Epidemiological data, the distribution of OGM genetic mutations, OGM histology / WHO grade, mutational OGM status and its relation to preoperative and postoperative olfactory function and radiological findings are summarized in Table 1.
Genetic analysis of OGM patients
|
|
Parameter
|
∑
|
AKT1
|
SMO_SUFU
|
Others#
|
Wild-type
|
p -value
|
|
|
All patients
|
[n(%)]
|
52
|
13 (25)
|
17 (33)
|
15 (29)
|
7 (13)
|
|
|
Gender
|
[n(%)]
|
|
|
|
|
|
|
|
Female
|
|
36 (69)
|
8 (22)
|
12 (33)
|
12 (33)
|
4 (11)
|
.643*
|
|
Male
|
|
16 (31)
|
5 (31)
|
5 (31)
|
3 (19)
|
3 (19)
|
|
Age
|
[n(%)]
|
|
|
|
|
|
|
|
≤ 65 Years
|
|
28 (54)
|
6 (21)
|
7 (25)
|
12 (43)
|
3 (11)
|
.118*
|
|
> 65 Years
|
|
24 (46)
|
7 (29)
|
10 (42)
|
3 (12)
|
4 (17)
|
|
WHO-Grade
|
[n(%)]
|
|
|
|
|
|
|
|
Grade WHO 1
|
|
43 (83)
|
9 (21)
|
13 (30)
|
15 (35)
|
6 (14)
|
.152*
|
|
Grade WHO 2-3
|
|
9 (17)
|
4 (44)
|
4 (44)
|
---
|
1 (11)
|
|
Histological subgrade
|
[n(%)]
|
|
|
|
|
|
|
|
Meningothelial
|
|
39 (75)
|
9 (23)
|
12 (31)
|
12 (31)
|
6 (15)
|
.163*
|
|
Atypic
|
|
9 (17)
|
4 (44)
|
4 (44)
|
---
|
1 (11)
|
|
Transitional
|
|
4 (8)
|
---
|
1 (25)
|
3 (75)
|
---
|
|
Tumor Volume (sphere) [Median(Range)cm³]
|
23(1-174)
|
13(3-45)
|
18(1-87)
|
42(2-174)
|
44(19-84)
|
.097***
|
|
AKT1 vs. Wild-type
|
|
|
|
|
|
|
.008****
|
|
AKT1 vs. Others
|
|
|
|
|
|
|
.108****
|
|
SMO_SUFU vs. Wild-type
|
|
4 (7)
|
---
|
1 (6)
|
3 (19)
|
---
|
.087****
|
|
Tumor Volume (sphere)
|
[n(%)]
|
|
|
|
|
|
|
|
≤ 25 cm³
|
|
27 (52)
|
10 (37)
|
9 (33)
|
6 (22)
|
2 (7)
|
.130*
|
|
> 25 cm³
|
|
25 (48)
|
3 (12)
|
8 (32)
|
9 (36)
|
5 (20)
|
|
AKT1 vs. Wild-type
|
|
|
|
|
|
|
.062**
|
|
Ethmoid cell infiltration (n= 45)
|
[n(%)]
|
|
|
|
|
|
|
|
yes
|
|
10 (22)
|
1 (10)
|
5 (50)
|
4 (40)
|
---
|
.280*
|
|
no
|
|
35 (78)
|
10 (29)
|
11 (31)
|
9 (26)
|
5 (14)
|
|
Planum hyperostosis- (n= 48)
|
[n(%)]
|
|
|
|
|
|
|
|
yes
|
|
36 (75)
|
5 (14)
|
14 (39)
|
11 (31)
|
6 (17)
|
.017*
|
|
no
|
|
12 (25)
|
7 (58)
|
3 (25)
|
2 (17)
|
---
|
|
Osseous-contrast enhancement (n= 44)
|
[n(%)]
|
|
|
|
|
|
|
|
yes
|
|
12 (27)
|
2 (17)
|
4 (33)
|
5 (42)
|
1 (8)
|
.558*
|
|
no
|
|
32 (73)
|
10 (31)
|
11 (34)
|
7 (22)
|
4 (13)
|
|
Perifocal edema (n= 42)
|
[n(%)]
|
|
|
|
|
|
|
|
yes
|
|
12 (29)
|
3 (25)
|
6 (50)
|
2 (17)
|
1 (8)
|
.684*
|
|
no
|
|
30 (71)
|
7 (23)
|
10 (33)
|
10 (33)
|
3 (10)
|
|
Preoperative
|
|
Threshold available (n= 22) [Median(Range)]
|
1(0-10)
|
1(1-4)
|
1(0-10)
|
n= 2
|
1(0-1)
|
.372***
|
|
Discrimination available (n= 21) [Median(Range)]
|
7(4-13)
|
8.5(5-11)
|
7(4-13)
|
n= 2
|
9(6-12)
|
.249***
|
|
Identification available (n= 27) [Median(Range)]
|
6(2-16)
|
7.5(5-14)
|
4(2-16)
|
5.5(2-8)
|
8(4-10)
|
.093***
|
|
Global olfactory performance (TDI) available (n= 22) [Median(Range)]
|
13(6-35)
|
13(11.5-29)
|
13(6-35)
|
n= 2
|
18(10-22)
|
.440***
|
|
Olfactory performance - Sniffin Sticks (n = 30)
|
[n(%)]
|
|
|
|
|
|
|
|
Normosmia
|
|
4 (13)
|
1
|
1
|
2
|
---
|
.298*
|
|
Hyposmia
|
|
8 (27)
|
2
|
2
|
1
|
3
|
|
Anosmia
|
|
18 (60)
|
5
|
8
|
4
|
1
|
|
Postoperative
|
|
Threshold available (n= 19) [Median(Range)]
|
2(1-11)
|
n= 2
|
1(1-4)
|
5(1-11)
|
n= 2
|
.404***
|
|
Discrimination available (n= 19) [Median(Range)]
|
7(2.5-13)
|
n= 2
|
5(3-7)
|
7(2.5-13)
|
n= 2
|
.256***
|
|
Identification available (n= 20) [Median(Range)]
|
5(2-14.5)
|
n= 2
|
3(2-6)
|
4(2-14.5)
|
n= 2
|
.402***
|
|
Global olfactory performance (TDI) available (n= 19) [Median(Range)]
|
14.5(6-38)
|
n= 2
|
11(7-16)
|
19(6-38)
|
n= 2
|
.404***
|
|
Olfactory performance - Sniffin Sticks (n = 21)
|
[n(%)]
|
|
|
|
|
|
|
|
Normosmia
|
|
3 (14)
|
---
|
---
|
3
|
---
|
.019*
|
|
Hyposmia
|
|
6(29)
|
2
|
---
|
2
|
2
|
|
Anosmia
|
|
12 (57)
|
1
|
7
|
4
|
---
|
|
# TRAF_PIC3CA_POLR2A_NF1 * Pearson's chi-squared test (2) ** Fisher’s Exact Test *** Kruskal-Wallis-Test **** Mann-Whitney-U-Test
|
|
|
|
|
|
|
|
|
TABLE 1: Women were over-represented (69%) and the average age was 62 years. The histological examination revealed 83% (n = 43) of OGM as WHO Grade I. Preoperatively odor threshold was assessed in 22, odor discrimination in 21, and odor identification in 27 patients. Due to technical reasons, the global olfactory score (TDI) was only obtained in 22 patients. Preoperatively, most of the patients were anosmic. The SMO/SUFU group had the most anosmic patients (n = 8; 73%), followed by the AKT1 group (n = 5; 63%) (p = .3). In perioperative CAT-Scans, planum hyperostosis was detected in 100% of the wild-type group (n = 6), in 85% of the other mutation group (n = 13), in 82% of the SMO_SUFU group (n = 17) and 42% of the AKT1-group (n= 12) (p = .017). When comparing the tumor volume of the mutational groups with wild-type (43 [19-83] cm3), the AKT1 (13 [2.5-45] cm3) group included the smallest tumor volume (p = .008). Postoperative olfactory performance testing was feasible in 19 (threshold), 19 (discrimination), 20 (identification) and 19 patients (TDI score). Postoperative olfactory performance was as follows: 3 AKT1 patients with 1 (33%) anosmia, 2 (67%) hyposmia; 7 SMO patients with 7 (100%) anosmia. In other mutations 9 patients were 4 (44%) anosmic, 2 (22%) hyposmic, and 3 (33%) normosmic. The examined wild-type group comprised 2 (100%) patients with hyposmia. Although postoperative availability of olfactory performance scores in our patient population was rarely, the result suggests that there is also a statistically significant difference between the mutational groups compared postoperatively (p = .019).
The median of the Tumor Volume Sphere (V = (4/3)·π·r3) for all OGM patients was 23.4 cm³. Due to the small patient cohort with available preoperative olfactory performance data, the patients were divided into two groups based on the median OGM volume of 25 cm3. In fact, odor identification was better in patients with smaller preoperative tumor volume (<25cm3 (n = 13); ID: 7.5 (2-16), ≥25cm3 (n = 14); ID: 4.5 (2-10); (p = .014); see TABLE 2.
Threshold available, all Patients (n= 22); 1(0-10) [Median(Range)]
|
Gender
|
Female (n= 16)
|
Male (n= 6)
|
p-value
|
1(0-10)
|
1 (0-2)
|
.407
|
Age
|
≤ 65 Years (n= 8)
|
> 65 Years (n= 14)
|
|
1(0-6)
|
1(0-10)
|
.764
|
WHO-Grade
|
Grade 1 (n= 20)
|
Grade 2-3 (n= 2)
|
|
1(0-10)
|
|
|
Tumor Volume (sphere)
|
≤ 25 cm³ (n= 9)
|
> 25 cm³ (n= 13)
|
|
2(0-10)
|
1(0-3.5)
|
.209
|
Ethmoid-Infiltration
|
yes (n= 6)
|
no (n= 13)
|
|
1(0-10)
|
1(0-6)
|
.926
|
Hyperostosis-planum
|
yes (n= 16)
|
no (n= 4)
|
|
1(0-10)
|
3(1-6)
|
.074
|
Osseous-enhancement
|
yes (n= 6)
|
no (n= 12)
|
|
1(1-2)
|
1(0-6)
|
.764
|
Perifocal-Edema
|
yes (n= 5)
|
no (n= 12)
|
|
4(1-10)
|
1(0-4)
|
.030
|
Discrimination available, all Patients (n= 21); 7(4-13) [Median(Range)]
|
Gender
|
|
Female (n= 15)
|
Male (n= 6)
|
p-value
|
8(4-13)
|
5(4-10)
|
.055
|
Age
|
|
≤ 65 Years (n= 8)
|
> 65 Years (n= 13)
|
|
6(4-13)
|
8(4-12)
|
.145
|
WHO-Grade
|
Grade 1 (n= 20)
|
Grade 2-3 (n= 1)
|
|
7.5(4-13)
|
|
|
Tumor Volume (sphere)
|
≤ 25 cm³ (n= 9)
|
> 25 cm³ (n= 12)
|
|
8(4-13)
|
7(4-12)
|
.591
|
Ethmoid-Infiltration
|
yes (n= 6)
|
no (n= 12)
|
|
4(4-10)
|
7.5(5-13)
|
.059
|
Hyperostosis-planum
|
yes (n= 15)
|
no (n= 4)
|
|
7(4-10)
|
10.5(5-13)
|
.055
|
Osseous-enhancement
|
yes (n= 5)
|
no (n= 12)
|
|
4(4-10)
|
7.5(4-13)
|
.151
|
Perifocal-Edema
|
yes (n= 5)
|
no (n= 11)
|
|
9(4-13)
|
7(4-11)
|
.229
|
Identification available (n= 27); 6(2-16) [Median(Range)]
|
Gender
|
|
Female (n= 20)
|
Male (n= 7)
|
p-value
|
6(2-16)
|
4(3-14)
|
.505
|
Age
|
|
≤ 65 Years (n= 12)
|
> 65 Years (n= 15)
|
|
6(3-16)
|
7(2-14)
|
.806
|
WHO-Grade
|
Grade 1 (n= 25)
|
Grade 2-3 (n= 2)
|
|
6(2-16)
|
|
|
Tumor Volume (sphere)
|
≤ 25 cm³ (n= 13)
|
> 25 cm³ (n= 14)
|
|
7.5(2-16)
|
4.5(2-10)
|
.014
|
Ethmoid-Infiltration
|
yes (n= 6)
|
no (n= 18)
|
|
3(2-14)
|
6(2-16)
|
.169
|
Hyperostosis-planum
|
yes (n= 20)
|
no (n= 5)
|
|
5(2-11)
|
13.5(7-16)
|
.005
|
Osseous-enhancement
|
yes (n= 6)
|
no (n= 17)
|
|
3(2-14)
|
7(2-16)
|
.105
|
Perifocal-Edema
|
yes (n= 6)
|
no (n= 16)
|
|
8(3-16)
|
5(2-14)
|
.081
|
Global olfactory performance (TDI) available (n= 22); 13(6-35) [Median(Range)]
|
Gender
|
|
Female (n= 16)
|
Male (n= 6)
|
p-value
|
14(6-35)
|
9.5(8-26)
|
.109
|
Age
|
|
≤ 65 Years (n= 9)
|
> 65 Years (n= 13)
|
|
11.5(8-35)
|
15.5(6-29)
|
.105
|
WHO-Grade
|
Grade1 (n= 20)
|
Grade 2-3 (n= 2)
|
|
13(8-35)
|
|
|
Tumor Volume (sphere)
|
≤ 25 cm³ (n= 9)
|
> 25 cm³ (n= 13)
|
|
25(6-35)
|
13(8-22)
|
.146
|
Ethmoid cell infiltration
|
yes (n= 6)
|
no (n= 13)
|
|
8(6-26)
|
13(9-35)
|
.121
|
Hyperostosis of planum
|
yes (n= 15)
|
no (n= 5)
|
|
13(6-25)
|
26(11.5-35)
|
.058
|
Osseous enhancement
|
yes (n= 5)
|
no (n= 13)
|
|
8(8-26)
|
13(6-35)
|
.212
|
Perifocal edema
|
yes (n= 5)
|
no (n= 12)
|
|
25(8-35)
|
13(6-29)
|
.136
|
TABLE 2: For each subgroup, the median score of the olfactory subtest is reported, along with the range and p-value of any statistically significant differences between subgroups. Olfactory threshold: The table shows that the olfactory threshold scores were available in 22 patients with OGM. The table includes the demographic and clinical characteristics of the patients, including gender, age, WHO grade, tumor volume, ethmoid infiltration, hyperostosis-planum, osseous-enhancement, and perifocal edema. The median olfactory threshold score for all patients was 1 (range: 0-10). The only significant difference in olfactory threshold scores was found between patients with perifocal edema and those without (p = .030). Patients with perifocal edema had a higher median olfactory threshold score of 4 (range: 1-10), while those without perifocal edema had a median score of 1 (range: 0-4). Olfactory discrimination: Data were available in 21 patients with a median score of 7 (range 4-13). No significant differences in olfactory discrimination have been detected between the groups. Olfactory identification: Olfactory identification scores were available in 27 patients with OGM. Of these 27 individuals, 20 were female and 7 were male, with no significant differences in their available olfactory identification scores. The median olfactory identification score for all patients was 6 (range: 2-16). There is a significant difference in olfactory identification between the two groups, stratified by the Tumor-volume (≤ 25 cm³ vs. > 25 cm³), with 13 individuals having a volume of 25 cm³ or less and 14 individuals having a volume greater than 25 cm³. Patients with planum-hyperostosis (n = 20) had a lower median olfactory identification score of 5 (range: 2-11), while those without planum-Hyperostosis (n= 5) had a median score of 13.5 (range: 7-16); p = .005. Global olfactory performance (TDI): Data were available from 22 individuals, and the median score was 13 (range: 6-35). Female (n=16) and male (n=6). The median TDI score was higher in females (14, range: 6-35) compared to males (9.5, range: 8-26), but the difference was not statistically significant (p=0.109).
Comparing the variance among OGM-mutated groups and their preoperative olfactory performance subtests, with imaging properties, that is, ethmoid infiltration, planum hyperostosis, osseous infiltration and perifocal edema, resulted in the following findings: The perioperative threshold was decreased in OGM with perifocal edema. The identification of the odor was poorer in OGM <25 cm3 and planum hyperostosis (n = 22, p = .03; n = 27, p = .014).
The multivariate regression analysis revealed several parameters as independent prognostic factors for preoperative olfactory subtests (TABLE 3).
Multivariate linear regression analysis: independent variables in all models:
AKT1_Mut, SMO_SUFU, Other-Mut, Age65, sex, VolSphere_25, loc._in both sides (Yes/No), EthmoidalCell_Inf_ (Yes/No), Hyperostose_Planum_yes (Yes/No), Bony-Enh_yes (Yes/No), Perifocal-edema_yes (Yes/No)
|
thre-pre
|
95,0% KI
|
Coefficient
|
b
|
SE
|
β
|
T
|
p
|
LB
|
UB
|
Hyperostosis-Planum (no/yes)
|
-2.003
|
0.652
|
-0.387
|
-3.073
|
0.008
|
-3.392
|
-0.614
|
Bony-Enhancement (no/yes)
|
-1.792
|
0.730
|
-0.347
|
-2.454
|
0.027
|
-3.348
|
-0.236
|
Comment N = 22; R² = 0.811; Adj. R² = 0.574; F(6,15) = 10..737; p< 0,001
|
dis-pre
|
Other- Mutations (no/yes)
|
-4.608
|
0.886
|
-0.605
|
-5.202
|
< 0.001
|
-6.477
|
-2.739
|
Sex (Female/Male)
|
-3.608
|
0.687
|
-0.612
|
-5.252
|
< 0.001
|
-5.057
|
-2.158
|
Hyperostosis-Planum (no/yes)
|
-3.294
|
0.664
|
-0.558
|
-4.959
|
< 0.001
|
-4.696
|
-1.893
|
Comment N = 21; R² = 0.786; Adj. R² = 0.749; F(3,1) = 20.842; p< 0,001
|
ID-pre
|
Hyperostose-Planum (nein/ja)
|
-5.220
|
0.998
|
-0.630
|
-5.232
|
< 0.001
|
-7.289
|
-3.151
|
Sonstige Mutation (nein/ja)
|
-3.240
|
1.104
|
-0.346
|
-2.934
|
0.008
|
-5.531
|
-0.950
|
Sex (Frau/Mann)
|
-3.116
|
1.003
|
-0.376
|
-3.108
|
0.005
|
-5.195
|
-1.037
|
Volumen (≤25/>25 cm³)
|
-2.396
|
0.858
|
-0.330
|
-2.793
|
0.011
|
-4.175
|
-0.617
|
Comment N = 27; R² = 0.718; Adj. R² = 0.667; F(4,22) = 14,037; p< 0,001
|
TDI-pre
|
Hyperostosis-Planum (no/yes)
|
-9.748
|
2.801
|
-0.598
|
-3.481
|
0.003
|
-15.632
|
-3.864
|
Perifocal-edema (no/yes)
|
-8.991
|
3.076
|
-0.590
|
-2.922
|
0.009
|
-15.454
|
-2.527
|
Comment N = 22; R² = 0.527; Adj. R² = 0.448; F(3,18) = 6.679; p= 0,003
|
|
Thre-post
|
AKT1-Mutation (no/yes)
|
-5.163
|
1.941
|
-0.498
|
-2.660
|
0.020
|
-9.357
|
-0.969
|
Volumen (≤25/>25 cm³)
|
-3.454
|
1.451
|
-0.542
|
-2.381
|
0.033
|
-6.588
|
-0.321
|
Comment N = 19; R² = 0.707; Adj. R² = 0.594; F(5,13) = 6.266; p= 0,004
|
dis-post
|
Volumen (≤25/>25 cm³)
|
-5.408
|
0.911
|
-0.885
|
-5.937
|
< 0.001
|
-7.362
|
-3.454
|
Ethmoidalzellinfiltraion (nein/ja)
|
3.241
|
1.182
|
0.467
|
2.741
|
0.016
|
0.705
|
5.776
|
Comment N = 19; R² = 0.737; Adj. R² = 0.662; F(4,14) = 9.832; p< 0,001
|
ID-post
|
Sex (Frau/Mann)
|
4.339
|
1.518
|
0.514
|
2.858
|
0.013
|
1.083
|
7.594
|
SMO-/SUFU-Mutation (no/yes)
|
-4.157
|
1.433
|
-0.588
|
-2.901
|
0.012
|
-7.230
|
-1.084
|
Alter (≤65/>65 Jahre)
|
3.686
|
1.641
|
0.473
|
2.247
|
0.041
|
0.167
|
7.205
|
Comment N = 20; R² = 0.661; Adj. R² = 0.540; F(5,14) = 5.453; p= 0,005
|
TDI-post
|
Perifocal-edema (no/yes)
|
-14.257
|
3.571
|
-0.760
|
-3.992
|
0.002
|
-21.972
|
-6.541
|
AKT1-Mutation (no/yes)
|
-9.957
|
3.972
|
-0.350
|
-2.507
|
0.026
|
-18.538
|
-1.375
|
Volume (≤25/>25 cm³)
|
-7.802
|
2.968
|
-0.447
|
-2.629
|
0.021
|
-14.214
|
-1.390
|
Comment N = 19; R² = 0.837; Adj. R² = 0.774; F(5,13) = 13.330; p< 0,001
|
TABLE 3: The table provides the estimated coefficients (in the second column), standard errors (in the third column), t values (in the fourth column), and p values (in the fifth column) for each of the independent variables. The sixth and seventh columns show the lower and upper bounds of the 95% confidence intervals for the coefficients, respectively. The last column provides the overall test statistics for the regression model, including the number of observations (N), the coefficient of determination (R²), the adjusted R², the F statistic, and the p-value for the overall model.
Multivariate regression analysis revealed several parameters as independent prognostic factors for preoperative olfactory subtests: Patients with planum-hyperostosis (p= .008) and osseous enhancement (p= .027) had lower thresholds before the operation. Men, the OGM group with planum hyperostosis and the patient population with other OGM mutations revealed inferior preoperative discrimination (p< .001). Decreased preoperative odour identification scores were associated with OGM with planum hyperostosis (p< .001), other mutations (p= .008), gender (men; p= .005) and Tumor-Volume ≥25 cm³ (p= .011). Among those, planum hyperostosis was the most influential independent prognostic parameter in ID-pre. The group of patients with planum hyperostosis (p= .003) and OGM with allied perifocal edema (p= .009) performed worse in global olfactory performance preoperatively (TDI). This implies that although there was a wide range in TDI scores and the percentage of variance explained by the variables was low (Adj.R² = .45), the presence of planum hyperostosis and OGM with associated perifocal edema had a significant negative impact on TDI scores, meaning that individuals with these conditions tended to have lower TDI scores.
Our results show that 45% of the influence of the independent parameters (sphenoid planum hyperostosis and OGM with associated perifocal edema) on the dependent variable (preoperative TDI score) has been explained in the study. However, this means that 55% of the influence remains unexplained, which requires further analysis to fully understand the relationship between sphenoid planum hyperostosis, OGM with associated perifocal edema, and preoperative TDI scores. Additionally, other factors can also play a role in determining preoperative TDI scores that were not included in our study.
It seems that gender also influences olfactory performance. The results show that 75% of the variance in odor discrimination and 67% in odor identification are accounted for by gender. This indicates that the male gender negatively predicts preoperative odor discrimination and identification (TABLE 3).
The presence of the AKT1 - OGM mutation (p= .02); and the tumor volume of OGM ≥ 25 cm3 (p = .033) had a significant negative impact on the postoperative threshold. The group of patients with OGM SMO-/SUFU-Mutation (p= .012) were worse at identifying odors postoperatively. The postoperative impairment of odor discrimination was due to tumor volume ≥25 cm³ (p< .001). The group of patients with ethmoid cell infiltration performed better postoperatively in the odor discrimination test (p= .016). Women and patients younger than 65 years outperformed men (p= .013) and patients older than 65 years (p= .041) postoperatively in olfactory identification scores (TABLE 3).
In descending order, OGM with allied perifocal edema (p= .002), OGM with AKT1 mutation (p= .026) and tumor volume ≥25 cm³ (p= .021) had a negative impact on postoperative TDI. OGM with tumor volume ≥25 cm³ showed postoperatively poorer odor discrimination performance (TABLE 3).
Although only 39% (n = 21) of OGM patients underwent postoperative olfactory testing, a difference could be identified, with a preponderance of anosmic patients in the SMO / SUFU mutation group (n = 7; p = .019). The same group was poor in identifying odors after surgery (TABLE 1).
For an overview, the results of the pre-and post-operative olfactory subtests are shown in Figure 1 as a regression Forrest plot analysis of significance in patients with OGM according to their examined characteristics.