Published Guidelines
f o r Ma n a g e m e n t o f
Thymoma
Yoshitaka Fujii, MD, PhD
KEYWORDS
 Thymoma  Thymic carcinoma  Staging  Classification
In 2009, three papers on the management of thy-
moma appeared in the literature, citing 58,1 69,2
and 783 references and including present day
guidelines or recommendations for the treatment
of thymoma. There also is a guideline available on-
line compiled by the National Cancer Institute
(NCI).4 This guideline is constantly updated, and
this article refers to the April 16, 2010, version.
This site lists 10 to 32 references in each of several
sections and also contains many useful links.
Canadian and British organizations additionally
have published online guidelines that are less
extensive. The published and online guidelines
are physicians’ opinions based on case series
and phase 2 clinical studies without control groups
and thus are at a low evidence level. However,
because of its rarity, randomized controlled trials
for thymoma (or thymic carcinoma) are extremely
difficult to plan. As for treatment options for thy-
moma, performing a randomized controlled trial
is not feasible, because recurrence (7.8%) or
death (survival 94.4% at 5 years) is a rare event
in thymoma.5 Thus, careful analysis of the results
of case series and phase 2 studies is the only
approach allowing to compile the guidelines for
thymoma treatment. Ongoing phase 2 studies on
thymoma are listed on the Internet.6 The results
of these studies will further help building
a consensus for the treatment of thymic epithelial
tumors based on better evidence.
This article used the three papers published in
20091e3 and the NCI’s guideline on the Internet4
to summarize the consensus on the management
of thymoma and thymic carcinoma. The readers
Department of Surgery II, Nagoya City University Medical School, 1 Kawasumi, Mizuhoku, Nagoya 467-8601,
Japan
E-mail address: yosfujii@med.nagoya-cu.ac.jp
Thorac Surg Clin 21 (2011) 125–129
doi:10.1016/j.thorsurg.2010.08.002
1547-4127/11/$ e see front matter Ó 2011 Elsevier Inc. All rights reserved.
are again reminded that all of these are based on
the physicians’ experience and the results of
phase 2 studies and retrospective case series
and are prone to future modifications.
HISTOLOGIC CLASSIFICATION AND STAGING
OF THYMOMA
The World Health Organization (WHO) histologic
classification7 and Masaoka clinical stage8
(Table 1) are widely used in the literature, in the
2009 published guidelines1e3 and also in the
NCI’s guidelines.4 Thymoma is a neoplasm arising
from thymic epithelial cells and is associated with
a variable degree of T lymphocyte proliferation.
These T lymphocytes are generated de novo
within the thymoma from the bone marrow
progenitor cells under the influence of the cortical
epithelial cell-like function of the thymoma’s trans-
formed epithelial cells. In this sense, thymoma is
a functional tumor. The WHO classification is
based on the morphology of these epithelial cells
and the amount of associated T lymphocyte,
which is an indicator of the biologic function of
the thymoma cells. While thymomas of WHO types
A, AB, B1, B2, and B3 all show a certain amount of
immature T lymphocytes, thymic carcinomas do
not have a measurable number of immature T
lymphocytes and are thus undifferentiated. This
functional distinction between thymoma and
thymic carcinoma is reflected in the 2004 revision
of the WHO classification, in which thymic carci-
noma is listed as a separate entity from thymoma.
Both WHO classification9,10 and the Masaoka
thoracic.theclinics.com
126 Fujii

Table 1
Masaoka staging of thymoma

Stage Description
1 Macroscopically, completely encapsulated; microscopically no capsular invasion
2 Invasion into surrounding fatty tissue, mediastinal pleura, or capsule (determined by
pathologya)
3 Macroscopic invasion into neighboring organs (pericardium, lung, and great vessels)
4a Pleural or pericardial dissemination
4b Lymphogenous or hematogenous metastases

a
Modification by Japanese Association for Research on the Thymus (JART).13
Data from Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their
clinical stages. Cancer 1981;48:2485e92.

staging system8,11 have proved to be strongly TREATMENT OPTIONS FOR THYMOMA

correlated with patient survival. These are impor- ACCORDING TO THE MASAOKA STAGING
tant factors affecting treatment decision for each SYSTEM
patient, and they should be reported in each study. Stage 1 Thymoma
TNM staging of thymoma12 is not widely accepted,
The recommended treatment options are summa-
because it is not more useful than the Masaoka
rized in Table 2. A Masaoka stage 1 thymoma is
system; in fact, lymph node metastases are rela-
completely resected by surgery, and excellent
tively rare.5 However, it may be useful for classi-
postoperative survival has been reported after
fying thymic carcinomas that are more frequently
surgery alone. No adjuvant therapy is recommen-
associated with lymphatic spread. The NCI guide-
ded. Although infrequent, late recurrence is
line does not list thymic neuroendocrine tumors as
possible, and patients should be followed for
part of the thymic carcinoma group. This may be
more than 10 years. Some thymomas show no
reasonable, because neuroendocrine tumors
histologically definable capsule; in these cases,
have a better prognosis than thymic carcinoma.5
there is no consensus among pathologists whether
The Japanese Association for Research on the
these tumors should be included in stage 1 or 2. In
Thymus (JART) has made a small modification to
patients with myasthenia gravis (MG), total thymec-
the Masaoka staging system in which invasion to
tomy is usually performed in the expectation that
the mediastinal pleura (stage 2) is now determined
the procedure will have therapeutic effects on the
by pathology instead of surgeon’s observation.13
autoimmune disease. However, in cases without
In fact, it is extremely hard for the surgeon to
MG, whether a stage 1 thymoma requires total
distinguish between benign adhesions to the
thymectomy for better survival is controversial,
mediastinal pleura and invasion.
and this is the main goal of a clinical study being

Table 2
Recommended treatment for thymoma (stage according to Masaoka)

Stage Recommended Treatment Option

1 Surgery, no adjuvant therapy1e4
2 Surgery; postoperative radiation should be reserved for patients with higher risk* of
recurrence,1,3,4 controversial2
3 Surgery; neoadjuvant chemotherapy (radiotherapy) when complete resection does not seem
feasible1,4
Adjuvant radiotherapy1,4 recommended when incompletely resected2
Adjuvant chemotherapy, recommended when resection is incomplete1e4
4a Surgery when feasible1,2,4; after neoadjuvant chemotherapy1,2,4
Chemotherapy1,4 with or without radiation1,4
4b Chemotherapy1e4

* Invasion through capsule1 close margin,4 WHO B2, B3.3


conducted by JART (UMIN000000614). In this trial,
clinical stage 1 or 2 thymomas without MG or serum
antiacetylcholine receptor antibodies are resected
with a wide margin, leaving part of the thymus in
the mediastinum. The surgical approach is not
clearly defined in the protocol, but most of the
cases are resected using video-assisted thoraco-
scopic surgery (VATS).
With the increased acceptance of low-dose
computed tomography (CT) screening for lung
cancer, incidental small (<1 cm) thymomas are
frequently found. These surely will not affect
long-term survival and may even not be resected.
However the tumor should be followed on a regular
basis, evaluating also the potential effect of thy-
moma on the onset of MG. However, at least anti-
acetylcholine receptor antibodies should be
regularly tested in patients with incidental thymo-
mas. Incidental thymomas of larger size are candi-
dates for surgery because of the risk of invasion
and dissemination to the thoracic cavity.
Stage 2 Thymoma
The invasion to capsule or mediastinal pleura is
rarely diagnosed before surgery; however, stage
2 thymomas are usually completely resectable.
Surgery alone confers excellent survival; adding
radiation therapy does not offer survival advan-
tages or reduce the rate of local recurrence.5,14
Adjuvant radiotherapy is not recommended as
a routine treatment.1,4 The recurrence rate of
totally resected stage 2 thymoma is 4.1%.5 Most
of these cases present with pleural dissemination.
Mediastinal irradiation will surely not prevent
pleural dissemination, which is presumably
present at time of operation or favored by medias-
tinal pleural opening. Prophylactic hemithorax
radiation is not recommended because of the
risk of complications associated with lung
irradiation.
Stage 3 Thymoma
Invasion of thymoma to the surrounding organs
(pericardium, brachiocephalic vein, superior vena
cava, lung, chest wall) is difficult to correctly diag-
nose at preoperative CT, which tends to overdiag-
nose. For example, a slight depression of the
mainstem pulmonary artery may not be an inva-
sion. In many preoperative stage 3 thymomas,
surgery should be considered unless the disease
is judged too extensive.
Resectable stage 3 thymoma
If complete resection is feasible, removal of the
thymoma en bloc with the invaded organs with
a wide negative margin and postoperative
Guidelines for Management of Thymoma 127
radiation therapy is recommended in all the pub-
lished guidelines. However, in a recent report of
a small series of stage 3 thymoma, survival was
not significantly better when adjuvant radiotherapy
was added.15 This needs to be clarified with
a larger prospective trial. When the pericardium
is involved, postoperative radiation to the heart
may result in constrictive pericarditis, which may
severely worsen the quality of life of the patient16
and should be reserved only for selected patients.
Neoadjuvant chemotherapy (radiotherapy) is also
an option.1,4 Adjuvant chemotherapy may be
considered but not actively recommended for
completely resected stage 3 thymomas.1,4 Adju-
vant chemotherapy is recommended for incom-
pletely resected stage 3 thymomas.1e4
One guideline1 posed strong recommendations
against bilateral phrenic nerve resection. This is
especially true in patients with MG who may
need well functioning bilateral phrenic nerves.
However, preserving the involved phrenic nerve
in these cases does not seem to affect survival.17
Therefore different considerations should be
made in patients with bulbar symptoms or respira-
tory difficulty caused by MG before the operation.
Unresectable stage 3 thymoma
Unresectable disease is defined as extensive tumor
involvement of the trachea, great arteries, or heart1
or vena cava obstruction, pleural involvement, or
pericardial implants.4 When complete resection
cannot be expected at preoperative work-up,
chemotherapy with or without radiation therapy is
recommended.1e4 Girard and colleagues2 and the
NCI guideline list surgery or irradiation after induc-
tion chemotherapy for inoperable disease,4 but this
option is probably applicable only to a few patients.
When surgery is performed, adjuvant radiotherapy
is recommended.2,4 When complete resection is
found not possible only at thoracotomy or sternot-
omy, maximal debulking is recommended,1
because this procedure seems to improve the
survival in the case of thymoma (but not in thymic
cancer).5
Stage 4A Thymoma (Pleural Dissemination)
Pleural dissemination is not uncommon but is
rarely cured. When few pleural implants are inci-
dentally found during surgery, they should be re-
sected, even if a separate surgical approach is
required. As many identifiable nodules as possible
should be removed with the aim of achieving
a macroscopic complete resection. However,
this approach may leave inside microscopic tumor
nests.
When pleural dissemination is evident preopera-
tively and is not extensive, surgery with or without
128 Fujii
neoadjuvant chemotherapy is recommended.1
The NCI guidelines also list surgery as a potential
option after induction chemotherapy.4 When
pleural dissemination is extensive, chemotherapy
is recommended.1,4 Radiation may be applied to
focal disease. However, entire hemithorax radia-
tion has been reported to have little impact on
the survival in a small group of patients with pleural
dissemination.18 As stated previously, irradiation
to the whole pericardium may result in debilitating
constrictive pericarditis and should be reserved for
selected patients.
A small series of extrapleural pneumonectomy
for stage 4A thymoma has been reported.19
However, because of the high morbidity of the
procedure, this indication should be considered
conservatively, and no published guideline recom-
mends it.
Stage 4B Thymoma
Chemotherapy is recommended by the published
guidelines.1e4 In cases with isolated local lymph
node metastasis, resection of the thymoma and
the affected mediastinal lymph nodes followed
by adjuvant chemotherapy may be indicated.
Recurrent Thymoma
Three published guideline recommends surgery
for recurrent thymoma when feasible.1,2,4 If unre-
sectable, chemotherapy is recommended.1,2 The
NCI guideline lists the administration of corti
costeroid therapy in patients with unresectable
thymoma. Steroid pulse therapy may be used for
immediate response and show fewer complica-
tions.20 The effect of steroid is probably exerted
via the deletion of immature T cells within the
tumor and is only temporary. Steroids may be
used as a neoadjuvant therapy before attempting
complete resection, because they may consider-
ably reduce the tumor volume, in particular if the
tumor contains a large number of immature T cells
(WHO type AB, B1, or B2).
Patients with MG
Two published guidelines mention the association
of MG as a factor that may influence the treatment
and survival of patients with thymoma.2,3 Thymoma
is a functional tumor as indicated by the presence
of a large number of immature T lymphocytes. As
stated before, these T cells are generated de
novo by the neoplastic epithelial cells. They are
not neoplastic but are not the same as those
generated by the normal thymic epithelial cells,
because various autoimmune diseases and auto-
antibodies21 are associated with thymoma. This
indicates that the epithelial cells of thymoma are
not fully competent in deleting the autoreactive T
cells that are generated within the tumor. As these
potentially autoimmune T cells have escaped from
the tumor seeding the peripheral lymphoid tissue
before the thymoma is resected, complete resec-
tion of the primary tumor does not prevent the
future onset of MG. Post-thymomectomy MG re-
ported in cases with negative preoperative titer
of antiacetylcholine receptor antibody may be an
indication of this.22 This should be taken into
account when a very small thymoma is acciden-
tally found on CT in an asymptomatic patient.
Also, as the mechanism mentioned previously
suggests, the appearance or exacerbation of MG
does not necessarily indicate a recurrence of thy-
moma.2 When an indication for operation exists
for a thymoma, the thymus should be totally re-
sected whenever the thymoma is associated with
MG or positive serum antiacetylcholine receptor
antibody. Thymomas associated with MG tend to
behave less aggressively than those without
MG,2,3,5 probably because the neoplastic epithe-
lial cells are functional and thus are more differen-
tiated than normal ones. Also they tend to be
found earlier during assessment of MG patients.
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Guidelines for Management of Thymoma 129
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