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Autoimmune Diseases
Volume 2011, Article ID 474512, 5 pages
doi:10.4061/2011/474512

Review Article
Thymoma in Myasthenia Gravis: From Diagnosis to Treatment

Fredrik Romi
Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway

Correspondence should be addressed to Fredrik Romi, [email protected]

Received 10 April 2011; Accepted 24 June 2011

Academic Editor: Robert P. Lisak

Copyright © 2011 Fredrik Romi. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

One half of cortical thymoma patients develop myasthenia gravis (MG), while 15% of MG patients have thymomas. MG is a
neuromuscular junction disease caused in 85% of the cases by acetylcholine receptor (AChR) antibodies. Titin and ryanodine
receptor (RyR) antibodies are found in 95% of thymoma MG and 50% of late-onset MG (MG onset ≥50 years), are associated
with severe disease, and may predict thymoma MG outcome. Nonlimb symptom profile at MG onset with bulbar, ocular, neck, and
respiratory symptoms should raise the suspicion about the presence of thymoma in MG. The presence of titin and RyR antibodies
in an MG patient younger than 60 years strongly suggests a thymoma, while their absence at any age strongly excludes thymoma.
Thymoma should be removed surgically. Prethymectomy plasmapheresis/iv-IgG should be considered before thymectomy. The
pharmacological treatment does not differ from nonthymoma MG, except for tacrolimus which is an option in difficult thymoma
and nonthymoma MG cases with RyR antibodies.

1. Thymoma in Myasthenia Gravis ryanodine receptor (RyR) [6, 7]. The muscle-like epitopes are
presented to T cells together with costimulatory molecules
Thymomas in myasthenia gravis (MG) are neoplasms de- [7]. Autoreactive T cells specific for AChR and titin are found
rived from thymic epithelial cells, and are usually of the both in thymomas and in thymoma MG patients’ sera [8].
cortical subtype (WHO type B) [1]. 50% of thymoma pa- Thymoma epithelial cells present AChR peptides to T-cell
tients develop MG (hereafter referred to as thymoma MG lines in thymoma MG patients, facilitating intrathymic im-
in this paper) [2, 3]. Cortical thymomas usually have some munization [9].
morphological similarities with thymic cortex; they share the The patient’s genetic profile and the thymic ability to
capacity to propagate the maturation of immature naive CD4 export autoreactive T cells are equally important in develop-
T cells and export mature naive T cells into the periphery. ing MG. MG has a genetic association to HLA-DR3 or ances-
Thymomas lacking this ability do not induce MG [4]. tral haplotype 8.1 in early-onset MG (MG onset before age
Thymomas with histological similarities to medullary thymic 50 years) with thymic hyperplasia and several weaker asso-
tissue or thymomas lacking developing T cells are seldom ciations to polymorphisms in immunoregulatory genes such
associated with MG [4]. Other thymoma characteristics that as FcγR, TNF-α/β, GM-phenotypes, CTLA-4 [10], HLA, and
can cause reduced self-tolerance include defective epithelial PTPN22 ∗ R620W [11]. The chance of having a thymoma
expression of the autoimmune regulator (AIRE) gene and/or increases with the number of thymoma-associated polymor-
of major histocompatibility complex class II molecules, ab- phisms in an MG patient, indicating that thymoma MG is a
sence of myoid cells, failure to generate FOXP3(+) regulatory polygenic disease and that thymoma patients with a particu-
T cells, and genetic polymorphisms affecting T-cell signalling lar genetic profile run higher risk of developing MG [11].
[5].
Histologically, thymomas are epithelial neoplastic cells 2. Thymoma MG
surrounded by maturing T cells. The epithelial cells are capa-
ble of expressing epitopes cross-reactive with skeletal muscle MG is a neuromuscular junction disease characterized by
proteins, such as acetylcholine receptor (AChR), titin, and muscular weakness and fatigability, caused in 85% of the
2 Autoimmune Diseases

Table 1: The occurrence of the various muscle autoantibodies (ab) in the different subgroups of MG [13].

MG subgroup AChR ab MuSK ab Titin ab RyR ab

Early onset (non Positive in 10% of the Negative in all
Positive in all patients Negative in all patients
MuSK nonthymoma) patients patients
Late onset
Positive in 58% of the Positive in 14% of the
(non-MuSK Positive in all patients Negative in all patients
patients patients
nonthymoma)
MuSK positive Negative in all No information No information
Positive in all patients
(regardless onset age) patients available available
Seronegative Negative in all Negative in all Negative in all
Negative in all patients
(regardless onset age) patients patients patients
Thymoma (regardless Positive in 95% of the Positive in 70% of the
Positive in all patients May occur in some patients
of onset age) patients patients

cases by AChR antibodies [12]. When MG occurs together at MG onset and a more severe disease. Neck weakness at MG
with a thymoma, MG is a paraneoplastic disease caused by onset is a distinctive feature of patients with RyR antibodies,
the presence of the thymoma. Thymoma MG accounts for while respiratory symptoms are also found in patients with
around 15% of all MG cases [13]. titin antibodies with and without RyR antibodies. Limb
The immune response against an epitope expressed on involvement with few or no bulbar signs is typical at MG
thymoma cells spills over to neuromuscular junction compo- onset in RyR-antibody-negative MG [27]. Since many thy-
nents sharing the same epitope [14]. In thymoma MG, epi- moma MG patients have RyR antibodies, neck weakness and
topes are shared between the thymoma and muscle proteins. nonlimb bulbar distribution of MG symptoms are initial
characteristic features associated with thymoma MG. Such
3. Antibodies in Thymoma MG symptom distribution should always raise the suspicion
about the presence of a thymoma in an MG patient.
AChR antibodies are the main cause of muscle weakness in Thymoma MG is equally frequent in males and females
thymoma MG [15]. Additional non-AChR muscle autoanti- and occurs at any age with a peak onset around 50 years [28].
bodies reacting with striated muscle titin and RyR antigens Thymoma MG and late-onset MG share similar serological
are found in up to 95% of MG patients with a thymoma and profile with high prevalence of titin and RyR antibodies and
in 50% of late-onset MG patients (MG onset at age of 50 lower AChR antibody concentrations compared to early-
years or later) [16]. These antibodies are usually associated onset MG [29]. About 95% and 70% of thymoma MG
with more severe MG [13, 17–19]. Striational antibodies patients have titin and RyR antibodies, respectively (Table 1).
demonstrated in immunofluorescence are largely made up Around 58% and 14% of late onset MG patients have titin
of titin antibodies [20]. and RyR antibodies, respectively (Table 1) [13].
Titin is the largest known protein, with a molecular mass Late MG onset age, similar serological profile, favorable
of 3000 kD stretching throughout the sarcomere, providing pharmacological treatment response, severe MG, frequent
a direct link between mechanical muscle strain and muscle use of immunosuppressive drugs, and the occurrence of
gene activation [21]. Myositis and myopathy with muscle at- MG related mortality are common features among thymoma
rophy are seen in some thymoma MG patients [22]. Sera MG and late-onset MG patients [29]. This profile differs
from MG patients also induce degenerative changes in mus- from early-onset MG [30], that has higher AChR anti-
cle cell cultures where both apoptosis and necrosis are impli- body concentrations, almost no titin or RyR antibodies, low
cated [23]. need for immunosuppressive drugs, less severe MG, very low
The RyR is the calcium channel of the sarcoplasmic ret- MG mortality rates, and a favorable thymectomy outcome
iculum (SR). Upon opening, the RyR releases Ca2+ into the [29].
sarcoplasm resulting in muscle contraction. In vitro, RyR Thymoma MG tends to be more severe than early-onset
antibodies can inhibit Ca2+ release from the SR [24]. There is nonthymoma MG [29]. In one study, MG patients with thy-
also a rat model with thymoma and MG with RyR antibodies moma or thymic atrophy (i.e., chiefly late-onset MG) had
but no AChR antibodies, indicating that RyR antibodies worse prognosis than MG patients with thymic hyperplasia
may cause MG symptoms irrespective of AChR antibodies (i.e., early-onset MG) [31]. The presence of a thymoma per
[25]. There are also several reports of excitation-contraction se does not give a more severe MG. Thymoma MG patients
coupling defects in thymoma MG [26]. and age-matched nonthymoma MG patients share similar
MG long-term prognosis [19]. The presence of titin and RyR
4. Recognizing the Clinical and Serological antibodies is associated with more severe disease in thymoma
Pattern of Thymoma MG MG and in late-onset MG [29]. The AChR antibody serum
concentration does not correlate with MG severity, mainly
MG patients with RyR antibodies are characterized by fre- because of individual variations in AChR epitope specificity
quent involvement of bulbar, respiratory, and neck muscles [32].
Autoimmune Diseases 3

5. Verifying the Diagnosis of Thymoma MG 7. Treatment of MG Crisis in Thymoma MG

The diagnosis of MG is based on clinical disease history and Plasmapheresis and immunoglobulin treatments are also
typical clinical findings. MG can be confirmed pharmaco- indicated in severe cases of thymoma MG regardless of thy-
logically by edrophonium (Tensilon) test which is positive mectomy, such as in MG crisis and in severe MG cases with
in 90% of MG patients, giving an immediate but transitory poor response to standard pharmacological treatment [41].
improvement of MG signs [33]. The diagnosis of MG Parallel to plasmapheresis and immunoglobulin treatment,
should be confirmed by the detection of AChR antibodies, the pharmacological treatment should be intensified in these
present in most MG cases. These antibodies are present in patients as explained in the next chapter.
virtually all patients with a thymoma [29]. In two thirds
of MG patients, failure of neuromuscular transmission in 8. Pharmacological Treatment of Thymoma MG
leads to decremental response to repetitive nerve stimulation
The first pharmacological choice in the treatment of thy-
by electromyographical (EMG) examination [34]. Increased
moma MG is acetylcholinesterase inhibitors. The second
jitter on single-fiber EMG is even more sensitive than repet-
choice is immunosuppressive drugs whenever additional
itive nerve stimulation when performed on affected muscles pharmacological treatment is needed before or after thymec-
[34]. tomy. Several immunosuppressive drugs are available, such
In addition to MG, a thymoma should be demonstrated as corticosteroids, azathioprine, cyclophosphamide, cyclos-
in order to fulfill the criteria of thymoma MG diagnosis. The porine, methotrexate, mycophenolate mofetil, rituximab,
diagnosis of a thymoma in MG is finally established by his- and tacrolimus. Steroids such as prednisolone are frequently
topathological examination postsurgery. Titin and RyR anti- given on alternate days, by gradually raising the dose to 60–
bodies and radiological examination of the anterior medias- 80 mg initially and then with slowly tapering to 20 mg or
tinum share similar sensitivity for the presence of a thymoma lower. If long-term treatment with steroids is regarded nec-
in MG [29, 35, 36]. However, the presence of titin and RyR essary, nonsteroid immunosuppressants such as azathioprine
antibodies in a MG patient younger than 60 years strongly should be introduced in addition (usually 100–150 mg a
suggests a thymoma, while the absence of such antibodies at day). While the steroid effect appears rapidly, the clinical ef-
any age strongly excludes thymoma [13, 37]. Retesting for fect of other immunosuppressants may take a few weeks to
these antibodies and a new radiological examination should several months to develop [29]. Overall, about 80% of MG
always be considered whenever clinical deterioration is seen patients and 95% of thymoma MG patients need immuno-
over time, to minimize the risk of a previously undetected suppressive drug treatment for more than one year [42].
thymoma in a MG patient. Tacrolimus, which is an immunosuppressant and en-
hancer of RyR-related sarcoplasmic calcium release, may be
6. Surgical Treatment of Thymoma MG especially beneficial in MG patients with RyR antibodies that
in theory might block the RyR interfering with its function.
When the diagnosis of a thymoma in a MG patient is Since most patients with thymoma MG have RyR antibodies,
established, the neoplasm should be removed surgically, tacrolimus may act specifically in these patients. It may have
and it is crucial to ensure radical excision of the neoplasm. a purely symptomatic effect in addition to its immunosup-
Thymectomy can be performed transternally or through a pressive impact [40]. Tacrolimus has demonstrated favorable
video-assisted thoracoscopic approach, usually with similar effects in the treatment of MG, both as monotherapy and
outcome [38]. Radical excision of a thymoma does in most as add-on to prednisolone [43, 44]. Patients should undergo
cases cure the thymic neoplasia, but patients will continue to a thorough cardiological investigation prior to commencing
suffer from MG after thymectomy, emphasizing the need of tacrolimus treatment.
continuing followup and pharmacological treatment. When Long-term observation of thymoma MG and age-
the thymoma invades the pleura or the pericardium, radical matched nonthymoma MG patients showed no difference
excision will not be possible and further oncological treat- in MG severity over time, and both groups improved to the
ment is necessary. Presurgery plasmapheresis or intravenous same degree after MG diagnosis as a result of pharmacolog-
infusion of immunoglobulin (iv-IgG) removes a great deal ical treatment and thymectomy. The need for immunosup-
of circulating pathogenic antibodies [36]. In our department pressive treatment in the two groups was similarly high. A
we give plasmapheresis or iv-IgG treatment to all patients thymoma that has been completely removed surgically does
with thymoma MG prior to thymectomy, to minimize the not necessarily mean worse MG prognosis in thymoma MG
risk of postthymectomy MG exacerbation and myasthenic [19].
crisis. This practice varies however from department to
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