Keywords
myasthenia gravis - VATS - thymectomy - outcomes - thymoma
Introduction
Over the last two decades, many approaches have been described, extensively analyzed
and published for the management of thymoma.[1]
[2]
[3] Total thymectomy via median sternotomy has been the preferred standard treatment
for thymoma for a long time despite the fact that this technique causes long postoperative
hospital stay, long-lasting postoperative pain, and poor cosmetic outcomes.[4]
[5]
In the last decade, minimally invasive techniques of thymectomy have been increasingly
performed for early stages thymomas.[6] Minimally invasive thymectomy improves postoperative outcomes, including reduced
postoperative pain, fewer postoperative complications, and shorter postoperative hospital
stay. Furthermore, it provides equivalent oncological clinical outcomes when compared
with standard sternotomy approach to the disease.[7]
[8]
[9]
[10]
[11]
[12] Several operative approaches for minimally invasive thymectomy have been described
including unilateral video-assisted thoracic surgery (VATS), bilateral VATS, robotic
video-assisted techniques, transcervical thymectomy, and subxiphoid thymectomy.[13]
[14]
[15] Unilateral thoracoscopic thymectomy is a simple procedure and oncologically feasible
for thymoma at early stages.[16] However, controversies exist regarding the side that provides the best postoperative
outcome. Unilateral VATS, performed on the right side, is generally preferred; in
this technique, the landmark of the superior vena cava, where the left innominate
vein converges, can be conveniently identified.[17]
[18] However, other researchers recommended left-sided VATS thymectomy.[19] This study presents our experience on unilateral VATS thymectomy, compares short-term
and oncological outcomes, and identifies differences of unilateral VATS thymectomy
conducted on both sides.
Methods
Between February 2001 and March 2020, 72 patients underwent surgery for thymoma in
our unit with different surgical approaches. We retrospectively collected and reviewed
data of 29 consecutive patients undergoing thoracoscopic thymectomy during that time
period. All surgeries were performed by four general thoracic surgeons, who are fellowship
trained in minimally invasive thoracic surgery and advanced minimally invasive surgery.
The study was approved by the local Ethics Committee. Patients with definitive histological
diagnosis of thymic carcinoid, thymic hyperplasia, thymolipoma, primary thymic lymphoma,
or thymic cyst were excluded from the study. Patients who received an open approach
as well as patients who underwent nonsurgical treatments were also excluded. Clinicopathologic
data, including gender, age at disease onset, date of surgery, clinical classification,
medication, surgery information, morbidity, thymoma histology, maximum diameter, and
position, were obtained from clinical and pathologic records. Comorbidities were defined
according to the Charlson Comorbidity Index score.[20] The histologic type of neoplasm was classified according to the 2015 World Health
Organization (WHO) Classification of Tumors of the Thymus.[21] The tumor stage was determined according to both Masaoka system[22] and tumor, node, and metastasis (TNM) classification system.[23]
[24] Postoperatively, all patients were checked for recurrence with an oncological follow-up.
The preoperative myasthenia gravis severity was evaluated according to the Myasthenia
Gravis Foundation of America (MGFA) classification system.[25] The postoperative patients' clinical symptoms were evaluated during the hospitalization
for thymectomy, and each patient had regular postoperative follow-up, which were performed
at least two times per year. The therapeutic response to thymectomy was compared with
the patient's preoperative status and assessed according to MGFA postintervention
status.
Surgical Technique
The access via left or right VATS was determined according to the position of the
tumor, as noted on the preoperative chest computed tomography (CT) ([Fig. 1]). Similar techniques for right- and left-sided VATS were performed. VATS was usually
performed with the patient positioned in ∼30 degrees semisupine position. The ipsilateral
arm is placed naturally and secured by the side and below the chest wall on the padded
board ([Figure 2]). The operating surgeon, the assistant, and the scrub nurse stand along the same
side. Three trocars were generally positioned between the third and sixth intercostal
spaces following the submammary line. CO2 insufflation was used to collapse the lung.
Fig. 1 Chest CT scans showing thymomas extending predominantly on le right side (A) or to the left side (B).
Fig. 2 Patient's positioning and submammary incisions.
The mediastinal pleura overlying the lower ends of the main thymic lobes was dissected
along the phrenic nerve, which has to be carefully preserved. The incision of the
mediastinal pleura was continued at the upper edge to open the connection to the neck
tissue. During further mobilization of the anterior mediastinal tissue portion by
retrosternal incision down to the diaphragm, the arterial thymic supply was divided.
The whole tissue portion was then mobilized from the pericardial surface. After complete
exposure of the innominate vein all thymic veins were resected. Finally, the totally
freed thymic tumor, thymic gland, and its accompanying mediastinal fatty tissues were
brought out. Contralateral phrenic nerve was visualized only in case of large thymic
tumors by means of opening the contralateral mediastinal pleura. Our treatment strategy
for thymoma was to perform an extended thymectomy, including the excision of bilateral
fat tissue, regardless of the presence of myasthenia gravis.
Statistical Analysis
For categorical variables, absolute and percentage frequencies were reported. In the
presence of symmetry of the distributions, the variables were represented with the
mean and standard deviation or, in the case of not-normal distribution, with the median
value and interquartile range (IQR). Statistical comparisons of continuous variables
were assessed using Student's t-test for normally distributed variables and using
Mann–Whitney U test in case of not-normal distribution, while for categorical variables
Pearson chi-squared test or Fisher's exact test were used depending on the minimal
expected count in each crosstab. 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), was calculated from the day of surgery. 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 log rank test.
Results
Twenty-nine patients (11 males and 18 females) were enrolled in the study. The mean
age was 63.1 ± 11.3 years and the female/male ratio was 1.73:1. Ten patients (34%)
presented with myasthenia gravis. Left-side video-assisted thoracoscopic extended
thymectomy was performed in 12 patients (41%), whereas right-side thoracoscopic extended
thymectomy was performed in 17 patients (59%). Patients' characteristics are listed
in [Table 1]. The median value of Charlson comorbidity score was 4 (IQR: 4–6) in the right approach
group and 4 (IQR: 3–5) in the left approach group (p = . 0.248). With regard to the
WHO classification, there were 4 type A, 10 type AB, 5 type B1, 7 type B2, one thymic
carcinoma, and one micronodular thymoma without significant differences between two
groups (p = 0.999). The mean tumor size of the resected specimens was 5.6 ( ± 2.5) cm for the
right side and 5.4 ( ± 1.3) cm for the left side in diameter (p = 0.490). Most of the patients (86%) had Masaoka stage I or II tumors, none were
in stage IV, but three patients (14%) were in stage III. Furthermore, no patient required
conversion to open thymectomy.
Table 1
Characteristics of 29 patients undergoing video-assisted thoracoscopic thymectomy
for thymoma
Variable
|
Right approach (17)
|
Left approach (12)
|
p-Value
|
Age (y) mean (SD)
|
65.2 (12.6)
|
59.9 (9.3)
|
0.230
|
(range)
|
(42–84)
|
(45–71)
|
|
Female, n (%)
|
8 (47.1)
|
10 (83.3)
|
0.047
|
Male, n (%)
|
9 (52.9)
|
2 (16.7)
|
0.064
|
Myasthenia gravis, n (%)
|
4 (23.5)
|
6 (50)
|
0.236
|
Preoperative MGFA clinical classification, n (%)
|
|
|
|
–I
|
1 (5.9)
|
1 (8.4)
|
0.999
|
–II
|
2 (11.8)
|
2 (16.7)
|
0.999
|
–III
|
3 (17.6)
|
1 (8.4)
|
0.622
|
–IV
|
0
|
0
|
0.999
|
COPD, n (%)
|
3 (17.6)
|
0 (0)
|
0.124
|
Hypertension, n (%)
|
12 (70.6)
|
3 (25)
|
0.025
|
Diabetes, n (%)
|
2 (11.8)
|
0 (0)
|
0.218
|
Charlson comorbidity score (median) (IQR)
|
4[4 6]
|
4[3 5]
|
0.248
|
Tumor location on chest CT
–Predominantly right side
–Predominantly left side
|
17 (100)
|
12 (100)
|
0.999
|
WHO, n (%)
|
|
|
|
A
|
2 (11.8)
|
2 (16.7)
|
0.999
|
AB
|
7 (41.2)
|
3 (25)
|
0.449
|
B1
|
2 (11.8)
|
3 (25)
|
0.624
|
B2
|
3 (17.6)
|
4 (33.3)
|
0.403
|
B3
|
1 (5.9)
|
0 (0)
|
0.999
|
Thymic carcinoma
|
1 (5.9)
|
0 (0)
|
0.999
|
Micronodular thymoma, n (%)
|
1 (5.9)
|
0 (0)
|
0.999
|
Tumor size (cm) mean, (SD)
|
5.9 (2.5)
|
5.4 (1.3)
|
0.490
|
Masaoka stage, n (%)
|
|
|
|
I
|
8 (47.1)
|
7 (58.3)
|
0.710
|
II
|
8 (47.1)
|
3 (25)
|
0.273
|
III
|
1 (5.8)
|
2 (16.7)
|
0.553
|
IV
|
0 (0)
|
0 (0)
|
0.999
|
TNM stage, n (%)
|
|
|
|
I
|
12 (70.6)
|
9 (75)
|
0.999
|
II
|
4 (23.5)
|
0 (0)
|
0.121
|
IIIA
|
0(0)
|
3 (25)
|
0.006
|
IIIB
|
1 (5.9)
|
0 (0)
|
0.999
|
Abbreviations: COPD, chronic obstructive pulmonary disease; CT, computed tomography;
IQR, interquartile range; MGFA, Myasthenia Gravis Foundation of America; SD, standard
deviation; TNM, tumor, node, and metastasis; WHO, World Health Organization.
As shown in [Table 2], the mean operation time for the right-side VATS and groups left-side VATS was,
respectively, 170.6 ± 47.9 versus 168.3 ± 49.5 minutes (p = 0.903). Curative resection (R0) was accomplished in 94% of cases in case of right
VATS and 92% of cases of left VATS approach (p = 0.798). The mean duration of chest drain was 2 days in both groups (p = 0.962). The mean hospital stay was 3 days (IQR: 3–4) for the left-side VATS and
3 days (IQR: 3–4) for right-side VATS groups (p = 0.723). One patient (5.9%) required intensive care unit (ICU) postoperative ICU
admission in the right-side group and two patients (16.9%) in the left-side group
(p = 0.533).
Table 2
Postoperative features
Variable
|
Right access (17)
|
Left access (12)
|
p-Value
|
Complications, n (%)
|
|
|
|
Bleeding
|
0 (0)
|
0 (0)
|
0.999
|
Phrenic nerve lesion
|
0 (0)
|
1 (8.3) left side
|
0.414
|
Respiratory failure
|
1 (5.9)
|
0 (0)
|
0.999
|
Operative time (min)
|
170.6 (47.9)
|
168.3 (49.51)
|
0.903
|
Complete resection, n (%)
|
16 (94.1)
|
11 (91.7)
|
0.798
|
Chest drain removal (postoperative days) Median (IQR)
|
2 (2.3)
|
2 (2.3)
|
0.962
|
Intensive care unit stay (no of patients)
|
1 (5.9)
|
2 (16.7)
|
0.533
|
Postoperative hospital stay (days) median (IQR)
|
3 (3.4)
|
3 (3.4)
|
0.723
|
Abbreviation: IQR, interquartile range.
Postoperative complications occurred in one patient (3%) for left-side VATS group
with phrenic nerve lesion on the left side and one patient (3%) for right-side VATS
with respiratory failure. The morbidity rate was similar in the two groups (p = 0.99). There was no surgery-related mortality in either group.
The mean follow-up time was 105 months (IQR: 72.5–150) for the left-side group and
40 months (IQR: 27–99.5) for the right-side group. There were two recurrences in the
left-side VATS group and two recurrences in the right-side VATS group; all the recurrences
were local on both sides. [Fig. 3] shows Kaplan–Meier estimate for DFS: there were no differences in the DFS between
the two groups (p = 0.7401).
Fig. 3 Kaplan–Meier estimate for DFS.
According to the MGFA postintervention status only one patient, in the left side group,
was considered in complete stable remission, whereas the pharmacological remission
in our study group was achieved in only three and one patients in the right- and left-side
group, respectively ([Table 3]). We also compared the postoperative outcome between the left-side surgical approach
(6 patients) and the right-side approach (4 patients) and we found similar patterns
of average operating time, mean length of hospitalization, and rates of complete resections.
Table 3
Outcomes of myasthenic patients considering the side of surgery
Myasthenic patients
|
Right-side approach (4)
|
Left-side approach (6)
|
p-Value
|
Complications, n (%)
|
1 (25)
|
0 (0)
|
0.40
|
Bleeding
|
0 (0)
|
0 (0)
|
0.99
|
Phrenic nerve lesion
|
0 (0)
|
1 (16.6)
|
0.40
|
Respiratory failure
|
1 (25)
|
0 (0)
|
0.40
|
Operative time (min)
|
172 min
|
181 min
|
|
Complete resection, n (%)
|
3 (75)
|
5 (83.3)
|
0.74
|
Postoperative hospital stay (avg days)
|
5.5
|
3.6
|
|
Intensive care unit stay (no of patients)
|
1 (25)
|
2 (33.3)
|
0.778
|
MGFA postoperative clinical status
|
0 Complete remission
|
1 Complete remission
|
0.40
|
3 Pharmacological remission
|
1 Pharmacological remission
|
0.19
|
0 Minimal manifestation
|
0 Minimal manifestation
|
–
|
0 Improvement
|
1 Improvement
|
0.40
|
0 Unchanged
|
0 Unchanged
|
–
|
1 Worse
|
3 Worse
|
0.57
|
Abbreviation: MGFA, Myasthenia Gravis Foundation of America.
In addition, we compared the postoperative outcome between myasthenic and nonmyasthenic
patients as shown in [Table 4]. The only significant difference was found in ICU stay, which was more commonly
needed in myasthenic patients (p = 0.032).
Table 4
Outcomes of myasthenic patients compared with nonmyasthenic patients
|
Myasthenia gravis (10)
|
No myasthenia gravis (19)
|
p-Value
|
Complications, n (%)
|
1 (10)
|
0 (0)
|
0.344
|
Bleeding
|
0 (0)
|
0 (0)
|
0.999
|
Phrenic nerve lesion
|
1 (10)
|
0 (0)
|
0.344
|
Respiratory failure
|
1 (10)
|
0 (0)
|
0.344
|
Operative time (min)
|
177 min
|
165 min
|
|
Complete resection, n (%)
|
8 (80)
|
19 (100)
|
0.118
|
Postoperative hospital stay (avg days)
|
4,4
|
3,0
|
|
Intensive care unit stay, no of patients (%)
|
3 (30)
|
0 (0)
|
0.032
|
Discussion
Traditionally, transsternal thymectomy has been the standard approach for thymomas.
However, with the surgical advances, VATS thymectomy has become an effective method
to treat early and small thymomas. Two recent large meta-analyses showed a significant
reduction in postoperative blood loss and blood products requirements, reduction in
postoperative pain scores, overall complications rates, and postoperative hospital
stay with VATS thymectomy compared with open thymectomy.[26]
[27] Furthermore, the probability of achieving microscopically complete resection (i.e.,
tumor-free margins at pathologic examination) and locoregional recurrence rates was
similar with either approach. In this study, no differences in terms of morbidity
between the two groups were found.
Thymoma has 5 + 1 subtypes according to the WHO classification: A, AB, B1, B2, B3,
and thymic carcinoma that differ in prognostic values. The thymoma types A, AB, and
B1 are considered at low risk of malignancy, whereas the types B2 and B3 have a high
risk of malignancy. Thymic carcinoma is considered a malignant neoplasm, associated
with a worse prognosis. In our study, most patients presented with the low-risk types
A, AB, and B1 (66%), followed by high-risk types B2 and B3 (31%). Taking this into
account, in clinical practice, preoperative estimation of the risk of malignancy is
also important to determine the treatment strategy and surgical method (endoscopic
vs. open surgery). Another important factor to be taken into consideration is the
tumor stage. Agasthian[17] suggested that early-stage thymomas can be safely resected with VATS; our data showed
that most of the patients had early-stage thymomas according to both Masaoka and TNM
staging systems, respectively, in 90 and 86% of cases. As shown in our experience,
the most important factor in the preoperative evaluation of patients undergoing minimally
invasive thymectomy is local infiltration of the tumor rather than to tumor size.
In fact, the mean size of tumors was 5.6 and 5.3 cm in the two groups.
During this study, we performed thymectomy via both left and right VATS. The choice
of left or right VATS depended on the surgeon's experience and the anatomy of the
tumor, which was normally assessed by preoperative chest CT. In our study, most thymomas
(59%) extended to the right anterior mediastinum, making right VATS a better choice
for complete thymectomy. The advantages of the right VATS are a better visualization
and control of the superior vena cava, aorta, right atrium, and phrenic nerve, thereby
a reduction in the potential risk of injury to these structures.[18] In our study, 41% of VATS thymectomies were performed using a left-side approach.
The left-sided enables an extensive removal of fat allocated in the aortocaval groove,
aortopulmonary window, and both pericardiophrenic sides.[19]
Nevertheless, this approach does have some disadvantages. When approaching from one
side of the chest, it is difficult to identify the contralateral phrenic nerve. In
our study, only one patient in the left side group had phrenic nerve palsy, which
occurred on the same side of the operation.
Despite the small sample size, our favorable results confirm the safety and benefits
of VATS thymectomy. Postoperative complications rate was low in line with literature
(only 1 patient for each side).[18]
[19] The mean hospital stay was 3 days (IQR: 3–4) for the left-side VATS and 3 days (IQR:
3–4) for right-side VATS groups (p = 0.723); this was also in line with literature like the 3 days of Mineo et al[19] and 4 days by Mack et al.[28] A shorter period of hospitalization is partly due to the minimally invasive thoracoscopic
technique that most of the time does not require a period in the ICU and therefore
shorter hospital stay.
The tumor recurrence rate in the VATS group was relatively low in both groups, and
all recurrences were local. These data suggest that VATS thymectomy does not increase
the risk of pleural dissemination. We managed to completely remove the thymoma in
most of the patients except in two cases where there were severe adhesions to the
great vessels. In terms of oncologic outcome, there are several reports of the oncologic
feasibility of VATS thymectomy for Masaoka stage I and II tumors. Jurado et al[8] reported no differences in terms of 5-year recurrence-free survival (RFS) and recurrence
rates between VATS and transternal thymectomy patients. Sakamaki et al, comparing
VATS and transternal approaches,[29] found that VATS improved the 5-year overall survival, whereas the 5-year RFS was
not different between the groups. In the present study, both left and right approaches
were easily manageable; the 5-year RFS comparison did not show significant difference
between two groups.
With regard to clinical outcomes in myasthenic patients, our analysis did not find
any statistical difference between patients who underwent the left and those who underwent
the right one.
Limitations
This investigation represents a single institution's experience; the cohort of patients
was assessed retrospectively with a small number of patients in each group and the
follow-up period is relatively short for this type of tumor. Therefore, we acknowledge
that there is inherent bias associated with this approach.
Conclusion
In conclusion, VATS thymectomy can produce satisfactory outcomes, reduce surgical
risks perioperatively, and shorten the hospitalization time. Unilateral VATS thymectomy
in patients with thymoma is a clinically acceptable procedure, and can be safely and
effectively performed on either side of the thorax.