Prognostic impact of non-clear cell histology on recurrence and cancer-free survival in renal cell carcinoma: a time-to-event analysis

Abstract

Objectives

To determine risk factors associated with the recurrence of renal cell carcinoma (RCC), either local recurrence or distant metastasis, and to characterize a contemporary cohort of patients with non-clear RCC (ncRCC) in terms of cancer-free survival (CFS) and time to such recurrence.

Methods

A retrospective review of prospectively collected data was performed for consecutive patients undergoing partial and radical nephrectomy at a tertiary care center in Saudi Arabia. Data collection included patients and tumor characteristics, perioperative parameters, and histopathological patterns. Multivariate logistic regression determined the predictors of tumor recurrence while Kaplan-Meier analyses assessed CFS and the time to recurrence.

Results

A total of 214 patients were analyzed, including 150 (70.1%) ccRCC and 64 (29.9%) ncRCC, with a mean age of 54.8 ± 1.7 years and tumor size of 6.9 ± 0.7 (1.2–24.0) cm. After a median follow-up of 47.6 ± 12.4 months, 32(14.9%) patients developed recurrence. In multivariate regression, tumor recurrence was significantly associated with tumors ≥ 6.9 cm [aOR (95% CI): 2.85 (1.67–5.43)], renal vein or inferior vena cava vascular invasion [aOR: 1.92 (1.32–4.21)], pathological staging ≥ 2b [aOR: 2.66 (1.95–5.34)] (8th edition of the AJCC Cancer Staging Manual, 2017), and positive lymph nodes in the specimen [aOR: 3.28 (2.97–5.15)]. The recurrence-free status was 85% at 5 years, while the mean time to recurrence was 9 (6–42) months. Patients with ncRCC had comparable recurrence rates to those with ccRCC (12.5% vs. 16.0% p = 0.64), respectively. The 5-year CFS was 62.8% (95% CI: 54.2–68.7) for ncRCC and 76.8% (95% CI: 67.4–87.2) for ccRCC (p = 0.77).

Conclusion

Compared to clear cell RCC, patients with non-clear cell RCC showed no significant differences in demographic, tumor, or perioperative characteristics. In our cohort, both histopathological subtypes demonstrated comparable recurrence rates and 5-year cancer-free survival.

Introduction

Renal cell carcinoma (RCC), the most common neoplasm of the renal cortex [1], accounts for 3–5% of all adult malignancies and has shown a steadily increasing incidence over the past decade [2]. Globally, it ranks as the 6th most frequently diagnosed cancer in men and the 10th in women [3]. Only about 10% of patients are present with the classic triad of flank pain, a palpable mass, and hematuria. Surgical resection remains the mainstay of curative treatment and plays a role in palliation for metastatic disease. Despite this, approximately 27% of patients experience disease recurrence [4, 5].

Partial nephrectomy (PN) is currently the standard of care for clinical T1 renal tumors, offering oncological outcomes equivalent to those of radical nephrectomy (RN) [6]. However, recurrence rates of 20–40% following nephrectomy for clinically localized disease highlight the aggressive and often insidious nature of RCC [7]. Notably, even patients diagnosed with localized RCC measuring less than 4 cm face a 7.5% risk of recurrence, which was significantly associated with decreased overall survival [8]. Although small RCCs have traditionally been considered indolent [9], they may still pose a risk for local invasion and metastatic spread, ultimately leading to poor prognosis [10].

Postoperative recurrence of RCC is significantly associated with increased mortality, higher all-cause and RCC-related healthcare resource utilization, and greater healthcare costs, underscoring the importance of preventing or delaying recurrence in high-risk patients, particularly when adjuvant therapies are limited [11]. Clear cell RCC (ccRCC) is the most common histologic subtype, accounting for 70–90% of all RCC cases, while the remaining tumors are classified as non-clear cell RCC (ncRCC) [10]. ncRCC encompasses a heterogeneous group of subtypes, each with distinct genetic and biochemical profiles that differ from one another and from ccRCC, often resulting in poorer clinical outcomes. Unfortunately, most clinical trials have primarily focused on ccRCC, leading to limited data on oncologic outcomes and the role of adjuvant systemic therapy in ncRCC.

Furthermore, ncRCC lacks molecular characterization due to its rarity, with subsequent less presentation in clinical trials with untailored management [12]. Therefore, this study aimed to identify risk factors associated with tumor recurrence following surgical management of RCC and to characterize a contemporary cohort of patients with ncRCC in terms of cancer-free survival (CFS) and time to recurrence.

Methods

Study design

A retrospective review of prospectively collected data was conducted on consecutive patients who underwent partial or radical nephrectomy at a tertiary care center. Due to the retrospective nature of the study, written informed consent was waived. Patients with benign histopathology, incomplete pathological reports, or missing follow-up data were excluded from the analysis. Data were collected retrospectively from medical and electronic records; therefore, ethics approval from the local institutional review board was not required, in accordance with local regulations. Therefore, a clinical trial registration number was not applicable. However, all patients included in the study provided written informed consent.

Data collection

Data collection included patient demographics, tumor characteristics, perioperative parameters, and histopathological features. Patient characteristics comprised age, body mass index (BMI), comorbidities, and the American Society of Anesthesiologists (ASA) score. Tumor characteristics included size, location, laterality, consistency, and clinical stage. Perioperative parameters covered the type of procedure, surgical approach, operative time, and postoperative complications. Histopathological data included tumor size (measured by maximum diameter), Fuhrman grade, histological subtype, surgical margin status, lymph node involvement, and evidence of vascular or lymphatic invasion.

Clinically localized RCC was defined as pathologically confirmed RCC at stage T1a to T2b, without lymph node involvement or distant metastasis at diagnosis. Pathologic staging was reassigned according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM classification. Tumor cell differentiation for clear cell RCC was assessed using the Fuhrman grading system.

Follow-up assessment

All patients were assessed after 3 months postoperatively and then semi-annually for 3 years and then annually for the fourth and fifth year. Follow-up assessments included history taking, physical examinations, urinalysis, renal profile, and other routine laboratory tests. In addition, chest and abdominal imaging were performed with contrast enhanced computed tomography (CT), unless there were contraindications, where magnetic resonance imaging (MRI) was used. Recurrence was defined as a newly observed abnormal enhanced lesion in the imaging studies during the follow-up period, either adjacent to the operative site (local recurrence) or in a distant organ (distant recurrence).

Data analysis

Data was analyzed using the Statistical Package for the Social Sciences (SPSS) software for Windows (IBM Co., Armonk, NY, USA), version 23. Categorical variables were presented as frequencies and percentages and were compared using Fisher’s exact test. Continuous variables were expressed as means with standard deviations and were compared using the student’s t-test. Two-tailed p-values < 0.05 were considered statistically significant. Kaplan-Meier survival analysis was used to assess cancer-free survival and time to recurrence of RCC. A multivariate logistic regression model was employed to identify predictors of tumor recurrence, including all variables that showed statistically significant differences in the univariate analysis. The cutoff points for the multivariate model were based on the means observed in the univariate analysis.

Results

A total of 214 patients were analyzed, including 150 (70.1%) with clear cell RCC (ccRCC) and 64 (29.9%) with non-clear cell RCC (ncRCC). The mean age of the cohort was 54.8 ± 1.7 years, and the mean tumor size was 6.9 ± 0.7 cm (range 1.2–24.0 cm). 55% of the patients were male, 57% had right-sided tumors, and 65% had multiple comorbidities. Sixty patients (20%) presented with ≥ stage 2b disease (Table 1). Laparoscopic and open surgical approaches were performed in 124 (57.9%) and 74 (34.6%) patients, respectively, while 16 (7.5%) patients required conversion to open surgery.

Table 1.

Baseline and histopathological parameters of patients with renal cell carcinoma

Parameter (n = 214)		Mean ± SD/No (%)
Age (years)		54.8 ± 1.7
BMI (kg/m2)		31.8 ± 10.2
Male gender		118 (55)
Comorbidities		140 (65)
ASA score > 2		88 (41)
Right-sided tumor		122 (57)
Tumor size (cm)		6.9 ± 0.7 (1.2–24.0)
Solid tumor		200 (94)
Renal/IVC extension		32 (15)
Procedure	Radical	166 (78)
	Partial	48 (22)
Approach *	Laparoscopic	124 (58)
	Open*	90 (42)
Staging	< 2b	154 (72)
	≥ 2b	60 (28)
Positive lymph nodes on specimen		22 (10)
Tumor necrosis		17 (7.9)
Vascular invasion		23 (10)
Fuhrman grade > 2*		28 (13)

*Fuhrman grade was done only for ccRCC

After a median follow-up of 47.6 ± 12.4 months, 32 patients (14.9%) developed recurrence, including 20 patients (9.3%) with distant metastasis. The median time to recurrence was 9 months (range 6–42 months). Tumor recurrence was significantly associated with left-sided tumors, age > 55 years, tumors larger than 6.9 cm, pathological stage ≥ 2b, tumor thrombus extending to the renal vessels, and tumors exhibiting sarcomatoid or necrotic changes on histopathological examination (Table 2).

Table 2.

Baselines criteria of recurrent versus non-recurrent renal cell carcinoma

Variable	Recurrence n = 32	No recurrence n = 182	P-value
Left-sided tumor	75%	45.1%	0.027
Patients ≥ 50-year-old	63%	56.5%	0.04
Tumors ≥ 6.9 cm	8 ± 3.6	5.7 ± 2.9	0.02
Tumor thrombus to renal vein/IVC	38%	11%	0.006
pT ≥ 2b	63%	30%	0.01
Sarcomatoid changes	60%	12.7%	0.02
Tumor necrosis	32%	10%	0.01
Positive lymph modes on specimen	37.5%	5.5%	< 0.001

However, in the multivariate logistic regression model, only tumor size greater than 6.9 cm [aOR (95% CI): 2.85 (1.67–5.43)], pathological stage ≥ 2b [aOR: 1.92 (1.32–4.21)], tumor thrombus extending to the renal vessels [aOR: 2.66 (1.95–5.34)], and positive lymph nodes in the histopathological specimen [aOR: 3.28 (2.97–5.15)] remained statistically significant and were predictors of tumor recurrence, after adjusting for other variables (Table 3).

Table 3.

Multivariate regression analysis to detect predictors of recurrence after radical and partial nephrectomy for renal cell carcinoma

Variable	aOR	95% CI	p-value
Patients ≥ 50-year-old	1.43	0.94–1.98	0.11
Left-sided tumor	0.86	0.58–1.12	0.82
Tumors ≥ 6.9 cm	2.85	1.67–5.43	0.01
Tumor thrombus to renal vein/IVC	1.92	1.32–4.21	0.02
pT ≥ 2b	2.66	1.95–5.34	< 0.001
Sarcomatoid changes	1.78	0.92–2.15	0.09
Tumor necrosis	1.98	0.98–3.32	0.08
Positive lymph modes on specimen	3.28	2.97–5.15	< 0.001

aOR adjusted Odds ratio, CI confidence interval

This suggests that patients with tumors ≥ 6.5 cm in their largest diameter or those with tumors extending to the main renal vein or inferior vena cava (IVC) may have a postoperative recurrence risk three times higher than those with smaller tumors. Similarly, tumor recurrence may be twice as high in patients with stage ≥ 2b disease. Kaplan-Meier survival analysis showed a recurrence-free rate of 85% at 5 years, with the mean time to recurrence being 9 months (range 6–42 months) (Fig. 1).

Fig. 1.

Recurrence-free status (A) and time to recurrence (B)

Patients with non-clear cell RCC (ncRCC) were comparable to those with clear cell RCC (ccRCC) in baseline and perioperative parameters (Table 4), including pathological stage ≥ 2b (37.5% for ncRCC vs. 25.3% for ccRCC, p = 0.20) and postoperative complications (12.5% for ncRCC vs. 8% for ccRCC, p = 0.21). Notably, postoperative recurrence rates were similar between the groups (12.5% for ncRCC vs. 16.0% for ccRCC, p = 0.64). The 5-year cancer-free survival (CFS) was 62.8% (95% CI: 54.2–68.7) for ncRCC and 76.8% (95% CI: 67.4–87.2) for ccRCC (p = 0.77) (Fig. 2).

Table 4.

Baselines criteria of non-clear versus clear renal cell carcinoma baseline criteria of non-clear versus clear renal cell carcinoma

Parameter		ncRCC n = 64	ccRCC n = 150	p-value
Mean age (years)		54.7 ± 4.5	52.6 ± 8.2	0.06
BMI (kg/m)2		31.3 ± 6.4	29.8 ± 8.5	0.21
Male gender		40 (63)	78 (62)	0.18
Comorbidities		38(59)	102 (68)	0.27
ASA score > 2		29 (45)	59 (39)	0.45
Right sided		36 (56)	86 (57)	0.88
Tumor size (cm)		6.4 ± 3.2	5.8 ± 1.8	0.08
Procedure	Radical	46 (72)	120 (80)	0.21
	Partial	18 (28)	30 (20)
Sold tumor		60 (94)	140 (93)	0.99
Vascular extension		14 (22)	18 (12)	0.81
Stage ≥ 2b		24 (37)	38 (25)	0.20
Tumor necrosis		8 (12.5)	9 (6.0)	0.06
Positive lymph modes on specimen		10 (15.6)	12 (8.0)	0.14

ccRCC clear cell renal cell carcinoma, nccRCC non-clear cell renal cell carcinoma, BMI body mass index

Fig. 2.

Recurrence free survival of non-clear cell (nccRCC) versus clear cell renal cell carcinoma (ccRCC)

Discussion

RCC accounts for 90% of all malignant kidney tumors and is twice as common in men as in women [13]. While radical and partial nephrectomy are well-established treatments for RCC, 20–40% of patients with localized tumors will experience disease recurrence [14]. The course and survival of these patients with recurrent neoplasms vary, partly depending on factors such as the time to recurrence, blood chemistry, and performance status.

In the present study, the overall recurrence rate was approximately 15%, with a median time to recurrence of 9 months, indicating that most recurrences occur within the first year after surgery. The surgical stage of RCC at diagnosis and large tumors that extend as venous tumor thrombus are the most significant predictors of local recurrence or distant metastasis. Mattila and colleagues found that metastasis-free survival after surgery for localized ccRCC can be predicted by three key tumor characteristics: tumor size, tumor grade, and microvascular invasion [15].

Son and colleagues reported a 9% recurrence rate after radical nephrectomy (RN) for localized RCC, with two-thirds of the recurrences diagnosed within 5 years postoperatively [16]. While tumor size and pathological stage were predictors of both early and late recurrence, consistent with our findings, late recurrence was associated with the presence of tumor necrosis in the resected specimen. Therefore, patients with tumor necrosis may require long-term, thorough surveillance after RN, as they are more likely to develop metastases in unusual sites [16]. In the present study, microscopic tumor necrosis was significantly associated with tumor recurrence; however, it lost statistical significance after adjusting for other variables, possibly due to the small number of patients with tumor necrosis in our cohort.

A recent multi-institutional cohort study of RCC with tumor thrombus found a 40% recurrence rate and a median recurrence-free survival of 37.3 months. Predictive factors for recurrence in the multivariate analysis included pT4, pN1, tumor necrosis, and tumor size > 10 cm [15]. Van der Mijn et al. reported a recurrence rate of 13.2%, like our findings, after a median follow-up of 4.9 years [17]. In their study, increasing pathological T-stage and nuclear grade were independently associated with RCC recurrence. Notably, diabetes mellitus was identified as an independent risk factor for recurrence in patients with T1-2 tumors, and it was significantly linked to shorter median overall survival and disease-free survival [18].

Regarding RCC recurrence by pathological stage, Levy and colleagues reported a 7% recurrence rate for pT1 lesions, with a median time to recurrence of 38 months (range 18–67) [19]. For pT2 tumors, several studies have documented recurrence after a median follow-up of 25–32 months [20, 21]. Stephenson and colleagues reported a median time to relapse of 14 months for pT3a tumors and 9 months for pT3b tumors [22]. In patients with positive lymph nodes, Canfield and colleagues observed a 70% recurrence rate, with a median time to recurrence of 17.7 months [22]. In the present study, 38% of patients with recurrent RCC had positive lymph nodes in the histopathological specimen. The most common sites of recurrence were retroperitoneal lymph nodes, lungs, liver, bone, renal fossa, pelvis, and brain [23].

Positive surgical margins (PSM) after partial nephrectomy (PN) significantly increase the risk of recurrence, suggesting that PN may not be a safe treatment option for patients with PSM in the final pathology [24]. In this study, however, PSM was not associated with RCC recurrence, likely due to the small number of specimens with positive margins, which may have limited the ability to detect a statistically significant difference. The major subtypes of non-clear cell RCC (ncRCC) include papillary, chromophobe, collecting duct, medullary, translocation-associated, and unclassified forms. Interestingly, in the present study, postoperative recurrence and 5-year cancer-free survival (CFS) rates were comparable between ncRCC and clear cell RCC (ccRCC). This result is noteworthy as it challenges the conventional understanding of distinct clinical courses between different pathological subtypes of RCC. ncRCC consists of a diverse range of tumor types, with survival outcomes varying considerably based on the specific subtype. For instance, some subtypes like collecting duct RCC and medullary RCC are recognized for their aggressive nature, while others, such as chromophobe RCC, typically exhibit a more indolent progression. However, our study contradicts this established view, revealing similar recurrence rates and 5-year cancer-free survival (CFS) between ncRCC and ccRCC. This suggests that, despite the histological differences between the two groups, factors like tumor size, pathological stage, and vascular invasion may have a more significant influence on prognosis than previously understood. Additionally, the relatively small sample size of ncRCC patients in our cohort may have limited our ability to identify distinct differences in outcomes.

Moreover, the treatment protocols and surgical strategies used in both ccRCC and ncRCC could have contributed to the comparable results. Both subtypes were treated with standard surgical resection, and improvements in perioperative care and surgical techniques, may have helped achieve more uniform outcomes across RCC subtypes. Furthermore, molecular and genetic factors that could potentially differentiate the prognostic trajectories of ncRCC and ccRCC may not have been fully explored in this study. Future research that integrates genetic profiling and biomarkers could offer a more detailed understanding of the factors influencing recurrence and survival. Therefore, these findings underscore the need for more tailored approaches in predicting outcomes and monitoring patients with RCC, irrespective of the histological subtype. The comparable outcomes observed between ncRCC and ccRCC in our study could indicate that clinical factors, rather than histological differences alone, play a pivotal role in determining prognosis.

Cheville et al.. reported significant differences in outcomes among different histologic RCC subtypes, with a poorer prognosis and lower cancer-specific survival in patients with ccRCC compared to those with papillary and chromophobe RCC [25]. However, the findings of this study should be interpreted cautiously, given the small number of cases of each ncRCC subtype.

The aggressive and insidious nature of RCC, reflected by postoperative recurrence even in clinically localized disease, highlights the need for evidence-based systems to monitor patients after nephrectomy, stratified by recurrence risk [26, 27]. Additionally, ongoing research into the natural history and biological characteristics of RCC has driven the evolution of recommendations for recurrence prediction and surveillance. A recent multicenter study found that local recurrence of RCC could be detected with 100% sensitivity, 80% specificity, and an overall accuracy of 0.98 using apparent diffusion coefficient (ADC) imaging [28]. However, the small number of locally relapsed RCC cases may limit the validity of this study, particularly due to the lack of correlation between enhancement patterns of suspicious renal lesions and ADC values. Moreover, Kim et al. developed an algorithm predicting the 5- and 10-year probabilities of RCC recurrence using a large RCC cohort from Korea, which helps clinicians devise personalized postoperative treatment strategies [29]. Despite these advancements, there is no consensus among different guidelines regarding the optimal duration and frequency of follow-up after nephrectomy for RCC.

Given the retrospective nature of the study, potential biases such as selection bias, information bias, and confounding were inherent. However, these biases were minimized through the exclusion of cases with incomplete data, comprehensive chart reviews, and statistical adjustments for key covariates. This study is also limited by the relatively small number of patients who experienced RCC recurrence, as well as the subsequent subdivision of these patients into clear cell and non-clear cell variants. Nevertheless, the study provides valuable insights into the recurrence rate and 5-year cancer-free survival of the less commonly occurring non-clear cell renal cell carcinoma.

Conclusion

Postoperative recurrence of RCC is significantly associated with larger tumor size, pathological stage greater than pT2b, the presence of vascular invasion, sarcomatoid features, necrosis, and renal fat invasion. Specifically, tumors larger than 6.9 cm, pathological stage ≥ pT2b, and tumor thrombus extending to the renal vessels are predictive of tumor recurrence. Compared to clear cell RCC, patients with non-clear cell RCC showed no significant differences in demographic, tumor, or perioperative parameters. In our cohort, both histopathological patterns exhibited similar recurrence rates and 5-year cancer-free survival. 

Abbreviations

aOR

Adjusted Odds Ratio

ASD

Apparent diffusion coefficient

CFS

Cancer free survival

ccRCC

Clear cell renal cell carcinoma

CI

Confidence interval

IVC

Inferior vena cava

ncRCC

Non-clear cell renal cell carcinoma

PN

Partial nephrectomy

PSM

Positive surgical margin

RCC

Renal cell carcinoma

RN

Radical nephrectomy

Authors’ contributions

WT: Project administration, planning, methodology, writing and editing; HN: Planning, data collection, methodology, writing and editing; MF: Planning, data collection, methodology, writing and editing; HB: Writing and editing; SM: Writing and editing, ME: Planning, methodology, statistics, writing, reviewing, and editing.

Funding

All authors declare that there is no funding for this research.

Data availability

Data is provided within the manuscript.

Declarations

Ethics approval and consent to participate

All the procedures performed in the studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Data were collected retrospectively from medical and electronic records; therefore, ethics approval from the local institutional review board was not required. All patients included in the study provided written informed consent.

Consent for publication

All authors have read and approved the final manuscript and agree with its submission and publication in BMC Urology.

Competing interests

The authors declare no competing interests.