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CA Corpus Uteri English
CA Corpus Uteri English
Table 1
Carcinoma of the corpus uteri: Surgical staging classification (FIGO nomenclature, Rio de Janeiro, 1988)
Correspondence to: FIGO Annual Report Editorial Office, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
fax: +39-0257489872, e-mail: figo@ieo.it
80 WT CREASMAN, F ODICINO et al
Fig. 1. Carcinoma of the corpus uteri. Staging uterine cancer. Primary tumor and metastases (FIGO).
CARCINOMA OF THE CORPUS UTERI 81
Table 3
Carcinoma of the corpus uteri: Clinical staging classification (1971) (no longer adopted for FIGO classification)
Table 4
Carcinoma of the corpus uteri: Definitions of treatments
Treatment Definition
None No treatment
Surgery alone Surgery as first therapy and no other therapy(ies) within 90 days from the date of surgery. Subsequently,
patients can be given any further treatment.
Radiotherapy alone External radiotherapy and/or intracavitary irradiation as first therapy(ies) and no other therapy(ies) within
90 days from the end of teletherapy/brachytherapy. Subsequently, patients can be given any further
treatment.
Radio-surgery Intracavitary irradiation and/or external radiotherapy as first therapy(ies) and then surgery within 60 days
from the end of brachytherapy/teletherapy. Subsequently, patients can be given any further treatment.
Surgery + adjuvant radiotherapy Surgery as first therapy and then external radiotherapy and/or intracavitary irradiation within 90 days
from the date of surgery. Subsequently, patients can be given any further treatment.
Surgery + adjuvant chemotherapy Surgery as first therapy and then chemotherapy within 90 days from the date of surgery.
Adjuvant hormonal therapy Surgery or radiotherapy or chemo-radiotherapy as first therapy and then hormonal therapy within 90 days
from the end of surgery/radiotherapy/chemo-radiotherapy. Subsequently, patients can be given any further
treatment.
with clinical staging is very small, further references will the use of postoperative radiation and chemotherapy
mainly refer to those who were surgically staged. remains relatively constant between data from Volumes
Multiple factors are again appreciated to be important 24 and 25. Whether or not this will remain the same
prognostically. Age increases with stage. Those patients subsequently, in view of the recent GOG data which
clinically staged were considerably older than those note that chemotherapy appears to be more effective than
surgically staged which may explain the reason for radiation therapy, remains to be seen.
clinical staging only in the older population. This almost Since the classic surgical staging studies done in the
decade difference in age per stage is also present in the 1970s and 1980s, lymph node metastasis has been a
data from Volume 24. major factor in staging and subsequent treatment in
Grade, and in particular myometrial invasion, appeared patients with endometrial cancer. Nodal metastasis both
to be related to stage as these prognostic factors increase to the pelvic and para-aortic area are related to depth
with age (Tables 12 and 14). Whether or not this is a of the invasion and grade. Volume 25 data suggests that
time sequence in progression of disease or just a later those patients with early disease (G1 endometrium only)
age occurrence is unknown. may have metastasis to the pelvic nodes in 3.5% of cases
Endometrioid carcinoma histotype is present in 85% where previous reports suggested it may be essentially
of patients reported (Table 17). Poor prognostic cell types zero. As grade and depth of invasion increases, the
(papillary and clear cell) represent only 6% of surgically chance of pelvic and para-aortic node metastasis also
staged patients, although the 501 reported cases probably increases in a linear fashion (3.4% for G1, endometrium
represent the largest reported number of these histotypes. only, to 28% in G3 deep muscle invasion) for pelvic
Of all endometrioid types, 86% are early stage (I or II) nodes and a similar situation with para-aortic nodes but
compared with 57% for papillary and 70% with clear cell to a lesser degree (Tables 22−26).
types. Survival is obviously stage related. This is true even
Age has been appreciated as an important prognostic within a given stage (Fig. 7) as those with Stage Ia
factor. Younger patients at each stage have a considerably have a 91% 5-year survival compared with 81% for
better prognosis than those who are older with the Stage Ic. The importance of surgical staging is again
greatest difference in those who are 80 years of age or noted in comparison with clinical staging (Fig. 8). Stage I
older (Table 18). The one exception is Stage IV in which patients had a 5-year survival of 88% compared with only
the numbers are small, but even there an age difference 51% of those clinically staged. This strongly suggests
is present. that those who are clinically staged have occult disease
In regards to treatment, the data suggest that as not appreciated clinically. Well known data suggests that
stage increases adjunctive therapy in addition to surgery about 25% of clinical Stage I patients have disease extant
is used (Tables 19, 20). It is interesting to note that to the uterus. This is also true for a grade within a given
CARCINOMA OF THE CORPUS UTERI 83
Table 5
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients by center and stage
Table 5, continued
Table 6
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients (%) by country and treatment (Stage I), n = 5823
All 5823 0 42 1 1 53 2 0 0
South Africa 22 – 77 – – 23 – – –
Argentina 28 – 75 – – 25 – – –
Brazil 10 – 50 – – 50 – – –
Canada 4 – 75 – – 25 – – –
Chile 28 – 21 – – 79 – – –
Peru 1 – 100 – – – – – –
USA 333 – 75 1 1 18 3 2 0
Uruguay 3 – 100 – – – – – –
China 109 – 72 – – 17 10 1 –
India 6 – 17 – – 83 – – –
Indonesia 4 – 25 – – 25 50 – –
Israel 28 – 68 – – 32 – – –
Japan 221 – 76 – – 8 15 – 0
Korea 79 – 78 – – 19 1 1 –
Philippines 69 – 65 1 – 29 4 – –
Thailand 85 – 58 1 1 39 1 – –
Austria 208 – 41 – 3 52 2 1 1
Croatia 135 – 19 4 7 67 – 1 3
Czech Republic 314 – 16 3 1 78 1 2 0
Finland 205 – 21 – – 78 1 – –
France 125 – 26 – 2 53 19 – –
Germany 349 0 52 1 1 44 1 – –
Greece 87 – 55 – – 45 – – –
Italy 114 – 86 – – 12 1 – 1
Poland 742 – 3 0 4 92 – 0 –
Portugal 275 – 19 1 1 76 4 – –
Slovakia 79 1 14 4 – 80 1 – –
Slovenia 363 – 47 0 1 51 1 1 –
Spain 541 1 58 0 – 40 1 – –
Sweden 1020 0 50 3 0 44 1 – 1
Switzerland 4 – – – – 100 – – –
Yugoslavia 137 – – 1 – 99 – – –
Australia 95 1 56 1 – 28 3 1 9
stage (Figs. 10−13). The significance of surgical staging Even within Stage I there is a difference in survival
should be self evident particularly in early stage disease. as endometrioid tumors have an 89% 5-year survival
Histotypes of endometrial cancers are well recognized compared with 82% for clear cell and 77% for papillary
important prognostic factors. Endometrioid tumors have cancers (Fig. 15). This holds true for all stages.
a 5-year survival of 81% compared with 60% for As previously noted, grade, depth of invasion within a
clear cell and 48% for papillary carcinoma (Fig. 14). given stage are prognostically important. It appears that
This is obviously related to a certain degree to the grade and depth of invasion are independently important
fact that poor histotypes have a more advanced stage. but complement each other. Stage Ia G1 has a 93%
86 WT CREASMAN, F ODICINO et al
Table 7
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients (%) by country and treatment (Stage II), n = 963
All 963 0 11 2 2 80 4 0 0
South Africa 4 – 25 – – 75 – – –
Argentina 10 – 30 – – 70 – – –
Brazil 3 – – – – 67 – 33 –
Chile 9 – 11 – – 89 – – –
Peru 3 – 33 33 – 33 – – –
USA 55 2 33 2 4 47 13 – –
Uruguay 2 – 50 – – 50 – – –
China 22 – 23 – 5 64 9 – –
India 1 – – – – 100 – – –
Indonesia 2 – – – – 50 50 – –
Japan 37 – 51 – – 19 30 – –
Korea 8 – 38 – 13 50 – – –
Philippines 15 – 13 – 7 80 – – –
Thailand 23 – 4 9 9 78 – – –
Austria 20 – 30 5 – 50 15 – –
Croatia 20 – – 10 10 80 – – –
Czech Republic 56 – – 7 – 91 2 – –
Finland 28 – – – – 93 7 – –
France 24 – 4 – 4 83 8 – –
Germany 50 2 26 6 – 64 2 – –
Greece 5 – – – – 100 – – –
Italy 17 – 35 – – 59 – – 6
Poland 185 – 1 – 1 98 – – –
Portugal 59 – 5 – 2 85 8 – –
Slovakia 19 – – 5 – 95 – – –
Slovenia 57 – 9 – 5 84 – 2 –
Spain 121 1 7 3 5 83 1 – –
Sweden 94 – 4 1 2 89 1 – 2
Switzerland 1 – – – – – 100 – –
Yugoslavia 9 – – – – 100 – – –
Australia 4 – – – – 100 – – –
five-year survival compared with Stage Ic G1 of 87% but but also for treatment. Adjunctive therapy has been used
Stage Ia G3 has a 75% survival compared with 66% in for indications that have in many instances been ill
those with a Stage Ic G3 cancer (Fig. 19). The relative defined. Historically, radiation therapy has been used
low survival for Ia G3 may be due to the relative number both pre- and postoperatively and in some cases routinely.
of patients reported (66) compared to several hundred Volume 25 suggests, as do previous volumes, that
or even thousand patients in other sub-stages. This is adjunctive radiation therapy may not be advantageous
true for all stages (Figs. 20−22). Again, knowing surgical over surgery alone. In Stages Ia and Ib surgery alone has
staging is extremely important as it relates to prognosis. a better survival than in patients treated with surgery plus
Surgery has served historically, not only for diagnosis radiation; however, in Stage Ic, radiation does appear to
CARCINOMA OF THE CORPUS UTERI 87
Table 8
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients (%) by country and treatment (Stage III), n = 1068
All 1068 1 11 3 2 61 19 1 3
South Africa 5 – – – – 100 – – –
Argentina 9 – 11 11 – 44 33 – –
Canada 1 – – – – – 100 – –
Chile 11 – 9 – – 91 – – –
USA 79 – 25 3 1 28 39 4 –
Uruguay 1 – 100 – – – – – –
China 21 5 10 – 5 81 – – –
India 1 – – – – – – 100 –
Israel 4 – – – – 100 – – –
Japan 77 – 12 – – 16 69 1 3
Korea 11 – 9 – 9 55 27 – –
Philippines 39 – 33 – 3 51 10 – 3
Thailand 30 – 13 – – 70 17 – –
Austria 31 – 19 – – 26 32 – 23
Croatia 17 – 12 18 6 47 18 – –
Czech Republic 42 – 2 5 2 74 10 – 7
Finland 21 – 10 – – 67 24 – –
France 31 – 6 – 10 48 29 6 –
Germany 77 1 13 5 – 61 14 3 3
Greece 22 – 27 – – 50 23 – –
Italy 14 – 21 7 7 29 29 7 –
Poland 165 – 1 1 2 88 8 – 1
Portugal 74 – 3 12 3 58 19 3 3
Slovakia 13 – 15 8 – 77 – – –
Slovenia 30 – 13 – – 70 13 3 –
Spain 109 3 17 3 2 67 6 – 2
Sweden 102 1 2 3 1 78 10 – 5
Yugoslavia 10 – – – – 90 10 – –
Australia 21 5 5 – – 52 19 5 14
increase survival, (72% compared with 83%) (Fig. 24). In Surgical staging Ia G1, Ib G1, Ia G2 and Ib G2 have a
Stages II−IV, the numbers are too small to draw a conclu- 5-year survival of 93.3%, 88.1%, 90.7% and 93%. This
sion concerning efficacy of radiation over surgery alone. is very similar to the data from Volumes 23 and 24.
It may be time to combine some of these groups as
treatment and survival are the same. This will make
CONCLUSIONS staging less cumbersome. Stage Ic, particularly Grades
2 and 3, do carry a worse prognosis and should be
Stage sub-staged.
This database continues to validate that stage is an
Age
extremely important prognostic factor. Grade and depth
of invasion also are important factors. The difference Multivariant analysis further defines important factors
in sub-stages particularly in Stage I appear minimal. and age continues to be a poor prognostic factor within
88 WT CREASMAN, F ODICINO et al
Table 9
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients (%) by country and treatment (Stage IV), n = 229
All 229 3 13 6 1 20 41 3 13
South Africa 1 – 100 – – – – – –
Argentina 3 – – 33 – – – – 67
Chile 1 – – – – – – 100 –
Peru 1 – – 100 – – – – –
USA 41 – 22 – – 10 61 – 7
China 6 – 67 – 17 – 17 – –
India 1 – – 100 – – – – –
Japan 9 – – – – – 78 – 22
Korea 4 – 50 – – 25 25 – –
Philippines 2 – – 100 – – – – –
Thailand 10 – 20 – – 50 30 – –
Austria 14 – 14 – – 7 50 – 29
Croatia 8 13 – 13 – 38 25 13 –
Czech Republic 5 – – – – 40 20 – 40
Finland 14 – 14 – 7 – 71 – 7
France 12 – 17 17 – 33 8 8 17
Germany 11 18 27 18 – 18 9 – 9
Greece 2 – – – – – – 100 –
Italy 9 – 11 – – – 67 11 11
Poland 6 – 17 17 – 33 33 – –
Portugal 11 18 – – – 45 36 – –
Slovakia 3 33 – 33 – – 33 – –
Slovenia 12 – – – – 42 25 17 17
Spain 8 13 13 13 – 25 25 – 13
Sweden 32 – – – – 28 50 – 22
Australia 3 – – – – – 67 – 33
Therapy Table 12
Carcinoma of the corpus uteri: patients treated in 1996–98. Mean age
Surgery remains primary therapy for endometrial cancer by grade of differentiation in surgically staged patients
although postoperative radiation continues to be used
even in early stage disease. The last several volumes Grade Patients (n) Mean age (yr)
would suggest radiation therapy in early stage disease Surgical Gx 503 62.9
(Stages Ia, Ib G1, G2) does not improve survival. Even G1 3304 61.2
in Stage II its benefits appear minimal at best. In the G2 2961 63.4
current volume, the number treated with chemotherapy G3 1315 63.9
remains small and conclusions regarding its efficacy are Total 8083
inconclusive. At least in one phase-3 study of advanced
disease, chemotherapy compared with radiation therapy
had a better survival. It will be interesting to note if
Volume 26 reflects this new data. Table 13
Carcinoma of the corpus uteri: patients treated in 1996–98. Mean age
by grade of differentiation in clinically staged patients
Table 15
Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients by stage and grade of differentiation in surgically staged
patients
Gx 86 145 63 34 41 60 7 30 8 29
G1 756 1488 529 158 134 143 14 51 7 24
G2 250 1207 621 182 227 254 36 124 16 44
G3 70 308 300 70 117 183 32 134 22 79
90 WT CREASMAN, F ODICINO et al
Table 16
Carcinoma of the corpus uteri: patients treated in 1996–98. Mean age by stage and grade of differentiation in surgically staged patients
Gx 58.6 62.3 65.3 67.4 63.8 60.7 68.0 66.1 68.9 65.9
G1 57.9 61.5 65.3 61.5 61.2 60.8 64.8 57.7 64.0 64.2
G2 62.4 63.1 65.5 62.9 62.7 61.9 67.8 60.3 64.4 66.6
G3 64.9 63.3 64.7 64.9 64.5 64.6 68.4 60.6 62.0 64.2
7000
6000
No of patients
5000
4000 Clinically staged
3000 Surgically staged
2000
1000
0
I II III IV
Stage
Clinically staged 277 a 59.1 73 15.6 67 14.3 52 11.1 469 100.0 5.3
Surgically staged 5823 72.0 963 11.9 1068 13.2 229 2.8 8083 100.0 92.0
Missing data – – – – – – – – 238 100.0 2.7
Total 5884 984 1086 241 8790 100.0
a Includes nine Stage 0 patients.
Fig. 2. Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients by stage and mode of staging (clinical and surgical).
3000
Age group Surgical Clinical
2500
No of patients
15-29 24 1
2000
30–39 155 9
Surgical
1500 40–49 723 14
Clinical 50–59 2172 53
1000 60–69 2821 128
500 70–79 1780 153
80+ 408 111
0
15-29 30-39 40-49 50-59 60-69 70-79 80+
Age groups
Fig. 3. Carcinoma of the corpus uteri: patients treated in 1996–98. Age distribution by mode of staging.
CARCINOMA OF THE CORPUS UTERI 91
Table 17
Carcinoma of the corpus uteri: patients treated in 1996–98. Percentage of histopathological type in early and advanced stages in surgically
staged patients
a Percentage within the same stage group. b Percentage within the same histological type.
Table 18
Carcinoma of the corpus uteri: patients treated in 1996–98. 5-year survival by stage/age group/mode of staging
Age group Surgical Patients Clinical Patients Age group Surgical Patients Clinical Patients
staging (%) (n) staging (%) (n) staging (%) (n) staging (%) (n)
Stage II Stage IV
15–29 100.0 4 – – 15–29 100.0 1 – –
30–39 88.9 16 11.1 2 30–39 – 0 100.0 1
40–49 96.2 102 3.8 4 40–49 88.9 16 11.1 2
50–59 98.7 228 1.3 3 50–59 89.1 49 10.9 6
60–69 94.4 336 5.6 20 60–69 79.2 84 20.8 22
70–79 90.2 221 9.8 24 70–79 78.8 67 21.2 18
80+ 73.7 56 26.3 20 80+ 80.0 12 20.0 3
Table 19
Carcinoma of the corpus uteri: patients treated in 1996–98. Surgical stage distribution by mode of treatment
Table 20
Carcinoma of the corpus uteri: patients treated in 1996–98. Percentage of surgically staged patients by mode of treatment
Surgery alone 31.22 52.93 6.53 2.05 1.83 2.72 0.37 1.23 0.15 0.97
Surgery + adj RT 5.56 34.49 27.64 7.81 9.15 9.35 0.99 4.01 0.33 0.66
Surgery + adj CT 2.97 14.01 11.46 3.61 4.46 22.08 2.55 18.68 4.03 16.14
Adjuvant HT 18.60 18.60 6.98 4.65 – 20.93 – 11.63 6.98 11.63
Other 12.36 10.11 10.11 2.25 1.12 8.99 5.62 16.85 7.87 24.72
Table 21
Carcinoma of the corpus uteri: patients treated in 1996–98. Lymphnodal status
P−, negative pelvic nodes A−, negative aortic nodes M0, no myometrial invasion
P+, positive pelvic nodes A+, positive aortic nodes M < 50%, myometrial invasion less than 50%
M > 50%, myometrial invasion more than 50%
6000
Histotype Stage
I II III IV
5000
s
s
us
ry
el
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ou
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lla
th
c
no
ri
m
am
O
ar
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i
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Pa
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M
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En
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Ad
Histotype
Fig. 4. Carcinoma of the corpus uteri: patients treated in 1996–98. Surgical stage distribution (in percentage) by histopathological type.
CARCINOMA OF THE CORPUS UTERI 93
Table 22 Table 23
Carcinoma of the corpus uteri: patients treated in 1996–98. Carcinoma of the corpus uteri: patients treated in 1996–98.
Lymphnodal status in G1 patients Lymphnodal status in G2 patients
P−A− (%) P+A− (%) P−A+ (%) P+A+ (%) P−A− (%) P+A− (%) P−A+ (%) P+A+ (%)
3000
2500
Ia
Ib
No of patients
2000
Ic
IIa
1500
IIb
IIIa
1000 IIIb
IIIc
500 IVa
IVb
0
id
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er
s
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et
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Sq
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N
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Ad
Histotype
No histology 11 5 3 2 3 3 2 2 1 7 38
Endometrioid 1016 2829 1322 381 411 485 61 231 32 100.0 6868
Adenosquamous 25 119 76 18 31 40 4 23 2 14 352
Mucinous 12 23 15 2 12 8 1 2 1 3 79
Papillary 36 62 32 22 24 48 7 41 11 27 310
Clear cell 31 42 28 11 21 24 5 15 1 13 191
Squamous 4 9 9 1 1 2 1 5 0 1 33
Other 27 59 28 7 17 30 8 20 5 11 212
Fig. 5. Carcinoma of the corpus uteri: patients treated in 1996–98. Distribution of patients by histopathological type and surgical stage.
94 WT CREASMAN, F ODICINO et al
Table 24 Table 25
Carcinoma of the corpus uteri: patients treated in 1996–98. Carcinoma of the corpus uteri: patients treated in 1996–98.
Lymphnodal status in G3 patients Percentage of positive pelvic nodes by grade and myometrial invasion
(with both positive and negative aortic nodes)
P−A− (%) P+A− (%) P−A+ (%) P+A+ (%)
G1 (%) G2 (%) G3 (%)
M0 75.68 13.51 5.41 5.41
M < 50% 84.97 8.09 0.58 6.36 M0 3.44 3.60 18.92
M < 50% 5.38 11.04 14.45
M > 50% 69.28 19.93 2.61 8.17
M > 50% 14.81 16.12 28.10
Table 26 Table 27
Carcinoma of the corpus uteri: patients treated in 1996–98. Carcinoma of the corpus uteri: patients treated in 1996–98.
Percentage of positive aortic nodes by grade and myometrial invasion Outcome of follow-up
(with both positive and negative pelvic nodes)
Vital status Patients (n) Percentage (%)
G1 (%) G2 (%) G3 (%)
Alive (NOS) 1447 16.46
M0 – 1.80 10.81 Alive disease free 5333 60.67
M < 50% 0.77 2.25 6.94 Alive with disease 348 3.96
M > 50% 4.94 4.90 10.78 Dead 1662 18.91
Table 28
Carcinoma of the corpus uteri: patients treated in 1996–98. Response to treatment by stage
Table 29
Carcinoma of the corpus uteri: patients treated in 1996–98. Relapses by stage
Local (regional) 11 43 24 11 19 13 5 11 3 2
Metastatic 8 37 49 18 22 37 6 27 5 9
Local and metastatic 3 8 6 4 7 9 2 11 2 5
Missing site 29 113 85 24 33 43 6 13 3 11
Total 51 201 164 57 81 102 19 62 13 27
Table 30
Carcinoma of the corpus uteri: patients treated in 1996–98. Multivariate analysis
Age
Aged <50 Reference Reference Reference Reference
Aged 50+ 2.03 (1.33–3.09) 1.62 (0.90–2.92) 2.26 (1.44–3.54) 0.53 (0.25–1.11)
Histological type
Endometrioid Reference Reference Reference Reference
Adenosquamous 1.33 (0.89–2.00) 1.06 (0.55–2.06) 0.74 (0.46–1.21) 0.61 (0.29–1.29)
Mucinous 1.06 (0.44–2.59) 1.24 (0.38–4.06) 0.70 (0.22–2.25) 0.93 (0.25–3.40)
Papillary 1.97 (1.28–3.04) 2.23 (1.27–3.90) 1.73 (1.27–2.35) 1.13 (0.67–1.89)
Clear cell 1.33 (0.79–2.25) 1.37 (0.64–2.94) 1.40 (0.86–2.28) 1.11 (0.58–2.11)
Squamous 1.54 (0.49–4.83) 0.96 (0.13–7.26) 2.75 (0.83–9.08) –
Other 2.11 (1.35–3.31) 1.84 (0.90–3.77) 1.78 (1.22–2.59) 1.09 (0.55–2.14)
No histology 1.52 (0.21–11.2) 12.7 (3.57–44.9) 0.37 (0.05–2.71) 1.06 (0.35–3.22)
Grade
Grade 1 Reference Reference Reference Reference
Grade 2 1.41 (1.15–1.73) 0.86 (0.58–1.27) 1.31 (0.92–1.86) 0.74 (0.40–1.37)
Grade 3 2.70 (2.14–3.40) 1.92 (1.26–2.90) 2.37 (1.70–3.31) 1.41 (0.82–2.44)
Grade unknown 1.35 (0.87–2.09) 1.19 (0.63–2.25) 1.72 (1.06–2.77) 2.03 (0.98–4.21)
Myometrial invasion
No myometrial invasion Reference Reference Reference Reference
Myometrial invasion 50% 1.21 (0.89–1.65) 1.17 (0.46–3.01) 0.88 (0.44–1.76) 0.88 (0.30–2.55)
Myometrial invasion >50% 2.18 (1.60–2.98) 1.58 (0.63–4.00) 1.43 (0.74–2.76) 0.89 (0.35–2.29)
Unknown 2.14 (1.48–3.10) 1.82 (0.66–4.99) 2.08 (1.04–4.18) 1.29 (0.50–3.35)
a From Cox proportional hazard regression model, also adjusted for country.