CLINICO-PATHOLOGICAL CONFERENCE
A case report of giant cell myocarditis and myositis
observed during the clinical course ofinvasive thymoma associated with myasthenia gravis
Norio Tanahashi, Hideki Sato, Shigeru Nogawa, Toru Satoh, Masafumi Kawamura1 and Masayuki Shimoda2
Departments of Internal Medicine, 1Surgery and 2Pathology, School of Medicine, Keio University, Tokyo, Japan

Abstract. The patient is a 62-year-old man who was diagnosed with myasthenia gravis and invasive
thymoma at the age of 45 years, and had received treatment by extended thymectomy and radiotherapy. At the age of 61, he had suffered from a myasthenic crisis, and been administered immunoadsorption therapy under managed ventilatory care. Treatment had then been continued with steroids; however, due to subsequent deterioration of his diabetic state, treatment was switched to theimmunosuppressant drug tacrolimus. Three months after the commencement of tacrolimus administration, the patient developed generalized malaise and dyspnea. The serum creatine phosphokinase(CPK) level was abnormally elevated, and abnormal electrocardiographic ﬁndings were noted,
including atrioventricular dissociation and ventricular escape contraction. Steroid pulse therapy was
therefore initiated, however, 4 days later, the patient suddenly died. Autopsy examination revealed
inﬂammatory cell inﬁltration with giant cells in the myocardium, diffuse myocardial degeneration, andpolymyositis. The case was therefore considered as one with the syndrome of myasthenia gravis, polymyositis, giant cell myocarditis, and thymoma. (Keio J Med 53 (1): 30–42, March 2004)
Key words: myasthenia gravis, thymoma, polymyositis, giant cell myocarditis

In February of the same year, the patient received chemotherapy (carboplatin, adriamycin, and etoposide; 2
courses) for intrapulmonary metastases from the invasive thymoma, which was followed by partial regressionof the tumor.
In June 2000, the patient developed generalized alopecia, including on the scalp, which was considered to
be a result of autoimmune disturbance. The alopecia
never resolved and persisted until the patient’s death in
2002.
In January 2001, recurrence of the invasive thymoma
was detected, for which chemotherapy (carboplatin anddocetaxel; 2 courses) was administered. In May 2001,
the patient developed a myasthenic crisis, which wasmanaged by mechanical ventilation, and immunoadsorption and steroid pulse therapy, followed by remission. At this time, no abnormality of the serum creatine phosphokinase (CPK) level was noted.
Thereafter, the patient was followed up as an out-

Dr. Tanahashi (Moderator): So, let us start the1064th Clinico-pathological Conference (CPC).
Dr. Sato, as the physician-in-charge of the present
patient, a 62-year-old man, will you please describe thechief complaints, history of present illness and life history of the patient?
Dr. Sato (H) (Internal Medicine): The patient was
a 62-year-old man, who presented with the chief complaints of dyspnea and generalized malaise.
As for the history of the present illness, he had ﬁrst
developed diplopia (double vision), blepharoptosis,
bulbar palsy, and easy fatigability in 1985, and was
examined at our hospital. He was then diagnosed tohave myasthenia gravis (MG) associated with an invasive thymoma, and was treated by extended thymectomy, radiotherapy (40 Gy; chest), and administrationof a steroid and a cholinesterase inhibitor(Mytelase1).
His condition relapsed in 1997, and treatment with acholinesterase inhibitor (Mestinon1) was started again.

This is a record of the 1064th CPC of Keio University Hospital, held on February 5, 2003.
This case has been published in Japanese as a case-report entitled ‘‘A patient with giant cell myocarditis and myositis associated with thymoma
and myasthenia gravis’’ by Sato H, et al. in Rinsho Shinkeigaku, 2003; 43: 496–499 (in Japanese)
Reprint requests to: Dr. Norio Tanahashi, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan, e-mail: tanahasi@sc.itc.keio.ac.jp30Keio J Med 2004; 53 (1): 30–42

patient while receiving treatment with a steroid. In
January 2002, he again developed exacerbation of his
myasthenic condition along with increase in the serum
level of the antiacetylcholine receptor (AChR) antibody. His diabetic state was found at this time to haveworsened markedly, therefore, tacrolimus administration was started at the daily dose of 3 mg, in order toavoid increasing in the steroid dose. An electrocardiograph (ECG) obtained at this time revealed non-speciﬁc ST-T changes, but no abnormal echocardiographic
ﬁndings were observed, and monitoring of the clinicalcourse was continued on an outpatient basis.
On April 9, 2002, a routine blood examination revealed elevation of the serum CPK level to 563 mg/dl,
even though there was no change in his symptom status.
On April 13, he developed generalized malaise anddyspnea. On April 15, he presented to our outpatient
clinic with epigastralgia, generalized malaise and exacerbation of dyspnea. He was suspected to have amyasthenic crisis, and was admitted immediately, on an
emergent basis, to our department.
As for past history of medical illness, the patient
had steroid-induced diabetes. At the age of 61 years, he
had also been diagnosed to have tongue cancer and had
undergone resective surgery. In the same year, he had
also undergone polypectomy for colonic polyps.
The family history was unremarkable. As for the
personal history, he was not habituated to either smoking or drinking.
Dr. Tanahashi: Any questions at this point?
Mr. Niihara (3rd-grade student): Was any test conducted for infectious diseases at the last admission?
Dr. Sato (H): We did not determine the antibody
titers of any viruses that could potentially cause myocarditis.
Dr. Tanahashi: This patient was diagnosed as havingof MG in 1985. Do you have any comments about thisdiagnosis? The patient had shown double vision, ptosis,
muscle weakness, and easy fatigability. When MG issuspected, what kind of tests should be conducted?
Mr. Nishi (3rd-grade student): It is important to detect waning phenomenon of the electrical muscle activity on an evoked electromyogram (EMG).
Dr. Tanahashi: How about the result of this examination early in the course of this patient’s disease, Dr.
Sato?
Dr. Sato (H): According to his medical record from1985, decrementing response during repetitive nerve
stimulation was observed, and the patient was also positive for the Tensilon1 test and his serum anti-AChR
antibodies level was elevated.
Dr. Tanahashi: The diagnosis of MG was thus madein 1985 in the early stage of the clinical course of thispatient. At this time, thymoma was also present, andextended thymectomy and radiotherapy were carried

31

out. Is there any description regarding the thymoma inthe early stage of the clinical course?
Dr. Kawamura (Surgery): Chest CT revealed pleuraldissemination on the left side. Extended thymectomy
was performed, as standard surgical fashion for thymoma with extensive dissection of the adipose tissue inthe following regions: around the ligament extending
from the upper pole of the thymic gland (thymus) to thelower pole of the thyroid gland (thyro-thymic ligament)on the cephalic side, at the level of the right and left
phrenic nerves on the lateral side, and in the mediastinum, at the level of the diaphragmatic on the caudal
side. Since the thymus gland is also converted into adipose tissue in association with thymic regression in
adults, it is impossible to precisely differentiate the adipose tissue surrounding the thymus from the residual
thymus gland. This is the reason why extensive adipose
tissue dissection, as described above, was conducted.
With regard to the pleural dissemination, although they
could also be treated by total pleuropneumonectomy ifradical surgical treatment is desired, usually, however,such an extensive procedure is not employed; in thispatient, the disseminated thymus were resected and radiotherapy was administered postoperatively.
Dr. Satoh (T) (Internal Medicine): Dr. Kawamura,please tell us whether or not the heart was also irradiated, and if it was, what was the radiation dose
employed?
Dr. Kawamura: Keio University Hospital follows its
own radiotherapeutic protocol for thymoma associatedwith pleural dissemination. The pleural disseminationin these cases usually occurs unilaterally. Therefore,
hemithorax irradiation is applied on the side of dissemination; the entire thorax on the affected side, extending from the apex of the lung to the lowest portion of
the diaphragm (up to the posterior aspect of the liveron the right side and the level of the spleen on the leftside) is widely irradiated at a daily dose of 1 Gy, over 10
sessions. This procedure is considered to allow reasonably satisfactory regression of the pleural metastases.
Irradiation at a higher daily dose of 2 or 3 Gy is often
associated with serious radiation pneumonitis, because
the irradiation ﬁeld is very wide. Slow irradiation, i.e.,
irradiation at a daily dose of 1 Gy over 10 sessions, isconsidered to allow adequate irradiation with a relatively lower risk of pneumonitis. I repeat that the irradiation ﬁeld in these cases is much wider as comparedwith that which is usually the case. The wide-ranging
irradiation ﬁeld includes the mediastinum as well. Subsequently, however, the irradiation ﬁeld is narrowed tocover the mediastinum alone, which is irradiated withapproximately another 20 Gy. Finally, the irradiationﬁeld is narrowed down even further to only the site of
the primary lesion, which is then irradiated at a total
dose of approximately 40–45 Gy. Accordingly, the32heart may receive a total radiation dose of approximately 30 Gy during the course of such radiotherapy.
Dr. Tanahashi: Although the patient showed remission initially, he developed a myasthenic crisis in May
2001, and was treated with a mechanical ventilator andimmunoadsorption and steroid pulse therapy. Do you
have comments on that?
Ms. Nishiyama (3rd-grade student): Myasthenic crisis
may be induced by various factors, including infection
and stress under the condition that physical state isdeteriorated. Since the physical condition is associatedwith respiratory muscle failure in myasthenic crisis, artiﬁcial ventilatory support is essential.
Dr. Tanahashi: During a crisis, in particular, artiﬁcial
ventilatory support is very essential. This patient wasalso administered immunoadsorption therapy and steroid pulse therapy for the myasthenic crisis. Dr. Sato,
could you please explain to us why the immunoadsorption therapy and steroid pulse therapy was done for the
myasthenic crisis in this case?
Dr. Sato (H): MG is generally treated with immunosuppressant drugs, because the condition is believed
to be an autoimmune disease. During a crisis, when thepatient develops respiratory failure due to respiratory
muscle failure and/or bulbar palsy, mechanical ventilatory support and suppression of the associated immunological abnormalities are essential. As a rule, bothmust be continued until recovery from the crisis.
Dr. Tanahashi: The patient survived the crisis, andfollow-up was continued on an outpatient basis while he
was under treatment with a steroid. In January 2002,
the patient’s condition deteriorated again, but this time,
it was not a myasthenic crisis, was it? The serum level ofanti-AChR antibody was found to be elevated. What
was the level?
Dr. Sato (H): It was increased to 200 nmol/ml.
Dr. Tanahashi: What are the normal levels of thisparameter?
Dr. Sato (H): 0.2 nmol/ml or less.
Dr. Tanahashi: So, the anti-AChR antibody level
was markedly elevated to 200 or so nmol/ml; However, since the patient, already known to be a diabetic,
showed marked deterioration of his diabetic state,
the steroid dose was not increased; instead, administration of tacrolimus, an immunosuppressant drug, wasstarted.
Mr. Harasawa (3rd-grade student): Some MG patients do not respond to steroid therapy following thymectomy, and such patients, as well as those with severe adverse reactions to steroids would be candidates
for receiving immunosuppressant drugs.
Dr. Tanahashi: Thereafter, the patient’s condition
was monitored by serial echocardiography, and no distinct electrocardiographic abnormalities, including STT changes were noted. However, elevated CPK levels

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis

were detected during a routine blood examination conducted on an outpatient basis on April 9 last year.
The serum CPK level was 563 mg/dl. What can we
make out from this level?
Mr. Harada (3rd-grade student): The normal range
for serum CPK is 67–210 mg/dl. Thus, the level inthis patient was markedly elevated; when the MM
fraction is elevated, skeletal myopathy and endocrinedisease-induced myopathy are considered. When the
MB fraction is elevated, cardiac muscle disease is considered.
Dr. Tanahashi: On April 13, the patient developed
generalized malaise and dyspnea, and on April 15, hevisited our outpatient clinic with the complaints of epigastralgia, malaise, and dyspnea. Based on the clinicalﬁndings, he was suspected to have a myasthenic crisis,
and was admitted to our department.
On admission, he was found to have dyspnea, andthe serum CPK level was markedly elevated, and amyasthenic crisis was suspected. Please explain theclinical course of the patient from the time of admission
until observation of the abnormal echocardiographic
ﬁndings.
Dr. Sato (H): Physical examination at the time ofadmission revealed a pulse of 88 per minute, bloodpressure of 146/90 mmHg, and a respiratory rate of 30
per minute; thus, the patient had tachypnea. Alopecia
involving the entire body, including the scalp, (alopecia
totalis) was observed, and the patient had very severe
generalized muscle tenderness. He could scarcely movehis body.
On neurological examination, because of severe
muscle tenderness, it was difﬁcult to deﬁnitively evaluate his muscle strength, but no deﬁnite phenomenon of
fatigue was noted on test of repetitive grasping.
Laboratory examination revealed elevation of the
red blood cell count, hematocrit and serum hemoglobin. These ﬁndings associated with elevation of the serum creatinine and blood urea nitrogen levels suggested
hemoconcentration, i.e., the patient was in a dehydrated condition. The white blood cell count was also
markedly increased to 18,200 per c.mm, and the serum
CRP was 7.42 mg/dl. From these ﬁndings, some inﬂammatory reaction was assumed. The serum CPK was
markedly elevated to 9835 IU/l, and the serum myoglobin and troponin T derived from myocandium levels
were also elevated to 16,400 ng/ml and 3.24 ng/ml, respectively. These ﬁndings suggested skeletal myopathy
and/or cardiomyopathy.
The serum anti-AChR antibody level was 56.0 nmol/ml, which was less than the level noted at the previous
examination. The blood level of tacrolimus was 6.2 ng/
ml, which was within the reference range.
Arterial blood gas parameters were within normal
range even when the patient was breathing room air:Keio J Med 2004; 53 (1): 30–42

pH, 7.406; pCO2 , 40.2 Torr; pO2 , 86.8 Torr; HCO3 , 24.7
mEq/l; BE, 0.6 mEq/l.
Dr. Tanahashi: So, myasthenic crisis was not considered as the diagnosis at this time point, was it?
Dr. Sato (H): Because the patient didn’t present
typical features of myasthenic crisis such as bulbar
palsy. When we started to treat him, we could not ruleout myasthenic crisis.
Dr. Tanahashi: Laboratory examination revealed
marked elevation of some myogenic enzymes; CPK,
9,800 IU/l, MM fraction, 96%, myoglobin, 16,400 ng/ml,
and troponin T, 3.24 ng/ml. What disease conditions
would be considered from these values?
Mr. Niihara: The serum CPK level was high, in particular, the MM fraction, in the present examination. In
this situation, skeletal myopathy and endocrine-diseaseinduced myopathy should be considered. In cardiac
diseases including acute myocardial infarction, elevation in the MM fraction is rare. Therefore, musculardisorders should be suspected.
Dr. Tanahashi: Do you mean that disorders of theskeletal muscle should be considered? How about serum troponin T? What are the conditions in which theserum level of troponin T is elevated?
Mr. Niihara: Serum troponin T is elevated in cases of
myocardial disease or myocardial infarction.
Dr. Tanahashi: So, the laboratory test data are suggestive of skeletal myopathy or cardiomyopathy. Will
you please present the roentgenographic, ECG, andechocardiographic ﬁndings now, Dr. Sato?
Dr. Sato (H): ECGs taken in February 1997 (Fig.
1A), November 2000 (Fig. 1B) and January 2001 (Fig.
1C) showed slight ST-T change, left axis deviation andleft atrial overload. The ECG taken in January 2002
(Fig. 1D) showed ST segment depression in precordial
leads V3 , V4 , V5 and V6 . The ECG recorded at thepresent admission (Fig. 1E) revealed atrioventriculardissociation (P/QRS dissociation). There is widening of
the QRS complexes. The contour of the QRS complexes is suggestive of left bundle branch block. Subsequently, QRS complexes had become wider (Fig. 1F).
Dr. Tanahashi: The ECG ﬁndings seem to show
considerable variability, don’t they? ST-T changes
associated with conduction disturbances and various
other changes. Can the ECG ﬁndings be considered to
be speciﬁc for any morbid condition, Dr. Sato?
Dr. Satoh (T): No, the changes are nonspeciﬁc, andvarious causes must be considered.
Dr. Tanahashi: Now then, will you please explain thechest x-ray ﬁndings and echocardiographic ﬁndings?
Dr. Sato (H): These are the chest X-rays. This one
was taken in January 2002 (Fig. 2). A nodular shadow
in the lung and a shadow along the chest wall are observed. There is evidence of repeated relapses and remissions of the malignant thymoma. The size of the

33

Feb., 1997

Nov., 2000

Jan., 2002

Apr. 15, 2002

Jun., 2001

Apr. 18, 2002

Fig. 1 Time course changes in electrocardiogram (ECG). The ECGs,
taken in February 1997 (A), November 2000 (B), January 2001 (C),January 2002 (D), April 15th 2002 (E), and April 18th 2002 (F) are
shown. Slight ST-T changes, left atrial overload and slight left axis
deviation were observed (A, B, C). The ST-T change appeared inanterior wall leads as well as in lateral wall leads (D). Atrioventriculardissociation and accelerated idioventricular rhythm were observed s(E). Finally, it changed to slow ventricular tachycardia (F).

cardiac shadow has remained unchanged, and there isno evidence of pulmonary congestion.
An echocardiogram taken on April 16, 2002 showed
the disturbance of left ventricular wall motion. The left
ventricular ejection fraction was 57.5%. The inferior
vena cava (IVC) diameter was 1.3 cm, suggestive ofslight venous stasis. The respiratory ﬂuctuations in thevein diameter are attenuated.
Dr. Tanahashi: Please explain the course after admission and the course before the death, Dr. Sato.
Dr. Sato (H): Blood gas analysis was conducted on
several occasions within the ﬁrst 24 hours after admission on April 15, 2002. A progressive increase in thearterial CO2 tension and severity of acidosis was noted.

34

Fig. 2 The chest X-ray ﬁlm taken in January, 2002. A nodular
shadow in the lung and pleural thickening were observed.

Since consciousness disturbance also worsened, tracheal intubation was performed, and the patient wasconnected to a ventilator. Based on all the informationand data available, it was considered highly probablethat the patient had myocarditis and myositis associatedwith MG. Under this assumption, steroid pulse therapy
was initiated. However, since the blood sugar shot up to
over 700 mg/dl the steroid pulse therapy was discontinued, and instead the patient was initiated on highdoze immunoglobulin therapy, which was then continued.
As for the heart, treatment with catecholamines was
initiated, but signs of cardiac decompensation, including
low blood pressure, persisted. Echocardiographic monitoring at the bedside also revealed daily worsening of
the left ventricular wall motion. On the dawn of April
19, 2002, the patient complained of an oppressive sensation on the chest, and soon thereafter, died of cardiac
arrest.
Dr. Tanahashi: The patient died relatively suddenly,
about 4 days after admission. Serial echocardiograms
revealed gradual worsening of the left ventricular wallmotion. The patient was treated under a presumptive
diagnosis of generalized myositis and myocarditis. Steroid pulse therapy was also employed for suspected
myasthenic crisis, while the patient was under artiﬁcial
ventilation. Cardiac conduction disturbances began tobe observed, and the patient eventually developed ventricular tachycardia and died.
Then, what do you think about the course of the patient from the cardiological standpoint, Dr. Sato?

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis

Dr. Satoh (T): Several diseases should be ruled out;
one is the ischemic heart disease, which is responsible
for the rapidly progressive ventricular dysfunction. He
is old enough to have ischemic heart disease. However,
he had few risk factors and no past history of chest pain,
nor left ventricular wall motion abnormality was notconsistent with the area perfused by any particular coronary artery. These evidence are against the ischemic
heart disease. Under these circumstances, the probability of ischemic heart disease seemed to be low.
On admission, the patient had mild hypertension.
There was no distinct past history of the condition, but
hypertensive heart disease must be enumerated in the
differential diagnosis. However, the eventual course of
the patient did not conform to this diagnosis. Then, thepossibility of myocarditis must also be considered. Troponin T, one of the myocardial enzymes, is highly speciﬁc for myocardial damage. The serum troponin T
level may also be elevated in the presence of heart
failure alone. The level of 3.24 ng/ml was high for heart
failure, and the serum CPK-MB level was approximately 4%, which is borderline, but this value shouldstill be considered as high. Therefore a morbid condition causing rapidly progressive damage of myocardium
should be considered. If ischemic heart disease is notprobable, myocarditis should be considered.
The diagnosis of myocarditis is often made from thecharacteristic ST segment elevation on ECG. Because
this patient had persistent VT, the ST segment could
not be assessed properly. Deﬁnitive diagnosis could
have been made by cardiac catheterization and myocardial biopsy, but this was impossible because of thepatient’s serious condition. Gallium scintigraphy mightalso have been speciﬁc if the patient had been positive,
but this was also difﬁcult to perform. Therefore, a myocarditis was most strongly suspected, but it could not be
conﬁrmed. The progression was rapid. Because the patient was on immunosuppressant drugs, he may havebeen predisposed to viral myocarditis, the commonest
cause of myocarditis.
Myocardial dysfunction due to irradiation may also
be considered. Radiation cardiomyopathy is frequently
associated with pericarditis and pericardial thickening;
however, in this case, no pericardial thickening was observed on CT. Therefore, the possibility of this condition would also be low. As another possibility that mustbe ruled out, tacrolimus-induced cardiomyopathy canbe enumerated, because the frequency of tacrolimus
use has recently increased. This possibility may not becompletely ruled out, but because of the rapid progression of the disease, this drug can hardly be considered
to be the cause of the myocardial dysfunction. Under
these circumstances, the diagnosis of myocarditis wasconsidered to be most probable.
Dr. Tanahashi: So, Dr. Sato has indicated that myo-

Keio J Med 2004; 53 (1): 30–42

carditis was suspected to be the cause of the rapidly
progressive cardiomyopathy in this case. As to the
etiology of the myocarditis, in turn, he suggests thepossibility of viral infection. He has also taken into
consideration various other causes, including immunosuppressant drug administration, radiation, etc. . . . In
any event, whatever the cause, the suspected diagnosis
was myocarditis.
The patient’s course towards death was very rapid;
progression of the cardiac condition rather than MG
were considered to be responsible for the rapidly fatal
course.
Dr. Sato (H): Circulatory-respiratory failure may becaused by heart failure due to myocarditis. It is difﬁcult
to determine whether or not myasthenic crisis was alsopresent, because the Tensilon test could not conducted
after the patient was connected to a ventilator. The
question therefore remained unresolved until the end.
Dr. Tanahashi: The present patient who had MG
associated with invasive thymoma developed symptomsof acute heart failure during the course of observation.
The heart failure was suspected to be caused by myocarditis. Dr. Kawamura, do you have any remarks to
make?
Dr. Kawamura: After extended thymectomy for MG,
we have often encountered patients who develop either
myasthenic crises or cholinergic crises postoperatively,
regardless of the presence or absence of a thymoma. On
the other hand, we have never encountered myocarditis
or acute heart failure in these cases.
Dr. Tanahashi: Dr. Shimoda from the Departmentof Pathology, will you please explain the pathologicalﬁndings?
Dr. Shimoda (Pathology): The present patient was
followed up for more than ten years after being diagnosed to have MG associated with invasive thymoma.
At autopsy, recurrent invasive thymoma, giant cell
myocarditis, polymyositis and alopecia totalis wereobserved in addition to MG. The autopsy ﬁndings are
summerized in Table 1.
The invasive thymoma had invaded the pericardium
and the left pleura in the surgically resected tissue in1985. Histologically, the tumor consisted of lymphocytes and epithelial cells, arranged in compartments
formed by ﬁbrous septa (Fig. 3A, B). Some areas of thistumor showed medullary differentiation. The tumor wasdiagnosed as invasive thymoma. At autopsy, the invasive thymoma recurred in the anterior septum, invaded
to the epicardium and metastasized to the bilaterallungs and the left pleura (Fig. 3E). The recurrent tumor
was composed of lymphocytes and epithelial cells incompartments formed by ﬁbrous septa (Fig. 3C, D). As
compared to the ﬁndings in the specimens resectedduring the operation, there is very marked proliferationof the epithelial cells, and on the other hand, the lym-

35
Table 1

Summary of Anatomical and Histopathological Findings[Major ﬁndings]
1. Myasthenia gravis
2. Invasive thymomaa) primary site:
Anterior mediastinum, 5.5  5.3  2.8 cmb) Recurrence at autopsy:
Anterior mediastinum, 3.0  3.0  1.0 cmc) Invasion & metastasis:
Epicardium, lungs (660 g, 650 g), left pleurad) Therapies:
Surgical resection, radiation therapy and chemotherapy
3. Giant cell myocarditisa) Inﬂammatory cell inﬁltration, severeb) Electron microscope:
No particle of virus was seen at autopsy.
c) Related lesions:
Congestion: Liver (1140 g), kidneys (150 g, 145 g) andlungs
4. Polymyositisa) Inﬂammatory cell inﬁltration:
Iliopsoas muscle, diaphragm (severe) pectoralis major
muscle, intercostal muscle, muscles of neck (moderate)b) Related lesions:
Myoglobinuria
5. Alopecia totalis
Lymphocyte inﬁltration around hair follicles[Minor ﬁndings]
6. Tongue carcinomaa) Primary site:
Margin of the tongue, right side, 1.5  1.0 cm
Moderately differentiated squamous cell carcinoma withulcer formation, stromal invasion (þ)b) Recurrence:
No recurrence was seen at autopsyc) Therapy:
Surgical resection
7. Hemorrhagic infarction, inferior lobe of right lung,
3.0  3.0  3.0 cm

phocytes were decreased. The epithelial cells showedsigniﬁcant nuclear atypia, compared to that observed in
the specimens resected at surgery. In terms of these
histological features, we have to distiguish invasive
thymoma from thymic carcinoma. It is said that thymoma retains the function of the thymus to attract immature T cells from bone marrow to make them mature
whereas thymic carcinoma has lost this function. In thepresent tumor, numerous CD1a-positive immature
lymphocytes and CD99-positive immature lymphocytes
were observed by immunohistochemistry. Therefore,
we could rule out the possibility of thymic carcinoma,
and diagnosed the tumor as recurrent invasive thymoma. As for the atypia of the lymphocytes in therecurrent tumor, the possibility of the inﬂuence of chemotherapy that the patient received during the clinicalcourse must be considered.

36

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis

Fig. 3 Invasive thymoma. A) Microscopic ﬁndings of the surgical
specimens. The tumor arranged in compartments formed by ﬁbrous
septa B) Higher magniﬁcation of the tumor. The tumor consisted oflymphocytes and epithelial cells. C) Microscopic ﬁndings of therecurrent tumor at autopsy. The tumor arranged in compartments
formed by ﬁbrous septa. D) Higher magniﬁcation of the tumor. The
tumor showed marked proliferation of the atypical epithelial cellswith decreased lymphocytes. E) Macroscopic ﬁndings of metastasis in
the lungs (arrow) and left pleura (arrow heads).

At the time of autopsy, giant cell myocarditis andpolymyositis were observed. The heart showed a widespread mononuclear inﬂammatory inﬁltrate containing
multinucleated giant cells with massive myocardium
degeneration (Fig. 4A–C). Although electron microscopy was carried out, viral particles were not detected.

All the muscle tissue specimens collected from the diaphragm, iliopsoas muscle, pectoralis major muscle, intercostal muscle and muscles of neck at autopsy showedmononuclear inﬂammatory cellular inﬁltrate containing
giant cells with degeneration and necrosis of the muscle(Fig. 4D, E). Immunohistochemical studies showed that

Keio J Med 2004; 53 (1): 30–42

37

Fig. 4 Giant cell myocarditis and polymyositis. A) Macroscopicﬁndings of the heart. Edema, opacity and swelling were observed in
the myocardium. B) Microscopic ﬁndings of the heart. A widespreadinﬂammatory cell inﬁltration with massive myocardium degeneration
was observed. C) Higher magniﬁcation of the heart. Inﬂammatory cellinﬁltration containing lymphocytes and macrophages with multinucleated giant cells (arrow) was observed. D) Microscopic ﬁndings ofthe iliopsoas muscle. Inﬂammatory cell inﬁltration with degenerationand necrosis of the muscle was observed. E) Higher magniﬁcation of
the iliopsoas muscle. Mononuclear inﬂammatory cell inﬁltration containing giant cells (arrow) was observed.

the giant cells were positive for myoglobin, suggestingthat these cells are derived from muscle.
The alopecia totalis had been present for one year
and ten months before death. At autopsy, lymphocyte
inﬁltration around the hair follicles and the skin appendages was observed (Fig. 5). Hair follicles wereobserved, but no hair tissue was observed within thehair follicles. Immunohistochemical studies revealed
that these lymphocytes were mostly T cell lymphocytes,
and CD8-positive cells predominanted over all others.
In summary, we have presented a case of giant cell
myocarditis and polymyositis associated with invasive

38

Fig. 5 Alopecia totalis. Macroscopic ﬁndings of the abdominal skin.
Lymphocyte inﬁltration (arrows) around the hair follicles and the skinappendages was observed.

thymoma and MG. In previous literatures, some casesof the syndrome of giant cell myocarditis and polymyositis associated with invasive thymoma and MG
have been reported. The present case is also thought tobelong to this syndrome.
Dr. Nogawa (Internal Medicine): As for the origin of
the giant cells in the myocardium and skeletal muscle,some literature has demonstrated that they are derived
from macrophages, is that right?
Dr. Shimoda: Yes, that is right.
Dr. Nogawa: The cells were myoglobin-positive giant
cells. How was the origin of the cells determined, i.e.,
whether they were derived from macrophages or myocytes?
Dr. Shimoda: Both origins can be considered; i.e.,
macrophages and myocytes, but we did not screen thegiant cells of the myocardium. In the skeletal muscle,
there were relatively more numerous giant cells thatwere positive for myoglobin and negative for CD68, asurface marker of macrophages. Therefore, the giant
cells in the present case were considered to have fundamentally been derived from myocytes.
Dr. Nogawa: Sarcoidosis should also be excluded
as a differential diagnosis, judging from the overall
picture. The presence or absence of epithelioid cells
should be considered. In the present patient, can we
exclude sarcoidosis of the myocardium?
Dr. Shimoda: With regard to the histological ﬁndingsin the myocardium, no typical granulomas. Characteristic asteroid bodies were not observed either. Clinicallyas well, there is no description of elevation of the serum
level of angiotensin-converting enzyme, or other characteristic clinical features. Therefore, sarcoidosis may
be excluded based on the clinical and pathological ﬁndings.

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis

Dr. Satoh (T): I have two questions; ﬁrst, I reviewed
the cardiac lesions complicated with MG. There havebeen many cases of chronic myocarditis reported. In
this patient, the ECG ﬁndings suggested rapid deterioration of the myocardial lesion over the last 2–3 years.
Did you ﬁnd any evidence of chronic myocarditis in thiscase?
Dr. Shimoda: Since some parts of the apex of theheart show marked ﬁbrosis, there is the possibility thatthe patient had chronic myocarditis. But we also haveto take into consideration the possibility of myocardial
infarction.
Dr. Satoh (T): Are there any abnormalities of thecoronary arteries?
Dr. Shimoda: No, there is no thickening or otherabnormalities of the coronary arteries.
Dr. Satoh (T): The second question. In spite of very
severe heart failure, the patient showed no evidence ofpulmonary congestion. Right-heart catheterization also
showed normal pulmonary arterial pressure and normal
left atrial pressure. From these ﬁndings, it was clinicallyestimated that the right ventricle was more severely
damaged. How about the pathological ﬁndings?
Dr. Shimoda: Both the left and right ventricles
showed very severe inﬂammatory cellular inﬁltration.
No marked differences were noted between the twoventricles.
Dr. Tanahashi: So, in this case, the features are consistent with the syndrome of invasive thymoma, MG,
myocarditis, and giant cell myocarditis or myositis.
Could you please give some comments, including on theclinical ﬁndings, Dr. Nogawa, from the standpoint of
the physician-in-charge.
Dr. Nogawa: MG is an autoimmune disease. Approximately 75% of MG patients are positive for AChR
antibody (like this patient). The remaining 25% who
are negative for the antibody are referred to as having‘‘sero-negative’’ MG. It has recently been reported thatan antibody to muscle-speciﬁc kinase (MuSK) is present in some cases of sero-negative MG. The characteristic clinical symptom in MG is diurnal ﬂuctuation of
the muscle strength, and in the Edrophonium (Tensilon1) test, recovery of muscle strength is noted following administration of this drug. On EMG, a waning
response is observed to repetitive 3-Hz stimulation.
Particularly noteworthy is the fact that 80% of thepatients have abnormalities of the thymus gland, and
10% of the patients have a thymoma. As for othercomplications, various autoimmune diseases have beenreported to be associated with MG. That is, abnormal thyroid function is associated with MG in 15–
25% of the patients, and rheumatoid arthritis (RA)and idiopathic systemic lupus erythematosus (SLE),
which are collagen diseases, are associated with MG insome cases. As for hematological diseases, pernicious

Keio J Med 2004; 53 (1): 30–42

anemia, hemolytic anemia, pure red cell aplasia andidiopathic thrombocytopenic purpura have been reported to be associated with MG. In addition, insulindependent diabetes mellitus, nephritis, nephrotic syndrome and alopecia totalis (as observed in the present
patient) or alopecia areata have also been reported inthese cases. Vitiligo, ulcerative colitis, multiple sclerosis, and Lambert-Eaton myasthenic syndrome (LEMS)
may occasionally be associated with MG.
The most common classiﬁcation to describe the clinical severity of MG is Osserman’s classiﬁcation. Types I,
II, III, IV, and V refer to ocular, generalized, acutefulminant, late grave, and the atrophic type of MG, respectively. However, in actuality, classiﬁcation according to this system may be rather difﬁcult. The clinicalclassiﬁcation of the MG Foundation of America hasrecently been published in Neurology1; class I corresponds to the ocular type, and classes II, III and IV
correspond to mild, moderate and severe MG, respectively, affecting other than ocular muscles. Subclass A
in each class indicates the involvement of muscles of all
the four extremities, and subclass B indicates the involvement of the pharyngeal and respiratory muscles.
Myasthenic crisis, i.e., the morbid condition requiringintubation, is categorized as class V. Therefore, thepresent patient may be included in class V, based on theclinical presentation.
The important clinical observations in this patient
before his death: Firstly, rapid progression of cardiorespiratory failure was observed. It became important
to determine whether or not the patient was in myasthenic crisis. The patient had little or no exacerbation of
ptosis, eye movement disorder, or swallowing difﬁculty,
which are all typical of MG. Elevation in the serum
level of the AChR antibody, which was observed earlier, was not marked during this admission. Therefore,
myasthenic crisis was not considered to be the causeof the rapidly progressive respiratory failure. Secondly,
the patient had acute heart failure, and on ECG, various abnormalities, including AV conduction block,were observed. Various causes for these abnormalities
were considered: (1) Viral infection, (2) idiopathic cardiomyopathy, (3) myocardial ischemia, (4) inﬁltrationof thymoma into the pericardium – this was revealed on
pathological examination, but the extent of the inﬁltration was not sufﬁcient to explain the condition, (5) cardiomyopathy due to tacrolimus [the present patient was
the ﬁrst case in which we used tacrolimus (FK-506)
for MG], (6) autoimmune involvement, and (7) otherdrug-induced, such as adriamycin, which exerts cardiotoxicity. Thirdly, marked hyper-CPKemia and myositis were present, but the muscle pain was not sosevere. Therefore, the patient’s condition appeared tobe slightly different from that typical of polymyositis(PM), which is a commonly encountered condition.

39

Fourthly, this patient has had alopecia totalis, and thesymptom became manifest long after the commencement of administration of the anticancerous drugs.
Therefore, the baldness could not have been caused by
the anticancerous drugs. However, the patient did nothave alopecia areata, which has been described in theliterature, but alopecia totalis. This became an issue.
As described earlier by Dr. Shimoda, macroscopically, the myocardium showed ﬁbrosis to a certain
degree and the presence of chronic lesions, and microscopically, giant cells were observed. Based on theseﬁndings, patients with thymoma, which has been reported to be associated with (giant cell) myocarditis in
the literature, were reviewed (Table 2). Nearly 20 cases
have been reported worldwide to date, and the present
patient was the 8th case of MG associated with myositis, myocarditis, and thymoma. The present patient was
the 3rd case in Japan, suggesting that the patient is avery rare case.
The cases that have been reported as ‘‘giant cellcardiomyositis’’ were reviewed. Pathologically, lesions
resembling granulomas, with giant cells but no epithelioid cells, are described. Myocardial necrosis andﬁbrosis are also observed. With regard to the origin of
the giant cells, some reports have suggested that they
are derived from macrophages, while others havesuggested that they are derived from myocytes. The
disease has been believed to be associated with autoimmune diseases, including thymoma, MG, SLE, abnormal thyroid function and RA. It must be differentiated from sarcoidosis, toxoplasmosis, mycotic
infection, tuberculosis, syphilis, and Chagas’ disease.
They show a common clinical course; some reports
have indicated that many cases with this disease show
rapidly progressive congestive heart failure or conduction disturbances, ST-T changes, and a fatal course.
Although the mechanisms still remain unknown, it has
been speculated in past reports that antimyocardial
antibodies or antiskeletal muscle antibodies may be responsible for the abnormalities, because many patientsof MG associated with thymoma are positive for these
antibodies.2 About half of the cases with myositis are
positive for antibodies to the ryanodine receptor (RyR)
present in abundance in the myocardium.3 These reports suggest the involvement of autoimmune mechanisms, although the underlying mechanisms have yet to
be clearly elucidated.
Regarding the recently established concept of the
syndrome of MG, giant cell polymyositis and myocarditis associated with thymoma, please allow me toreview this a little. In 1944, Giordano & Haymond4
reported the ﬁrst autopsied case with the four diseases, MG, thymoma, giant cell polymyositis, and cardiomyositis. In 1969, Burke et al.,5 who observed ST
segment depression and T wave inversion on the ECG

40
Table 2

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis
Myasthenia Gravis, Myositis and Cardiomyositis Associated with Thymoma

Author

Year

Age

Sex

MG

Myositis

Cardiomyositis

Thymoma

GioranoMendelow
Mendelow
Mendelow
RowlandWallerLangston
Funkhouser
RundleKlein
Burke
Suzuki
Namba
Reznik
Shoback
Daniels
Tomimotode Jongste
GlennonKilgallenPentz
present case

1944
1954
1954
1954
1955
1956
1959
1961
1963
1966
1969
1972
1974
1974
1977
1981
1985
1986
1996
1998
1999
2002

57
37
51
27
31
64
75
53
60
69
47
33
57
66
32
76
33
48
57
46
17
60

M
F
M
F
F
F
F
F
F
F
F
M
M
M
F
F
F
M
M
F
M
M

c

c
c
c

c

c
c
c

c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c

c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c

in one case, reported that the patient suddenly died due
to rapid progression of heart failure. Namba et al.6
summarized 13 cases of giant cell polymyositis, cardiomyositis and thymoma in an article entitled ‘‘Idiopathic giant cell myositis’’. In this article, the presenceof MG was not considered. In 1976, Dr. Hiromichi
Suzuki7 of our University reported a patient with all ofthese diseases. In actuality, the present patient is considered to be the ﬁrst case reported in Japan. In 1985, aneurologist, Dr. Tomimoto8 of (Faculty of Medicine)
Kyoto University reported a similar case. Thereafter, areview of 11 patients was reported,9 and another report
has called attention to the possibility of ventriculartachycardia occurring in these cases,10 and one report
has referred to elevation of the ST segment.11 Recently, 14 cases have been reviewed in a report entitled‘‘Giant cell myocarditis and malignant thymoma’’,12and another report has indicated the occurrence of
cardiac block in a case of malignant thymoma.13 In a
recent issue of Rincho Shinkeigaku, a case of MG associated with Hashimoto’s disease associated with thedevelopment of giant cell myocarditis was reported.14
In this case, thymoma was absent.
Another noteworthy feature in the present patient
was alopecia totalis. Figure 6 shows the present patient’s photograph taken when he was well. The head iscompletely bald (A). He was also found to have atrichia
involving the hair of the axilla (B), the nostrils (C), andpubes. Figure 7 shows the mechanisms underlying theimmunological abnormalities that may occur in cases of

c
c
c
c
c

c
c
c
c

c
c

c
c

c

c

thymoma, i.e., thymoma-associated syndrome. The following have become increasingly clear: The presence of
thymoma induces abnormalities in the humoral immunity. When anti-AChR antibody or anti-MuSK antibody is produced, MG results; LEMS results when theanti-voltage-gated calcium channel (VGCC) antibody is
produced. In the presence of anti-voltage-gated potassium channel (VGKC) antibody, neuromyotonia, i.e.,
Isaacs syndrome occurs. As in the present patient,presence of antibodies to the skeletal muscle or myocardium may be associated with giant cell myositis or
giant cell myocarditis. In particular, the anti-RyR antibody is drawing much attention [3]. Furthermore, thepresent patient had alopecia totalis. Although this has
not been reported yet, the condition (alopecia totalis)may occur if the anti-follicle antibody is produced.
Pathological examination of tissue specimens revealed
intrafollicular inﬁltration by CD8-positive cells, suggesting that abnormal cellular immunity occurring after
thymectomy may be involved in such inﬁltration. Thus,
as described above, while many issues still need to beresolved, very interesting conditions were observed in
the present patient.
Ultimately, the present patient was the ﬁrst case inwhich we used tacrolimus for treatment. The patientdied only several months after the commencement of its
administration. The blood concentration was within thenormal range, but let me touch on the possibility of thisdrug having adversely inﬂuenced the patient’s condition. As described even earlier by Dr. Toru Sato,Keio J Med 2004; 53 (1): 30–42

41

Fig. 6 The present patient’s photographs taken in January 2002. Alopecia of the scalp (A), the axilla (B), and the nostrils (C) was noted(alopecia totalis).

Atkins et al.15 reported in 1995 that cardiomyopathy
may occur with the use of tacrolimus. The underlying
mechanism may be as follows: Calcium is stored in thesarcoplasmic reticulum (SR) in the myocytes and skeletal muscle cells. Intracellular recruitment of calcium
induces further intracellular release of calcium via RyR
type 2 on the SR surface [calcium-induced calcium
release (CICR)]. Usually, FKBP12, a FK-506-binding
protein, is bound to the RyR. It was reported in an issue of the journal Cell in 1994, that the bond of RyR to
FKBP12 regulates CICR.16 However, when the level of
intracellular cyclic AMP increases following catecholamine stimulation to activate PKA, the RyR becomes
phosphorylated and FKBP12 is separated from the
RyR, facilitating the release of calcium. Therefore, it
has been speculated that the intracellular calcium concentration may be elevated by dissociation of FKBP
which may result in cardiomyopathy, when tacrolimus isused. Another report has shown the induction of rhabdomyolysis in not only the myocardium, but also in theskeletal muscle.17 Recently, however, a report has suggested that tacrolimus does not induce cardiomyopathy.18 No deﬁnitive consensus has been arrived yet
regarding the possibility of existence of tacrolimusinduced cardiomyopathy. In the present patient, theblood tacrolimus concentration was approximately onethird of that observed following administration of the
drug at doses actually used for transplantations, andit remained consistently within the normal range.
Changes in the ECG and echocardiogram were present
even before tacrolimus administration was started.
Light-microscopic observation suggested chronic ﬁbrosis of the myocardium. Such a syndrome has been
actually reported, and the present patient was the ﬁrst
case in which tacrolimus was used. Based on these circumstances, we believe that the possibility of tacrolimus

42

Tanahashi N, et al: Giant cell myocarditis and myasthenia gravis

2.

3.

4.
5.

6.

Fig. 7 Possible mechanisms underlying the immunological disorders
associated with thymoma. The thymoma may trigger abnormal humoral immune response, resulting in production of various abnormal
autoimmune antibodies, which can cause corresponding disorders. In
the present patient, giant cell myositis and cardiomyositis may be
associated with the anti-skeletal and heart muscle antibodies (e.g.
anti-RyR antibody). Similarly, presence of the anti-follicle antibody
that can mediate alopecia totalis is speculated, although it has notbeen proven. Alternatively, abnormality in the T cell-mediated immunity induced by thymectomy might trigger alopecia totalis. Abbreviations: AChR; acetylcholine receptor, MG; myasthenia gravis, RyR;
ryanodine receptor, VGCC; voltage-gated calcium channel, VGKC;
voltage-gated potassium channel.

7.

8.

9.

10.

11.

having been involved in the development of the cardiomyopathy is low. Furthermore, we also consideredthat it was possible that the drug predisposed the patient to viral infections because of its immunosuppressive actions. However, electron-microscopic examination showed the absence of viral particles. Therefore,
this possibility was probably ruled out. Under these circumstances, along with the aforementioned pathological ﬁndings, the present patient is clinically considered
to be a case with the syndrome of MG, giant cell polymyocarditis, myositis and thymoma.
Dr. Tanahashi: The present case was indeed a very
interesting one. I now declare the CPC closed. Thankyou very much for your participation.
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