A Large Contemporary Experience of Renal Tumors in Young: Clinico-pathological Profile and Long-Term Survival Patterns

Abstract

Renal tumors in young population are relatively rare. We reviewed our experience with renal masses in patients below 45 years of age. Our objective was to analyze clinico-pathological and survival characteristics of renal malignancy in young adults in contemporary era. The medical records of patients below 45 years of age who underwent surgery for renal mass at our tertiary care center between 2009 and 2019 were retrospectively analyzed. Pertinent clinical information was compiled, including age, gender, year and type of surgery, histopathology and survival data. A total of 194 patients who underwent nephrectomy for suspicious renal masses were included. Mean age was 35.5 (14–45) years and males were 125 (64.4%). A total of 29/198 (14.6%) specimens had benign disease. In addition, 155 (91.7%) out of 169 malignant tumors were renal cell carcinomas, clear cell variant being the most common type (51%). Compared to RCC, non-RCC tumors were more common in females (27.7 vs 78.6%, p < 0.0001), had an early age of diagnosis (27.2 vs 36.9 year, p < 0.00001) and poorer progression-free (58.3 vs 72.0%, p = 0.03) and overall survival (63.6 vs 84.2%, p = 0.02) at 6 years of follow-up. Renal masses in young adults are most commonly RCC but can also include other diverse types. RCC in young adults is usually organ confined and has good prognosis. As compared to RCC, non-RCC malignant tumors occur in young age, are more in females, and have worse prognosis.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13193-022-01643-2.

Introduction

Renal cell carcinoma (RCC) which comprises majority of renal masses is the third most common genitourinary malignancy. A cumulative risk of 1 in 620 with a incidence of nearly 18,000 cases has been reported from India [1]. Earlier studies looking at RCC indicate that the age at presentation is somewhat lower in India and at higher stage [2]. Renal tumors are most frequently encountered in fifth to seventh decade of life, being relatively uncommon in children and young adults.

An increase in the incidence of renal masses in young has been noticed in the recent decades and can be attributed to the surge in use of imaging modalities like ultrasonography and computed tomography for various reasons. This has led to a rising trend of patients being discovered incidentally with localized and smaller tumors and resulting in an improved 5 year survival [3].

Tumors in young and adolescents differ histopathologically from those in adults with relative preponderance of translocation type RCC, chromophobe RCC, and other rarer variants [4]. Besides, in younger patients, these tumors are more likely to develop secondary to hereditary syndromes like von Hippel-Lindau, Birt-Hogg-Dube, tuberous sclerosis, and hereditary papillary RCC. These patients tend to have bilateral disease and may also present with multiple tumors [5, 6].

Tumors in young and adolescents differ histopathologically from those in adults with relative preponderance of translocation type RCC, chromophobe RCC, and other rarer variants [4]. Besides, in younger patients, these tumors are more likely to develop secondary to hereditary syndromes like von Hippel-Lindau, Birt-Hogg-Dube, tuberous sclerosis, and hereditary papillary RCC. These patients tend to have bilateral disease and may also present with multiple tumors [5, 6].

Materials and Methods

We retrospectively reviewed the medical records of all patients less than 45 years of age who underwent nephrectomy (radical or partial, open, laparoscopic, or robotic) at our tertiary care center between January 2009 and April 2019. Institute ethical committee clearance was obtained for the same IEC-349/5/2022. We identified 194 such patients with solid renal masses or complex cystic lesions (Bosniak III or IV). Patients undergoing nephro-ureterectomy for upper tract TCC were excluded.

All patients underwent preoperative staging evaluation that consisted of abdominal computed tomography (CT) and/or magnetic resonance imaging (MRI) and chest X-ray. CT chest was done depending upon presenting symptoms, locally advanced stage of disease or surgeon’s discretion.

All hospital and clinic records were reviewed for presenting signs and symptoms, age, gender, preoperative testing, date and type of surgery, surgical pathology, and survival data. All RCCs were staged according to the American Joint Commission on Cancer 2009 TNM staging system and graded according to the Fuhrman grading system. Follow-up of the patients was obtained from uro-malignancy clinic and OPD records. Additionally, the cases were contacted individually on telephone and called for visits to OPD. Desired investigations and imaging were done according to recent American Urological Association (AUA) guideline panel recommendations for surveillance of RCC [7].

Data was analyzed using Strata 14 descriptive statistics. Kaplan Meier analysis was carried out to see the survival/progression pattern. Log rank test was applied to compare the survival/progression pattern of various parameters. p value < 0.05 was considered statistically significant. Continuous variables were compared among the group by independent t test whereas categorical variables were compared by Fisher’s exact test/chi-square test.

Results

Population Characteristics (Table 1)

Table 1.

Patient characteristics

Total patients, n	194
Mean age in years ± SD	35.5 ± 7.8
Sex, n (%)
Males	125 (64.4%)
Females	69 (35.6%)
Side, n (%)
Right	91 (46.9%)
Left	99 (51.0%)
Bilateral	4(2%)

A total of 194 young patients with solid or suspicious complex renal masses, who underwent nephrectomy (radical or partial) were analyzed. Mean age of patients was 35.5 (range: 14–45) years. Males undergoing surgery for renal masses were higher in number than females (64.4 vs 35.6%). Left side was more commonly involved than right (51 vs 46.9%). Mean follow-up was 41 (3–123) months.

Pathology (Table 2)

Table 2.

Pathology and procedure

Surgical procedure (n = 198)	No	(%)
Open radical nephrectomy	57	(28.7)
Laparoscopic radical nephrectomy	42	(21.2)
Robotic assisted radical nephrectomy	6	(3.0)
Open partial nephrectomy	26	(13.1)
Laparoscopic partial nephrectomy	19	(9.5)
Robotic partial nephrectomy	27	(13.6)
Radical nephrectomy with IVC thrombectomy	12	(6)
Cytoreductive nephrectomy	9	(4.5)
Final histopathology (n = 198)
Benign (n = 29)	No	(%)
Angiomyolipoma	15	(7.5)
Oncocytoma	10	(5.0)
Adenoma	2	(1.0)
Mixed epithelial stromal tumor	2	(1.0)
Malignant (n = 169)	No	(%)
Renal cell carcinoma (RCC)
Clear cell	101	(51.0)
Papillary	24	(12.1)
Variant histology	18	(9.0)
Chromophobe	12	(6.0)
Non-RCC
PNET	5	(2.5)
Ewing’s sarcoma	3	(1.5)
Wilm'stumor	2	(1.0)
Rhabdomyosarcoma	1	(0.5)
Extra intestinal GIST	1	(0.5)
Metastasis	1	(0.5)
Liposarcoma	1	(0.5)
Pathological Stage* (n = 169)	No	(%)
T1a	47	(27.8)
T1b	46	(27.2)
T2a	21	(12.4)
T2b	18	(10.6)
T3a	23	(13.6)
T3b	8	(4.7)
T3c	4	(2.3)
T4	2	(1.1)
Nodes	3	(1.7)*
Metastasis	9	(5.3)*

^*Pathological stage, node positivity and metastasis taken in relation to malignant tumors

There were 198 specimens from 194 cases. Twenty-nine (14.6%) specimens had benign disease while 169 (85.4%) were diagnosed with malignant tumor on final histology. Four patients had bilateral tumors, three of which had clear cell RCC while one had papillary RCC on pathology. Out of 198 total lesions, 155 (78.3%) were RCC. Clear cell variant was the most common RCC type with 101 (51%) patients, followed by papillary variant 24 (12.1%). In 18 (9%) patients, other variants of RCC were seen, including unclassified variant, multilocular cystic RCC with low malignant potential, eosinophilic variant, and sarcomatoid types. Fourteen (7%) patients had non-RCC tumors. Five (2.5%) were PNET, 2 (1%) Wilm’s tumor, and 3 (1.5%) Ewing’s sarcoma. Liposarcoma, rhabdomyosarcoma, extra-intestinal gastrointestinal stromal (GIST), and metastasis from other organ were found in 1 (0.5%) patient each.

Staging (Table 2)

T1a was the most common pathological stage comprising of 47/169 (27.8%) patients, closely followed by T1b disease in 46 (27.2%). Locally advanced disease was seen in 37 (21.8%) cases as per details in Table 2. T4 disease infiltrating adjacent structures like colon, spleen, or tail of pancreas was found in 2 patients (1.1%). Three patients had node positive disease at the time of diagnosis having histopathology of clear cell in two and papillary RCC in one respectively.

Surgery Type (Table 2)

Radical nephrectomy was the most common surgery performed using open (n = 57, 28.7%) or laparoscopic approach (42, 21.2%). Open partial nephrectomy was done in 26 (13.1%) while robotic partial nephrectomy and laparoscopic partial nephrectomy in 27 (13.6%) and 19 (9.5%) patients respectively. Radical nephrectomy with IVC tumor thrombectomy was done in 12 (6%) patients out of which 7 (58.3%) had clear cell RCC, 2 (16.7%) PNET, 2 (16.7%) papillary RCC, and 1 (8.3%) Ewing’s sarcoma.

Cytoreductive nephrectomy was done in 9 (4.5%) patients for metastatic disease at presentation. In this group, 5 patients had clear cell RCC while PNET, Wilm’s tumor, papillary RCC, and sarcomatoid differentiation of clear cell RCC was seen in 1 patient each.

RCC vs Non-RCC Malignant Tumor (Table 3)

Table 3.

Comparison between RCC and non-RCC malignant tumors

	RCC	non-RCC	p value
Total no. of patients	155	14
Age ± SD (years)	36.9 ± 7.1	27.14 ± 9.3	0.00001
No. of male patients (%)	112(72.2)	3(21.4)	0.0001
No. of female patients (%)	43(27.7)	11(78.6)	0.0001
No. of patients dead (%)	9(5.8)	4(28.6)	0.0006
Progression-free survival at 72 months in % (SE) for n = 131	72.0 (6.4)	58.3 (14.2)	0.03
Overall survival at 72 months in % (SE) for n = 131	84.2 (5.6)	63.6 (14.5)	0.02

There was significant difference between mean age at presentation of RCC (36.9 years) versus non-RCC (27.1 years) group at p = 0.00001. Male to female ratio was 2.6:1 in RCC group and 1:2.7 in non-RCC group respectively (p = 0.0001). Nine patients died in RCC group and 4 patients died in non-RCC group. Progression-free survival (72 vs 58.3%) and overall survival (84.2 vs 63.6%) at 72 months were found significantly higher in RCC group when compared with non-RCC malignant tumors (Table 3).

Progression-Free and Overall Survival (Fig. 1)

Fig. 1.

Kaplan–Meier survival estimates compared between RCC vs non-RCC and Right or Left sided tumors

Only 131 malignant tumor cases were included for progression-free and overall survival analysis (Supplementary material) with 38 cases being lost to follow-up for various reasons. T stage (T1, T2, and T3–4) and M stage (M0 and M1) were only factors affecting both progression-free survival (p = 0.02 and p = 0.03 respectively) and overall survival (at p = 0.04 and p = 0.03 respectively). There were not sufficient cases with N1 status for analysis. Interestingly, when comparing progression-free survival according to various other sub-sets, the right sided tumors depicted poorer outcome (p = 0.003), though overall survival was not statistically different at p = 0.26. Progression-free survival was not statistically different with respect to age groups (< 35 and > 35 year, p = 0.48), gender (male and female, p = 0.34), or type of surgery (partial and radical nephrectomy, p = 1.0). Similarly, overall survival was also not statistically different with respect to age groups (< 35 and > 35 year, p = 1.0), gender (male and female, p = 0.41), and type of surgery (partial and radical nephrectomy, p = 0.76).

Partial vs Radical Nephrectomy in T1 Disease (Fig. 2)

Fig. 2.

Kaplan–Meier survival estimates compared between Partial vs Radical nephrectomy for T1a and T1b tumors

We evaluated 93 histopathological proved malignant renal masses with T1a or T1b disease. In T1a group, 38/47 underwent partial nephrectomy while 9 underwent radical nephrectomy. Further progression-free survival and overall survival of these patients were compared for evaluable 75 cases for which follow-up data was available. Out of 38 T1a patients who underwent partial nephrectomy, 4 progressed and 2 deaths were recorded while no progression or death was recorded in radical nephrectomy group. Similarly, comparing partial and radical nephrectomy in 37 patients with T1b disease, 2 patients out of 15 progressed in partial nephrectomy group and 1 death was recorded. In radical nephrectomy group, 2 patients out of 22 progressed and 1 death was recorded. There was no statistical difference in overall or progression-free survival in patients undergoing radical nephrectomy or partial nephrectomy for T1 disease.

Discussion

To our knowledge, this is the largest series of solid or suspicious complex renal cystic masses in young adults and adolescents, which included benign as well as malignant renal masses.

Approximately 80% of renal masses in adult population represent cancers, with clear cell carcinoma accounting for the vast majority of malignant lesions [8]. In younger population, a higher percentage may be malignant as also seen in our series with 85.4% lesions being malignant ones. Also, a higher percentage of cases may have variant histology. Moreover, there is concern that these tumors are potentially more frequently familial, genetic, or having syndromic associations when compared to renal tumors occurring in elderly. Clearly, renal tumors in young and adolescents may be different from those presenting late in life and merited a more detailed evaluation.

We found that the most common type of malignant tumor in young adults, < 45 years of age, is still RCC [91.7% (155/169) vs 8.3% (14/169)] and clear cell carcinoma was most a common type of RCC forming 59.8% of all malignant tumors and 51% of all renal tumors (benign and malignant). Studies including all patient ages have shown that clear cell carcinoma is the most common of all renal cancer subtypes, accounting for approximately 75% of renal cancers, followed by papillary carcinoma (10%), chromophobe (5%), and other unclassified or undifferentiated subtypes [8]. Papillary subtype had higher prevalence than chromophobe RCC in our study (12.1% and 6.0%).

In our study, there were 18 cases of variant histology of RCC, the most common being multilocular cystic clear cell renal cell neoplasm of low malignant potential. It was found in 8 (4.0%) cases at mean age of 34.8 years. Male to female ratio was 3:1 and all patients were found to be recurrence-free on follow-up. Similar observations were seen in adult population by Chen J et al. [9]. Sarcomatoid differentiation of RCC was seen in 3 (1.5%) patients with mean age of 34.8 years. Out of these, one was lost to follow-up and the other two died within 8 months of diagnosis making it the most aggressive tumor as observed in older individuals [10]. Eosinophilic RCC was seen in 4 patients and 3 had unclassified variant of RCC respectively.

PNET was the most common non-RCC malignant renal tumor observed affecting 2.5% of total renal tumors. One among these had metastatic disease at presentation and 2 had IVC tumor thrombus. Mean age of presentation was 33.1 years and it was more common in females with male to female ratio 1:1.5. The overall survival (OS) of PNET was good with an average OS of 51.6 months. Yuvaraja B et al. presented a series of PNET in a single institute. They reported the median age at presentation of 27 years and overall median survival of 40 months with 3- and 5-year survival of 60% and 42%, respectively [11]. Unfortunately, in our series, 2 patients were lost to follow-up; hence, survival could not be accurately measured.

Benign renal neoplasms in adults have characteristic histology and variable clinic-biological profiles. Kutikov et al. studied 143 patients with renal mass and found that 16.1% of patients who underwent partial nephrectomy had benign masses [12]. Benign renal masses were found to be 14.6% in our study in young adult patients undergoing surgical procedure for suspicious renal mass. Snyder et al. analyzed 815 nephrectomies and 134 (16.4%) were associated with benign lesions, including oncocytoma in 87 (10.7%), angiomyolipoma in 17 (2%), simple cysts in 10 (1.2%), metanephric adenoma in 8 (1%), cystic nephroma in 5 (0.6%), and other in 7 [13]. In our observation, we found renal angiomyolipoma to be the most common benign tumor (7.5%) followed by oncocytoma (5.0%) of total renal tumors. Most of the patients of benign renal masses were normal on follow-up; one patient of AML developed tumor on contralateral side for which she was managed conservatively. Two patients had benign histopathology only not classified into any of the tumors.

A large number of young patients with RCC have small renal masses (SRM) (≤ 4 cm) at diagnosis. This may be related to diagnosis being incidental during evaluation for unrelated clinical issues. There are various treatment options available for such patients with SRM including partial or radical nephrectomy and open, laparoscopic, or robotic approaches. In our study, T1a and T1b were the most common T stage (overall 55% T1 lesions) supporting the fact that young adults are more likely to harbor localized disease. A majority of T1a and few T1b lesions underwent partial nephrectomy. Overall, partial nephrectomy (36%) could be feasible only in 36% cases.

Among 169 malignant tumors, 12(7.1%) patients presented with IVC tumor thrombus (T3). In these, open radical nephrectomy with IVC thrombectomy was our preferred approach. Seven (58%) patients had clear cell RCC on histopathology, two (16%) patients had PNET, two (16%) had papillary RCC, and one (8%) patient had Ewing’s sarcoma each respectively. The median survival in these patients was 13 months and 33% of the patients either died or had progression of the disease on follow-up. The prognosis of PNET with IVC tumor thrombus was good with one patient with 57 months of progression-free survival. Ewing’s sarcoma had worst prognosis and patient developed pulmonary metastasis within 2 months of surgery.

According to literature, overall incidence of renal masses presenting with IVC tumor thrombus is between 5 and 10% [14] which correlates with our study; however, the histopathological features and outcomes of renal mass presenting with IVC tumor thrombus in young adult population have not been previously described.

Metastatic disease was seen in 9 patients for which cytoreductive nephrectomy was performed. In our series, metastatic disease was found in 4.6% at the time of diagnosis; however, some authors have reported higher incidence up to 16% [15]. Three (33.3%) out of 9 patients with metastatic disease died within first year of diagnosis which shows that metastatic disease has dismal outcome in this group of patients. Also, relative lack of usage and efficacy of targeted therapy may contribute to such aggressive clinical course.

Interesting fact which was observed while comparing RCC with non-RCC malignant tumors was that non-RCC group encountered the disease at early age when compared to RCC group (36.9 years vs 27.1 years, p = 0.00001). This observation may be due to the fact that PNET and Wilms tumors tend to occur at early age [12].

Another finding which was observed is that non-RCC malignant tumor is more common in females (78.6 vs 27.7%, p value < 0.0001). Eggener et al. divided all renal masses into RCC and non-RCC group. The non-RCC group included benign as well as malignant lesions. They also concluded that young women are more likely to encounter non-RCC disease and survival in RCC group was better [16].

We observed that patients in RCC group 72% were alive and recurrence free at 72 months of follow-up as compared to non-RCC 58.3% (p value 0.03); and overall survival was also better in RCC group (84.2% vs 63.6% p value 0.02). These findings support the fact that RCC has a better prognosis as well as disease-free survival when compared to non-RCC in malignant renal tumors.

Positive points of our study were inclusion of all patients undergoing nephrectomy rather than only patients with RCC, which allowed us to define pathological outcomes. Also, we compared malignant tumors dividing them into RCC and non-RCC group categories which to the best of our knowledge has not been done in any other study. We retrospectively evaluated and obtained the follow-up of young adults presenting with IVC tumor thrombus. A relative shortcoming of our study was a 22.4% lost to follow-up rate, which is somewhat high but explained on the basis of long-distance referral catchment of the hospital.

Conclusions

Renal masses in young adults and adolescents are most commonly RCC. Non-RCC malignant tumor is more common in females and has worse prognosis. AML is the most common benign tumor leading to surgical excision. Our data suggest that RCC in young adults is usually organ-confined and typically associated with a favorable prognosis..

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Conflict of Interest

The authors declare no competing interests.