Japanese Journal of Clinical Oncology, 2021, 51(8)1197–1203

https://doi.org/10.1093/jjco/hyab102
Advance Access Publication Date: 2 July 2021
Review Article (Invited)

Review Article (Invited)

Downloaded from https://academic.oup.com/jjco/article/51/8/1197/6312969 by National Science & Technology Library Root Admin user on 02 May 2022
Limited resection for early-stage thymoma:
minimally invasive resection does not mean
limited resection
Kazuo Nakagawa1 ,* and Hisao Asamura2
1
Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan and 2 Division of Thoracic Surgery,
Keio University School of Medicine, Tokyo, Japan
*For reprints and all correspondence: Kazuo Nakagawa, Department of Thoracic Surgery, National Cancer Center Hospital,
5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: kznakaga@ncc.go.jp
Received 9 April 2021; Editorial Decision 14 June 2021; Accepted 16 June 2021

Abstract
Standard resection for patients with thymoma is resection of thymoma with total thymectomy
(TTx) via median sternotomy. Hence, limited resection for thymoma means a lesser extent of
resection of normal thymus compared with a standard procedure, i.e. resection of thymoma with
partial thymectomy (PTx). In contrast, minimally invasive resection has been defined as resection
of thymoma with TTx via a less-invasive approach. However, to date, few studies have precisely
evaluated the differences in surgical and oncological outcomes among these three procedures.
This report summarizes the differences among these three procedures with a review of studies
(January 2000 to December 2020) focusing on the difference in surgical and oncological outcomes
and presents current issues in the surgical management of thymoma. In this report, 16 studies were
identified; 5 compared standard resection to limited resection, 9 compared standard resection to
minimally invasive resection and 2 compared limited resection to minimally invasive resection.
Most studies reported that the surgical and oncological outcomes of limited resection or minimally
invasive resection were similar to those of standard resection in patients with early-stage thymoma.
However, they did not include a sufficient follow-up period. Both limited resection and minimally
invasive resection for early-stage thymoma might be reasonable treatment options. However, they
are still promising modes of resection. Further studies with a long follow-up period are needed.

Key words: thymoma, surgery, standard resection, limited resection, minimally invasive resection

Introduction tumor. It has been considered to be an adequate alternative mode

The standard surgical procedure for thymoma has been considered
to be resection of thymoma with total thymectomy (TTx) via median
sternotomy regardless of the presence or absence of myasthenia
gravis (MG) (1–3). Several authors have pointed out that the opti-
mal mode of resection for thymoma in non-myasthenic patients is
still controversial (4–6) because of the lack of prospective studies
to clarify the need for and efficacy of TTx in these patients. In
fact, limited resection [resection of thymoma with partial thymec-
tomy (PTx)] is sometimes performed in institutions that specialize
in oncology (4,7,8). Limited resection has been widely performed
to preserve organ function and to make the surgical procedure
less invasive, particularly for compromised patients with malignant
of resection in various kinds of tumors such as lung cancer and
kidney cancer. Therefore, the appropriateness of limited resection
in non-myasthenic patients with early-stage thymoma should also
be evaluated. However, only a few studies have investigated the
differences in surgical and oncological outcomes between standard
resection and limited resection (9–13). This may be due to the
influence of video-assisted thoracic surgery (VATS). When VATS was
first applied in routine clinical practice, TTx via VATS was performed
for the surgical treatment of patients with MG. It was then gradually
applied to resection of early-stage thymoma (14–16). As a result, it is
thought that most thoracic surgeons have only been interested in TTx
via VATS rather than a lesser resection of normal thymus via VATS,

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1198 Limited resection for early-stage thymoma
even for non-myasthenic patients with early-stage thymoma. Thus,
the extent of resection for non-myasthenic patients with thymoma in
minimally invasive resection has been clearly defined as a ‘complete
thymectomy’ (complete removal of the thymic gland) (17). More
recently, robot-assisted thoracic surgery (RATS) is being gradually
applied to patients with mediastinal tumors.
Some studies have investigated the differences in surgical and
oncological outcomes of resection of thymoma with median ster-
notomy and VATS regardless of the extent of resection of normal
thymus (18–20). These studies are similar to studies that compared
lung resection via thoracotomy to lung resection via VATS regardless
of the extent of resection of pulmonary parenchyma, such as lobec-
tomy, segmentectomy and wide wedge resection, in patients with
lung cancer. Accordingly, they seem to make little sense, since the
extent of resection of normal thymus rather than the nature of the
surgical approach is an essential oncological issue in the treatment
of thymoma. Furthermore, several recent systematic reviews with or
without a meta-analysis have compared minimally invasive thymec-
tomy to open thymectomy (21–23). However, the difference between
resection of thymoma with TTx and that with PTx has not been fully
investigated.
When the surgical and oncological outcomes of several surgical
procedures are investigated, the extent of resection of the organ and
the approaches used should be evaluated separately. Even though
thymoma is a rare tumor, we should correctly evaluate these issues.
In this review, we evaluated the surgical and oncological outcomes
of several surgical procedures for patients with early-stage thymoma,
focusing on both the extent of resection of normal thymus and the
surgical approach. We then discuss the issues concerning surgical
procedures for these patients.
Materials and methods
We searched PubMed, EM-Premium and ScienceDirect for articles
written in English between January 2000 and December 2020 using
the key words ‘thymoma’, ‘surgery’, ‘standard resection’, ‘limited
resection’, ‘minimally invasive resection’, ‘VATS’, ‘RATS’, ‘thymo-
mectomy’ and ‘thymectomy’. The inclusion criteria were clinical
studies with results on surgical and oncological outcomes, focusing
on the difference between standard resection and limited resection
or the difference between standard resection and minimally invasive
resection for patients with early-stage (Masaoka stage I or II (1))
thymoma. Exclusion criteria were letters, editorials, case reports,
studies with less than 40 patients and those without enough specific
data on the surgical treatment.
Since there are two surgical approaches (median sternotomy and
minimally invasive approach: VATS or RATS) and two modes of
resection of normal thymus (TTx and PTx), there are four possible
combinations. However, resection of thymoma with PTx via median
sternotomy seems to be performed only rarely. Accordingly, the
distinction between resection of thymoma with PTx via median
sternotomy and resection of thymoma with PTx via VATS or RATS is
not relevant. Hence, the following three groups are evaluated in this
review: group 1; resection of thymoma with TTx via median ster-
notomy versus resection of thymoma with PTx (standard resection
vs. limited resection), group 2; standard resection versus resection of
thymoma with TTx via VATS or RATS (minimally invasive resection)
and group 3; limited resection versus minimally invasive resection.
In this review, a median sternotomy approach is identical to a trans-
sternal approach or open approach for TTx.
Table 1. Terms used for the extent of resection of normal thymus
in standard resection or limited resection for thymoma
Standard resection
Thymothymomectomy
Complete thymectomy
Total thymectomy
Radical thymectomy
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Extended thymectomy
Thymectomy
Limited resection
Thymomectomy
Limited thymectomy
Partial thymectomy
Subtotal thymectomy
Results
Nineteen articles were selected for this review. Among them, three
studies that compared VATS thymectomy to open thymectomy were
excluded because they included resection of thymoma with TTx and
resection of thymoma with PTx together in each group (18–20).
Many terms have been used to describe standard resection or limited
resection for thymoma, and they are summarized in Table 1.
Standard resection versus limited resection
for early-stage thymoma
Five studies have investigated the differences in surgical and onco-
logical outcomes between standard resection and limited resection
(9–13). The details are shown in Table 2. Among the five studies,
four included only non-myasthenic patients (9,11–13). Most studies
included a relatively small number of patients (less than 100 patients
in each group).
Among them, the Japanese Association for Research on the Thy-
mus (JART) study investigated the surgical and oncological outcomes
in the largest number of non-myasthenic patients with TNM-stage
I thymoma who underwent thymothymomectomy (n = 276) or
thymomectomy (n = 276) using a propensity-score analysis (13).
Post-operative complications were seen more frequently in the thy-
mothymomectomy group than in the thymomectomy group (8.3 vs.
4.3%; P = 0.0397). The 5-year overall survival rate was 96.9% in
the thymothymomectomy group and 97.3% in the thymomectomy
group (P = 0.487). Thymomectomy seemed to be acceptable for
TNM-stage I thymoma with regard to post-operative complications
and prognosis. To date, most studies have reported that the surgical
and oncological outcomes of limited resection were similar to those
of standard resection. However, the follow-up period in the limited
resection group was still short compared with that in the standard
resection group, and the appropriateness of limited resection needs
to be further evaluated with an adequate follow-up period.
Standard resection versus minimally invasive
resection for early-stage thymoma
Nine studies (24–32) have compared the surgical and oncologi-
cal outcomes of standard resection to those of minimally invasive
resection. To date, only two studies have evaluated the difference
in peri-operative outcomes between trans-sternal thymectomy and
robotic thymectomy for patients with early-stage thymoma (29,
31). Table 3 shows the details. Six of the 9 studies also included a
Table 2. Clinical profiles and outcomes of standard resection and limited resection for early-stage thymoma

Author Number of Mode of Approach Age Tumor size Follow-up LOS (days, Morbidity 5-year Recurrence Post-
(year) patients resection (y, mean) (cm, mean) (months, mean) overall operative
mean) survival MG

Odaka et al. 40 TTx: n = 18 TTx: TS, n = 18 PTx: TTx: 51.1 TTx: 5.0 TTx: 58.6# TTx: 11.2 TTx: 22% NA TTx: 0% NA
(9), (2010) PTx: n = 22 VATS, n = 22 PTx: 51.9 PTx: 4.4 PTx: 21.6# PTx: 4.6 PTx: 0% PTx: 0%
Onuki et al. 79a TTx: n = 61 TTx: TS, n = 61 PTx: TTx: 56.2 TTx: 5.0 TTx: 67.3 NA TTx: 0% TTx: TTx: 0% TTx: 0%
(10), (2010) PTx: n = 18 VATS, n = 4; PTx: 54.7 PTx: 6.1 PTx: 104.2 PTx: 0% 82.0%∗ PTx: 5.6% PTx: 5.6%
Thoracotomy, n = 7; PTx: 100%∗
TS, n = 7
Tseng et al. 95 TTx: n = 42 TTx: TS, n = 42 PTx: TTx: 48.8 TTx: 6.6 TTx: 62# TTx: 8.1 TTx: 2.4% TTx: 100% TTx: 4.8% TTx: 0%
(11), (2013) PTx: n = 53 VATS, n = 22; PTx: 55.5 PTx: 6.2 PTx: 55# PTx: 6.5 PTx: 3.8% PTx: 100% PTx: 1.9% PTx: 0%
Thoracotomy, n = 31
Nakagawa 173 TTx: n = 73 TTx: TS, n = 72; TTx: 55.1 TTx: 6.3 TTX: 108 NA TTx: 0% TTx: 94.0% TTx: 5% TTx: 8%
et al. (12), PTx: VATS, n = 1 PTx: PTx: 57.7 PTx: 5.7 PTx: 108 PTx: 0% PTx: 96.7% PTx: 2% PTx: 3%
(2014) n = 100 VATS, n = 41;
Thoracotomy,
n = 58; TS, n = 1
Nakagawa 552b TTx: TTx: TS, n = 276 TTx: 61.0 TTx: 5.0 TTx: 59# NA TTx: 8.3% TTx: 96.9% TTx: 1.8% NA
et al. (13), n = 276 PTx: VATS, n = 169; PTx: 60.6 PTx: 4.9 PTx: 48# PTx: 4.3% PTx: 97.3% PTx: 4.0%
(2016) PTx: Thoracotomy,
n = 276 n = 64; TS, n = 43

VATS, Video-assisted thoracic surgery; TS, trans-sternal approach; LOS, length of hospital stay; NA, not assessed; TTx, resection of thymoma with total thymectomy; PTx, resection of thymoma with partial thymectomy;
MG, myasthenia gravis.
∗ Ten-year overall survival.
#
Median value.
a
Twenty-seven patients (44.2%) in the TTx group and 1 patient (5.6%) in the PTx group had MG.
b
Among 1286 patients, 552 were evaluated after propensity score matching.
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1200 Limited resection for early-stage thymoma
relatively small number of patients (less than 100 patients in each
group). The minimally invasive resection group seems to have a short
hospital stay and low morbidity rate. In contrast, the tumor size
tended to be small and the follow-up duration tended to be short.
Among them, the JART investigated the surgical and oncological
outcomes in the largest number of patients (sternotomy group:
n = 140, VATS group: n = 140) with stage I-II thymoma using
a propensity-score analysis (29). They concluded that VATS
thymectomy seemed to be acceptable with regard to post-operative
complications and prognosis. More recently, Burt et al. evaluated
short-term outcomes of minimally invasive thymectomy (MIT:
n = 296; robotic 59.7% and thoracoscopic, 40.3%) compared with
open thymectomy (OT: n = 648) using the National Cancer Database
(32). The probability of achieving R0 resection was not influenced by
a minimally invasive approach, and MIT was equivalent to OT in this
regard. Thus, the oncologic outcomes with the two procedures seem
to be comparable. However, in a study by Kimura et al., three patients
(6.7%) in the VATS thymectomy group had recurrent disease with
pleural dissemination, and they concluded that an open sternotomy
approach could be recommended in patients with thymoma larger
than 5 cm to avoid capsule injury (25). The superiority of minimally
invasive resection to standard resection with regard to the prognosis
has not yet been fully clarified because most studies do not include a
sufficient follow-up period.
Limited resection versus minimally invasive resection
for early-stage thymoma
Only two studies have investigated the differences in surgical and
oncological outcomes between limited resection and minimally inva-
sive resection (33, 34). Narm et al. compared oncological outcomes
between patients with limited thymectomy (LT group: n = 141)
and those with complete thymectomy (CT group: n = 141) using a
propensity-score analysis. Although most (53.9%) of the approaches
in the CT group were VATS, sternotomy (33.3%) was also included.
The 10-year OS rate in the LT group was 88.3% and that in the
CT group was 99.2%. The LT group had significantly shorter OS
than the CT group (P = 0.01). In contrast, the 10-year freedom-from-
recurrence (FFR) rate in the LT group was 89.7% and that in the CT
group was 85.0%. No significant difference was observed between
the two groups with respect to FFR (P = 0.86). They concluded that
limited thymectomy may be a viable treatment option for early-stage
thymoma (34).
At present, neither procedure is considered to be standard.
Accordingly, it is still unclear whether or not such investigations
will have much impact on clinical practice.
Discussion
To date, several studies have compared standard resection with
limited resection or minimally invasive resection for early-stage
thymoma. Most studies were conducted at a single institution. Fur-
thermore, most studies did not have a sufficient number of patients
or a sufficient post-operative observational period. In terms of the
presence or absence of MG, studies on limited resection did not
include patients with MG. In contrast, studies on minimally invasive
resection included patients with MG to some extent. The frequency
of myasthenic patients with thymoma in these studies should be
adequately considered in these analyses. There are still many issues
regarding studies on the surgical treatment of thymoma. Several
crucial arguments for the mode of resection in patients with thymoma
are discussed below.
Approaches for limited resection or minimally invasive
resection
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As described in Table 2, the limited resection group includes various
approaches, including median sternotomy, thoracotomy and VATS.
In terms of invasiveness, it is questionable whether limited resection
via median sternotomy is a less invasive procedure. Accordingly, it
might not be preferable for limited resection via median sternotomy
and that via other less invasive approaches to be included in the
same group. However, thoracic surgeons would no longer resect
a relatively small lesion of the thymus via median sternotomy or
standard thoracotomy. On the other hand, limited resection via RATS
might not have any advantages compared with VATS. Hence, limited
resection should be performed via either mini-thoracotomy or VATS
according to the tumor size and tumor location.
Furthermore, various approaches have been used even for min-
imally invasive resection (3,17). To date, only one study evaluated
the difference in surgical and oncological outcomes between TTx
via VATS and that via RATS (35). To our knowledge, no one has
definitively demonstrated which approach is the most appropriate
for minimally invasive resection, and this issue needs to be evaluated
in the near future.
What is the rationale for the necessity of TTx for
non-myasthenic patients with early-stage thymoma?
Resection of the entire thymus gland can be performed safely and
may not greatly influence the patient’s life after surgery. However,
the oncological rationale for its necessity is still unclear; hence,
limited resection should be considered. As noted previously, there
are three arguments for the necessity for TTx (12). First, post-
operative MG has been considered to be the most critical ratio-
nale (36,37). In fact, the rate of post-thymectomy MG has been
reported to be 3–5% (38,39). Several studies have demonstrated
that there is no difference in the frequency of post-operative MG
between standard resection and limited resection (10–12). In addi-
tion, two studies on post-operative MG concluded that TTx could
not prevent post-operative MG (39,40). Anti-ACH antibody in the
serum may play an important role when we determine the extent
of resection of normal thymus (41). Second, multiple thymomas
may occur simultaneously or metachronously. In addition, thymoma
can manifest as a macroscopic or microscopic tumor (42,43). It
is rare for non-myasthenic patients to simultaneously have both
macroscopic thymoma and microscopic thymoma. Accordingly, a
strategy in which all non-myasthenic patients with thymoma undergo
standard resection since they might have simultaneous microscopic
thymoma seems to be overtreatment. Third, we should consider the
possibility of an increase in local recurrence, particularly recurrence
at the resection margin. Although the details of local recurrence are
not yet clear, and, in several studies, the rate of local recurrence
after limited resection did not appear to be higher than that after
standard resection (9,11,12), surgeons should be careful to achieve
a sufficient surgical margin when they perform limited resection for
thymoma.
Table 3. Clinical profiles and outcomes of standard resection and minimally invasive resection for early-stage thymoma

Author Number of Approach Age (y, Tumor size Follow-up LOS (days, Morbidity 5-year Recurrence
(year) patients mean) (cm, mean) (months, mean) overall
mean) survival

Pennathur 40a Open: n = 22 VATS: Open: 64.0# Open: 5.8 Open: 58# Open: 6.2 NA Open: 88% Open: 4.5%
et al. (24), n = 18 VATS: 64.0# VATS: 3.5 VATS: 27# VATS: 2.9 VATS: 100% VATS: 0%
(2011)
Kimura et al. 74b ,c Open: n = 29 VATS: Open: 57.0 Open: 6.5 Open: 49.6 Open: 19 NA NA Open: 0%
(25), (2013) n = 45 VATS: 55.0 VATS: 4.8 VATS: 53.7 VATS: 14 VATS: 6.7%
Liu et al. 120d TS: n = 44 VATS: TS: 51.8 TS: 6.07 TS: 69.7 TS: 9.14 NA TS: 96.8% TS: 2.3%
(26), (2014) n = 76 VATS: 50.5 VATS: 4.63 VATS: 61.9 VATS: 7.13 VATS: 100% VATS: 2.6%
Yuan et al. 129e Open: n = 91 VATS: Open: 49.6 Open: 6.8 NA Open: 8.32 Open: 0% NA NA
(27), (2014) n = 38 VATS: 50.5 VATS: 5.4 VATS: 5.26 VATS: 0%
Ye et al. 262 TS: n = 137h VATS: TS: 50.0 TS: 3.38 TS: 42# TS: 10# TS: 3.6% NA TS: 0.7%
(28), (2014) n = 125 VATS: 51.9 VATS: 3.23 VATS: 41# VATS: 8# VATS: 4.8% VATS: 0.8%
Ye et al. 74 TS: n = 51 TS: 50.1 TS: 3.26 TS: 18.1 TS: 11.6 TS: 0.4% NA TS: 0%
(29), (2014) RATS: n = 23 RATS: 52.5 RATS: 2.96 RATS: 16.9 RATS: 3.7 RATS: 0.4% RATS: 0%
Agatsuma 280f ,g TS: n = 140 VATS: TS: 57.3 TS: 3.9 TS: 62# NA TS: 9.3% TS: 97.1% TS: 2.9%
et al. (30), n = 140 VATS: 56.9 VATS: 3.9 VATS: 44# VATS: 5.7% VATS: VATS: 2.1%
(2017) 97.9%
Marulli et al. 164 TS: n = 108 TS: 59.4 TS: 7.62 TS: 90.7# TS: 6# TS: 15% TS: 95% TS: 2%
(31), (2018) RATS: n = 56 RATS: 55.8 RATS: 4.33 RATS: 30.9# RATS: 3# RATS: 4% RATS: 98% RATS: 2%

TS, trans-sternal; RATS, Robot-assisted thoracic surgery; LOS, length of hospital stay; NA, not assessed.
#
Median value.
a
Four patients (18.1%) in the Open group and 7 patients (38.9%) in the VATS group had MG.
b
Several patients who underwent hemithymectomy were included.
c
Nine patients (31.0%) in the TS group and 14 patients (31.1%) in the VATS group had MG.
d
Fourteen patients (31.8%) in the TS group and 35 patients (46.1%) in the VATS group had MG.
e
Fourteen patients (15.4%) in the Open group and 5 patients (13.2%) in the VATS group had MG.
f
Fifty-one patients (36.4%) in the TS group and 46 patients (32.9%) in the VATS group had MG.
g
Among 1436 patients, 280 were evaluated after propensity score matching.
h
One patient with thymic carcinoma was included.
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1202 Limited resection for early-stage thymoma
Issues of non-therapeutic TTx
Another issue concerns unnecessary TTx. Two studies have con-
sidered this problem (44,45); they reported that the rate of non-
therapeutic thymectomy (TTx for lymphoma and benign disease)
was 30–40%. The accuracy of radiological diagnosis will need to
be improved to reduce the rate of unnecessary TTx for mediastinal
lesions. Thoracic surgeons should strive to avoid unnecessary TTx
in patients with a thymic lesion. If limited resection is considered
to be a relevant option for non-myasthenic thymoma, the frequency
of unnecessary TTx could be reduced. In such a case, if the lesion
turns out to be invasive disease or if the resected lesion is diagnosed
as thymic carcinoma, Yano et al. recommended that the procedure
should be converted to the standard procedure (46).
Is minimally invasive resection equivalent to standard
resection in terms of precision of resection of the
entire thymus gland?
The existence of various approaches for minimally invasive resec-
tion raises the question of whether minimally invasive resection is
equivalent to standard resection in terms of precision of resection
of the entire thymus gland. Shiono et al. investigated this issue and
demonstrated that about 3% by weight of the entire thymus gland
was left behind in the cervical region through a minimally invasive
approach without a cervical approach (47). Their result suggests that
minimally invasive resection could be inferior to standard resection
in terms of the precision of resection of the entire thymus. We
emphasize that the precision of resection of the entire thymus by
minimally invasive resection, as well as its invasiveness, surgical
outcome and prognosis, should be investigated in the near future
before the procedure becomes widely used in routine clinical practice.
Conclusion
In conclusion, minimally invasive resection and limited resection
for patients with early-stage thymoma are still promising modes of
resection. Further studies with a long follow-up period are needed.
Because of the wide range of histologic subtypes and degree of
malignancy, and their unique biologic behavior, patients with surgery
for early-stage thymoma need to be observed for 10 years after
surgery, which is recommended in the NCCN guidelines to evaluate
the presence or absence of recurrence and postoperative MG (1).
The surgical and oncological outcomes should be compared for
standard resection versus limited resection, standard resection versus
minimally invasive resection and limited resection versus minimally
invasive resection. Ideally, the value of each surgical procedure
should be determined by randomized control studies, but it might be
difficult to conduct such studies because this is a fairly rare disease.
Prospective registration may play an important role in evaluating
these surgical procedures.
Conflicts of interest and source of funding
The authors have stated that they have no conflicts of interest. This
research did not receive any specific grant from funding agencies in
the public, commercial or not-for-profit sectors.
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