis. Different combinations of the following keywords were used in a title/abstract search, applying Boolean operators: kidney, renal, pelvis, calyx, ureter, upper, urinary tract, UTUC, stone, calculi, lithiasis, urolithiasis, squamous, tumor, neoplasia, carcinoma. Additionally, the reference lists of retrieved articles were manually screened to identify further relevant studies. The literature search was restricted to English-language articles and studies on human subjects. No restrictions were applied regarding the publication date.

Study selection

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines^[9]. The SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type)^[10] framework was used to define the inclusion criteria.

(1) Sample (S): Male and female patients with urolithiasis;

(2) Phenomenon of Interest (PI): Presence of SCC of the upper urinary tract;

(3) Design (D): Prospective and retrospective studies (including case series and case reports);

(4) Evaluation (E): Diagnosis based on imaging or pathological examination;

(5) Research type (R): Qualitative, quantitative, or mixed-methods studies.

A two-step screening process was implemented. Initially, titles and abstracts were reviewed to identify potentially relevant studies. Full-text articles that met the inclusion criteria underwent a detailed assessment to confirm eligibility.

Data extraction

The following data points were extracted from each included study: first author, publication year, country of origin, number of patients, age, sex, symptoms, stone characteristics, site of tumor, presence of hydronephrosis, radiological diagnosis of tumor, incidental diagnosis of tumor, microscopic findings, pathological stage, treatment of tumor, follow-up, and prognosis.

Quality assessment

The level of evidence (LoE) was evaluated according to the Oxford Center for Evidence-Based Medicine 2011^[11]. Study quality was assessed using the Murad scale^[12] and arbitrarily categorized according to the total score as follows:

(1) Low quality: 0-3 points;

(2) Intermediate quality: 4-5 points;

(3) High quality: 6-8 points.

Data analysis and synthesis

Due to the expected paucity, low quality, and heterogeneity of the available data, we decided not to perform a meta-analysis. Consequently, the results were reported in a narrative fashion. In particular, the extracted data were presented in the text and tables as shown in the original articles. However, when deemed necessary for a better overview, they were combined into sums, percentages, ranges, and medians.

Other methodological details

The review methods were established before the study began, and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the ID “CRD42024625816”. Study selection, data extraction, and quality assessment were performed independently by two authors (MS, ST), while a third author (CM) resolved any disagreements.

Quality assessment

The methodological quality of the included studies was generally low. All studies corresponded to a Level of Evidence 4, reflecting the retrospective design and the predominance of case reports and small case series. According to the Murad scale, 29 studies (82.8%) were classified as low quality (score 0–3), 5 (14.3%) as intermediate quality (score 4–5), and only 1 (2.8%) as high quality (score ≥6). These findings highlight the limited robustness of the available evidence and the considerable risk of bias, which must be considered when interpreting the clinical and prognostic outcomes of this review.

Among the 8 case series, a total of 36 patients were identified. Sex was reported for 29 patients, of whom 17 were male (59%) and 12 were female (41%). The most frequently reported symptoms included pain (81%), hematuria (30%), and infection (51%). Regarding stone characteristics, staghorn calculi (62%) and multiple calculi (19%) were the most common types. Table 2 summarizes data from case series.

Among the 27 case reports, 17 men (63%) and 10 women (37%) were detected. The most commonly reported symptoms were pain (74.1%), hematuria (22%), and infection (22%). The most frequent types of stones were staghorn calculi (40.7%) and multiple calculi (29.6%). Table 3 presents findings from case reports.

Almost all SCCs (97%) developed in the calyceal-pelvic system. Hydronephrosis was observed in 54 patients (85.7%). A radiological suspicion of SCC was raised in 38% of cases, whereas in 44% it was incidentally detected during pathological examination after nephrectomy for a non-functional kidney.

Pathological findings

Histological evaluation confirmed that the majority of tumors were pure SCC; although occasional cases with mixed histology (verrucous components) were described, studies reporting transitional variants were excluded from the analysis. Tumor grade was variably reported, with poorly differentiated forms prevailing among advanced cases. Pathological staging, available in a subset of patients, showed that 40% of patients presented with advanced disease [mainly pathologic T3-T4 (pT3-pT4), and, when available, node-positive status (pN+)], while early-stage tumors (pT1-pT2) were rare and usually detected incidentally. Distant metastases were reported in 16% of cases. Lymph node involvement was inconsistently documented but, when present, was associated with adverse outcomes. Overall, advanced stage and poor differentiation correlated with long-standing staghorn calculi, hydronephrosis, and poor survival. Prognosis remained dismal, with a median survival of approximately 6 months in metastatic cases and 1–2 years in patients with locally advanced disease, whereas incidentally detected, well-differentiated tumors tended to show more favorable outcomes.

Summary of findings

The collected case series and case reports highlighted the rare yet aggressive nature of SCC of the upper urinary tract; all cases included in this review were reported in association with urolithiasis. Therefore, the actual incidence of this condition among SCC of the upper tract cannot be determined. Most of patients presented with hematuria, pain, or mass effect, and a strong correlation was observed between SCC and the presence of staghorn or multiple calculi. At diagnosis, the disease was often locally advanced or metastatic, leading to poor outcomes despite surgical intervention. Treatment primarily involved nephrectomy or radical nephroureterectomy, sometimes combined with chemotherapy or radiotherapy, although no standard systemic therapy had been established. Although the available data should be interpreted with caution, as they mainly derive from advanced-stage cases, they suggest that SCC of the upper urinary tract is characterized by a generally poor prognosis.

Pathophysiological mechanisms

The findings highlight a recurrent coexistence of stones and upper tract tumors, suggesting a potential relationship, although the strength of this association cannot be defined and the underlying mechanisms remain unclear. Several factors have been hypothesized to contribute to SCC development in the upper urinary tract.

(1) Mechanical Stimulation and Chronic Inflammation: persistent mechanical irritation from kidney stones led to chronic inflammation, which in turn promotes urothelial metaplasia, hyperplasia, and eventually malignant transformation^[45-48].

(2) Cytokines and Oxidative Stress: chronic inflammation triggers the release of cytokines, chemokines, and free radicals, which promote cellular damage, uncontrolled proliferation, and tumor growth^[49].

(3) Carcinogen Retention: urinary tract obstruction caused by stones may lead to prolonged exposure to potential carcinogens, accelerating tumor progression^{[39,41,44,50]}.

In summary, kidney stones contribute to an environment of chronic inflammation, oxidative stress, and carcinogen exposure, creating favorable conditions for malignant transformation of the urothelium. Further molecular investigations are required to clarify these mechanisms.

Studies have not been able to identify specific environmental or occupational risk factors due to the limited accuracy in reporting this information. Regarding epidemiology, slight predominance of males over females has been observed, and the median age at diagnosis was 60 years.

Our review has confirmed that SCC of the upper urinary tract predominantly originated in the renal pelvis, with only a small percentage (3%) of cases affecting the ureter. The lower occurrence in the ureter had suggested that differences in epithelial exposure to irritants or site-specific immune responses may influence carcinogenesis^[4,30].

Additionally, SCC has been reported in kidneys with congenital or acquired abnormalities, including horseshoe kidney, ectopic kidney, polycystic kidney disease, and renal calyceal diverticula^[51,52]. These findings suggested that structural anomalies may predispose certain individuals to chronic irritation and subsequent malignant transformation.

Clinical management

Direct comparison with conventional UTUC could not be performed, as no control group was included in this review. However, this differs from clinical practice and guideline recommendations, where conventional urothelial carcinoma of the upper tract is used as the standard reference for assessing the prognostic and therapeutic implications of distinct histological entities such as SCC.

The frequent coexistence of large calculi and chronic inflammation may lead to an initial misdiagnosis as chronic pyelonephritis^[3,37]. Moreover, SCC often presents insidiously, with symptoms frequently overlapping with those of urolithiasis, including flank pain and hematuria. This nonspecific clinical picture makes early recognition difficult, often leading to a delayed diagnosis. Consequently, in most cases, SCC is detected incidentally following nephrectomy for a non-functioning kidney rather than through preoperative imaging findings^[53,54].

In several studies^{[21,27,29,42,44]}, the diagnosis of SCC has been made through biopsies. Therefore, in cases of suspicious stone-related lesions observed during surgery, it is advisable to perform multiple histological biopsies.

Despite advances in imaging techniques, SCC remains challenging to detect radiologically. Ultrasound and computed tomography (CT) scans often fail to differentiate SCC from chronic inflammatory conditions, leading to misinterpretation or underestimation of the disease burden^[19,28]. Although contrast-enhanced CT can provide valuable insights into tumor extent, its diagnostic accuracy remains limited, particularly in patients with chronic kidney disease who cannot undergo contrast studies. Furthermore, urine cytology has low sensitivity due to the presence of stones, which may prevent tumor cell shedding into the urinary tract or may cause confounding inflammatory changes in the exfoliated cells^[44,55].

Given these diagnostic challenges, periodic imaging evaluations, particularly in patients with long-standing urolithiasis, hydronephrosis, or renal dysfunction, should be considered.

Therapeutic approaches remain non-standardized, with radical nephroureterectomy and lymph node dissection being the preferred surgical strategy. However, due to frequent late-stage presentation, surgery alone rarely improves long-term survival. Unlike urothelial carcinoma, where chemotherapy and immunotherapy have improved outcomes, no systemic therapies have been established for SCC. Although radiotherapy and chemotherapy have been attempted in select cases, their efficacy remains largely uncertain, underscoring the urgent need for further research into targeted therapies^[17,46].

Prognosis

The prognosis of SCC of the upper urinary tract is markedly worse than that of urothelial carcinoma (UTUC), largely due to the frequent occurrence of delayed diagnosis, limited systemic treatment options, and the aggressive biological behavior of the tumor^[4,39]. In our review, most patients were diagnosed at an advanced stage, with local invasion or distant metastases present in a significant proportion of cases (44% and 16%, respectively).

Where available, survival data revealed median overall survival (OS) ranging between 5 and 7 months in patients with metastatic disease, and 12 to 24 months in those with locally advanced but non-metastatic disease. Disease-free survival (DFS) was rarely reported in the literature, but isolated case reports indicated recurrence within 2 to 8 months after surgery in several patients with high-grade tumors.

Only a minority of patients - fewer than 10% - achieved survival beyond 5 years. Long-term survivors were more likely to have been diagnosed incidentally at an early stage and to have undergone radical surgery without evidence of lymphovascular invasion or metastasis at presentation^[4,55].

Several potential prognostic factors were identified:

(1) Tumor stage at diagnosis: Strongly associated with survival, with metastatic cases faring worst.

(2) Histological grade: Particularly poorly differentiated tumors, correlated with shorter OS.

(3) Mode of diagnosis: Patients with incidentally discovered tumors following nephrectomy for presumed benign conditions had better outcomes than those diagnosed based on imaging.

(4) Stone burden: Presence of staghorn calculi and prolonged stone disease was frequently associated with delayed diagnosis and more advanced disease.

In contrast, UTUC generally has a more favorable prognosis when detected early, supported by the availability of standardized staging, risk stratification systems, and established systemic treatments including chemotherapy and immune checkpoint inhibitors.

These findings underscore the urgent need for earlier detection, consistent staging, and more effective systemic therapies in this patient population.

Strengths, limitations, and future directions

To the best of our knowledge, this is the first systematic review specifically investigating the association between upper urinary tract SCC and urolithiasis. It provides a comprehensive synthesis of the existing evidence and highlights recurring clinical and radiological patterns in a condition that remains poorly understood. This work offers a valuable reference point for clinicians and researchers confronted with this rare malignancy.

The main limitation of the available literature is the predominance of low-quality retrospective evidence, primarily composed of isolated case reports and small case series, which limits the generalizability of findings and hinders the development of evidence-based recommendations. Additionally, there is a lack of standardized reporting regarding imaging findings, pathological details, and follow-up outcomes across the included studies.

(1) Future research should focus on clearly defined and feasible objectives, including the establishment of multicenter registries or collaborative databases to systematically collect data on SCC cases in patients with urolithiasis;

(2) Prospective studies assessing the incidence of SCC in high-risk populations (e.g., those with long-standing staghorn stones or non-functioning kidneys);

(3) Implementation of standardized imaging protocols and diagnostic algorithms aimed at distinguishing SCC from chronic pyelonephritis or xanthogranulomatous pyelonephritis;

(4) Histopathologic and molecular profiling studies to identify biomarkers that may enable earlier diagnosis or serve as therapeutic targets;

(5) Clinical trials or retrospective cohort analyses evaluating the effectiveness of systemic treatments (e.g., chemotherapy, immunotherapy) in SCC of the upper tract, possibly adapted from urothelial carcinoma protocols.

Clarifying the pathophysiologic mechanisms linking chronic inflammation, urolithiasis, and malignant transformation of the urothelium will also be critical. A deeper mechanistic understanding could support the development of targeted preventive strategies, such as timely surgical treatment of high-risk stone disease and surveillance imaging in selected patients.

Ultimately, strengthening the quality of evidence through well-structured research will be essential to guide clinical decision-making and allow for the development of specific diagnostic and therapeutic guidelines.

In conclusion, SCC of the upper urinary tract is an exceptionally rare and aggressive malignancy, most frequently associated with chronic and complex urolithiasis. Its nonspecific clinical features and overlap with benign conditions often result in delayed or incidental diagnosis, which contributes to a generally poor prognosis. The current literature is limited to low-quality retrospective studies, mostly case reports and small series, which hinders the ability to draw definitive conclusions regarding epidemiology, pathogenesis, and optimal management. Furthermore, there is a lack of validated diagnostic algorithms and no standardized systemic therapies tailored to SCC of the upper urinary tract. Clinicians should maintain a high index of suspicion in patients with long-standing staghorn or infected stones, particularly in the setting of a non-functioning kidney. However, given the scarcity of robust evidence, caution is warranted in extrapolating management strategies from other urologic malignancies. Future research should prioritize prospective multicenter data collection, improved radiologic and histopathologic diagnostic protocols, and translational studies aimed at identifying molecular targets. High-quality studies are needed to clarify the natural history of the disease, define risk factors, and guide the development of evidence-based clinical guidelines.