Histopathologic features and parameters predicting recurrence potential of small renal masses

Abstract

Background

Small renal masses (SRMs) are defined as contrast-enhanced masses with a diameter of ≤4 cm, usually consistent with clinical stage T1a renal cell carcinoma (RCC). This study aimed to explore the histopathological features of a contemporary series of SRMs and investigate parameters that could predict their pathological nature, metastatic potential, and recurrence potential.

Materials and methods

Small renal masses were identified in 166 of 427 patients who underwent surgery for suspected RCC. The radical nephrectomy/partial nephrectomy ratio was 1:44, and autotransplantation was performed in a single case. Variables associated with metastatic recurrence of SRM were analyzed using χ² and logistic regression models.

Results

Renal cell carcinoma was confirmed in 86% (n = 143) of cases, whereas benign tumors were present in 14% (n = 23) of cases. Seventeen percent of the RCC cases were high-grade (Fuhrman G3–4). Among SRMs with a diameter of >2 cm, 71% were malignant. The mean ± standard deviation diameter of the removed SRMs was 28 ± 12 mm, significantly higher in the malignant SRMs group (31 ± 8 vs. 24 ± 9 mm) (p = 0.005). During follow-up, local recurrence was identified in 4 patients versus new distant metastasis in 11 patients. Metastatic lesions were detected in the lungs (1.8%), bone (1.2%), distant (1.9%) and regional lymph nodes (1.2%), liver (0.6%), and multiple organs (2.4%). Patients with malignant SRMs were significantly older than those with benign tumors (p = 0.036). The multivariate analysis identified tumor size, Fuhrman grade, stage, nodal and distant metastasis status, tumor localization, and treatment modality as characteristics significant for tumor recurrence.

Conclusions

The majority of treated neoplasms were malignant, but their incidence was low among SRMs with a diameter of <2 cm. Our results emphasized the importance of histopathological features and treatment modalities in predicting malignant recurrence.

1. Introduction

Small renal masses (SRMs) are contrast-enhanced masses with a diameter of ≤4 cm that are usually consistent with clinical stage T1a renal cell carcinoma (RCC).^[1] They represent a heterogeneous group of tumors with various metastatic potential ranging from benign tumors and cystic masses to indolent and more aggressive tumors. Most cases are incidentally found during routine radiological investigations for other conditions, often in previously asymptomatic patients. Consequently, small incidental masses present a diagnostic and treatment challenge.

However, the true incidence of SRMs remains unknown. The estimated rate of detection is increasing by 3%–4% annually using imaging procedures such as computed tomography (CT) and magnetic resonance imaging (MRI). Approximately 85% of patients with asymptomatic RCC are diagnosed with lesions <4 cm resembling SRM. Meanwhile, benign renal masses represent 15%–20% of surgically resected tumors <4 cm.^[2]

The epidemiological factors involved in the risk of developing RCC include smoking, hypertension, obesity, and chronic kidney disease (CKD). More than 50% of SRMs are incidentally discovered, mostly in elderly individuals with notable comorbidities, and 16%–23% are benign. The possibility of the SRM being aggressive is less than 20%. For each 1-cm increase in tumor size, the risk of malignant features increases by 16%.^[3]

According to a previously proposed classification, SRMs can be malignant, benign, or inflammatory. They can also be classified based on their radiographic appearance (simple cystic, complex cystic, or solid).^[4] Small renal masses can be divided into cystic and solid types. Furthermore, these categorizations have been improved according to contemporary reports of different RCC subtypes and other benign and malignant renal tumors.^[3,5] Malignant renal tumors include RCC, urothelium-based cancers, sarcomas, embryonic and carcinoid tumors, lymphomas, metastases, and invasions by adjacent neoplasms. Benign renal masses include cystic and solid lesions. Inflammatory and vascular lesions, such as abscesses, infected cysts, tuberculosis, rheumatic granulomas, and focal xanthogranulomatous pyelonephritis, should also be considered.^[6]

During the last 20 years, the surgical treatment of SRMs has progressed from radical nephrectomy (RN) for all renal masses to elective partial nephrectomy (PN) regardless of size. In recent years, novel methods such as renal tumor biopsy, percutaneous thermal ablation, and laparoscopic and robotic renal surgery have been increasing in popularity.

Numerous SRM management options have been developed, including active surveillance (AS), focal ablative techniques, and surgical excision via RN or PN. Choosing the most appropriate management requires careful consideration of both patient and tumor characteristics.^[1,2]

This study aimed to explore the histopathological features of a contemporary series of solitary renal masses measuring ≤4 cm and determine SRM occurrence and characteristics after surgical intervention. Furthermore, it investigated whether sex, age, tumor size, stage, grade, localization, and treatment modality could predict the pathological nature, metastasis, and recurrence potential of such masses.

2. Materials and methods

2.1. Patients

A total of 427 patients underwent surgery for suspected renal cancer between January 2015 and January 2019. Of them, 166 (39%90 men, 76 women) had a small renal tumor (≤4 cm). The mean ± standard deviation age of patients with SRMs was 56 ± 14 years. Radical nephrectomy was performed in 98 patients versus PN in 68 patients. One patient underwent autotransplantation after a PN.

The analysis of the factors underlying the metastatic and recurrence potential of SRMs comprised the assessment of anthropometric data, medical history, laboratory findings, objective examination results, X-ray imaging results, and final histological data.

2.2. Study design

This retrospective prospective study included patients with kidney tumors. The inclusion criteria included 1 or more solitary, nonmetastatic renal mass measuring ≤4 cm, and having undergone kidney surgery at the Urology Clinic Clinical Center University of Sarajevo. The exclusion criteria were having undergone other treatment procedures or AS and presence of upper tract urothelial neoplasms, retroperitoneal sarcomas, or end-stage renal disease.

Pathological data, including tumor type and size, Fuhrman grade, and stage, were obtained from each patient's histopathological report.

2.3. Radiological imaging

Radiological ultrasound examinations were supplemented by CT or MRI of the kidney. The MRI machine had an Avanto 1.5 T magnet, whereas a Somat CT machine was used (both devices manufactured by Siemens Healthcare, Germany). The radiological analysis was performed by radiologists at several radiological centers.

2.4. Surgical procedure

The operative procedure was performed with the analysis of radiological images using open surgery or laparoscopic urological procedures. Operative procedures included RN and PN. The surgical procedures were performed by several urologists from a single urology center.

2.5. Histopathological assessment

The histopathological analysis was performed by a clinical pathologist. Biopsy specimens were obtained after the renal surgery according to the procedure accepted by urological societies.

Malignant SRMs were staged using the tumor nodule metastasis classification of malignant tumors based on histopathological examinations. The widely used grading schema of RCC is the nuclear grading system described by Fuhrman et al.,^[7] which evaluates nuclear size and shape and nuclear prominence. The material was subjected to standardized testing in the histopathological laboratory according to internationally accepted criteria of professional societies.

2.6. Ethical considerations

All data were collected after obtaining informed consent from all participants, and the study was approved by the Clinical Center University of Sarajevo Ethics Committee.

2.7. Statistical analysis

The data were processed using descriptive statistics, analysis, and statistical processing of the results using appropriate statistical methods. Parametric data were tested using Student t test, whereas nonparametric data were processed using the Mann-Whitney U test and proportions, regression analysis, and multivariate analysis. The χ² test and Fisher exact test were used to analyze the dependence between categorical variables.

Among the multivariate statistical methods, discriminant, cluster, and binary logistic regression analyses were used. The sensitivity and specificity of the values as well as other indicators for assessing prediction validity were determined. Statistically significant differences were defined according to common standards and values of p < 0.05.

The statistical analyses were performed using IBM SPSS Statistics software (version 19.0; IBM Corporation, Chicago, IL). The 95% confidence intervals were calculated using SAS 9.2 (SAS Institute, Cary, NC).

3. Results

The baseline characteristics of the patients with SRMs are presented in Table 1. Overall, 166 SRMs (≤4 cm) were identified. The histopathological analysis confirmed RCC in 143 cases (86%) and benign tumors in 23 cases (14%). However, when the tumor diameter was >2 cm, malignancy was detected in 71% of cases, and benign tumors occurred in 29% of cases. The mean ± standard deviation diameter of the resected tumors was 28 ± 12 mm. The mean tumor diameter was significantly larger in the group of patients with malignant masses (31 ± 8 vs. 24 ± 9 mm, respectively; p = 0.005).

Table 1.

Baseline characteristics of patients with small renal masses.

Characteristics	n = 166
Sex, n
Male	90
Female	76
Age, mean ± SD, yr	56 ± 14
Tumor size
Diameter, mean ± SD, mm	28 ± 12
Malignant	31 ± 8
Benign	24 ± 9
Operative treatment, n
Open nephrectomy	128
Laparoscopic nephrectomy	38
PN	68
RN	98

PN = partial nephrectomy; RN = radical nephrectomy; SD = standard deviation.

The differentiation of malignant tumors was grade 1 in 44 cases (27%), grade 2 in 92 patients (56%), grade 3 in 24 specimens (15%), and grade 4 in 6 cases (2%). Undifferentiated carcinomas represent only 17% of small tumors. Among the benign SRMs there were 3 adenomas, 6 angiomyolipomas, 8 oncocytomas, and 6 atypical cysts.

During the follow-up period, local recurrence was diagnosed in 4 patients, whereas new distant metastasis developed in 11 patients. There were metastatic lesions in the lungs of 3 patients (1.8%), bones of 2 (1.2%), distant lymph nodes of 3 (1.9%), regional lymph nodes of 2 (1.2%), and liver of 1 (0.6%). Multiple metastatic lesions were detected in several organs of 4 patients (2.4%). The mean age of the patients with malignant SRMs was significantly higher than that of the patients with benign lesions (p = 0.036). These results are presented in Table 2.

Table 2.

Characterization, differentiation, and metastasis of small renal tumors.

Values	n	%
Type of small renal mass
Benign
Adenoma	3	13
Angiomyolipoma	6	26
Oncocytoma	8	35
Atypical cysts	6	26
Malignant
Grade 1	39	27
Grade 2	80	56
Grade 3	21	15
Grade 4	3	2
Metastasis
Lungs	3	1.8
Bones	2	1.2
Distant lymph nodes	3	1.9
Regional lymph nodes	2	1.2
Liver	1	0.6

Data are presented as absolute (n) and relative (%) numbers.

Open surgery was performed in 128 patients, whereas the laparoscopic approach was used in 38 patients. Radical nephrectomy was performed in 98 patients with SRMs versus PN in 68. Autotransplantation was performed in 1 patient because of a solitary kidney with a tumor located in the renal hilum.

Preoperative biopsy of the SRM was performed in 10% of patients. Adequate material for histopathological analysis was not obtained in 2% of cases, in which operative treatment was performed without a preoperative diagnosis. Active monitoring of the lesion after a renal mass biopsy was indicated in only 1% of cases.

Univariate regression showed that sex, age, and body mass index, as independent variables, were not statistically significant for predicting tumor recurrence (p = 0.370, p = 0.783, and p = 0.94, respectively). Similar results on the univariate and multivariate analyses showed that tumor stage was T2 (p = 0.053 and p = 0.130, respectively). Univariate Cox analysis of tumor recurrence identified Fuhrman grade, nodal and distant metastases status, tumor size, and location as significant independent variables (p = 0.001, p = 0.001, p = 0.001, p = 0.005, and p = 0.01, respectively). Moreover, multivariate analysis identified treatment modality as a significant characteristic (p = 0.001) (Table 3).

Table 3.

Univariate and multivariate Cox regression analyses of tumor recurrence.

Characteristic	Univariate HR (95% CI)	p	Multivariate HR (95% CI)	p
Female vs. male	0.49 (0.25–0.93)	0.37	0.38 (0.19–0.74)	0.56
Age ≥50 vs. <50 yr	0.969 (0.772–1.215)	0.783
Body mass index >25 vs. ≤25 kg/m2	1.02 (0.59–1.76)	0.944
T stage				0.015
T1	Reference	0.013	Reference
T2	2.50 (0.99–6.35)	0.053	2.21 (0.85–5.73)	0.103
T3	3.25 (1.30–8.11)	0.012	3.38 (1.33–8.60)	0.011
T4	4.49 (1.78–11.31)	0.001	4.12 (1.62–10.48)	0.003
Fuhrman grade
G1/G2	Reference		Reference
G3/G4	3.817 (3.213–4.535)	0.001	1.265 (0.831–1.927)	0.017
Distant metastasis M0/M1	2.606 (2.145–3.165)	0.001	1.495 (1.214–1.841)	0.001
Nodal metastasis N+/N0	3.154 (2.651–3.751)	0.001	1.721 (1.369–2.162)	0.001
Tumor size >2 cm	1.96 (1.23–3.13)	0.005	1.86 (1.11–3.12)	0.018
Treatment			Reference
PN	0.0 (0.0–22.80)	0.309	0.154 (0.140–0.169)	0.001
RN			0.408 (0.387–0.431)	0.001
Tumor localization hilum/polar	1.765 (1.147–2.715)	0.01	1.55 (1.23–2.841)	0.01

CI = confidence interval; HR = hazard ratio; PN = partial nephrectomy; RN = radical nephrectomy.

4. Discussion

The number of incidentally detected SRMs is increasing with the development of modern radiological imaging for specific and nonspecific renal indications. Technological progress has led to a dramatic increase in the early diagnosis of asymptomatic solid tumors, allowing earlier treatment with evident survival benefits.^[1,2]

Small renal masses <4 cm, corresponding to clinical stage T1a RCC, are among the most common renal tumors encountered in clinical practice.^[3] Approximately 95% of SRMs are localized at diagnosis, usually demonstrating slow growth kinetics.^[8] In addition, the majority of small RCC tumors are low grade (Fuhrman G1–2). Frank et al.^[9] found that 221 of 947 renal masses (23.3%) measuring <4 cm were benign and that 18.7% had high-grade histopathological features. In the present study, RCC was confirmed in 143 cases (86%), whereas benign tumors were present in 23 cases (14%). Only 17% of all cases were high-grade (Fuhrman G3–4). Univariate and multivariate analyses identified Fuhrman grade as a significant predictor of tumor recurrence.

The results of the first observation study of SRMs showed an overall average growth rate of 0.1 cm/yr without correlation with initial size or mass type. This raises the possibility of a period of initial observation in selected patients without disease progression or negative effects on survival rate.^[10] Other studies have shown a growth rate of renal masses of 0.28–0.36 cm/yr, demonstrating a 1%–2% probability of progression to metastatic disease. Pierorazio et al.^[11] showed in a multicenter nonrandomized study 5-year cancer-specific survival rates of 99% and 100% after primary treatment and AS, respectively.

A literature review by Ristau et al.^[12] showed that a period of initial AS is safe for most patients with SRMs. To determine tumor growth, it is necessary to perform frequent imaging and follow-up examinations during this period. It is significant that, when delayed intervention occurs, cancer outcomes are not compromised by the choice of AS when patients adhere to close follow-up regimens. Cancer-specific and metastasis-free survival rates are reportedly 98%–100%.^[12] However, before selecting AS, the risk of morbidity and mortality must be compared with that of surgical intervention.

Renal surgery via PN or RN is the standard treatment for cT1a neoplasia. It should be strongly recommended to healthy patients at low risk of mortality, particularly younger patients who are at risk of repeated ionizing radiation exposure.^[1,2,13] Surgical options for the treatment of SRMs encompass different interventions ranging from radical extirpation of the entire kidney to those that are nephron sparing and minimally invasive. Over the past decade, the percentage of PN performed has exceeded the percentage of RN performed on patients with renal masses <4 cm.^[13]

The oncological outcomes of RN or PN for the treatment of SRMs are generally acceptable. Nephron-sparing surgery is recommended for the treatment of SRMs, especially in young and otherwise healthy patients, unless it is unfeasible owing to tumor location within the renal vessels. Unlike RN, PN is not associated with increased cardiovascular risk and renal function impairment but shows the same oncological outcomes.^[14]

Furthermore, the challenging laparoscopic approach provides benefits such as a shortened operative time, decreased operative bleeding, and a reduced length of hospital stay. Overall, PN is the preferred treatment strategy for SRMs with suspected malignancy in patients who requiring definitive treatment. Partial nephrectomy is technically more challenging than RN because of the imperative of a negative surgical margin to preserve renal function. According to urological guidelines, older age and tumor complexity are indications for RN. In our study, more RN than PN were performed, as the majority of SRMs were well-differentiated malignant tumors. A low number of laparoscopic procedures was performed because of a delayed acquisition of the required equipment.

According to societal recommendations, PN should be the priority for the management of cases of cT1a renal masses, solid or Bosniak 3/4 complex cystic renal masses, anatomic or functionally solitary kidneys, bilateral tumors, known familial RCC, preexisting CKD, or proteinuria and comorbidities that are likely to affect renal function. Partial nephrectomy minimizes the risk of CKD or its progression and is associated with favorable oncological outcomes, including excellent local control.^[2,15] Choi et al.^[16] presented the risks of CKD after nephrectomy, stating that 53.1% of patients who underwent RN developed renal failure versus only 13.9% of patients who underwent PN. They also showed that hyperfiltration and a higher estimated glomerular filtration rate leading to proteinuria was more common after RN.^[16] However, RN is a reasonable management option in cases in which SRMs show increased oncologic potential, renal function is normal, and PN is technically challenging.^[2] A study of 500 patients randomized to the treatment of tumors ≤5 cm with PN versus RN showed no difference in oncological outcomes and a slight difference in renal function.^[17] Our multivariate analysis showed that operative modality could be a predictor of tumor recurrence.

Generally, whenever possible, PN should be selected over RN. Guidelines recommend RN for SRMs only for patients with complex tumors that are not treatable using PN or in cases in which PN may cause morbidity.^[1] In addition, the European Association of Urology guidelines do not recommend minimally invasive RN for patients with T1 renal tumors if PN is possible using any approach.^[18]

With the increased incidental detection of SRMs, there has been much interest in revealing the histopathological features of progression and possible preoperative parameters that could predict their aggressive potential. According to some authors, classical preoperative parameters important for the management of SRMs can be classified into 2 groups: patient-related parameters, such as age and sex, and factors closely related to the tumor, such as tumor size, histologic type, Fuhrman nuclear grade, and stage.^[19,20]

The potential impact of age on SRM characteristics and malignant potential remains unknown. The relationship between age and tumor aggressiveness was examined by Verhoest et al.,^[21] who concluded that SRMs diagnosed at a younger age were characterized by lower tumor stages and grades. Moreover, patients younger than 40 years were more likely to have favorable histologic patterns and papillary or chromophobe RCC and less likely to have clear cell RCC.^[21] Another study reported that SRM stage increased with advanced age. More precisely, the authors noted that the incidence of SRM finally staged as pT3 tumors in patients younger than 45 years, 45–75 years, and older than 75 years was 2.3%, 6.9%, and 14.3%, respectively.^[22] In contrast, DeRoche et al.^[20] reported that patient age was not associated with the pathological classification of SRMs. However, their study showed a strong correlation between female sex and the benign pathologic nature of SRMs, with benign neoplasms being almost twice as common in men.^[20] In the present study, the mean patient age was significantly higher in cases of malignant versus benign SRMs (p = 0.036).

Sex is an important predictor of malignancy in SRMs. More precisely, females appear to be protected from malignancy as discussed by Zisman et al.^[23] in a retrospective study that stated that female sex was associated with an increased risk of benign histology of renal masses, with 21% having benign disease versus 13% of men. A more recent study by Violette et al.^[24] investigating predictors of SRM malignancy reported that females with masses <2 cm had a significantly reduced odds of malignancy. Moreover, for patients with renal masses, the probability of metastatic recurrence was greater among men after 12 years of follow-up.^[25] However, our results showed that sex, age, and body mass index were not statistically significant predictors of metastatic recurrence.

Furthermore, among all preoperative parameters, tumor size appears to be the most valuable predictor of malignant features. Bhindi et al.^[26] recently showed that the probability of both malignant and aggressive histology increases with tumor size. Precisely, 2-cm tumors showed a lower risk of both malignant features (84% vs. 88%) and aggressive histology (18% vs. 29%) than 4 cm tumors. Interestingly, male patients have a greater risk of an aggressive histology independent of tumor size.^[26] Frank et al.^[9] found a higher incidence of malignant masses >4 cm than those <4 cm (23.3% vs. 8%), whereas 18.7% had high-grade histopathological features. With increases in tumor size, the risk of clear cell RCC versus papillary RCC increases, as does the risk of high- versus low-grade histopathological features.^[9]

Thompson et al.^[27] suggested that an increase in renal tumor size is highly associated with the likelihood of malignancy. They observed that each 1-cm increase in tumor size was associated with a 16% increase in the risk of malignancy. Furthermore, renal tumors 3–4 cm in size have a 13% chance of being benign versus an 87% chance of being RCC. Because preoperative imaging modalities are still unable to precisely predict the histologic nature of SRMs, the presumptive diagnosis of most renal tumors is currently limited to tumor size on radiographic imaging.^[27]

In our study, the mean tumor diameter was significantly larger in patients with malignant masses. When considering tumors with a diameter of up to 4 cm, malignant masses were present in 86% of specimens. However, when the tumor diameter was <2 cm, malignancy was detected in only 15% of cases. Univariate and multivariate analyses showed that tumor size, grade, stage T3–T4, nodal and distant metastasis status, and tumor localization were significant predictors of tumor recurrence.

The evaluation and selection of adequate treatment options for SRMs depend on the tumor characteristics, patient preference, and physician preference. The important characteristics that require consideration are the risk of recurrence, survival, renal outcomes, and complications. Further research is needed to improve overall survival and quality of life. Consequently, health care providers should be cautious when selecting appropriate techniques based on patient comorbidities and lifestyle factors.

5. Conclusions

The majority of small renal tumors in our study were malignant, but the incidence of renal cancer was low among SRMs with a diameter of <2 cm. Small renal carcinomas are mainly well- and moderately differentiated tumors. Furthermore, our results identified that tumor size, Fuhrman grade, stage, nodal and distant metastasis status, tumor localization, and treatment modality as characteristics with significance for predicting tumor recurrence.

Consequently, proper treatment decisions should be considered after assessment of the patient's age, comorbidities, tumor characteristics, imaging features, and pathohistological diagnosis. Researchers and clinicians are challenged to explore the most suitable diagnostic methods and treatment techniques to improve patient care and outcomes.

Conflict of interest statement

No conflict of interest has been declared by the author.