Evaluation of central non-enhancement in solid renal masses

Author

Lu Mao

Published

August 12, 2025

Statistical analysis

Categorical variables are summarized by frequency and percentage; continuous variables are summarized by median and interquartile range (IQR). The agreement between two readers is assessed using the kappa coefficient for binary variables and the intraclass correlation coefficient (ICC) for continuous variables. The Wilcoxon rank sum test is used to compare histologic percent necrosis between groups with and without central non-enhancement (CNE). The correlation between volumetric non-enhancement to mass ratio and histologic percent necrosis is assessed using the Spearman correlation coefficient. Associations of histologic percent necrosis or volumetric non-enhancement to mass ratio with clinical outcomes are evaluated using the Spearman correlatione or Wilcoxon rank sum test as appropriate. P-values less than 0.05 are considered statistically significant. All statistical analyses are performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

Patient characteristics are summarized by site and overall in Table 1 below.

Table 1: Patient characteristics

Characteristic	Overall, N = 290¹	UTSW, N = 51¹	MGB, N = 26¹	NYU, N = 51¹	Stanford, N = 53¹	Umich, N = 59¹	UW, N = 50¹
Age (years)	65 (56, 72)	67 (58, 74)	62 (55, 69)	66 (59, 73)	65 (56, 74)	63 (57, 70)	66 (54, 70)
Gender
Female	89 (31%)	13 (25%)	6 (23%)	13 (25%)	27 (51%)	20 (34%)	10 (20%)
Male	201 (69%)	38 (75%)	20 (77%)	38 (75%)	26 (49%)	39 (66%)	40 (80%)
Clinical T Stage
3	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
p1b	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
pT1a	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
pT1b	13 (5.0%)	0 (0%)	0 (NA%)	0 (0%)	13 (27%)	0 (0%)	0 (0%)
pT2a	3 (1.2%)	0 (0%)	0 (NA%)	0 (0%)	3 (6.3%)	0 (0%)	0 (0%)
pT2b	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
pT3	2 (0.8%)	0 (0%)	0 (NA%)	0 (0%)	2 (4.2%)	0 (0%)	0 (0%)
pT3a	18 (6.9%)	0 (0%)	0 (NA%)	0 (0%)	18 (38%)	0 (0%)	0 (0%)
pT3a, M1	2 (0.8%)	0 (0%)	0 (NA%)	0 (0%)	2 (4.2%)	0 (0%)	0 (0%)
pT3a, N1	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
T1a	15 (5.8%)	0 (0%)	0 (NA%)	15 (29%)	0 (0%)	0 (0%)	0 (0%)
T1b	141 (54%)	32 (63%)	0 (NA%)	18 (35%)	0 (0%)	50 (85%)	41 (82%)
T2	37 (14%)	19 (37%)	0 (NA%)	0 (0%)	0 (0%)	9 (15%)	9 (18%)
T2a	11 (4.2%)	0 (0%)	0 (NA%)	11 (22%)	0 (0%)	0 (0%)	0 (0%)
T2b	7 (2.7%)	0 (0%)	0 (NA%)	7 (14%)	0 (0%)	0 (0%)	0 (0%)
T3a	3 (1.2%)	0 (0%)	0 (NA%)	0 (0%)	3 (6.3%)	0 (0%)	0 (0%)
T3a, N1	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
T3b	1 (0.4%)	0 (0%)	0 (NA%)	0 (0%)	1 (2.1%)	0 (0%)	0 (0%)
Unknown	31	0	26	0	5	0	0
WHO/ISUP Grade
Grade 1	6 (2.5%)	1 (2.3%)	2 (8.3%)	2 (5.4%)	0 (0%)	0 (0%)	1 (2.2%)
Grade 2	92 (39%)	22 (50%)	7 (29%)	18 (49%)	16 (44%)	10 (20%)	19 (42%)
Grade 3	93 (39%)	14 (32%)	9 (38%)	11 (30%)	12 (33%)	33 (65%)	14 (31%)
Grade 4	46 (19%)	7 (16%)	6 (25%)	6 (16%)	8 (22%)	8 (16%)	11 (24%)
Unknown	53	7	2	14	17	8	5
AJCC TNM Stage
Stage I	117 (40%)	24 (47%)	9 (35%)	0 (0%)	15 (28%)	40 (68%)	29 (58%)
Stage II	25 (8.6%)	6 (12%)	6 (23%)	0 (0%)	7 (13%)	6 (10%)	0 (0%)
Stage III	134 (46%)	19 (37%)	8 (31%)	50 (98%)	24 (45%)	13 (22%)	20 (40%)
Stage IV	13 (4.5%)	2 (3.9%)	3 (12%)	1 (2.0%)	6 (11%)	0 (0%)	1 (2.0%)
Unknown	1 (0.3%)	0 (0%)	0 (0%)	0 (0%)	1 (1.9%)	0 (0%)	0 (0%)
Pathology Report Necrosis > 0%	118 (41%)	13 (25%)	25 (96%)	16 (31%)	24 (45%)	21 (36%)	19 (38%)
Rhabdoid Features
Present	21 (7.2%)	5 (9.8%)	2 (7.7%)	3 (5.9%)	3 (5.7%)	3 (5.1%)	5 (10%)
Not Present	241 (83%)	42 (82%)	24 (92%)	48 (94%)	26 (49%)	56 (95%)	45 (90%)
Unknown	28 (9.7%)	4 (7.8%)	0 (0%)	0 (0%)	24 (45%)	0 (0%)	0 (0%)
Sarcomatoid Features
Present	21 (7.2%)	3 (5.9%)	1 (3.8%)	5 (9.8%)	7 (13%)	3 (5.1%)	2 (4.0%)
Not Present	257 (89%)	46 (90%)	25 (96%)	46 (90%)	36 (68%)	56 (95%)	48 (96%)
Unknown	12 (4.1%)	2 (3.9%)	0 (0%)	0 (0%)	10 (19%)	0 (0%)	0 (0%)
Presence of CNE (Reader 1)	215 (74%)	38 (75%)	26 (100%)	27 (53%)	45 (85%)	46 (78%)	33 (66%)
Presence of CNE (Reader 2)	227 (78%)	44 (86%)	26 (100%)	25 (49%)	53 (100%)	37 (63%)	42 (84%)
¹ Median (IQR); n (%)

Reader agreement

For the presence of central non-enhancement, the two reader assessments are cross-tabulated in Table 2 below. The kappa coefficient is 0.621 (p<0.001), indicating a moderate agreement.

Table 2: Cross-tabulation of central non-enhancement presence by reader

	Presence of CNE (Reader 2)		Total	p-value¹
	No	Yes	Total	p-value¹
Presence of CNE (Reader 1)				<0.001
No	49 (17%)	26 (9.0%)	75 (26%)
Yes	14 (4.8%)	201 (69%)	215 (74%)
Total	63 (22%)	227 (78%)	290 (100%)
¹ Pearson’s Chi-squared test

For the quantitative volumetricnon-enhancement to mass ratio, the scatter plot of the two reader assessments is shown in Figure 1 below. The ICC indicates a stronger agreement.

Figure 1: Scatter plot of non-enhancement to mass ratio by reader

CNE vs. histologic percent necrosis

Binary presence/absence of CNE

Consider Reader 1, Reader 2, and combinations of their assessments by AND and OR. The histologic percent necrosis is compared between groups with and without CNE for each definition of CNE presence. The results are summarized in Table 3 and Figure 2 below. Most of histologic percent necrosis is zero in the absence of CNE, and all comparisons are statistically significant.

Table 3: Wilcoxon rank sum test of histologic necrosis (%) vs. presence of CNE (N; median (IQR))

	No	Yes	P
Reader 1	N = 73; 0 (0, 0)	N = 205; 0 (0, 10)	<0.001
Reader 2	N = 63; 0 (0, 0)	N = 215; 0 (0, 10)	<0.001
Both present	N = 87; 0 (0, 0)	N = 191; 0 (0, 10)	<0.001
Either present	N = 49; 0 (0, 0)	N = 229; 0 (0, 10)	<0.001

Figure 2: Boxplot of histologic necrosis by reader-rated presence of CNE

Volumetric non-enhancement to mass ratio

The volumetric non-enhancement to mass ratio, by each reader and their average, is correlated with histologic percent necrosis in Figure 3. The correlations are moderately strong and statistically significant.

Figure 3: Correlation of non-enhancement to mass ratio with histologic necrosis (%)

Histologic percent necrosis vs. clinical outcomes

The histologic percent necrosis is compared between groups stratified by WHO/ISUP grade, AJCC TNM stage, rhabdoid features, and sarcomatoid features. The results are summarized in Table 4 (binary \(0\%\) vs. \(>0\%\)) and Figure 4 (quantitative) below.

Table 4: Association of histologic necrosis (%) vs. clinical outcomes

Characteristic	0%, N = 172¹	>0%, N = 118¹	p-value²
WHO/ISUP Grade			<0.001
Grade 1	3 (2.1%)	3 (3.1%)
Grade 2	70 (50%)	22 (23%)
Grade 3	55 (39%)	38 (40%)
Grade 4	13 (9.2%)	33 (34%)
Unknown	31	22
AJCC TNM Stage			<0.001
Stage I	79 (46%)	38 (32%)
Stage II	10 (5.8%)	15 (13%)
Stage III	80 (47%)	54 (46%)
Stage IV	2 (1.2%)	11 (9.3%)
Unknown	1 (0.6%)	0 (0%)
Rhabdoid Features			<0.001
Not Present	154 (98%)	87 (83%)
Present	3 (1.9%)	18 (17%)
Unknown	15	13
Sarcomatoid Features			<0.001
Not Present	161 (98%)	96 (85%)
Present	4 (2.4%)	17 (15%)
Unknown	7	5
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Figure 4: Boxplot of histologic necrosis by clinical outcomes

Due to large noise in \(>0\%\) group, quantitative test generally less significant than binary test in Table 4.

CNE vs. clinical outcomes

The reader-averaged non-enhancement to mass ratio is compared between groups stratified by WHO/ISUP grade, AJCC TNM stage, rhabdoid features, and sarcomatoid features. The results are summarized in Figure 5 and Table 5 below.

Figure 5: Correlation of non-enhancement to mass ratio with clinical outcomes

Table 5: Association of non-enhancement to mass ratio (reader average) vs. clinical outcomes

Reader-Averaged Ratio by WHO ISUP Grade
Characteristic	Grade 1, N = 6¹	Grade 2, N = 92¹	Grade 3, N = 93¹	Grade 4, N = 46¹
Median (IQR)	0.04 (0.02, 0.10)	0.09 (0.02, 0.17)	0.14 (0.05, 0.24)	0.09 (0.04, 0.18)
Unknown	2	37	21	8
¹ Median (IQR)

Reader-Averaged Ratio by AJCC TNM Stage
Characteristic	Stage I , N = 117¹	Stage II , N = 25¹	Stage III , N = 134¹	Stage IV , N = 13¹	Unknown, N = 1¹
Median (IQR)	0.08 (0.03, 0.16)	0.16 (0.04, 0.29)	0.10 (0.03, 0.19)	0.18 (0.12, 0.37)	0.01 (0.01, 0.01)
Unknown	36	3	49	1	0
¹ Median (IQR)

Reader-Averaged Ratio by Rhabdoid Features
Characteristic	Not Present, N = 241¹	Present, N = 21¹
Median (IQR)	0.11 (0.03, 0.20)	0.10 (0.04, 0.16)
Unknown	82	2
¹ Median (IQR)

Reader-Averaged Ratio by Sarcomatoid Features
Characteristic	Not Present, N = 257¹	Present, N = 21¹
Median (IQR)	0.10 (0.03, 0.19)	0.14 (0.06, 0.30)
Unknown	82	4
¹ Median (IQR)

Moderate correlations with WHO/ISUP grade and AJCC TNM stage;
Weak to no correlation with rhabdoid and sarcomatoid features.