Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients
Abstract
:Simple Summary
Abstract
1. Background
2. Methods
2.1. Study Cohort
2.2. Validation Cohorts
2.3. Histomorphologic Parameters Analyzed
2.4. Cutoff Determination
2.5. ITBCC Grading Scheme
2.6. Statistical Methods
2.7. Ethics
3. Results
3.1. Metrics of Histomorphologic Parameters
3.2. Mutual Correlations of Histomorphologic Parameters
3.3. Clinicopathologic Correlations of Histomorphologic Parameters
3.4. Prognostic Significance of Histomorphologic Parameters in Univariate Survival Analysis
3.5. Prognostic Significance of Histomorphologic Parameters in Cox Proportional Hazard Analyses
3.6. Validation of the Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CNV | Copy number variation |
CPTAC | Clinical Proteomic Tumor Analysis Consortium |
DSS | Disease-specific survival |
FIGO | Fédération Internationale de Gynécologie et d’Obstétrique |
GDC | Genomic Data Commons |
H&E | Hematoxylin and eosin |
HPF | High-power field |
LVSI | Lymphovascular space invasion |
MELF | Microcystic, elongated, fragmented |
MSI | Microsatellite instability |
OS | Overall survival |
PFS | Progression-free survival |
POLE | Polymerase ε |
TB | Tumor budding |
TCGA | The Cancer Genome Atlas |
TIL | Tumor infiltrating lymphocytes |
TSR | Tumor–stroma ratio/stromal desmoplasia |
UCEC | Uterine Corpus Endometrial Carcinoma |
WHO | World Health Organization |
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TCGA | Munich | CPTAC | ||||
---|---|---|---|---|---|---|
Number of Patients with Available Data | % | Number of Patients with Available Data | % | Number of Patients with Available Data | % | |
Age (median, interquartile range) | 61.0, 13.0 | 69.7, 11.8 | 64.2, 5.7 | |||
N/A | 2 | 0 | 0 | |||
FIGO stage | ||||||
I | 172 | 75.4 | 28 | 59.6 | 21 | 84.0 |
II | 19 | 8.3 | 9 | 19.1 | 2 | 8.0 |
III | 34 | 14.9 | 6 | 12.8 | 2 | 8.0 |
IV | 3 | 1.3 | 4 | 8.5 | 0 | 0 |
Grading | ||||||
G1 | 61 | 26.8 | 9 | 19.1 | 8 | 32.0 |
G2 | 106 | 46.5 | 14 | 29.8 | 13 | 52.0 |
G3 | 61 | 26.8 | 24 | 51.1 | 4 | 16.0 |
pT | ||||||
1 | 120 | 75.9 | 29 | 61.7 | 20 | 83.3 |
2 | 23 | 14.6 | 11 | 23.4 | 2 | 8.3 |
3 | 15 | 9.5 | 7 | 14.9 | 2 | 8.3 |
4 | 0 | 0 | 0 | 0 | 0 | 0 |
N/A | 70 | 0 | 0 | 1 | ||
pN | ||||||
N0 | 187 | 85.0 | 43 | 91.5 | 16 | 66.7 |
N1/N2 | 21 | 9.5 | 4 | 8.5 | 0 | 0 |
NX | 12 | 5.5 | 0 | 0 | 8 | 33.3 |
N/A | 8 | 0 | 0 | 1 | ||
Lymphovascular space invasion | ||||||
absent | 187 | 82.0 | 33 | 75.0 | 17 | 94.4 |
present | 41 | 18.0 | 11 | 25.0 | 1 | 5.6 |
N/A | 0 | 3 | 7 | |||
Perineural invasion | ||||||
absent | 226 | 99.1 | 42 | 95.5 | 18 | 100 |
present | 2 | 0.9 | 2 | 4.5 | 0 | |
N/A | 0 | 0 | 7 | |||
Residual tumor | ||||||
R0 | 163 | 88.1 | 41 | 89.1 | 14 | 60.9 |
R1/R2 | 10 | 5.0 | 3 | 6.5 | 2 | 8.6 |
RX | 12 | 6.5 | 2 | 4.3 | 7 | 30.4 |
N/A | 43 | 1 | 2 | |||
Subtype | ||||||
MSI | 107 | 46.9 | 44 | 100 | 25 | 100 |
CN-LOW | 121 | 53.1 | - | - | - | - |
Grading | TB in 1 HPF | TB in 10 HPF | Minimal Cell Nest Size | TSR | TIL | MELF | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Low | High | p | Low | High | p | Low | High | p | Small | Big | p | Low | High | p | Low | High | p | Absent | Present | p | |
Age (median; IQR) | 60 (12.5) | 62 (17) | 0.632 | 61 (12.5) | 60 (14.5) | 0.446 | 60.5 (13) | 64.5 (19.5) | 0.899 | 59.5 (14.5) | 61 (12.25) | 0.308 | 61.5 (17.25) | 61 (13) | 0.844 | 61 (13) | 60.5 (10.75) | 0.974 | 61 (15) | 61 (7.5) | 0.919 |
N/A | 2 | 2 | |||||||||||||||||||
pT | |||||||||||||||||||||
1 | 90 (80.4) | 30 (65.2) | 0.108 | 110 (76.4) | 10 (71.4) | 0.259 | 114 (78.1) | 6 (50.0) | 0.045 | 17 (70.8) | 103 (76.9) | 0.401 | 5 (50.0) | 115 (77.7) | 0.012 | 115 (76.2) | 5 (71.4) | 0.194 | 103 (76.9) | 30 (69.8) | 0.227 |
2 | 14 (12.5) | 9 (19.6) | 22 (15.3) | 1 (7.1) | 20 (13.7) | 3 (25.0) | 3 (12.5) | 20 (14.9) | 1 (10.0) | 22 (14.9) | 23 (15.2) | 0 (0.0) | 20 (14.9) | 5 (11.6) | |||||||
3 | 8 (7.1) | 7 (15.2) | 12 (8.3) | 3 (21.4) | 12 (8.2) | 3 (25.0) | 4 (16.7) | 11 (8.2) | 4 (40.0) | 11 (7.4) | 13 (8.6) | 2 (28.6) | 11 (8.2) | 8 (18.6) | |||||||
N/A | 70 | 70 | |||||||||||||||||||
pN | |||||||||||||||||||||
0 | 142 (88.8) | 45 (75.0) | 0.001 | 176 (87.6) | 11 (57.9) | <0.001 | 177 (87.2) | 10 (58.8) | 0.007 | 23 (67.6) | 164 (88.2) | 0.003 | 12 (75.0) | 175 (85.8) | 0.249 | 179 (85.2) | 8 (80.0) | 0.324 | 164 (86.3) | 41 (77.4) | 0.007 |
+ | 8 (5.0) | 13 (21.7) | 14 (7.0) | 7 (36.8) | 16 (7.9) | 5 (29.4) | 9 (26.5) | 12 (6.5) | 3 (18.8) | 18 (8.8) | 19 (9.0) | 2 (20.0) | 14 (7.4) | 11 (20.8) | |||||||
X | 10 (6.2) | 2 (3.3) | 11 (5.5) | 1 (5.3) | 10 (4.9) | 2 (11.8) | 2 (5.9) | 10 (5.4) | 1 (6.2) | 11 (5.4) | 12 (5.7) | 0 (0.0) | 12 (6.3) | 1 (1.9) | |||||||
N/A | 8 | 8 | |||||||||||||||||||
FIGO stage | |||||||||||||||||||||
1/2 | 146 (87.4) | 45 (73.8) | 0.024 | 178 (85.6) | 13 (65.0) | 0.026 | 178 (84.8) | 13 (72.2) | 0.182 | 27 (75.0) | 164 (85.4) | 0.139 | 10 (62.5) | 181 (85.4) | 0.028 | 185 (84.9) | 6 (60.0) | 0.060 | 169 (85.8) | 39 (72.2) | 0.028 |
3/4 | 21 (12.6) | 16 (26.2) | 30 (14.4) | 7 (35.0) | 32 (15.2) | 5 (27.8) | 9 (25.0) | 28 (14.6) | 6 (37.5) | 31 (14.6) | 33 (15.1) | 4 (40.0) | 28 (14.2) | 15 (27.8) | |||||||
Grading | |||||||||||||||||||||
Low-grade | - | - | - | 165 (79.3) | 2 (10.0) | <0.001 | 164 (78.1) | 3 (16.7) | <0.001 | 9 (25.0) | 158 (82.3) | <0.001 | 11 (68.8) | 156 (73.6) | 0.770 | 162 (74.3) | 5 (50.0) | 0.137 | 144 (73.1) | 37 (68.5) | >0.999 |
High-grade | - | - | 43 (20.7) | 18 (90.0) | 46 (21.9) | 15 (83.3) | 27 (75.0) | 34 (17.7) | 5 (31.2) | 56 (26.4) | 56 (25.7) | 5 (50.0) | 53 (26.9) | 17 (31.5) | |||||||
Lymphovascular space invasion | |||||||||||||||||||||
Absent | 146 (87.4) | 41 (67.2) | <0.001 | 174 (83.7) | 13 (65.0) | 0.061 | 177 (84.3) | 10 (55.6) | 0.006 | 25 (69.4) | 162 (84.4) | 0.055 | 11 (68.8) | 176 (83.0) | 0.175 | 178 (81.7) | 9 (90.0) | 0.695 | 164 (83.2) | 44 (81.5) | 0.322 |
Present | 21 (12.6) | 20 (32.8) | 34 (16.3) | 7 (35.0) | 33 (15.7) | 8 (44.4) | 11 (30.6) | 30 (15.6) | 5 (31.2) | 36 (17.0) | 40 (18.3) | 1 (10.0) | 33 (16.8) | 10 (18.5) | |||||||
Perineural invasion | |||||||||||||||||||||
Absent | 167 (100) | 59 (96.7) | 0.071 | 207 (99.5) | 19 (95.0) | 0.168 | 209 (99.5) | 17 (94.4) | 0.152 | 35 (97.2) | 191 (99.5) | 0.291 | 15 (93.8) | 211 (99.5) | 0.136 | 216 (99.1) | 10 (100.0) | > 0.999 | 195 (99.0) | 54 (100.0) | >0.999 |
Present | 0 (0.0) | 2 (3.3) | 1 (0.5) | 1 (5.0) | 1 (0.5) | 1 (5.6) | 1 (2.8) | 1 (0.5) | 1 (6.2) | 1 (0.5) | 2 (0.9) | 0 (0.0) | 2 (1.0) | 0 (0.0) | |||||||
Residual tumor | |||||||||||||||||||||
R0 | 125 (91.9) | 38 (77.6) | <0.001 | 152 (90.5) | 11 (64.7) | <0.001 | 154 (90.6) | 9 (60.0) | 0.002 | 21 (72.4) | 142 (91.0) | 0.002 | 13 (92.9) | 150 (87.7) | 0.511 | 156 (89.1) | 7 (70.0) | 0.101 | 144 (90.0) | 38 (84.4) | 0.048 |
R1/R2 | 2 (1.5) | 8 (16.3) | 5 (3.0) | 5 (29.4) | 6 (3.5) | 4 (26.7) | 6 (20.7) | 4 (2.6) | 1 (7.1) | 9 (5.3) | 9 (5.1) | 1 (10.0) | 6 (3.8) | 5 (11.1) | |||||||
RX | 9 (6.6) | 3 (6.1) | 11 (6.5) | 1 (5.9) | 10 (5.9) | 2 (13.3) | 2 (6.9) | 10 (6.4) | 0 (0.0) | 12 (7.0) | 10 (5.7) | 2 (20.0) | 10 (6.2) | 2 (4.4) | |||||||
N/A | 43 | 43 | |||||||||||||||||||
Subtype | |||||||||||||||||||||
MSI | 63 (37.7) | 44 (72.1) | <0.001 | 93 (44.7) | 14 (70.0) | 0.036 | 93 (44.3) | 14 (77.8) | 0.007 | 25 (69.4) | 82 (42.7) | 0.004 | 7 (43.8) | 100 (47.2) | >0.999 | 99 (45.4) | 8 (80.0) | 0.049 | 92 (46.7) | 28 (51.9) | 0.846 |
CN-LOW | 104 (62.3) | 17 (27.9) | 115 (55.3) | 6 (30.0) | 117 (55.7) | 4 (22.2) | 11 (30.6) | 110 (57.3) | 9 (56.2) | 112 (52.8) | 119 (54.6) | 2 (20.0) | 105 (53.3) | 26 (48.1) | |||||||
Depth of myometrial invasion | |||||||||||||||||||||
Inner half | 113 (75.3) | 19 (40.4) | <0.001 | 123 (68.0) | 9 (56.2) | 0.407 | 127 (69.0) | 5 (38.5) | 0.033 | 14 (46.7) | 118 (70.7) | 0.019 | 8 (57.1) | 124 (67.8) | 0.556 | 128 (67.4) | 4 (57.1) | 0.686 | 120 (69.4) | 23 (51.1) | 0.056 |
Outer half | 37 (24.7) | 28 (59.6) | 58 (32.0) | 7 (43.8) | 57 (31.0) | 8 (61.5) | 16 (53.3) | 49 (29.3) | 6 (42.9) | 59 (32.2) | 62 (32.6) | 3 (42.9) | 53 (30.6) | 22 (48.9) | |||||||
N/A | 31 |
Grading (Low vs. High) | TB in 1 HPF (Low vs. High) | TB in 10 HPF (Low vs. High) | MCNS (Low vs. High) | TSR (Low vs. High) | TIL (Low vs. High) | MELF (Absent vs. Present) | Lymphovascular Space Invasion (Absent vs. Present) | ITBCC Grading Scheme (Bd1 vs. Bd2 vs. Bd3) | ||
---|---|---|---|---|---|---|---|---|---|---|
TCGA | DSS | <0.001 | <0.001 | <0.001 | <0.001 | 0.022 | 0.276 | 0.028 | <0.001 | <0.001 |
OS | <0.001 | <0.001 | <0.001 | <0.001 | 0.014 | 0.077 | 0.549 | 0.078 | <0.001 | |
PFS | 0.011 | <0.001 | 0.001 | 0.066 | 0.879 | 0.813 | 0.987 | 0.034 | 0.026 | |
MSI | DSS | 0.007 | <0.001 | <0.001 | 0.002 | 0.004 | 0.503 | 0.014 | 0.008 | 0.001 |
OS | 0.067 | <0.001 | <0.001 | <0.001 | 0.034 | 0.403 | 0.217 | 0.115 | <0.001 | |
PFS | 0.045 | <0.001 | 0.007 | 0.066 | 0.334 | 0.230 | 0.258 | 0.339 | 0.064 | |
CN-low | DSS | <0.001 | 0.061 | 0.043 | 0.212 | 0.735 | <0.001 | 0.666 | 0.041 | 0.168 |
OS | 0.010 | 0.377 | 0.326 | 0.723 | 0.215 | <0.001 | 0.644 | 0.523 | 0.682 | |
PFS | 0.240 | 0.177 | 0.115 | 0.692 | 0.366 | 0.034 | 0.281 | 0.049 | 0.483 |
TB in 1 HPF | TB in 10 HPF | Minimal Cell Nest Size | |||||||
---|---|---|---|---|---|---|---|---|---|
HR | p | HR | p | HR | p | ||||
TCGA | Age | 0.95 (0.90–1.01) | 0.091 | Age | 0.95 (0.89–1.01) | 0.085 | Age | 0.94 (0.88–1.00) | 0.061 |
FIGO stage 3/4 (1/2 = 1) | 2.72 (0.70–10.52) | 0.148 | FIGO stage 3/4 (1/2 = 1) | 3.14 (0.83–11.91) | 0.093 | FIGO stage 3/4 (1/2 = 1) | 3.76 (1.06–13.36) | 0.040 | |
Grading high-grade (low-grade = 1) | 7.60 (1.47–39.22) | 0.015 | Grading high-grade (low-grade = 1) | 9.03 (1.81–45.17) | 0.007 | Grading high-grade (low-grade = 1) | 9.89 (1.85–52.91) | 0.007 | |
LVSI present (absent = 1) | 5.83 (1.57–21.66) | 0.008 | LVSI present (absent = 1) | 5.22 (1.43–19.00) | 0.012 | LVSI present (absent = 1) | 5.38 (1.48–19.58) | 0.011 | |
TB in 1 HPF high (low = 1) | 3.41 (0.76–15.36) | 0.111 | TB in 10 HPF high (low = 1) | 2.21 (0.48–10.31) | 0.311 | Minimal cell nest size (absent = 1) | 1.31 (0.29–5.90) | 0.726 | |
MSI | Age | 0.96 (0.89–1.04) | 0.296 | Age | 0.97 (0.89–1.05) | 0.414 | Age | 0.98 (0.90–1.06) | 0.576 |
FIGO stage 3/4 (1/2 = 1) | 7.33 (1.19–45.08) | 0.032 | FIGO stage 3/4 (1/2 = 1) | 6.75 (1.16–39.14) | 0.033 | FIGO stage 3/4 (1/2 = 1) | 7.60 (1.40–41.25) | 0.019 | |
Grading high-grade (low-grade = 1) | 4.08 (0.36–46.58) | 0.257 | Grading high grade (low-grade = 1) | 5.66 (0.57–55.89) | 0.138 | Grading high-grade (low-grade = 1) | 4.46 (0.40–49.44) | 0.223 | |
LVSI present (absent = 1) | 1.79 (0.31–10.38) | 0.518 | LVSI present (absent = 1) | 1.62 (0.27–9.80) | 0.598 | LVSI present (absent = 1) | 2.68 (0.56–12.87) | 0.219 | |
TB in 1 HPF high (low = 1) | 11.90 (1.53–92.36) | 0.018 | TB in 10 HPF high (low = 1) | 6.48 (0.89–46.94) | 0.064 | Minimal cell nest size (absent = 1) | 3.72 (0.58–24.04) | 0.167 | |
CN-low | Age | 0.81 (0.67–0.99) | 0.039 | Age | 0.81 (0.67–0.99) | 0.039 | Age | 0.82 (0.67–0.99) | 0.036 |
FIGO stage 3/4 (1/2 = 1) | 0.31 (0.00–73.02) | 0.676 | FIGO stage 3/4 (1/2 = 1) | 0.31 (0.00–68.35) | 0.669 | FIGO stage 3/4 (1/2 = 1) | 0.91 (0.00–1437.06) | 0.979 | |
Grading high-grade (low-grade = 1) | 37.78 (1.88–757.32) | 0.018 | Grading high-grade (low-grade = 1) | 37.73 (1.87–760.53) | 0.018 | Grading high-grade (low-grade = 1) | 41.91 (2.29–767.91) | 0.012 | |
LVSI present (absent = 1) | 24.61 (1.19–509.08) | 0.038 | LVSI present (absent = 1) | 24.67 (1.20–508.78) | 0.038 | LVSI present (absent = 1) | 20.76 (0.91–471.82) | 0.057 | |
TB in 1 HPF high (low = 1) | 0.72 (0.00–181.61) | 0.907 | TB in 10 HPF high (low = 1) | 0.74 (0.00–179.96) | 0.913 | Minimal cell nest size (absent = 1) | 0.21 (0.00–579.03) | 0.703 | |
TSR | MELF | ITBCC scheme | |||||||
HR | p | HR | p | HR | p | ||||
TCGA | Age | 0.93 (0.87–0.99) | 0.017 | Age | 0.97 (0.90–1.04) | 0.341 | Age | 0.95 (0.89–1.01) | 0.089 |
FIGO stage 3/4 (1/2 = 1) | 2.95 (0.77–11.30) | 0.115 | FIGO stage 3/4 (1/2 = 1) | 2.64 (0.66–10.53) | 0.169 | FIGO stage 3/4 (1/2 = 1) | 3.08 (0.79–11.95) | 0.105 | |
Grading high-grade (low-grade = 1) | 11.61 (2.43–55.53) | 0.002 | Grading high-grade (low-grade = 1) | 9.29 (1.90–45.42) | 0.006 | Grading high-grade (low-grade = 1) | 8.31 (1.57–44.09) | 0.013 | |
LVSI present (absent = 1) | 4.25 (1.11–16.21) | 0.034 | LVSI present (absent = 1) | 4.94 (1.22–19.98) | 0.025 | LVSI present (absent = 1) | 6.22 (1.61–24.00) | 0.008 | |
TSR (high = 1) | 4.04 (0.59–27.82) | 0.156 | MELF (absent = 1) | 2.81 (0.68–11.54) | 0.152 | ITBCC scheme (Bd1/Bd2 = 1) | 2.21 (0.42–11.61) | 0.349 | |
MSI | Age | 0.94 (0.86–1.02) | 0.133 | Age | 1.03 (0.94–1.14) | 0.521 | Age | 0.98 (0.90–1.06) | 0.575 |
FIGO stage 3/4 (1/2 = 1) | 5.19 (0.87–30.94) | 0.070 | FIGO stage 3/4 (1/2 = 1) | 8.29 (0.97–70.51) | 0.053 | FIGO stage 3/4 (1/2 = 1) | 6.05 (1.08–33.98) | 0.041 | |
Grading high-grade (low-grade = 1) | 9.29 (1.06–81.38) | 0.044 | Grading high-grade (low-grade = 1) | 6.09 (0.45–82.29) | 0.174 | Grading high-grade (low-grade = 1) | 3.97 (0.36–44.35) | 0.263 | |
LVSI present (absent = 1) | 1.79 (0.30–10.67) | 0.524 | LVSI present (absent = 1) | 5.21 (0.57–47.97) | 0.145 | LVSI present (absent = 1) | 3.27 (0.64–16.74) | 0.155 | |
TSR (high = 1) | 5.38 (0.51–56.31) | 0.160 | MELF (absent = 1) | 14.14 (1.52–131.48) | 0.020 | ITBCC scheme (Bd1/Bd2 = 1) | 5.00 (0.72–34.68) | 0.103 | |
CN-low | Age | 0.81 (0.67–0.99) | 0.038 | Age | 0.82 (0.68–0.99) | 0.039 | Age | 0.81 (0.67–0.99) | 0.035 |
FIGO stage 3/4 (1/2 = 1) | 0.24 (0.01–10.75) | 0.463 | FIGO stage 3/4 (1/2 = 1) | 0.27 (0.00–201.15) | 0.701 | FIGO stage 3/4 (1/2 = 1) | 0.76 (0.00–2271.29) | 0.947 | |
Grading high-grade (low-grade = 1) | 35.18 (1.95–636.22) | 0.016 | Grading high-grade (low-grade = 1) | 30.37 (1.68–548.13) | 0.021 | Grading high-grade (low-grade = 1) | 40.88 (2.15–778.76) | 0.014 | |
LVSI present (absent = 1) | 24.55 (1.22–492.96) | 0.036 | LVSI present (absent = 1) | 24.82 (1.24–496.83) | 0.036 | LVSI present (absent = 1) | 22.47 (1.04–484.32) | 0.047 | |
TSR (high = 1) | 0.00 (0.00–Inf) | 0.999 | MELF (absent = 1) | 0.94 (0.00–417.53) | 0.984 | ITBCC scheme (Bd1/Bd2 = 1) | 0.27 (0.00–1388.68) | 0.762 |
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Stögbauer, F.; Geß, B.; Brambs, C.; Lautizi, M.; Kacprowski, T.; Ourailidis, I.; Bronger, H.; Kiechle, M.; Noske, A.; Keller, G.; et al. Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients. Cancers 2023, 15, 3832. https://doi.org/10.3390/cancers15153832
Stögbauer F, Geß B, Brambs C, Lautizi M, Kacprowski T, Ourailidis I, Bronger H, Kiechle M, Noske A, Keller G, et al. Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients. Cancers. 2023; 15(15):3832. https://doi.org/10.3390/cancers15153832
Chicago/Turabian StyleStögbauer, Fabian, Barbara Geß, Christine Brambs, Manuela Lautizi, Tim Kacprowski, Iordanis Ourailidis, Holger Bronger, Marion Kiechle, Aurelia Noske, Gisela Keller, and et al. 2023. "Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients" Cancers 15, no. 15: 3832. https://doi.org/10.3390/cancers15153832