Introduction
Thymoma is the most common mediastinal neoplasm in adults accounting for 50% of all
mediastinal neoplasms. However, it can be considered a rare disease with an incidence
of 3/1,000,000 inhabitants per year.[1 ] It is well known for its heterogeneous oncology behavior, variability in histological
appearance, and association with autoimmune diseases, the most common of them being
myasthenia gravis (MG). A new staging for thymoma was proposed in 2014 and subsequently
published in the eighth edition of the tumor nodes metastasis (TNM) classification
of malignant tumors.[2 ]
[3 ] This study aims to describe the correlation between the new TNM staging and the
World Health Organization (WHO) classification and to identify, through regression
models, how these two variables relate to each other and whether they have a prognostic
value in predicting survival and recurrence of disease.
Methods
Patients
The study was conducted in Ferrara University hospital, which is a tertiary center
for thoracic surgery. All patients receiving surgery with curative intent for thymoma
at our department between January 1995 and December 2016 were identified using the
institution's database. A retrospective analysis of these patients' records was performed.
Therefore, patients with definitive histological diagnosis of thymic carcinoma, thymic
carcinoid, thymic hyperplasia, thymolipoma, primary thymic lymphoma, or thymic cyst
were excluded from the study. Patients who received nonsurgical treatments were also
excluded. Preoperative assessment in a patient with a suspected thymoma includes routine
blood tests, electrocardiography, pulmonary function tests and arterial blood gas
analysis, computed tomography scan of the chest and upper abdomen, neurologic consultation
in case of associated MG, and chest magnetic resonance imaging in selected cases.
Comorbidities and postoperative complications were defined according Charlson Comorbidity
Index score.[4 ] Ethical approval for this study was sought and obtained from the local ethic committee.
Histological and Clinical-Pathological Staging
The histologic type of neoplasm was classified according to WHO 1999 criteria, updated
in 2004.[5 ]
[6 ] All samples were reclassified according to the most recent 2004 criteria. The tumor
stage was determined according to the new TNM classification system.[2 ]
[3 ] Myasthenic patients were divided into five stages, depending on muscular involvement
and symptom severity, following the guidelines of the Medical Scientific Advisory
Board of the MGFA.[7 ]
Surgical Treatment
Surgery included resection of the thymoma, always associated with total thymectomy.
Extended resections were performed in cases of gross involvement of surrounding organs
including mediastinal pleura, lung, pericardium, and superior vena cava. Where radical
resection (R0) was not possible because of the invasiveness of the tumor, the resection
was defined incomplete (R1). Surgical approaches included median sternotomy, thoracotomy,
clamshell incision, and video-assisted thoracoscopic surgery (VATS). The choice of
technique was accomplished in relation to age, clinical condition of the patient,
size, and invasiveness of the neoplasm found both preoperatively and surgically.
Statistical Analysis
For categorical variables, absolute and percentage frequencies are reported, while
for numeric variables average and standard deviation are reported. The graphic description
was made using bar graphs and pie charts. The comparison between groups was performed
using t -test for numeric variables, while for categorical variables Pearson chi-square test
or, in case of low number, the exact Fisher's exact test was adopted. Overall survival
(OS) and disease-free survival (DFS) defined as freedom from recurrence in case of
complete resection (R0) or as time-to-progression in case of incomplete recurrence
(R1–R2) were calculated from the day of surgery. For survival analysis, time was calculated
in months, from the date of thymectomy until the date of death for reasons related
to thymic neoplasia or other causes. The disease-free follow-up, expressed in months,
was evaluated over the 10 years after surgery. Survival analysis was undertaken using
the Kaplan–Meier method. The comparison between groups was evaluated using the Cox
regression model by reporting its hazard ratio (HR) and p value.
Results
Clinical
[Table 1 ] illustrates the patients' characteristics. Our cohort included 54 patients, 27 women,
and 27 men with a mean age at the time of surgery was 60.8 years (range, 23–84 years).
Twenty patients (37.04%) presented with MG and their mean age was 59 years (range,
30 and 83 years). Thirty-five patients (64.8%) had the following onset symptoms: two
(5.7%) patients with pneumonia, three (8.6%) with retrosternal pain, six (17.1%) with
cough, one with dyspnea (2.9%), one with mediastinal syndrome (2.9%), two with pleural
effusion (5.7%), and twenty patients (57.1%) with myasthenic symptoms. The mean Charlson
Comorbidity Index was of 4.7, ranging between 2 and 13.
Table 1
Clinical characteristics of patients
Number
%
Male/female
27/27
50/50%
Average age (range)
60.8 (23–84)
–
Myasthenic
20
37%
Onset symptoms
Asymptomatic
19
35.2%
Symptomatic
35
64.8%
Myasthenia
20
57.1%
Cough
6
17.1%
Retrosternal pain
3
8.6%
Pneumonia
2
5.7%
Pleural effusion
2
5.7%
Dyspnea
1
2.9%
Mediastinal syndrome
1
2.9%
Charlson Comorbidity Index average (range)
4.7 (2–13)
–
Surgical Approach
Twenty-two (40.7%) thymectomies were performed using thoracoscopic approach and 32
(59.3%) cases underwent open procedures with the following surgical approaches: 5
clamshells (9.3%), 10 thoracotomies (18.5%), and 17 median sternotomies (31.5%), including
2 VATS (3.7%) thymectomies were converted to thoracotomy.
Complete resection (R0) was achieved in 43 (79.63%) patients; the remaining 11 cases
(20.37%) underwent partial resection (R1).
Mean operative time was 210 minutes for open procedures and 150 minutes for minimally
invasive approaches.
Mean hospital stay was 3 days in case of the mini-invasive procedures, and 9 days
for open approaches (p = 0.027). It has to be noted that one patient had a 68-day hospital stay without
whom the average hospitalization would have been 7 days. In 16 cases, intensive care
unit (ICU) stay was required. Twelve of these (75%) received open surgeries. Almost
half of myasthenic patients (45.0%, 9/20) required ICU stay.
Correlation between Histology and TNM
On the basis of WHO histological classification, 9 patients (16.7%) were detected
with type A thymoma, 14 (25.9%) with type AB, 15 (27.8%) with type B1, 10 (18, 5%)
with type B2, and 6 (11.1%) with type B3. Regarding the new TNM staging 37 (68.4%)
patients were found at stage I, 1 (1.9%) at stage II, 9 (16.7%) at stage IIIA, 3 (5.6%)
at stage IIIB, 4 (7.4%) at stage IVA, and zero patients at stage IVB.
The relationship between the WHO histological type and the new TNM staging is shown
in [Fig. 1 ].
Fig. 1 Histogram representing the relationship between tumor nodes metastasis (TNM) stages
and World Health Organization (WHO) types.
There is an association between staging system and histology (p = 0.003), but it is challenging to define recurring groups because for some TNM stages
the sample size is too small. TNM stages are divided into two groups: early stages
(stage E) made by stages I and II, and advanced stages (stage A) determined by stages
IIIA, IIIB, and IV. Stage E consisted of 38 cases (70.4%) and stage A of 16 cases
(29.6%). The correlation between early and advanced stages and histological subtypes
is shown in [Table 2 ].
Table 2
Correlation between TNM stages and WHO types
A
AB
B1
B2
B3
Stages E (I, II)
7
12
13
6
0
Stages A (IIIA, IIIB, IV)
2
2
2
4
6
Abbreviations: TNM, tumor nodes metastasis; WHO, World Health Organization.
Histological subtypes were also subdivided in two groups: Group 1 made by A, AB, B1
and group 2 consisting in types B2 and B3. Group 1 included 38 patients (70.4%) and
group 2 16 patients (29.6%).
[Table 3 ] shows a significant correlation between histological subtypes and TNM stages with
a 78% of global agreement (p <0.001).
Table 3
Relationship between the two WHO groups and the two TNM stages
Early stages (TNM stages I–II)
Advanced stages (TNM stages III–IV)
p -Value
Group 1 (WHO types A, AB, B1)
32
6
<0.001
Group 1 (WHO types B2, B3)
6
10
<0.001
Abbreviations: TNM, tumor nodes metastasis; WHO, World Health Organization.
Correlation between Masaoka and the 8th Edition of TNM Staging System
[Table 4 ] shows the correlation between Masaoka and the new TNM staging system: Masaoka stage
II cases only were redistributed in TNM stage I for 8 (80%), stage II (10%), and stage
IIIA (10%).
Table 4
Correlation between TNM and Masaoka stages
Stage I
Stage II
Stage IIIA
Stage IIIB
Stage IV
Masaoka I
29
0
0
0
0
Masaoka IIA
7
0
1
0
0
Masaoka IIB
1
1
0
0
0
Masaoka III
0
0
8
3
0
Masaoka IVA
0
0
0
0
4
Abbreviation: TNM, tumor nodes metastasis.
Regression Analysis
[Table 5 ] shows the results of the regression model considering TNM staging as the outcome
variable: Stage E showed a higher proportion of myasthenic patients (p = 0.07) and complete resection (R0) surgeries (p < 0.001). The 10-year recurrence rate was 5.6% for stage E and 60% for stage A (p < 0.001). The 5-year survival was 94.7% for stage E and 62.6% for stage A as shown
in [Fig. 2 ] (p = 0.002). The 10-year survival rate was 81.58% for stage E and 62.58% for stage A
as shown in [Fig. 3 ] (p = 0.001).
Fig. 2 Five-year adjusted survival curves.
Fig. 3 Ten-year adjusted survival curves.
Table 5
Relationship between TNM stage and other variables
Stage E
Stage A
p -Value
Average age (±SD)
61.6 (±12.47)
58.9 (±15.5)
0.50
Sex M/F
18/20 (47.37/52.63%)
9/7 (56.25/43.75%)
0.55
Myasthenic
17 (85%)
3 (15%)
0.07
Charlson Comorbidity Index average (±SD)
4.2 (±1.4)
5.9 (±3)
0.03
Surgery VATS/open
18/20 (47.37/53.63%)
4/12 (25/75%)
0.002
R0/R1
38/0 (100/0%)
11/5 (68.75/31.25%)
<0.001
Recurrence yes/no
2/36(5.26/94.74)
9/6 (60/40%)
<0.001
Death at 5 years yes/no
2/36 (5.26/94.74%)
6/10 (37.5/62.58%)
0.002
Death at 10 years yes/no
7/31 (18.42/81.58%)
6/10 (37.5/62.58%)
0.001
Abbreviations: SD, standard deviation; TNM, tumor nodes metastasis; VATS, video-assisted
thoracoscopic surgery.
Note: Regression model considering TNM staging as the outcome variable.
[Table 6 ] demonstrates the results of the regression model considering WHO histology as the
outcome variable: a complete resection (R0) was achieved 94.74% of patients in group
1 and 43.75% in group 2 (p < 0.001). In addition, the recurrence was found in 10.53% of cases of group 1 and
46.67% of group 2 (p = 0.003).
Table 6
Relationship between WHO groups and other variables
Group 1
Group 2
p -Value
Average age (±SD
59.7 (±13.9)
63.6 (±12.1)
0.03
Sex M/F
21/17 (55.26/44.74%)
6/10 (37.5/62.5%)
0.23
Myasthenic
15 (75%)
5 (25%)
0.57
Charlson Comorbidity Index average (±SD)
4.1 (±1.5)
6.1 ( ± 2.7)
0.005
Surgery VATS/open
17/21 (44.74/55.26%)
5/11 (31.25/68.75%)
–
R0/R1
36/2 (94.74/5.26%)
7/9 (43.75/56.25%)
<0.001
Recurrence yes/no
4/34 (10.53/89.47%)
7/8 (46.67/53.33%)
0.003
Death at 5 years yes/no
3/35 (7.89/92.11%)
5/11 (31.25/68.75%)
0.03
Death at 10 years yes/no
9/29 (23.68/76.32%)
8/8 (50/50%)
0.057
Abbreviations: SD, standard deviation; VATS, video-assisted thoracoscopic surgery;
WHO, World Health Organization.
Note: Regression model considering WHO histology as the outcome variable.
The survival at 5 and 10 years was 92.11 and 76.32%, respectively, for group 1; while
in group 2 it was 68.75% at 5 years and 50% at 10 years (p = 0.03 and 0.057, respectively) ([Table 6 ]; [Figs. 2 ] and [3 ]).
Survival Analysis
Overall 5- and 10-year survival was 85.2 and at 75.9%, respectively. When stratified
by stage and histology, a significant 5-year OS difference was observed in stage E
and A patients (p = 0.015) but in histological subgroups ([Fig. 2 ]), the probability of death at 5 years for stage A patients was approximately seven
times higher than for stage E patients (HR = 7.62). This value was corrected with
possible confounding factors. For all the corrections made in this study (age, gender,
MG, radicality, Charlson Comorbidity Index), only the Charlson Comorbidity Index was
found related to survival and recurrence, so it was the only factor taken into account
to adjust the results. We found that stage only was a 5-year OS strong independent
prognostic factor (p value corrected = 0.034) and the HR resulted to be 6.44.
[Fig. 3 ] illustrated 10-year survival analysis: a significant correlation with stage only
(p = 0.002) was found. The adjusted 10-year OS analysis showed that stage is a strong
independent prognostic factor (p = 0.044). Stage A patients have a 10-year death probability which is three times
higher than stage E patients (HR = 3.15).
[Fig. 4 ] shows survival analysis using DFS as a measure of outcome: a significant relationship
with both histology (p = 0.005) and stage (<0.001) was identified. After the correction of the results,
the relationship remained significant. Group 2 had a risk of recurrence 10 years,
which was five times higher than group 1 (HR = 4.89 and p = 0.021). Stage A is likely to have recurrence 15 times higher than stage E (HR = 15.18
and p = 0.001).
Fig. 4 Disease-free adjusted survival curves.
Discussion
In 2014, a new staging for thymoma was proposed, which was subsequently published
in 2016 in the eighth edition of the TNM classification of malignant tumors.[2 ]
[3 ] There are no studies in literature analyzing the correlation between the new staging
system with other variables such as the WHO histotypes and MG. The main objective
of this study was to evaluate the correlation between the new TNM staging system and
histological WHO classification. Another goal of this study was to analyze how these
two elements interrelate one another in terms of clinical presentation and the long-term
outcome. Different studies have been published to evaluate the prognostic role of
WHO classification with conflicting results.[8 ]
[9 ]
[10 ] Although most authors showed trend toward a survival decrement proceeding from A
to B3 histotypes, there is still no clear evidence of the histologic subgroups impact
on outcome.[11 ]
[12 ] The results indicate that there is a significant correlation between the new TNM
staging and the histological grade WHO: stages I and II are more frequently associated
with histologic groups A, AB, and B1, as well as stages III and IV are more associated
with groups B2 and B3. It can also be seen how the percentage of stages III and IV
is much higher in B2 than A, AB, and B1, reaching 100% in B3. We can, therefore, define
that histologic degrees B2 and B3 are closely associated with stages III and IV of
the new TNM staging.
These results may have important clinical repercussions: in the case of preoperative
diagnosis of thymoma type B2 and B3, neoadjuvant treatments may increase the full
resection rate, according to Lucchi and Gregory.[13 ]
[14 ] In addition, patients with definitive diagnosis of type B2 or B3 thymoma, even in
the case of complete resection, may be eligible for adjuvant treatments. In fact,
the clinical practice guidelines of the European Society for Medical Oncology suggest
considering both stage and histology in the evaluation of postoperative radiotherapy
treatment.[15 ] Further prospective studies are required to confirm this preliminary data in the
future.
Margaritora et al[16 ] found a significant survival advantage in thymoma patients with MG both in terms
of OS and DFS; however, they pointed out no correlation between stage and MG. In our
study, MG is a positive predictive factor of survival (p = 0.07): it is more frequent in stages I and II thymomas (17 cases), and rare in
stages III and IV (only 3 cases). This association was also reported by other authors[17 ]
[18 ] and in our opinion could be explained by the stricter and prompt radiological examination
performed on every myasthenic patients to exclude thymic disease.[19 ]
In literature, it is widely documented that the possibility of performing a complete
resection is one of the most important prognostic factors influencing survival.[20 ]
[21 ] Not surprisingly, in our study the impact of the extent of surgical resection on
outcome was confirmed: this was achieved in 100% of cases at early stages and in 69%
of invasive stages, as reported by Detterbeck et al.[2 ] Furthermore, the possibility of performing a complete resection is statistically
different between the two histological groups with a possibility to achieve a 95%
radical resection in groups A, AB, and B1 and 44% in the B2 and B3 groups.
Our study also shows how stage and histological grading are an important prognostic
factor for DFS. There is a significant difference between early stages and invasive
stages, as well as between groups A, AB, B1, and groups B2 and B3. In stages III and
IV, the 10-year recurrence rate was 60% and patients affected by B2 and B3 thymomas
have a five times higher risk of recurrence than patients with A, AB, and B1 histotypes.
We also highlighted that patients with invasive stages have risk of relapse at 10
years 15 times higher than early stages. The eighth edition thymic stage classification
provides different advantages: it focuses on invasion of adjacent structures and therefore
it reflects the ability to resect thymic malignancies and survival.[22 ] The association between histology and outcome could have important clinical consequences:
it could justify stricter follow-up programs for patients with histopathologic diagnosis
B2 or B3.
Several studies reported the role of open and thoracoscopic approach in terms of survival.[23 ] In the present study, comparing the data concerning the possible surgical approaches
(open and mini-invasive), for stage and grading, it was found that the open approach
has been used in the majority of cases. The percentages of use of this technique increase
with increasing TNM stage (53% in early stages and 75% in advanced stages). However,
it is important to point out that the mini-invasive approach significantly reduces
the average time of the intervention (150 minutes) compared with the open technique
(210 minutes) and also dramatically reduces the average stay time (3 vs 9 days).
Limitations
This investigation represents a single institution's experience, the cohort of patients
was assessed retrospectively, and we acknowledge that there is inherent bias associated
with this approach.
Conclusion
Our study shows that there is a correlation between the two WHO groups and the two
TNM groups. MG is more frequently associated with early stage tumors. The ability
to implement a full resection, the rate of recurrence, and survival are closely related
to the thymoma stage. It also shows how both histotype and stage correlate with DFS.
In fact, the least aggressive stages, both WHO and TNM, have a disease-free time superior
to advanced stages.
