Neurology 1997;48(Suppl 5):S76-S81
Myasthenia gravis with thymoma
Robert E. Lovelace, MD, and David S. Younger, MD
Progress in the pathogenesis, diagnosis, and treat-
ment of thymomatous myasthenia gravis (MG) has
been made in the past several decades. These ad-
vances have occurred along diverse lines of immunol-
ogy, molecular genetics, and tumor cytopathology.
The most widely used classification for thymoma
closely correlates with tumor biology, prognosis, and
the likelihood of association with MG. There is a
sensitive immunoassay for the detection of stria-
tional autoantibodies, which are closely related to
the presence of thymoma, although their precise ori-
gin is still debated. Chest computed tomography
(CT) can delineate a thymoma with extraordinary
accuracy and sensitivity. The goal of treatment is
complete removal of the tumor and remission or sus-
tained improvement of MG. This is usually achiev-
able with trans-sternal maximal thymectomy and
chronic immunosuppressant medication. In this arti-
cle, we consider aspects of the historical background,
pathogenesis, diagnosis, and treatment of thymoma-
tous MG.
Historical background. There was no mention of
thymic abnormalities in the classic descriptions of
myasthenia patients by Wilks,l Erb; G ~ l d f l a mand
,~
Jolly: or among the autopsies reported by Campbell
and Bramwell at the turn of the century5 until 1901
when Laquer and Weigert6.7described a patient with
myasthenia and a thymic tumor. Later, Bell,s Bla-
l o ~ k and, ~ others
~ ~ found that the thymus gland in
myasthenia was enlarged or the site of a tumor in
the majority of patients at surgery o r autopsy.
Thymectomy, with the intention t o resect the gland
totally became standard treatrnent.l1-l5
The estimated overall frequeny of thymoma in MG
varies from 15 to 30%.16-22 It is more common with
increasing age, with an estimated frequency of 3%
for age 20 years or younger, 12% for ages 21 to 45,
and 35% for age 46 years and older.23Although de-
tection of thymoma most often follows the clinical
diagnosis of MG, myasthemia may follow detection
and removal of the tumor in patients up to age 22
years ,24-26
Associated autoimmune disorders. Patients
with thymoma have an increased tendency for asso-
ciated autoimmune disorders in keeping with Simp-
son's assertion,27including limbic encephalitis,28neu-
From the Department of Neurology, Columbia-Presbyterian Medical Center, and the College of Physicians and Surgeons, Columbia University, New York,
NY.
Address correspondence to and reprint requests to Dr. Robert E. Lovelace, Neurological Institute of Columbia-Presbyterian Medical Center, 710 West 168
Street, New York, NY 10032.
S76 Copyright 0 1997 by the American Academy of Neurology
romyotonia and peripheral neuro~athy,~~
polymyositis and dermatornyositi~,~"~~~ pure red blood
cell a p l a ~ i a , pancytopenia,
~~,~~ rheumatoid arthritis,
hyperthyroidi~m,~~ systemic lupus e r y t h e m a t ~ s i s , ~ ~
giant cell myocarditis,36 Addisons disease,35and cryo-
g l ~ b u l i n e m i a .Extrathymic
~~ neoplasms also occur
with increased frequency including those of the
breast, liver, lung, stomach, thyroid, lymphoprolif-
erative cancers, and carcinoid tumors.38 Whereas
Lambert-Eaton myasthenic syndrome (LEMS) and
MG can occur separately with thymoma, and both
LEMS and MG have at times been documented to-
gether in the same ~ a t i e n t ~ ~the " . ~presence
, of all
three together has not been convincingly shown.
Histopathology. For the purpose of this discus-
sion, we consider thymic epithelial cell neoplasms.
Thymic lymphoid malignancy rarely occurs in associ-
ation with MG.39940Thymomas constitute approxi-
mately 15%of all mediastinal masses.41They usually
contain a mixture of small lymphocytes and plump
ovoid epithelial cells associated with perivascular
spaces cuffed by lymphocytes.4z They are usually
well encapsulated by dense calcified plaque. In up to
a third of tumors there is variable extension beyond
the capsule with deposition of discrete nodules or
implants in the pleura, pericardium, and anterior
mediastinum; however, there are no true hematoge-
nous or lymphatic metastases. Traditional classifica-
tions that distinguished between epithelial and lym-
phoid types based on the predominant cell type in a
pathologic specimen did not accurately predict tumor
behavior. Moreover, the cellular composition often
differed in adjacent lobules making firm designa-
tions difficult. A histologic classification (table) based
on the cellular differentiation of thymic medullary or
cortical epithelium is prognostically useful in pre-
dicting invasiveness, metastatic behavior and the
tendency for association with MG.43.44 It has been
repeately validated, even in separate geographic
groups where pathogenetic factors may differ.45,46 Six
categories of thymic epithelial tumors are recog-
nized, including four categories of thymoma: medul-
lary, cortical, predominantly cortical, mixed; and two
subgroups of thymic carcinoma: well differentiated
thymic carcinoma (WDTC) and high grade carcino-
mas. Medullary and mixed thymomas are benign tu-
mors with no risk of recurrence, even when capsular
Table Thymoma and tumor types and association with MG
Association % of Cases
with MG Tumor type (N = 155)
Common WDTC 77
Cortical thymoma 66
Less common Mixed thymoma 39
Predominantly cortical thymoma 33
Medullary thymoma 33
Other thymic carcinomas 0 AChR a l p h a - s ~ b u n i tThe
Modified from reference 54.
WDTC = well differentiated thymic carcinoma.
invasion is present, and have a low association with
MG. Compared to the other tumor types, they sel-
dom require adjuvant therapy after surgical resec-
tion. Cortical and predominantly cortical thymomas,
which are most often associated with MG, demon-
strate intermediate invasiveness and a low but sig-
nificant risk of late relapse. WDTC are generally
invasive and carry a significant risk of relapse with
high mortality.
Immunopathogenesis. The origin of MG in asso-
ciation with thymoma is not well understood but
epithelial-thymocyte interactions appear to be a pre-
requisite to the process of thymoma-related
autoimmunity. Thymic epithelial cells, present in
both normal and abnormal hyperplastic and
thymoma glands are the source of thymosin and
thymopoiten.’6,47They participate in the instruction
of immature thymocytes to become more immuno-
competent forms and trigger the autoimmune re-
sponse to native acetylcholine receptor (AChR).I6
Thymosin alpha-1 immunoreactivity is increased in
thymoma tissue extracts using a mouse monoclonal
antibody (Mab) assay.4BMyoid cells, the only thymic
elements capable of expressing intact AChR, are
rarely found in thymomas except in tumor free adja-
cent residual thymus tissue. In contrast to hyper-
plastic thymus, thymomas do not express significant
levels of AChR-specific RNA.49Nonetheless virtually
all patients with thymoma have elevated AChR anti-
body titers.50The observed autoantibody response to
the AChR may originate in the tumor itself.51Non-
myoid cells might express both AChR and myogen as
suggested by the finding of AChR alpha-subunit and
myogen mRNAs in several thymoma specimens from
patients with MG when analyzed by polymerase
chain reaction immunocytochemistry.52
Two findings in thymic epithelial tumors appear
to correlate with the occurrence of MG: the expres-
sion of an AChR-like epitope in the neoplastic epithe-
lium, and the preservation of thymus-like features in
the neoplasms as indicated by the presence of imma-
ture t h y m ~ c y t e s CD1’
. ~ ~ immature lymphocytes are
the hallmark of nearly all thymic tumors.54 The in-
teraction of CDl+ cells and thymoma epithelial cells
are believed to be important in the selection and
expression of tumor-associated AChR epitopes by the
thymoma. Epithelial cells that stain positively with
Mabs to the medullary and cortical epitopes MR19
and MR3, respectively, are observed in hyperplastic
and thymomatous glands, but not in normal thy-
muses, suggesting a possible common origin for thy-
mic neoplasm^.^^,^^ Neoplastic epithelial cells also
bind to an AChR-specific Mab 155 which recognizes
a highly immunogenic cytoplasmic epitope of the
. ~ ~ binding of Mab 155 can
be correlated with tumor histologic subtypes and is
greatest in cortical thymomas and well-
differentiated thymic carcinomas which exhibit high
MG association, intermediate in predominantly cor-
tical thymomas, and virtually negative in medullary
and mixed thymoma s ~ b t y p e s . ~ ~
The role of genetic predisposition in thymomatous
MG is still unclear. There are inconsistent reports of
the association of HLA class I1 allelic determinants
with some reports of positive correlation with the
DQB1*0604,”7 DRB1*120258and HLA-B835,59 halplo-
types, with other reports negative or inconsis-
tent.47.60.61
Diagnosis. The clinical diagnosis of MG is made
by recognizing the characteristic pattern of weakness
in cranial and limb muscles, and confirmed by un-
equivocal and reproducible improvement with intra-
venous edrophonium chloride, a decremental re-
sponse to 3/sec repetitive nerve stimulation, and
elevation of the serum AChR antibody titer. An im-
portant consideration is whether there is an associ-
ated thymoma. Apart from MG, which is often more
severe at presentation, symptoms related to the
presence of the tumor or even local invasion are sur-
prisingly uncommon. However, an unexplained per-
sistent cough, dysphonia suggesting recurrent laryn-
geal nerve involvement, and elevation of a
hemidiaphgram implicating a phrenic nerve lesion,
may all be clues to underlying invasive thymoma.
Virtually all patients with thymomatous MG have
elevated AChR antibody titers, and their serum
should be appropriately analyzed for the presence of
AChR antibody activity. Experience suggests that
the accuracy of diagnosing associated thymoma is
probably better than 95% when striational autoanti-
body (StrAb) serology and contrast CT of the chest
and mediastinum are performed.
The StrAb enzyme immunoassay (EIA) employs a
mixture of muscle proteins as antigen and is equiva-
lent in sensitivity and specificity to the indirect im-
munofluorescence assay.62The incidence of StrAb se-
ropositivity increases with age, as does thymoma.
They are detected in high titers in 80 to 90% of
patients with thymoma and MG and in 25% of pa-
tients with thymoma without clinically manifest
MG,62and in lower titers in 11to 30% of myasthenic
patients without t h ~ m o r n a .The
~ ~ ,stimulus
~~ for pro-
duction of these antibodies is not well understood.
April 1997 NEUROLOGY 48(Suppl5) 577
Titin has been proposed as a target of StrAb autoim-
munity. Up to 97% of patients’ serum with thymoma-
tous MG demonstrate IgG anti-titin a u t ~ a n t i b o d i e s . ~ ~tumor implants including the diaphragms.
They are restricted to the sera of patients with thy-
momatous MG and bind to striated elements in med-
ullary myoid cells supporting the hypothesis that
titin is a major specificity for IgG S t r A b ~ It
been suggested that titin autoimmunity results from
cross-reactivity of other tumor antigens, or might be
a secondary phenomenon that follows its release
from skeletal muscle.65Components of the sarcoplas-
mic reticulum may also be relevant antigens in thy-
momatous MG because up t o one-half of thymoma-
tous MG sera demonstrated IgG autoantibodies to
the ryanodine receptor.66
The radiographic detection of thymoma has been
extensively s t ~ d i e d . ~CT ~ ,was ~ ~ -85% ~ ~ sensitive,
98.7% specific, and 95.8% accurate overall, in the
preoperative diagnosis of t h y m ~ m aChest . ~ ~ CT is the
recommended screening study for thymoma and tu-
mor recurrence in all ages. The radiographic evalua-
tion of thymoma may however be complicated by the
fat content of the thymus gland which normally in-
creases with age, and the variability of the size of the
gland. Starting at about age 20, cellular elements in
the thymus gland gradually decrease in extent and
are replaced by fatty i n f i l t r a t i ~ n . ~This
~ . ~ ’ so-called thenia.
involution is complete by age 60, at which time 90%
or more of the gland consists of fat. Despite increas-
ing age, microscopic remnants of thymus are always
present.15 Interpretive errors resulting in missed
small tumors may occur in patients age 20 years or
younger due t o partial preservation of adjacent
dense thymic parenchyma, and glandular hyperpla-
sia in those age 21 to 45 years. CT scanning was
most accurate in still older patients with predomi-
nant fatty involution. Magnetic resonance imaging
(MRI) does not appear to be superior to CT scanning
in the detection of t h y m o m a ~ . ~ ~ J ~
Treatment. The clinician must choose the appro-
priate sequence and timing of thymectomy, cholin-
ergic and immunosuppressant medication, and adju-
vant therapies for the patient with thymomatous
MG, sadly without the benefit of clinical trials. The
chief reason for thymectomy was t o prevent the
spread of the tumor.74There is now a general consen-
sus that all patients with thymomatous MG should
undergo early and total thymectomy with complete
removal of the thymoma and adherent structures, to
prolong survival, prevent thymoma recurrence, and
to induce remission or asymptomatic ~ t a t u s . ~ ~At- ~ O tively, and are more apt to be considered for adju-
the Columbia-Presbyterian Medical Center between
1977 and 1985, 65% of patients with non-malignant
thymomatous MG were free of myasthenic symptoms
when evaluated 6 months to 7 years after maximal
thymectomy, including 13% in sustained remission,
6.5% on minimal doses of cholinergic medication,
and 45.5% on prednisone or azathioprine therapy
alone or in ~0mbination.l~ Maximal thymectomy with
en-bloc exenteration of the tumor and all thymic tis-
578 NEUROLOGY 48(Suppl5) April 1907
sue is the preferred procedure in patients with thy-
moma, with inspection of the entire chest cavity for
The case against transcervical thymectomy, lim-
ited trans-sternal, and other potentially incomplete
procedures in thymomatous MG is based on the ob-
. ~has
~ servations of incidental thymomas at operation,81the
later development of a tumor,82recurrent t h y m ~ m a , ~ ~
the possible spread of tumor in the course of an in-
complete the overall lower rates of remis-
sion or improvement with the more limited
resections,82-86 residual thymus found at reoperation
after earlier transcervical surgery and the subse-
quent improvement with trans-sternal exentera-
tion.87~ss The prognosis of thymomatous MG is best
predicted by stage of the tumor determined intraop-
eratively and is poorer in patients with incomplete
resection than in those with complete r e ~ e c t i o n . ~ ~
Nevertheless, there are still advocates of the
transcervical a p p r o a ~ h In . ~ major
~ ~ ~ ~centers, the
maximal operation carries a negligible morbidity and
mortality in virtually all ages due to technical refine-
ments in anesthesia, surgery, and postoperative
care, and the judicious use of preoperative plasma-
pheresis, intravenous gammaglobulin, and oral im-
munosuppressive agents to improve serious myas-
There is no definite consensus about several re-
lated issues. Should surgery be considered in the
extremes of age, in the “elderly” who are more likely
to have serious co-morbid illnesses, and in children
in whom there is fear of potential acquired immuno-
deficiency? It appears that the term “elderly” has
become increasingly difficult to define, and patients
of increasingly advanced age have undergone the
maximal operation without difficulty. There were no
permanent effects in several children who under-
went resection of thymoma and coexisting thymic
~ , ~ ~ area of uncertainty is the role of
t i s ~ u e . lAnother
postoperative radiation therapy and adjuvant che-
motherapy in thymoma. Although there has been no
prospective controlled trial of postoperative adjuvant
radiation or chemotherapy in patients with thymoma
of different tumor types or degrees of myasthenia, it
stands to reason that the long-term prognosis for
recurrence, distant spread, and the later develop-
ment of more serious MG should be improved by
postoperative radiation and chemotherapy especially
in the more malignant tumor types. For example,
WDTC and cortical thymomas, which demonstrate
high or intermediate degrees of malignancy, respec-
vant therapy than medullary or mixed thymomas,
which are always encapsulated, show mild invasion
through the capsul, and are typically cured surgical-
iy.92
Controversy also abounds in the choice of chronic
immunusuppressive agents in thymomatous MG. Al-
though prednisone is standard and customary ther-
apy for both the thymoma and MG, there is persis-
tent uncertainty as to suggested dosages and
regimens, the appropriate duration of therapy before 5 . Campbell H, Bramwell E. Myasthenia gravis. Brain 1900;23:
deeming treatment failure or apparent benefit. 277-336.
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April 1997 NEUROLOGY 48(Suppl5) 581
 Myasthenia gravis with thymoma
Robert E. Lovelace and David S. Younger
Neurology 1997;48;76S-81S
DOI 10.1212/WNL.48.Suppl_5.76S

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