A total number of 103 patients (38 F, 65 M) were analyzed. Overall, the mean age at the time of surgery was 72.23 ± 4.76 years (median age: 71 years; range: 65–83 years). Grouping the patients by age, 73 patients were < 75 years old and 30 patients were \(\ge\)75 years old.
The majority of tumors was macroadenomas (83%) vs (macro- vs microadenoma: 86 vs 17). Based on immunohistochemical results, 54 FSH/LH, 7 ACTH-, 14 GH-, 2 TSH-, 3 PRL- and 23 null cell adenomas were identified. A total number of 30 tumors showed surgical and/or pathological invasion of the cavernous sinus, while 8 tumors showed sphenoid bone invasion. A high mitotic index (≥ 2) was found in 16 patients, Ki-67 ≥ 3% in 24 cases and p53 was positive in 29 cases.
In term of extent of resection (EOR), a gross total resection (GTR) was achieved in 60 patients in overall population (58%), while subgrouping by age, a GTR was confirmed in 46/73 (63%) of young elderly and 14/30 (47%) of old elderly (p = 0.126).
According to Trouillas' classification criteria, 57 tumors resulted to be grade Ia, 8 were grade Ib, 33 were grade 2a, and 5 were grade 2b.
Based on KNOSP classification, 11 patients were grade 0 (11%), 31 were grade 1 (30%), 36 were grade 2 (35%), 20 were grade 3 (19%), 5 were grade 4 (5%).
The mean follow-up period was 54.84 months (24–96.8 months); 13 patients developed tumor recurrence after apparent total resection or disease progression after subtotal surgical resection.
Demographic, clinical and pathological characteristics have been summarized in Table 1.
Table 1
Predictive factors of Time to Recurrence (TTR) in elderly patients.
|
Pts no.
|
TTR (months)
|
Univariate (p-value)
|
Multivariate (p-value)
|
Age
|
|
|
0.520
|
|
65–74
|
73
|
75
|
|
≥ 75
|
30
|
66
|
Gender
|
|
|
0.819
|
|
Male
|
65
|
79
|
|
Female
|
38
|
65
|
Tumor size
|
|
|
0.584
|
|
Micro
|
17
|
64
|
|
Macro
|
86
|
81
|
Cavernous Sinus Invasion
|
|
|
0.013
|
0.090
|
No
|
65
|
90
|
|
Yes
|
38
|
58
|
Tumor type
|
|
|
0.461
|
|
FSH/LH
|
54
|
|
|
ACTH
|
7
|
|
GH
|
14
|
|
TSH
|
2
|
|
PRL
|
3
|
|
Null cell
|
23
|
|
Ki-67
|
|
|
0.003
|
0.077
|
< 3
|
79
|
77
|
|
> 3
|
24
|
56
|
p53
|
|
|
0.021
|
0.075
|
Negative
|
74
|
75
|
|
Positive
|
29
|
63
|
Mitoses
|
|
|
0.008
|
0.024
|
< 2/HPF
|
87
|
81
|
|
> 2/HPF
|
16
|
47
|
Extent of resection
|
|
|
0.041
|
0.092
|
GTR
|
60
|
77
|
|
STR
|
43
|
70
|
|
Trouillas grade
|
|
|
0.010
|
0.048
|
1a
|
57
|
91
|
|
1b
|
8
|
55
|
2a
|
33
|
62
|
2b
|
5
|
45
|
KNOSP grade
|
|
|
0.009
|
0.125
|
0
|
11
|
66
|
|
1
|
31
|
71
|
2
|
36
|
85
|
3
|
20
|
52
|
4
|
5
|
40
|
Statistical analysis of predictive factors of Disease-Free Survival (DFS) in elderly patients. Univariate analysis were performed considering age, gender, tumor size, cavernous sinus invasion, KNOSP grade, tumor type, Ki-67, p53, mitoses and Trouillas grade; cavernous sinus invasion, KNOSP grade, Ki-67, p53, mitoses and Trouillas grade were the factors considered in multivariate analysis.
Table 2
Statistical analysis of predictive factors of Time to Recurrence (TTR) comparing Young Elderly and Old Elderly patients
|
Young Elderly
|
Old Elderly
|
|
Pts no.
|
TTR (months)
|
Univariate (p-value)
|
Multivariate (p-value)
|
Pts no.
|
TTR (months)
|
Univariate (p-value)
|
Multivariate (p-value)
|
Gender
|
|
|
> 0.05
|
> 0.05
|
|
|
> 0.05
|
|
Male
|
48
|
79
|
|
17
|
54
|
|
Female
|
25
|
63
|
13
|
68
|
Tumor size
|
|
|
> 0.05
|
> 0.05
|
|
|
0.014
|
> 0.05
|
Micro
|
12
|
69
|
|
5
|
70
|
|
Macro
|
61
|
76
|
25
|
51
|
Invasion
|
|
|
0.009
|
0.038
|
|
|
> 0.05
|
|
No
|
44
|
91
|
|
19
|
68
|
|
Yes
|
29
|
56
|
11
|
66
|
Tumor type
|
|
|
> 0.05
|
> 0.05
|
|
|
> 0.05
|
> 0.05
|
None
|
16
|
NA
|
|
7
|
NA
|
|
ACTH
|
5
|
NA
|
2
|
NA
|
GH
|
13
|
NA
|
1
|
NA
|
FSH/LH
|
37
|
NA
|
17
|
NA
|
TSH
|
0
|
NA
|
2
|
NA
|
PRL
|
2
|
NA
|
1
|
NA
|
Ki-67
|
|
|
0.009
|
> 0.05
|
|
|
> 0.05
|
> 0.05
|
< 3%
|
56
|
76
|
|
23
|
67
|
|
> 3%
|
17
|
56
|
7
|
34
|
p53
|
|
|
0.047
|
> 0.05
|
|
|
> 0.05
|
> 0.05
|
Negative
|
54
|
73
|
|
23
|
67
|
|
Positive
|
19
|
58
|
7
|
34
|
Mitoses
|
|
|
> 0.05
|
> 0.05
|
|
|
> 0.05
|
> 0.05
|
< 2/HPF
|
62
|
77
|
|
20
|
69
|
|
> 2/HPF
|
11
|
48
|
10
|
62
|
Extent of resection
|
|
|
0.009
|
> 0.05
|
|
|
0.048
|
> 0.05
|
GTR
|
46
|
78
|
|
16
|
68
|
|
STR
|
27
|
64
|
|
14
|
64
|
|
Trouillas grade
|
|
|
0.017
|
> 0.05
|
|
|
0.042
|
0.017
|
1a
|
41
|
96
|
|
16
|
68
|
|
1b
|
3
|
56
|
|
5
|
36
|
|
2a
|
24
|
65
|
|
9
|
56
|
|
2b
|
5
|
45
|
|
0
|
|
|
KNOSP
|
|
|
0.006
|
> 0.05
|
|
|
> 0.05
|
> 0.05
|
0
|
8
|
66
|
|
3
|
48
|
|
1
|
20
|
72
|
|
11
|
66
|
|
2
|
29
|
87
|
|
7
|
56
|
|
3
|
12
|
63
|
|
8
|
24
|
|
4
|
4
|
48
|
|
1
|
12
|
|
Time to Recurrence (TTR)
The mean Time to Recurrence was 32.3 months ± 18.5. The univariate analysis showed that in the elderly population Ki-67 > 3% (median TTR: 77 vs 56 months, p = 0.003), the expression of p53 (median TTR: 75 vs 63 months, p = 0.021), the invasion of the cavernous sinus or sphenoid sinus (median TTR: 90 vs 58 months, p = 0.013), a mitotic index mitotic index ≥ 2/HPF (median TTR: 81 vs 47 months, p = 0.008), EOR (median TTR: 77 vs 70 months, p = 0.041) were associated with higher risk of recurrence.
Trouillas grade showed to be highly related with TTR at univariate analisys, particularly regarding tumor’s proliferation (median TTR: 91 (grade 1a) vs 55 (grade 1b) vs 62 (grade 2a) vs 45 (grade 2b) months, p = 0.010) (Fig. 2a), as well as KNOSP grade (median TTR: 66 (grade 0) vs 71 (grade 1) vs 85 (grade 2) vs 52 (grade 3) vs 40 (grade 4) months, p = 0.009).
In the multivariate analysis, the Trouillas grade (p = 0.048) and the mitotic index (p = 0.024) maintained statistical significance (Fig. 2a-b).
Young Elderly vs Old Elderly Patients
Grouping patients in young and old elderly patients, higher rates of TTR was observed at univariate analysis among young elderly patients with Ki-67 < 2% (median TTR: 76 vs 56 months; p = 0.009), p53 negative (median TTR: 73 vs 58 months; p = 0.047), absence of invasion (median TTR: 91 vs 56 months; p = 0.009) and GTR (median TTR: 78 vs 64 months; p = 0.009).
Among them, only invasiveness confirmed statistical significance in the multivariate analysis (p = 0.018) (Fig. 2e).
Trouillas’s grade and KNOSP classification showed a statistical significative correlation with TTR at univariate analisys (median TTR related to Trouillas’ grade: 96 (grade 1a) vs 56 (grade 1b) vs 65 (grade 2a) vs 45 (grade 2b) months, p = 0.017; KNOSP median TTR: 66 (0) vs 72 (1) vs 87 (2) vs 63 (3) vs 48 (4) months, p = 0.006), but they did not confirm statistically significance at multivariate analisys.
On the other hand, when old elderly patients were studied, a better TTR was observed in case of GTR (median TTR: 68 vs 64 months; p = 0.048) and lower Trouillas’grade (median TTR: 68 (grade 1a) vs 36 (grade 1b) vs 56 (grade 2a) months, p = 0.042); only Trouillas’grade maintained statistical significance at multivariate analysis (p = 0.017) (Fig. 2d).
Extent of Resection
Considering all the population in the study, a statistically significant correlation was found between EOR and the absence of invasion (67%, p = 0.036), Ki67 < 3% (65%, p = 0.019) and KNOSP grade (45.5%, 68%, 72%, 30%, 40% respectively, p = 0.017)..
Grouping by age, the possibility to reach a GTR for young elderly patients was related to Ki-67 < 3% (72%, p = 0.001), absence of p53 mutation (70%, p = 0.028) and KNOSP grade (50%, 75%, 76%, 33%, 25% respectively, p = 0.028); whereas, within the group of old elderly patients, only KNOSP grade showed a statistically significant relationship (33%, 63%, 57%, 25%, 0% respectively, p = 0.018) (Table 3).
Table 3
Correlation between radiological and histopathological features and extent of resection (EOR)
|
GTR/Patients ratio (%)
|
|
General population
|
p-value
|
Young Elderly
|
p-value
|
Old Elderly
|
p-value
|
Tumor size
|
|
0.118
|
|
0.307
|
|
|
Micro
|
7/17 (41%)
|
|
6/12 (50%)
|
|
|
|
Macro
|
53/86 (62%)
|
|
40/61 (87%)
|
|
|
|
Invasion
|
|
0.036
|
|
0.096
|
|
0.105
|
No
|
39/58 (67%)
|
|
28/39 (72%)
|
|
11/19 (58%)
|
|
Yes
|
21/45 (47%)
|
|
18/34 (53%)
|
|
3/11 (27%)
|
|
Ki-67
|
|
0.019
|
|
0.001
|
|
0.419
|
< 3%
|
51/79 (65%)
|
|
41/56 (73%)
|
|
10/23 (43.5%)
|
|
> 3%
|
9/24 (37.5%)
|
|
5/17 (29%)
|
|
4/7 (57%)
|
|
p53
|
|
0.084
|
|
0.028
|
|
|
Negative
|
47/74 (63.5%)
|
|
38/54 (70%)
|
|
9/20 (45%)
|
|
Positive
|
13/29 (45%)
|
|
8/19 (42%)
|
|
5/10 (50%)
|
|
Mitoses
|
|
0.860
|
|
0.528
|
|
0.512
|
< 2/10 HPF
|
51/87 (59%)
|
|
40/62 (64.5%)
|
|
11/25 (44%)
|
|
> 2/10 HPF
|
9/16 (56%)
|
|
6/11 (54.5%)
|
|
3/5 (60%)
|
|
Trouillas grade
|
|
0.099
|
|
0.104
|
|
0.516
|
1a
|
38/57 (67%)
|
|
29/41 (71%)
|
|
9/16 (56%)
|
|
1b
|
3/8 (37.5%)
|
|
1/3 (33%)
|
|
2/5 (40%)
|
|
2a
|
18/33 (54.5%)
|
|
15/24 (62.5%)
|
|
3/9 (30%)
|
|
2b
|
1/5 (20%)
|
|
1/5 (20%)
|
|
14/30 (47%)
|
|
KNOSP
|
|
0.017
|
|
0.028
|
|
0.018
|
0
|
5/11 (45.5%)
|
|
4/8 (50%)
|
|
1/3 (33%)
|
|
1
|
21/31 (68%)
|
|
15/22 (75%)
|
|
7/11 (63%)
|
|
2
|
26/36 (72%)
|
|
22/29 (76%)
|
|
4/7 (57%)
|
|
3
|
6/20 (30%)
|
|
4/12 (33%)
|
|
2/8 (25%)
|
|
4
|
2/5 (40%)
|
|
1/4 (25%)
|
|
0/1 (0%)
|
|
Complications
Surgical complications occurred in 8 patients (7.3%): CSF leak was registered in 3 patients (2.9%), epistaxis in 2 (1.9%), 2 patients had meningitis (1.9%) and one patient experienced pneumocephalus (1%).
Comparing young and old elderly patients, a higher rate of surgical complications in the young elderly was observed (8.2% vs 6.7%), although this difference was not statistically significant. Interestingly, surgical complications were more frequent in patients with Trouillas’ grade 2a and 2b (1.8% vs 7.8%, p = 0.009), but this difference did not remain statistically significant by dividing young and old elderly (2.6% vs 14.7% p = 0.06; 0% vs 6.7% p = 0.054, respectively).
Regarding endocrinological complications, 24 patients developed hypocortisolism (23.1%), 32 developed hypothyroidism (30.8%) and 6 developed diabetes insipidus (5.8%). Higher rates of hypocortisolism were registered in old elderly (17.8% vs 36.7%, p = 0.004) as well as hypothyroidism (26% vs 43.3%), while postoperative DI was more frequent in younger ones (6.8% vs 3.3%), although did not reach statistical significance. Specifically, 5 patients developed DI among the group of young elderly and for three of them the disorder was permanent, while in the group of old elderly only one patient developed a permanent DI.
Finally, Trouillas grade did not seem to be a predictive factor of endocrinological complications (Table 4).
Table 4
Postoperative complications and distribution among groups.
Complications
|
General population
|
Young Elderly
|
p-value
|
Old Elderly
|
p-value
|
Surgical Complications
|
8 (7.3%)
|
6 (8.2%)
|
> 0.05
|
2 (6.7%)
|
> 0.05
|
CSF leak
|
3 (2.9%)
|
3 (4.1%)
|
> 0.05
|
0 (0%)
|
> 0.05
|
Epistaxis
|
2 (1.9%)
|
1 (1.4%)
|
> 0.05
|
1 (3.3%)
|
> 0.05
|
Meningitis
|
2 (1.9%)
|
1 (1.4%)
|
> 0.05
|
1 (3.3%)
|
> 0.05
|
Pneumocephalus
|
1 (1%)
|
1 (1.4%)
|
> 0.05
|
0 (0%)
|
> 0.05
|
Early Endocrinological deficit
|
|
Hypocortisolism
|
24 (23.1%)
|
13 (17.8%)
|
> 0.05
|
11 (36.7%)
|
0.004
|
Hypothyroidism
|
32 (30.8%)
|
19 (26%)
|
> 0.05
|
13 (43.3%)
|
> 0.05
|
Diabetes Insipidus
|
6 (5.8%)
|
5 (6.8%)
|
> 0.05
|
1 (3.3%)
|
> 0.05
|
Table 5
Correlation between radiological and histopathological features and recurrence
|
Recurrence/Patients ratio (%)
|
|
General population
|
p-value
|
Young Elderly
|
p-value
|
Old Elderly
|
p-value
|
Tumor size
|
|
0.138
|
|
0.744
|
|
0.014
|
Micro
|
4/17 (23.5%)
|
|
2/12 (17%)
|
|
2/5 (40%)
|
|
Macro
|
9/86 (10.5%)
|
|
8/61 (13%)
|
|
1/25(10%)
|
|
Invasion
|
|
0.010
|
|
0.003
|
|
0.900
|
No
|
3/58 (5%)
|
|
1/39 (3%)
|
|
2/19 (10.5%)
|
|
Yes
|
10/45 (22%)
|
|
9/34 (26.5%)
|
|
1/11 (9%)
|
|
EOR
|
|
0.032
|
|
0.002
|
|
|
GTR
|
4/60 (7%)
|
|
2/46 (4%)
|
|
2/14 (14%)
|
|
STR
|
9/43 (21%)
|
|
8/27 (30%)
|
|
1/16 (6%)
|
|
Ki-67
|
|
0.005
|
|
0.003
|
|
0.666
|
< 3%
|
6/79 (8%)
|
|
4/56 (7%)
|
|
2/23 (9%)
|
|
> 3%
|
7/24 (29%)
|
|
6/17 (35%)
|
|
1/7 (14%)
|
|
p53
|
|
0.028
|
|
0.063
|
|
0.197
|
Negative
|
6/74 (8%)
|
|
5/54 (9%)
|
|
1/20 (5%)
|
|
Positive
|
7/29 (24%)
|
|
5/19 (26%)
|
|
2/10 (20%)
|
|
Mitoses
|
|
0.015
|
|
0.155
|
|
0.014
|
< 2/10 HPF
|
8/87 (9%)
|
|
7/62 (11%)
|
|
1/25 (4%)
|
|
> 2/10 HPF
|
5/16 (31%)
|
|
3/11 (27%)
|
|
2/5 (40%)
|
|
Trouillas grade
|
|
0.003
|
|
0.004
|
|
0.464
|
1a
|
3/57 (5%)
|
|
2/41 (5%)
|
|
1/16 (6%)
|
|
1b
|
1/8 (12.5%)
|
|
0/3 (0%)
|
|
1/5 (20%)
|
|
2a
|
6/33 (18%)
|
|
5/24 (21%)
|
|
1/9 (11%)
|
|
2b
|
3/5 (60%)
|
|
3/5 (60%)
|
|
NA
|
|
KNOSP
|
|
0.085
|
|
0.026
|
|
0.597
|
0
|
1/11 (9%)
|
|
0/8 (0%)
|
|
1/3 (33%)
|
|
1
|
3/31 (10%)
|
|
2/20 (10%)
|
|
1/11 (9%)
|
|
2
|
2/36 (6%)
|
|
2/29 (7%)
|
|
0/7 (0%)
|
|
3
|
5/20 (25%)
|
|
4/12 (33%)
|
|
1/8 (12.5%)
|
|
4
|
2/5 (40%)
|
|
2/4 (50%)
|
|
0/1 (0%)
|
|
Recurrence
13 patients developed recurrence (6 in the young elderly group and 7 in the old ederly one, respectively).
A mean increase of 4 mm (range 2–12 mm) was reported. 8 patients were managed conservatively, 2 cases with medical therapy, 1 patient was treated with radiotherapy and two patients (Trouillas grade 2b) underwent to second surgery. Both patients who were managed surgically belonged to the young elderly group and developed a visual deficit due to tumor regrowth. A clinicoradiological follow-up was the multidisciplinary choice for all cases of recurrence in the old elderly group.
Invasion (22%, p = 0.010), Ki67 > 3% (29%, p = 0.005), p53 mutation (24%, P = 0.028), number of mitoses (31%, p = 0.015), STR (21%, p = 0.032) and Trouillas’Grade (1a 5%, 1b 12%, 2a 18%, 2b 60%, p = 0.017) resulted statistically correlated with an increased incidence of recurrence in the elderly.
Among young elderly patients, a higher recurrence rate was remarked by the presence of invasion (26.5%, p = 0.003), Ki-67 > 3% (35%, p = 0.003), STR (30%, p = 0.002), Trouillas’Grade (1a: 5%, 1b: 0%, 2a: 21%, 2b: 60%, p = 0.017) and KNOSP (grade 0: 0%, grade 1: 10%, grade 2: 7%, grade 3: 33%, 4 50%, p = 0.018).
Conversely, in the old elderly group only microadenoma (40%, p = 0.014) and mitoses > 2/HPF (40%, p = 0.014) were statistically associated with recurrence.