Vol. 89 • No. 5
SINGLE CASE REPORTS
10. Greenspan D, Greenspan JS, Conant M, Petersen V, Silverman S
Jr, DeSouza Y: Oral "hairy" leucoplakia in male homosexuals:
Evidence of association with both papillomavirus and a
herpes-group virus. Lancet 1984;2:831-834.
11. Greenspan JS, Greenspan D, Lennette ET, et al: Replication of
Epstein-Barr virus within the epithelial cells of oral "hairy"
leukoplakia, an AIDS-associated lesion. N Engl J Med
1985;313(25): 1564-1571.
12. Kaminski GW, Sutler IJ: Human infection with Dermatophilus
congolensis. Med J Aust 1976;1:443-447.
13. Lechevalier MP, Horriere F, Lechevalier HA: The biology of
Frankia and related organisms. Develop Indust Microbiol
1982;23:51-60.
14. Luedemann GM: Geodermatophilus, a new genus of the DermaropAiVaceae(Actinomycetales). J Bacterid 1968;96:1848-1858.
15. Momotani E, Yoshino T, Ishikawa Y, Azuma R: Morphology of
experimental actinomycotic abscess in mice with Dermatophilus-like microorganisms from porcine tonsil. Mycopathologia 1983;81:99-105.
687
16. Oduye 0 0 : Histopathological changes in natural and experimental Dermatophilus congolensis infection of the bovine skin,
Dermatophilus infection in animals and man. Edited by DH
Lloyd, K.C Sellers. New York, Academic Press, 1976, pp
172-181.
17. O'Hara PJ, Cordes DO: Granulomata caused by Dermatophilus in
two cats. New Zealand Vet J 1963; 11:151 -154.
18. Oppong ENW: Epizootiology of Dermatophilus infection in cattle
in the Accra Plains of Ghana, Dermatophilus infection in animals and man. Edited by DH Lloyd, K.C Sellers. New York,
Academic Press, 1976, pp 17-32.
19. Roberts DS: The histopathology of epidermal infection with the
actinomycete Dermatophilus congolensis. J Pathol Bacterid
1965;90:213-216.
20. Rubel LR: Pitted keratolysis and Dermatophilus congolensis. Arch
Derm 1976;105:584-586.
21. Woodgyer AJ, Baxter M, Rush-Munro FM, Brown J, Kaplan W:
Isolation of Dermatophilus congolensis from two New Zealand
cases of pitted keratolysis. Aust J Derm 1985;26:29-35.
Myasthenia Gravis with Thymoma and
Pure Red Blood Cell Aplasia
RONALD O. BAILEY, M.D., HARRY G. DUNN, M.D., ALAN M. RUBIN, M.D., AND ANTHONY L. RITACCIO, M.D.
A case of myasthenia gravis with histopathologic confirmation
of spindle cell thymoma and pure red blood cell aplasia is
reported. This is the twelfth case in the literature in which a
simultaneous occurrence of all three disorders, with documented thymic pathology, is noted. Immunologic observations
in this patient include an elevated acetylcholine receptor antibody and antinuclear antibody titer, agglutination of mouse red
blood cells when combined with the patient's serum, and lack
of inhibition of binding of radioactive erythropoietin to mouse
red cell receptors when combined with the patient's serum.
Although both myasthenia with thymoma and pure red blood
cell aplasia may have a common immunologic denominator,
our findings in this case indicate that inhibition of erythropoiesis is unrelated to erythropoietin receptor blockade. An alternative hypothesis is offered based on defective T-cell function.
(Key words: Myasthenia gravis; Thymoma; Pure red blood cell
aplasia; Autoimmune) Am J Clin Pathol 1988;89:687-693
MYASTHENIA GRAVIS (MG) is an autoimmune disorder, characterized clinically by weakness and ease of
fatigue of skeletal muscles which improve with rest. The
immunopathogenesis of this disorder is well estab-
Recejved May 4, 1987; received revised manuscript and accepted for
publication June 25, 1987.
Supported in part by the Veterans Administration and the Muscular
Dystrophy Association of America.
Address reprint requests to Dr. Bailey: Neurology Section, Riverside
Medical Clinic, Riverside, California 92506.
Neurology Service and Hematology Section, Veterans
Administration Medical Center and Departments of
Neurology and Medicine, Albany Medical College
of Union University, Albany, New York
lished. 9 The basic problem is a reduction in the number
of junctional nicotinic acetylcholine receptors (AChRs)
in skeletal muscle, brought about by an antibody-mediated attack against the AChR. Although cell-mediated
aspects of immunity are involved, the autoimmune response to the AChR in MG is primarily induced by
acetylcholine receptor antibodies (AChR Abs). Impairment of neuromuscular transmission is a direct result of
a reduction in AChR number. AChR activity altered by
bound AChR Ab and complement-mediated focal lysis
of the postsynaptic end-plate region also contribute significantly.
An autoimmune etiology for M G is confirmed in part
by the identification of thymic abnormalities in a large
percentage of patients with this disorder. Histopathologic changes have ranged from thymic hyperplasia to
thymoma. In 25% of patients, the thymus is histologically normal. 22 The role of the thymus gland in the genesis of M G is undisputed; myoepithelial cells of the
thymus bear AChRs. 1 7 It is hypothesized that a viral
BAILEY ET AL.
688
insult may lead to an alteration in these receptors, which
then serve as antigenic stimuli to which AChR Abs are
produced. These antibodies in turn cross-react with
AChR determinants of skeletal muscle leading to an
accelerated endocytosis and degradation of the receptor.10
Hematologic disorders are rarely associated with MG
and thymoma. Pure red blood cell aplasia (PRCA) can
occur with this disease complex, although an exact incidence is unknown. Conversely, 5 to 10% of patients
having only thymoma develop PRCA.34 Ten reports of
myasthenia with histologically documented thymoma
and associated PRCA are reported in the literat u r e 3,4,6,8,12,15,30,32,36.37 I n a n o t h e r c a s e j findings suggestive of a lymphoepithelial thymic neoplasm are noted.34
The autoimmune association of PRCA and MG with
thymoma is not clearly defined. Having had a recent
opportunity to evaluate a patient with MG with thymoma and PRCA, the present study was undertaken to
determine whether common autoimmune factors are
involved in the genesis of both disorders.
Report of a Case
An 81 -year-old white man was diagnosed as having MG in 1978. His
symptoms were adequately controlled over a two-year period with
pyridostigmine bromide. When seen by us in 1981, he had experienced
clinical deterioration. At that time, his chief complaints included bilateral lid droop, double vision when fatigued, dysphagia for both liquids
and solids with nasal regurgitation, nasal speech, facial weakness,
proximal muscle weakness, ease of fatigue in a shoulder girdle distribution, and severe shortness of breath. His past medical history was
significant for chronic obstructive pulmonary disease, prior myocardial infarction, and peripheral vascular disease.
On examination, he had severe shortness of breath at rest with
marked bulbar dysfunction characterized by nasal speech, swallowing
problems, and nasal regurgitation. His respiratory rate was 28 per
minute and labored. A forced vital capacity was 1.2 L (58% of predicted). Other vital signs were normal. Abnormalities on general examination included an increased antero-posterior chest diameter with
hyperresonance to percussion, and diminished peripheral pulses. The
patient developed fatigue of shoulder muscles in 30 seconds when arms
were held in abduction. With forced upward gaze, lid droop developed
at 45 seconds. On neurologic examination, mental status testing was
normal. Cranial nerve examination revealed incomplete adduction of
either eye on lateral gaze, a bilateral facial diplegia with "myasthenic
snarl", bilaterally depressed gag reflexes, and a weak tongue. He developed nasal speech within minutes after hefirstspoke. On motor examination there was mild weakness of the shoulder girdle muscles with
demonstrable ease of fatigue on repetitive testing. Coordination, gait,
and station were normal. Flexor responses were present to plantar
stimulation. All other reflexes were equal and symmetric throughout.
Sensory examination was normal.
Because of the patient's age and marginal respiratory reserve, thymectomy was not performed. He was titrated to a dose of 50 mg of
prednisone per day. The dose was subsequently tapered and the patient
was placed on an alternate day regimen of 25 mg. He continued on
pyridostigmine bromide, 60 mg every six hours. Impressive clinical
improvement occurred one month following steroid administration.
His forced vital capacity had increased to 2.8 L and, from a neuromus-
A.J.C.P. • May 1988
cular standpoint, the only abnormality noted was continued mild facial weakness and "myasthenic" snarl. Serial neurologic examinations
over a four-year period revealed stable mild generalized MG.
Erythrocyte sedimentation rate, collagen vascular screening, thyroid
function studies, serum protein electrophoresis, quantitative immunoglobulins, B12 level, folate level, and serial hematologic and chemistry
profiles were normal. AChR Ab titers ranged from 11 nmol/mL to 13
nmol/mL (normal, less than 0.5 nmol/mL). Electrocardiogram was
normal. Chest x-ray revealed anterior mediastinal calcification. Computerized tomography (CT) of the chest confirmed the presence of an
anterior mediastinal mass thought to be thymoma (Fig. 1). Pulmonary
function studies were consistent with both obstructive and restrictive
pulmonary disease. Proximal repetitive nerve stimulation testing (performed by stimulating the axillary nerve at Erb's point with pick-up
electrodes over the deltoid muscle) yielded a significant decrement of
33% at 3 Hz and 28% at 5 Hz frequencies of stimulation. No facilitation or decrement was recorded at low frequencies or tetanic rates of
distal stimulation. An electromyogram was normal.
Clinical Course
A number of medical problems subsequently developed. Following a hemorrhoidectomy in October 1985,
slurred speech and right-sided weakness were noted. A
diagnosis of left internal capsular lacunar infarction was
made. In addition, family members noted recent memory deficits, short attention span, and personality
change. On admission he was found to be severely anemic and, based on hematologic evaluation, a diagnosis
of PRCA was made. The patient was treated conservatively with periodic transfusions. No change in his MG
was noted.
Subsequent Laboratory Procedures
When admitted in November, 1985, the patient's hematocrit was 21 % with a hemoglobin of 8 g/dL. Reticulocyte counts were persistently abnormal at 0%. An
ANA titer was noted to be positive at 1:116 (homogeneous pattern). A peripheral blood smear revealed red
blood cells which were normochromic, normocytic.
White blood cells and platelets in the peripheral blood
appeared normal. Bone marrow aspirate and biopsy revealed complete absence of normoblasts (Fig. 2). Routine screening tests for other etiologies of his anemia
were negative.
Serum obtained on the patient prior to transfusion
was evaluated for antibody to erythropoietin receptor
using mouse erythroid precursors as a source of receptor. Details concerning the procedure have been described by Krantz and Goldwasser.18 Although the patient's sera tended to agglutinate mouse cells, no inhibition of binding of radioactive erythropoietin to the
receptor was observed.
CT scan of the head revealed superficial cerebral and
deep brain atrophy and a left internal capsular lacune.
SINGLE CASE REPORTS
Vol. 89 • No. 5
689
FIG. 1. CT scan of the mediastinum demonstrating a calcined 2 cm X 3 cm substernal mass. Scale at right indicates 5 cm.
Subsequent Clinical Course
The patient was rehospitalized in January 1986, for
femoral artery thrombosis. A revascularization procedure failed, and a right leg amputation was performed.
The patient succumbed following cardiac arrest in the
post-operative period.
Thymic Pathology
A noninvasive, well-encapsulated thymoma was demonstrated at autopsy (Fig. 3). Light microscopy demonstrated spindle shaped epithelial cells and sparse lymphocytes (Fig. 4). A distinct lack of germinal centers and
Hassall's corpuscles was noted. There was no evidence
of hyperplasia. On electron microscopy, epithelial cells
contained oval to elongated nuclei with marginated
chromatin. Tonofilaments were present in the cytoplasm, and highly developed desmosomes were present
between neighboring cells.
Discussion
Since the first description of MG with thymoma and
PRCA in 1954,6 20 patients with this clinical triad have
been reported in the literature.3-4'6,8'"-15'2930'32-34-37 Of
this group, ten patients had histopathologic confirmation of thymoma (Table i).3.4,6.8,i2.is.3o.32.36.37 I n a n o t h e r
patient, a necrotic nodular mass was identified with pathology suggestive for thymoma.34 Histopathologically,
the lymphoepithelial thymoma was the most common,
occurring in 7 of 11 patients. Spindle cell thymomas
were rare and occurred in only 3 of the 11 cases. Our
patient is unusual in that he is the fourth documented
case of spindle cell thymoma associated with MG and
PRCA.
Several clinical observations regarding MG with thymoma and PRCA can be made. First, in all reported
cases, PRCA developed in a setting of well-controlled
MG. None of the patients reported had decompensation
in their neuromuscular condition with onset of this hematologic disorder. Second, in all cases except one,34
PRCA developed years after the onset of MG. Thymoma was confirmed by chest x-ray, CT scan of the
mediastinum, or at the time of thymectomy or autopsy.
Third, within the group of histopathologically documented cases of thymoma with MG and PRCA, the
incidence appeared proportionately divided between the
sexes. This is contrary to previous observations in which
a distinct female predominance was reported.13
An autoimmune etiology is postulated for PRCA. As
BAILEY ET AL.
690
*- .r**a&*«i&-« .Ate
A * ' T « f eA™'
^ 51 «
ST.**
- . ^ tfe . - W *
A.J.C.P. • May 1988
-*
FIG. 2. Bone marrow biopsy. There is complete absence of red blood cell precursors.
A normal appearing granulocytic series is present. Hematoxylin and eosin (X300).
in MG, details concerning a humoral-mediated immune
response have been more extensively investigated than
cell-mediated effects. Findings in support of a humoral
autoimmune etiology for PRCA have included the
identification of a serum IgG erythropoietic inhibitor
which may be present in sera of patients with and without thymoma,16"20 and the disappearance of this IgG
inhibitor following thymectomy,2 immunosuppressive
treatment,5,27 and plasmapheresis.28 This IgG antibody
may be heterogeneous and exert a variety of humoralmediated effects in PRCA. An antigen-antibody interaction with erythroblast nuclei,20 erythroid progenitor
cells,24,25 and circulating erythropoietin has been demonstrated.5 A complement-dependent factor, cytoxic to
erythroblasts, has also been identified in some patients.21
The effect of erythropoietin as an inducer and regulator of red blood cell proliferation and differentiation is
well recognized. The biological action of this hormone is
receptor mediated via erythroid progenitor cells.19 In
our patient, there was no inhibition of binding of radioactive erythropoietin to the erythropoietin receptor
when serum was incubated with enriched progenitor
cells obtained from mice infected with Friend virus.
This finding implies that antibody directed against the
erythropoietin receptor was not responsible for the development of PRCA in our patient and that the inhibition of erythropoiesis may be unrelated to erythropoietin receptor blockade. The additional finding of agglutination of mouse red blood cells when incubated with
our patient's serum indicates that other humoral-mediated factors may be involved in the genesis of PRCA
in our patient. Alternatively, this finding may merely
represent nonspecific cross-reactivity of antibody with
some component of mouse red blood cells.
Defects in cell-mediated immunity are common to
FIG. 3 (upper). Encapsulated thymoma (with central cystic area) in a background of mediastinal fat.
Scale below the thymoma indicates 2 cm (left), 3 cm (right).
FIG. 4 (lower). Spindle cell thymoma. Epithelial cells contain oval to elongated nuclei with marginated chromatin.
Lymphocytes (thymocytes) are rare. Hematoxylin and eosin (X300).
Vol. 89 • No. 5
SINGLE CASE REPORTS
691
BAILEY ET AL.
692
A.J.C.P.-May 19
Table J. Pathologically Documented Cases of MG with Thymoma and PRCA
Reference, Year
6
Chalmers and Boheimer, 1954
Bakker,3 1954
Weinbaum and Thompson,36 1955
Castaigne et al.,4 1961
Radermecker et al.,30 1964
Roland,32 1964
Hinrichs and Stevenson,12 1965
DeSevilla et al.,8 1975
Imamuraetal.,15 1978
Zeoketal.,37 1979
Socinski et al.,34 1983
Age/Sex
Onset of PRCA in
Relation to MG
Pathology of Thymus
48/M
62/F
67/F
33/F
59/F
68/F
47/M
55/M
68/M
58/M
72/F
1.5 yrs. after MG
NA
4.0 yrs. after MG
3.0 yrs. after MG
17.0 yrs. after MG
4.0 yrs. after MG
5.0 yrs. after MG
10.0 yrs. after MG
4.0 yrs after MG
14.0 yrs. after MG
10.0 mos. before MG
Lymphoepithelial thymoma
Spindle cell thymoma
Lymphocytic thymoma
Metastatic lymphocytic thymoma
Lymphocytic thymoma
Spindle cell thymoma
Lymphoepithelial thymoma
Metastatic thymoma
Spindle cell thymoma
Epithelial thymoma
Suggestive of lymphoepithelial thymoma
both MG and PRCA. Altered populations of lymphoid
cells in the thymus of myasthenic patients,1 alteration in
peripheral blood T-cell subsets including increases in the
T4 + /T8 + (helper-inducer/suppressor-cytotoxic T-cell)
ratio in the thymectomized and nonthymectomized patients with MG,7 and the identification of autologous
suppressor cells within the T8 + population which exert a
regulatory control over AChR production have been
noted.23 T-cells capable of inhibiting erythropoiesis may
play an important role in the immunopathogenesis of
PRCA in some patients25,33 as has been shown in patients with PRCA associated with chronic lymphocytic
leukemia, hepatitis, and certain lymphoproliferative
disorders.26 It is unclear whether altered T-cell function
is a universal phenomenon in PRCA; only one report
has implicated this defect in PRCA associated with thymoma. '' Disruption of T-cell function, however, may
be a mutual phenomenon in both MG and PRCA.
The development of PRCA in patients with MG and
thymoma may be more than coincidence. AChRs are
demonstrated on myoepithelial thymic cells, skeletal
muscle, and lymphocytes. Lymphocytic nicotinic
AChRs exert an inhibitory effect on lymphoproliferation31 which in turn may affect erythrogenesis. Receptor
modulation is, therefore, an important consequence in
both disorders. In MG a reduction in skeletal muscle
AChR number is a direct consequence of an autoimmune attack by AChR Abs. An autoimmune response
directed against lymphocytic nicotinic AChRs, initiated
by AChR Abs, may lead to an alteration in that receptor.
Such injury may eventuate in an impaired activation of
T4 + /T8 + ratios and thus enhanced susceptibility to
other autoimmune diseases including PRCA. Alternatively, such a situation in MG could potentiate an autoimmune response to skeletal muscle AChRs and lead
to the production of other antibodies common to both
MG and PRCA.
Acknowledgment. The authors thank Dr. S. B. Krantz and his colleagues from the V.A. Medical Center, Nashville, TN, for performing
the preparative and erythropoietic receptor binding assays.
References
1. Abdou NI, Lisak RP, Zweiman B, Abrahamsohn I, Penn AS: The
thymus in myasthenia gravis: Evidence for altered cell populations. N Eng J Med 1974;291:1271-1275.
2. Al-Mondhiry M, Zanjani E, Spirack M, et al: Pure red cell aplasia
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3. Bakker PM: Enkele opmerkigen bij twee gezwellen van de thymus.
Ned Tijdschr Geneeskd 1954;98:386-387.
4. Castaigne R, Lhermitte F, Escourolle R, Martin, Binet JL:
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5. Cavalcant J, Shadduck RK, Winkelstein A, Zeigler Z, Mendelow
H: Red cell hypoplasia and increased bone marrow reticulin in
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6. Chalmers JNM, Boheimer K: Pure red-cell anaemia in patients
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7. Cox A, Lisak RP, Skolnik P, Zweiman B: Effect of thymectomy on
blood T-cell subsets in myasthenia gravis. Ann Neurol 1986;19:297-298.
8. DeSevilla E, Forrest JV, Zivnuska FR, Sagel SS: Metastatic thymoma with myasthenia gravis and pure red cell aplasia. Cancer
1975;36:1154-1157.
9. Drachman DB: The biology of myasthenia gravis. Ann Rev Neurosci 1981;4:195-225.
10. Drachman DB, Angus CW, Adams RN, Michelson J, Hoffman
GJ: Myasthenic antibodies cross-link acetylcholine receptors to
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11. Harris SI, Weinberg JB: Treatment of red cell aplasia with antithymocyte globulin: Repeated inductions of complete remissions in two patients. Am J Hematol 1985;20:183-186.
12. Hinrichs VR, Stevenson TD: Thymoma, myasthenia gravis and
aplastic anemia. Ohio State Med J 1965;61:31-35.
13. Hirst E, Robertson TI: The syndrome of thymoma and erythroblastopenic anemia. Medicine (Baltimore) 1967;46:255-264.
14. Houghton JB, Toghill PJ: Myasthenia gravis and red cell aplasia.
Br J Med 1978;2:1402-1403.
15. Imamura S, Takigawa M, Ikai K, Yoshinaga H, Yamada M:
Pemphigus foliaceus, myasthenia gravis, thymoma and red cell
aplasia. Clin Exp Dermatol 1978;3:285-291.
16. Jepson JH, Gardner FH, Degnan T, Vas M: A gamma globulin
inhibitor of erythropoiesis in erythroblastopenic plasma from
patients with thymoma. Clin Res 1968;16:536.
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17. Kao I, Drachman DB: Thymic muscle cells bear acetylcholine
receptors: Possible relation to myasthenia gravis. Science
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18. Krantz SB, Goldwasser E: Specific binding of erythropoietin to
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19. Krantz SB, Jacobson LO: Erythropoietin and the regulation of
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20. Krantz SB, Kao V: Studies in red cell aplasia: I. Demonstration of
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21. Krantz SB, Moore WH, Zaentz SD: Studies of red cell aplasia: V.
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23. Lisak RP, Laramore C, Levinson AI, Zweiman B, Moskovitz AR:
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34. Socinski MA, Ershler WB, Frankel JP, et al: Pure RBC aplasia and
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Cutaneous and Pericardial Extramedullary Hematopoiesis with
Cardiac Tamponade in Chronic Myeloid Leukemia
LEE-YUNG SHIH, M.D., FUN-CHUNG LIN, M.D., AND TSENG-TONG KUO, M.D., PH.D.
A 48-year-old woman with Philadelphia chromosome-positive
chronic myeloid leukemia developed skin and pericardial extramedullary hematopoiesis. The echocardiogram revealed
massive pericardial effusion with signs of tamponade. The cytocentrifuge preparation of pericardial fluid demonstrated all
three hematopoietic components. Assays for the granulocytemacrophage progenitor cells and erythroid progenitors on her
pericardial fluid gave rise to colony numbers comparable to
those of normal bone marrow cells. The patient was success-
Received July 30, 1987; received revised manuscript and accepted
for publication October 6, 1987.
Supported by part by the Chang Gung Medical Research Grant
MRP-159.
Address reprint requests to Dr. Shih: Division of Hematology-Oncology, Department of Medicine, Chang Gung Memorial Hospital,
199, Tung-Hwa North Road, Taipei, Taiwan, Republic of China.
Department of Medicine, Divisions of Hematology-Oncology
and Cardiology; and Department of Pathology, Chang Gung
Memorial Hospital, Taipei, Taiwan, Republic of China
fully treated with pericardiocentesis followed by short-term
indwelling catheter drainage and administration of hydroxyurea. There was no reaccumulation of fluid at ten months. (Key
words: Chronic myeloid leukemia; Cutaneous extramedullary
hematopoiesis; Pericardial extramedullary hematopoiesis;
Cardiac tamponade) Am J Clin Pathol 1988;89:693-697
A L T H O U G H extramedullary hematopoiesis can occur
in any organ in patients with agnogenic myeloid metaplasia (AMM), skin or pericardial involvement is extremely rare. 819,28 We report a patient with Philadelphia