Clinicopathological characteristics and typing of multilocular cystic renal neoplasm of low malignant potential

Abstract

BACKGROUND

Up until now, no research has been reported on the association between the clinical growth rate of multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) and computed tomography (CT) imaging characteristics. Our study sought to examine the correlation between them, with the objective of distinguishing unique features of MCRNLMP from renal cysts and exploring effective management strategies.

AIM

To investigate optimal management strategies of MCRNLMP.

METHODS

We retrospectively collected and analyzed data from 1520 patients, comprising 1444 with renal cysts and 76 with MCRNLMP, who underwent renal cyst decompression, radical nephrectomy, or nephron-sparing surgery for renal cystic disease between January 2013 and December 2021 at our institution. Detection of MCRNLMP utilized the Bosniak classification for imaging and the 2016 World Health Organization criteria for clinical pathology.

RESULTS

Our meticulous exploration has revealed compelling findings on the occurrence of MCRNLMP. Precisely, it comprises 1.48% of all cases involving simple renal cysts, 5.26% of those with complex renal cysts, and a noteworthy 12.11% of renal tumors coexisting with renal cysts, indicating a statistically significant difference (P = 0.001). Moreover, MCRNLMP constituted a significant 22.37% of the patient population whose cysts demonstrated a rapid growth rate of ≥ 2.0 cm/year, whereas it only represented 0.66% among those with a growth rate below 2.0 cm/year. Of the 76 MCRNLMP cases studied, none of the nine patients who underwent subsequent nephron-sparing surgery or radical nephrectomy following renal cyst decompression experienced recurrence or metastasis. In the remaining 67 patients, who were actively monitored over a 3-year postoperative period, only one showed suspicious recurrence on CT scans.

CONCLUSION

MCRNLMP can be tentatively identified and categorized into three types based on CT scanning and growth rate indicators. In treating MCRNLMP, partial nephrectomy is preferred, while radical nephrectomy should be minimized. After surgery, active monitoring is advisable to prevent unnecessary nephrectomy.

Key Words: Renal cysts, Multilocular cystic renal neoplasm of low malignant potential, Computed tomography, Diagnosis, Treatment

Core Tip: A rather uncommon type of renal cell carcinoma, multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), exhibits distinct clinicopathological traits and often has a good prognosis. Although it bears resemblances to clear cell renal cell carcinoma in terms of clinical manifestations, pathology, diagnosis, and therapeutic approaches, there are notable differences as well. Despite ongoing discussions regarding the best practices for diagnosing and treating MCRNLMP, it is essential for clinicians to take into account its imaging features alongside other pertinent clinical considerations. This holistic approach should encompass selecting tailored treatment options and determining optimal follow-up schedules.

INTRODUCTION

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), previously termed multilocular cystic renal cell carcinoma (MCRCC), is a benign kidney lesion[1]. It typically accounts for merely 2% to 4% of cases of clear cell renal cell carcinoma (CCRCC) and often has a very favorable prognosis[2,3]. Despite MCRNLMP's distinctively benign prognosis, which is devoid of recurrence or progression, the International Society of Urological Pathology recognized its genetic and histopathological similarities to CCRCC and adopted it as a classification in 2012[2-4]. Based on the 2016 World Health Organization (WHO) classification, MCRNLMP is categorized as a tumor consisting exclusively of multiple cysts. These cysts are morphologically akin to low-grade CCRCC, as their septa contain small clusters of clear cells that lack expansive growth[5]. Although histopathological and genetic characteristics have received significant attention, preoperative computed tomography (CT) imaging features and clinical growth rates have been largely overlooked[6,7]. Despite its rarity, constituting < 2% of all cystic RCC cases, and its nonaggressive nature, distinguishing MCRNLMP from renal cysts and MCRCC remains clinically challenging. Accurate diagnosis of MCRNLMP is crucial as it can significantly impact patient management and outcomes. Delayed diagnosis or misdiagnosis may lead to inappropriate treatment or surgical intervention, potentially increasing the risk of morbidity and mortality. Comprehensive patient management and prognostic outcomes for MCRNLMP are not yet reported[8].

Therefore, our research has been dedicated to distinguishing MCRNLMP from renal cysts, taking into account clinical symptoms, medical imaging, and histopathological considerations. This study concentrated on preoperative CT imaging and growth rates to identify distinct characteristics between MCRNLMP and renal cysts in tumor imaging. Additionally, we investigate optimal management strategies for MCRNLMP by analyzing postoperative prognostic outcomes. With the aim of exploring this matter further, we embarked on a retrospective study, delving into the clinicopathological data of 76 patients diagnosed with MCRNLMP at the Second Hospital of Tianjin Medical University, spanning the period from January 2013 to December 2021.

MATERIALS AND METHODS

Study population

Study participants were 1520 patients treated for renal cystic disease at our institution between January 2013 and December 2021. This group comprised 1444 patients with renal cysts and 76 with MCRNLMP, who underwent renal cyst decompression, radical nephrectomy, or nephron-sparing surgery by laparoscopy. The pathology of each tumor was classified according to the 2004 WHO Histologic Classification of Kidney Tumors[9].

Study design

We reviewed the medical records and clinical data of the 1520 patients, assessing factors such as age, gender, tumor side, multiplicity, size, operation method, pathological type, and Fuhrman grade. According to European and United States guidelines, recurrent tumors and adverse reactions were monitored during postoperative follow-up[10]. The Bosniak classification system evaluates the malignant potential of renal cysts.

Inclusion and exclusion criteria

The Bosniak classification categorizes renal cysts into several classes, from I to IV, ranging from lowest to highest malignancy risk; Bosniak IIF to IV can be defined as complex renal cysts with the following characteristics: (1) Irregular or thick walls, with the cyst potentially having thickened or uneven walls; (2) enhancement features, indicating potential malignancy when contrast imaging shows enhancement inside or around the cyst; (3) septations or partitions, with the cyst possibly containing septa or multiple compartments; (4) calcifications on the cyst walls or septa; and (5) solid components, suggesting the presence of a tumor if solid tissue is found[6]. Exclusion criteria: patients with a history of RCC, other variant morphologies, or concomitant RCC. Preoperative imaging diagnosed 746 patients with simple renal cysts, 419 with complex renal cysts, and 355 with renal cysts combined with solid tumor components. We analyzed various factors affecting cyst growth rates during the preoperative period. From the initial diagnosis of renal cystic disease, we recommend that patients undergo imaging examinations, including ultrasound or CT scans, every 6 months until there is an indication for surgery. The number of examinations and the duration of follow-up vary for each patient. We set 2 cm/year as a critical threshold: 304 patients exhibited a cyst growth rate ≥ 2 cm/year, and 1216 < 2 cm/year. Postoperative histopathology confirmed 1444 patients with renal cysts and 76 with MCRNLMP. Of the 76 MCRNLMP patients, 67 underwent active monitoring following renal cyst decompression, while nine required additional kidney-sparing surgery or radical nephrectomy. The study design is shown in Figure 1.

Figure 1 A flow chart summarizing all the information in the study design. MCRNLMP: Multilocular cystic renal neoplasm of low malignant potential.

Surgical pathology

The pathology of surgically removed cystic renal masses was examined by our institutional pathologists. Three representative slides from each patient’s sections were independently reviewed by three pathologists with at least 3 years of genitourinary pathology experience at our institute, to identify pathological findings. The 2016 WHO criteria were utilized to define MCRNLMP[11]. Gross and microscopic features of the cystic renal masses were classified according to the Fuhrman nuclear grade (1 and 2: low grade, 3 and 4: High grade) and tumor, node, and metastasis staging[12].

Statistical analysis

This study utilized continuous and categorical statistical variables. For comparing categorical data, we applied the Fisher’s probability and χ² independence test. For continuous parameters, independent samples t-test was performed. The χ² test was used when no expected cell counts less than 1 and at most 20% of expected cell counts less than 5. Fisher’s exact probability test was used when expected cell count was < 1[13,14]. All statistical analyses were conducted using SPSS 22 (IBM Corporation, Armonk, NY, United States).

RESULTS

Baseline clinical data

Most renal cysts are simple cysts and are asymptomatic, and many of them are found incidentally through routine physical examinations and rarely require therapy. However, when the diameter of the cyst is > 5 cm and renal parenchyma (collection system) compression is present, regardless of the presence of flank or abdominal pain, surgical intervention is required[15]. A laparoscopic approach for renal cyst unroofing was the first described in 1992 and has since become the gold standard of treatment[16]. Our study included 1520 patients confirmed by pathological examination, comprising 1444 with renal cysts and 76 with MCRNLMP. Table 1 offers a detailed breakdown of the patients' general characteristics, clinical manifestations, imaging insights, surgical approaches, and pathological outcomes. The pathological examination confirmed the presence of MCRNLMP in 1.48% (11/746) of patients with simple renal cysts, 5.26% (22/419) with complex renal cysts, and 12.11% (43/355) with renal cysts combined with renal tumors. There were significant differences in the positive rates among these groups.

Table 1 General information of patients.

Medical data1	Renal cyst	Cyst combined with renal tumor	P value
Age (continuous)			0.35
Mean (IQR)	62 (50–72)	59 (51–68)
Sex (No. of cases)			0.72
Male, n (%)	675 (57.94)	180 (50.70)
Side (No. of cases)			0.16
Left, n (%)	561 (48.15)	165 (46.48)
Cyst diameter (cm)			0.27
Mean (IQR)	12 (9–14)	7 (6–9)
Operation method (No. of cases), n (%)			< 0.001
Renal cyst topping decompression	1165 (100.0)	346 (97.46)
Radical nephrectomy	0	3 (0.85)
Nephron sparing surgery	0	6 (1.69)
Pathological type (No. of cases), n (%)			< 0.001
Renal cyst	1132 (97.18)	312 (87.89)
MCRNLMP	33 (2.82)	43 (12.11)
Fuhrman grade (No. of cases), n (%)			0.06
I	13 (39.39)	26 (60.47)
II	20 (60.61)	17 (39.53)

¹Continuous variables were compared by independent samples t-test.

IQR: Interquartile range; MCRNLMP: Multilocular cystic renal neoplasm of low malignant potential.

CT imaging

Within the vast pool of 1520 patients afflicted with renal cystic disease, a significant portion consisting of 746 individuals were distinctly categorized as harboring simple renal cysts, whereas a subset of 419 patients presented with the more intricate complex renal cysts (Figures 2A and B). Additionally, 355 cases involved renal cysts combined with solid tumors (Figure 2C). Histopathology confirmed all cases, with 1444 diagnosed as renal cysts and 76 as MCRNLMP postoperatively (Figure 3). The tumor tissue, consisting of cysts of various sizes with inner walls that were solely lined by a single layer of clear cells, accounted for 5.0% of the patients.

Figure 2 Three types of computed tomography imaging of 1520 patients afflicted with renal cystic disease. A: Computed tomography (CT) imaging manifestations of a simple renal cyst in the left kidney, Bosniak grade I, with clear and smooth borders, uniform simple fluid density (0-20 HU), and no separation or calcification; B: CT imaging manifestations of a complex renal cyst in both kidneys, Bosniak grade II, with compartmental enhancement and irregularities; C: CT imaging manifestations of a renal cyst in the left kidney with a tumor in the right kidney, and the cyst is of Bosniak grade II, with clear boundaries, uniform high-density signals, and without enhancement.

Figure 3 The operative specimens and histopathology of multilocular cystic renal neoplasm of low malignant potential. A: The fresh operative specimens of multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) postoperatively; B: Microscopic histopathologic observations of MCRNLMP (Hematoxylin-Eosin staining and counted under microscopy with 400-fold magnification), the tumor tissue is composed of cysts in different sizes, and the inner wall is covered with a single layer of clear cells.

Postoperative pathological results and preoperative CT imaging

Postoperative pathology identified MCRNLMP in 11 of 746 cases (1.48%) of simple renal cyst, 22 of 419 (5.26%) cases of complex renal cyst, and 43 of 355 cases (12.11%) of renal cysts combined with renal tumors. The χ² test yielded P < 0.001, indicating significant differences among the three groups. Consequently, heightened vigilance is required for renal cysts combined with renal tumors in imaging. In cases of suspicion, nephron-sparing surgery should be considered over renal cyst decompression, along with frozen pathological examination (Table 2). Based on preoperative CT imaging observations, MCRNLMP can be comprehensively classified into three discrete groups: Group I, encompassing simple renal cysts; Group II, comprising complex renal cysts; and Group III, featuring renal cysts in conjunction with renal malignancies (Tables 2 and 3). When a tumor is highly suspected of malignancy, we recommend nephron surgery in combination with frozen pathology.

Table 2 Comparison of postoperative pathological positive rates between simple renal cysts and cysts combined with renal tumors diagnosed preoperatively, n (%).

Index1	Group	Benign	MCRNLMP	P value
Preoperative diagnosis	Simple renal cyst (type I)	735 (98.52)	11 (1.48)	< 0.001
	Complex renal cyst (type II)	397 (94.74)	22 (5.26)
	Cysts combined with renal tumors (type III)	312 (87.89)	43 (12.11)

¹The above results with χ² test showed significant difference in the pathological positive rate of various preoperative diagnosis (P < 0.001).

MCRNLMP: Multilocular cystic renal neoplasm of low malignant potential.

Table 3 Univariate cox regression analysis of positive rates in patients with multilocular cystic renal neoplasm of low malignant potential.

Univariate analysis	Odds ratio	95%CI	P value
Preoperative diagnosis			< 0.001
Simple renal cyst (type I)	1 (reference)
Complex renal cyst (type II)	3.67	2.57–5.13
Cysts combined with renal tumors (type III)	9.19	6.46–12.88
Growth rates			< 0.001
< 2.0 cm/yr	1 (reference)
≥ 2.0 cm/yr	43.51	30.90-61.66

Cyst growth rates during the preoperative monitoring period and postoperative pathological results

During the preoperative period, we analyzed various factors influencing cyst growth rates, setting 2 cm/year as a critical threshold. Of the 1520 patients diagnosed with renal cystic disease, 304 exhibited a growth rate of at least 2.0 cm/year, among which 68 (22.37%) were postoperatively confirmed as MCRNLMP. Conversely, 1216 had a growth rate < 2.0 cm/year, with eight (0.66%) diagnosed as MCRNLMP. The χ² test showed P < 0.001, signifying a significant difference between the two groups. Furthermore, among the 304 patients who exhibited a growth rate of at least 2.0 cm/year, postoperative pathology revealed MCRNLMP in 30 out of 197 patients with simple renal cysts (15.23%), and in 38 out of 107 patients with complex renal cysts (35.51%). This significant difference suggests a distinction between the two groups. Thus, monitoring the growth rate of renal cysts is crucial, regardless of suspected malignant transformation. This is important for patients with complex cysts on imaging, where early surgical intervention may be necessary (Tables 3 and 4). Therefore, vigilance should be paid to the possibility of malignancy in the case of growth rate ≥ 2.0 cm/year and complex renal cysts.

Table 4 Comparison of postoperative pathological positive rates in various growth rates during preoperative monitoring, n (%).

Index1	Group	Benign	MCRNLMP	P value
Growth rates	≥ 2.0 cm/yr	236 (77.63)	68 (22.37)	< 0.001
	< 2.0 cm/yr	1208 (99.34)	8 (0.66)

¹The above results of χ² test showed the significant difference in the pathological positive rate of various growth rates (P < 0.001).

MCRNLMP: Multilocular cystic renal neoplasm of low malignant potential.

No significant difference was observed in positive recurrence rate with various treatment methods

Postoperative follow-up of 76 patients with MCRNLMP ranged from 12 to 72 months, with an average of 42 mo. Nine patients who initially underwent renal cyst decompression subsequently required a second operation, and pathological analysis confirmed the presence of MCRNLMP in all cases. None of these patients showed recurrence or metastasis during postoperative follow-up. Sixty-seven patients underwent active monitoring without additional surgery after renal cyst decompression, with MCRNLMP confirmed pathologically. During the third year of postoperative follow-up, only one case exhibited suspicious recurrence on CT, but the patient refused to undergo reoperation. According to an exact probability test, the calculated P value was 1, suggesting that there was no statistically significant difference between the two groups (Table 5). Among the nine MCRNLMP patients who underwent secondary surgical procedures, six underwent partial nephrectomies, while three underwent radical nephrectomies. Postoperative specimens revealed residual tumors in only two of these patients. During the follow-up period, none of these patients experienced recurrence or metastasis (Table 6). It can be seen that MCRNLMP had low malignancy and good prognosis.

Table 5 Comparison of differences in the positive recurrence rate of various treatments, n (%).

Index1	Group	Renal cyst topping decompression + active monitoring	Renal cyst topping decompression + nephron-sparing surgery or radical nephrectomy	P value
Re-examination	No recurrence or metastasis	66 (98.50)	9 (100.0)	1
	Recurrence or metastasis	1 (1.50)	0 (0.00)

¹The above statistical results of the Fisher’s probability test showed that the positive rate of recurrence after various surgical methods was not significant (P = 1).

Table 6 Comparison of differences in the positive recurrence rate of various surgical methods, n (%).

Index1	Group	Renal cyst topping decompression + nephron-sparing surgery	Renal cyst topping decompression + radical nephrectomy	P value
Re-examination	No recurrence or metastasis	6 (100.0)	3 (100.0)	1
	Recurrence or metastasis	0	0

¹The above statistical results of the Fisher’s probability test showed that the positive rate of recurrence after various surgical methods was not significant (P = 1).

DISCUSSION

The 2016 WHO standards classify RCC into 10 pathological types[9]. MCRCC is a rare form, comprising only 1%–2% of renal malignancies. MCRNLMP is even less common, representing < 1%[17]. Generally, these tumors are low-grade with few malignant cells, resulting in good prognosis. Notably, there is no clear correlation between tumor size and prognosis[7]. The clinical diagnosis of MCRNLMP poses significant challenges due to its rarity and the absence of distinct clinical or histopathological characteristics. Like renal cysts, most MCRNLMP patients show no noticeable symptoms. However, patients with large tumors may experience abdominal or flank discomfort. Imaging studies typically reveal renal cysts as single, fluid-filled cystic structures with clear boundaries, whereas MCRNLMP is characterized by a multilocular cystic structure, comprising multiple separated cystic chambers. However, MCRNLMP is often incidentally identified and can be difficult to distinguish from other complex cystic renal tumors in imaging, leading to a high risk of misdiagnosis or missed diagnosis[18].

Our findings demonstrated that MCRNLMP comprised less than 5% of kidney diseases, corroborating prior reports that estimated its occurrence to be between 2% and 4% among various kidney ailments, encompassing both cystic and renal tumor conditions[6]. Significant challenges are posed by the cystic growth pattern of MCRNLMP in preoperative diagnosis. Currently, Bosniak grading remains the primary diagnostic standard for renal cystic lesions. Recently, a Chinese scholar introduced the Renal CYST INDEX (RCI), a new weighted quantitative scoring system based on CT performance, currently undergoing prospective validation[19]. The RCI system evaluates four parameters—cyst wall, separation, solid nodules, and contents—potentially offering greater accuracy than Bosniak grading, particularly in suspected malignant cysts[20]. However, this new scoring system has not yet supplanted Bosniak grading and requires further exploration and validation. Previous studies suggest that MCRNLMP can occur across various Bosniak grades[21-24]. In our study, pathological examination confirmed MCRNLMP in 1.48% (11/746) of patients with simple renal cysts, 5.26% (22/419) with complex renal cysts, and 12.11% (43/355) with renal cysts combined with renal tumors, showing significant differences in positive rates among these groups. Consequently, we suggest the following hypothesis for clinical application: MCRNLMP should be categorized into three distinct types, utilizing preoperative CT imaging as the basis for classification. Type I typically manifests as simple renal cysts, Type II as complex renal cysts, and Type III as a combination of renal cysts and renal tumors. Given the varying postoperative pathological positive rates, each type necessitates distinct treatment approaches. Given the significant risk of MCRNLMP, utmost vigilance is imperative when managing renal cysts, especially those of the complex nature, that are comorbid with renal tumors.

The diameter of a kidney mass is critical for assessing its severity. In kidney cancer T staging, tumors < 7 cm are classified as T1, while those > 7 cm but < 10 cm are classified as T2[25,26]. Presently, various surgical methods exist for RCC, with the tumor diameter being a vital criterion in selecting the surgical approach[27]. Current guidelines, including those of the European Association of Urology and the American Urological Association, dictate treatment strategies for renal cysts based on their size. Cysts < 4 cm warrant observation, close follow-up, and regular imaging rechecks; cysts between 4 and 8 cm may be treated with puncture and aspiration sclerotherapy under color Doppler ultrasound; and cysts > 8 cm typically require laparoscopic operation[28]. Our investigation delved deep into numerous factors that could potentially impact the rates of cyst growth during the crucial preoperative surveillance stage. Setting 2 cm/year as the critical growth rate, we found that ≥ 2.0 cm/year is a high-risk factor. In our study of 304 patients with a cyst growth rate ≥ 2.0 cm/year, 30 of 197 patients with simple renal cysts (15.23%) and 38 of 107 with complex renal cysts (35.51%) were confirmed as MCRNLMP postoperatively, indicating a significant difference between the two groups. Therefore, monitoring the growth rate of renal cysts is important. For cysts with an annual growth rate > 2 cm, and particularly complex cysts visible on imaging, early surgical intervention is crucial due to the increased likelihood of MCRNLMP.

Several studies with follow-up > 5 years have been conducted. Highlighting this fact, one study found zero recurrences or metastases among the 45 MCRNLMP patients who underwent either radical resection or partial nephrectomy[29]. Another study confirmed 16 cases of polycystic kidney cancer as MCRNLMP. Following decompression of the renal cysts, 15 patients underwent supplementary nephrectomies, and residual cancer cells were detected in eight of them. The remaining case, closely monitored for 96 mo, showed no recurrence. The above studies indicate that patients undergoing supplementary radical nephrectomy after renal cyst topping decompression experienced no recurrence or metastasis, and the likelihood of residual cancer tissue exceeded 50%, suggesting the necessity of supplementary radical nephrectomy. However, our results differed. Among 76 MCRNLMP patients, only one suspected recurrence occurred. Nine patients underwent secondary operations after renal cyst topping decompression: Six had secondary partial nephrectomies, three had radical nephrectomies, and only three cases showed residual tumors in postoperative samples. No recurrence or metastasis was noted during follow-up, suggesting a potential for overtreatment in MCRNLMP. As a result, patients with preoperative imaging revealing simple renal cysts and normal cyst walls can be closely monitored postoperatively, thereby avoiding unnecessary secondary surgical procedures. Nonetheless, nephron-sparing surgery remains crucial for those patients who exhibit complex renal cysts, which are preoperatively indicated and subsequently confirmed as MCRNLMP through pathological examination. Clinically, caution is advised when managing renal cystic diseases. Special attention should be given to preoperative examinations and imaging of renal cysts combined with tumors, with vigilance for MCRNLMP. Simple renal cyst topping surgery should be avoided. For rapidly growing renal cystic lesions, particularly those with complex cysts identified on imaging, prompt surgical intervention is necessary. For patients with preoperative diagnoses of simple renal cysts, surgery should not be delayed based on the small size of the cyst. Additionally, we propose that potential predictors such as CT scanning and growth rate can aid in differentiating MCRNLMP from renal cysts. If postoperative pathology reveals MCRNLMP in patients initially diagnosed with simple renal cysts and treated with decompression, proactive monitoring is recommended to avoid unnecessary secondary surgeries.

Our study has several limitations, including the retrospective observational design, the relatively small number of patients, single-center data, and the lack of long-term follow-up. Despite these shortcomings, we have gained some experience and hope to provide some information for surgeons.

CONCLUSION

MCRNLMP, a rare type of RCC, with unique clinicopathological features and favorable prognosis. It shares similarities with, but also differs from, CCRCC in clinical presentation, pathology, diagnosis, and treatment. While controversies remain in the diagnosis and treatment of MCRNLMP, clinicians should consider its imaging characteristics and other clinical factors comprehensively. This approach includes adopting suitable and personalized treatment methods and determining the appropriate follow-up intervals.