Inclusion body myositis and transitional cell carcinoma of the bladder: Significant resolution of symptoms after tumor excision

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Inclusion Body Myositis and Transitional Cell Carcinoma of the Bladder: Significant Resolution of Symptoms After Tumor Excision Michael L. Jensen, DO, J. Michael Wieting, DO, Michael T. Andary, AID, Margaret J. Fankhauser, DO, Margaret J. Jones, MD ABSTRACT. Jensen ML, Wieting JM, Andary MT, Fankhauser M J, Jones MJ. Inclusion body myositis and transitional cell carcinoma of the bladder: significant resolution of symptoms after tumor excision. Arch Phys Med Rehabil Rehabil 1997;78:327-9. Inclusion body myositis (IBM) is a separate class of the inflammatory myopathies with recently proposed clinical and pathological diagnostic criteria. An association between inflammatory myopathies and malignancy has been questioned in the literature. Recent reviews of the inflammatory myopathies suggest that only dermatomyositis is associated with malignancy. The largest study to date of patients with IBM found that 15% had a malignancy (6 of 40). We report the first documented case of IBM and concurrent transitional cell carcinoma of the bladder. We suggest that a causal relationship between IBM and malignancy may exist because of significantly improved functional strength gained after tumor removal.

© 1997 by the American Congress of Rehabilitation Medicine

and the American Academy of Physical Medicine and Rehabilitation NFLAMMATORY MYOPATHIES are commonly divided into three classes: dermatomyositis, polymyositis, and inclusion body myositis (IBM). IBM was recognized as a separate class of inflammatory myopathies by the presence of intranuclear microtubular filaments and cytoplasmic autophagic vacuoles.l 3 Commonly associated clinical features include an insidious, painless, and progressive onset of proximal and distal muscle weakness. The disease, which has a male predominance, usually occurs after age 50. Patients are usually resistant to steroid treatment. 4-6 Diseases previously described in association with inflammatory myopathies include collagen vascular, autoimmune, and malignancy. 6 Only a few cases of IBM with malignancy have been reported, however] We present the first reported case of IBM diagnosed concurrently with transitional cell carcinoma of the bladder which also featured significant resolution of skeletal muscle weakness after tumor resection.

I

CASE REPORT A 64-year-old man initially presented to the emergency department with a 3- to 4-week history of progressive weakness, fatigue, cough, and severe hypotension (blood pressure of 80/ From the Department of Physical Medicine and Rehabilitation (Drs. Jensen, Wieting, Andary, Fankhauser) and Department of Pathology (Dr. Jones), College of Osteopathic Medicine, Michigan State University, East Lansing. Submitted for publication March 21, 1996. Accepted May 10, 1996. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Michael Andary, MD, Department of Physical Medicine and Rehabilitation, College of Osteopathic Medicine, Michigan State University, B-401 West Fee Hall, East Lansing, MI 48224-1316. © 1997 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/97/7803-395553.00/0

60mmHg). He was unable to transfer or ambulate independently and required minimal to moderate assistance with activities of daily living (ADL). The patient denied having a history of progressive weakness. His medical history was significant for alcohol abuse (reportedly alcohol intake was discontinued 1 month prior to admission), congestive heart failure, and chronic obstructive pulmonary disease. His social history revealed that prior to admission he was independent in ADL and lived alone in a single-story home. Initial laboratory studies revealed elevated creatinine phosphokinase (CPK) of 1,790 U/L, lactate dehydrogenase (LDH) of 428 U/L, and hypoalbuminemia of 1.4 G/DL. The acute hospital course was complicated by a right lower extremity deep venous thrombus, pulmonary embolism, upper gastrointestinal bleed, and paroxysmal supraventricular tachycardia. A diagnosis of probable polymyositis was made based on progressive weakness associated with an elevated CPK and no dermatological manifestations. Prednisone (40rag every 8 hours) was prescribed and then tapered slowly over a 3-month course before being discontinued. At the time of transfer to medical rehabilitation, the patient' s manual muscle test revealed bilateral proximal shoulder and hip 2 strength to be 7- His distal muscle groups in all extremities were 4 3 7. The quadriceps were g bilaterally. Neurological examination found no cranial nerve deficits. Muscle stretch reflexes were 1 2 equal bilaterally at ~ for the biceps and triceps and g for the patella. The Babinski reflex was present bilaterally; there were no proprioceptive deficits. Sensory testing revealed a "stocking glove distribution" of decreased sensation over both the hands and feet. Multiple laboratory evaluation results found to be within normal limits included: thyroid studies, prostatic specific antigen, hepatitis profile, rheumatoid factor, antinuclear antibody, antineuronal antibody, IgG, VDRL, and cerebrospinal fluid analysis. Magnetic resonance imaging showed minimal cerebral and cerebellar atrophy. Electrodiagnostic studies showed evidence of a mixed myopathy and neuropathy with positive waves and fibrillations in all the proximal and most of the distal muscles. The right vastus medialis muscle exhibited early full recruitment with a maximal amplitude at lmV. Large polyphasic units were seen in the right first dorsal interosseous muscle. Sensory nerve conduction studies showed prolonged latencies in the right median and ulnar distribution and absent latencies in the right radial and sural nerves. Motor nerve conduction studies revealed prolonged distal latencies of the right ulnar and peroneal nerves along with slowed conduction velocities. During acute care rehabilitation and steroid therapy the patient developed increased functional strength to the point of attaining independence with ADL and mobility using a roller walker. The patient was discharged home approximately 7 weeks after initial admission to acute medical care and a 4week rehabilitation stay. The patient was discharged on prednisone (10mg per day), which he discontinued 2 weeks after discharge. Six weeks after his rehabilitation discharge the patient experienced functional decline similar to that of his previous acute

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INCLUSION BODY MYOSITIS AND BLADDER CANCER, Jensen

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Table 1: Motor FIM Scores of Patient at Different Admissions and Follow-up First Admission to Medical Rehab Admission (11/14/94)

Discharge (12/20/94)

Second Admission to Medical Rehab

Follow-Up After Discharge (02/07/95)

Admission (02/20/95)

Transfer (03/13/95)

Third Admission to Medical RehabAfter Surgery Admission (05/09/95)

Transfer (07/17/95)

Follow-Up After Discharge (09/06/95)

FIM subtotal scores Self-care subtotal Transfers subtotal Locomotion subtotals

17 5 2

38 18 12

29 11 9

18 8 6

22 12 9

14 6 2

27 10 6

37 18 12

Motor Score

24

68

49

32

43

22

43

67

hospital admission. He was readmitted to medical rehabilitation after developing progressive weakness again with an elevated CPK of 4,845 U/L, an erythrocyte sedimentation rate of 63mm/ h, and an LDH of 520 U/L. The patient required maximal assistance in all ADL, transfers, and ambulation. He was restarted on prednisone (60mg per day) without satisfactory response. Left deltoid muscle biopsy found evidence of an inflammatory myopathy, with numerous filamentous intranuclear "inclusion bodies" in skeletal muscle. Routine screening urinalysis showed microscopic hematuria. Urine cytology revealed abnormal cells suspicious for malignancy; subsequent cystoscopy with bladder biopsy revealed transitional cell carcinoma. Radical cystoprostatectomy with ileal loop urinary diversion was performed. After postoperative stabilization the patient was again admitted to medical rehabilitation, at which time he was noted to be dependent with many ADL, mobility, and transfers. Repeat electrodiagnostic evaluation showed findings similar to the previous exam, consistent with a picture of myopathy coexistent with diffuse axonal polyneuropathy. The patient received two series of gamma globulin treatments, each consisting of 25mg per day for 4 consecutive days. The patient made slow functional progress with therapies and was discharged to subacute rehabilitation requiring minimal to moderate assistance with ADL and minimal assistance with transfers. He was able to ambulate 100 feet with a roller walker and stand-by assistance. On follow up evaluation 2 months later, the patient was living alone in his own home, independent with all ADL, transfers, and ambulation without an assistive device. Manual muscle testing improved postoperatively with more significant changes in the proximal versus distal muscles; hip flexors and extensors improved from grade ~ t o 4 and shoulder • abduction from ~2 to ~ . The patient's increased strength is also evident by improved motor scores in the Functional Independence Measure (table 1). DISCUSSION Inclusion body myositis has been considered a separately identified entity of the inflammatory myopathies in the last 29 years. Clinical and objective evidence for IBM has grown as it has been recognized with increased frequency. 5 Specific clinical and pathological diagnostic criteria of IBM have been proposed (table 2). 5,8 Pathological criteria for diagnosis of IBM include ultrastructural evidence for microtubular filaments in inclusions, immunohistochemistry revealing beta amyloid protein in rimmed vacuoles, light microscopic evidence of congophilic rimmed vacuoles, intranuclear and intracytoplasmic inclusions, and both atrophied and hypertrophic fibers.5 Clinical criteria for the diagnosis include: proximal and distal muscle weakness, mild elevation of CPK, electrodiagnostic evidence consistent with generalized inflammatory myopathy, and a poor response to high dose corticosteroids.5 For definitive diagnosis of inclusion body myositis, there must be electron microscopic evidence

Arch Phys Med Rehabil Vol 78, March 1997

of microtubular filaments in inclusions, plus two of the above clinical criteria. 5 Our patient met clinical, pathological and electrophysiological diagnostic criteria for inclusion body myositis. In addition the patient's electrodiagnostic studies showed evidence for both myopathic and neuropathic disease. A mixed myopathic and neuropathic picture has been documented in several electrodiagnostic studies of IBM. 9-11 Other possibilities for this patient's mixed myopathic and neuropathic picture include his history of alcohol abuse or a paraneoplastic syndrome. The patient's concurrent diagnosis of transitional cell carcinoma is unique. Only 10 cases of IBM with malignancy have been reported (table 3). 4'7'12 One study reported two cases of renal cell carcinoma and IBM, but concluded no etiopathologic relationship existed partially because there was no improvement in strength after tumor excision] In dermatomyositis there are a few reports of increased function and sometimes remission of the muscle disease after operative removal of an associated neoplasm. 13 The patient described here regained much of his strength, resumed ADL, and was able to live independently after tumor removal. This strength improvement is most consistent with resolution of the myopathic process and less likely due to deconditioning alone. None of the previously described cases of IBM with malignancy have reported any functional improvement after tumor excision. Considerable debate exists about the association of malignancy with other inflammatory myopathies. 6'14'15 A recent review of inflammatory myopathies shows an apparent increased incidence of malignant conditions associated only with dermatomyositis. 6 Other studies have shown an increased incidence of Table 2: Proposed Diagnostic Criteria for Inclusion Body Myositis Pathological Criteria for IBM Electronmicroscopy (EM) 1. Microtubular filaments in incisions Immunohistochemistry (IH) 1. B-Amyloid protein/ubiquitin in rimmed vacuoles Light Microscopy (LM) 1. Congophilic rimmed (lined) vacuoles 2. Intranuclear & intracytoplasmic inclusions 3. Atrophied fibers/hypertrophic fibers Clinical Criteria for IBM Clinic Criteria (CC) 1. Proximal muscle weakness (insidious onset) 2. Distal muscle weakness 3. EMG findings of generalized inflammation myopathy 4. Mild elevation of creatine kinase and/or aldolase 5. Refractory to high dose corticosteroids (for 3 to 4 months) Diagnosis for IBM 1. Definite diagnosis of IBM requires EM1 or IH1 + CC1 + one other CC 2. Probable diagnosis of IBM requires IH1 or LM1 and 2 + CC1 + three other CC 3. Possible diagnosis of IBM requires LM2 and 3 or LM1 and 3 + any 3 CC Adapted and reprinted with permission?

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INCLUSION BODY MYOSITIS AND BLADDER CANCER, Jensen Table 3: Reported Cases of Patients Diagnosed with IBM and a Malignancy Patient (Reference) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Carpenter et al, 19784 Yoshimura, 1988 TM Lotz et al, 198917 Lotz et al, 198917 Letz et al, 1989 ~7 Lotz et al, 198917 Lotz et al, 198917 Lotz et al, 198917 Ytterberg et al, 19937 Ytterberg et al, 19937 This report, 1995

Age/Sex

Malignancy

84/M 75/M 69/F 67/F NR/NR NR/M NR/F NR/NR 64/M 63/M 64/M

Mesenchymoma Hepatocellular carcinoma Carcinoma of breast Carcinoma of uterus Melanoma Carcinoma of prostate Carcinoma of breast Squamous cell carcinoma of lip Renal cell carcinoma Renal cell carcinoma, carcinoma of prostate Transitional cell carcinoma of bladder

Occurrence of Malignancy Relative to Inclusion Body Myositis 3 years after Concurrent "Shortly after" "'Shortly after" 5 years before 10 years before 19 years before 2 years after Concurrent 9 years after Concurrent

Abbreviations: NR, not reported. Adapted and reprinted with permission]

malignancy with both polymyositis and dermatomyositis. 14-16 The largest study of IBM patients reports that 6 of 40 patients had a malignancy (15%). However there were differing time intervals between the diagnosis of IBM and the onset of malignancy, with one occurring up to 19 years later} 7 Differing time intervals can vary interpretations and pathogenetic implications) 4 In our case, however, the amelioration of symptoms in a close relationship to the removal of the tumor suggests that it might have been a pathogenetic mechanism of the IBM. CONCLUSION A causal association between IBM and malignancy remains undetermined. The clinical features and criteria for IBM are likely to be modified as new cases are documented. 5 W e believe this is the first reported case with a concurrent diagnosis of transitional cell carcinoma of the bladder and improvement in functional strength after tumor excision. W e raise the possibility that cancer was causally related to I B M in this patient. The nature of the association between IBM and malignancy remains to be seen. To determine the precise association between IBM and malignancy, well-designed case controlled studies with larger populations are needed.

Acknowledgment: We thank Judy Barnes and staff, and Bunny Lane-Patenge for their technical support with this paper. References 1. Yunis EJ, Samaha FJ. Inclusion body myositis. Lab Invest 1971;3: 240-8. 2. Carpenter S, Karpati G, Wolff L. Virus-like filaments and phospholipid accumulation in skeletal muscle: study of a histochemically distinct chronic myopathy. Neurology 1970;20:889-903.

3. Chou SM. Myxovirus-like structures in a case of human chronic polymyositis. Science 1967; 158:1453-5. 4. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978;28:8-17. 5. Chou SM. Inclusion body myositis. Ballieres Clin Neurol 1993;2: 557-77. 6. Dalakas MC. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 1991;325:1487-98. 7. Ytterberg SR, Roelofs RI, Mahowald ML. Inclusion body myositis and renal cell carcinoma. Arthritis Rheum 1993;36:416-21. 8. Calabrese LH, Mitsujoto H, Chou SM. Inclusion body myositis presenting as treatment-resistant polymyositis. Arthritis Rheum 1987; 30: 397-403. 9. Dumitru D, Newell-Eggert M. Inclusion body myositis, an electrophysiologic study. Am J Phys Med Rehabil 1990;69:2-5. 10. Joy JL, Oh SJ, Baysal AI. Electrophysilogical spectrum of inclusion body myositis. Muscle Nerve 1990; 13:949-51. 11. Lindberg C, Oldfors A, Hedstrom A. Inclusion body myositis: peripheral nerve involvement. J Neurol Sci 1990; 99:327-38. 12. Yoshimura N, Nishizawa M, Hozumi I, Atsumi T, Miyatake T. A case of chronic myositis associated with rimmed vacuole formation and hepatocellular carcinoma--on the entity of inclusion body myositis. Rinsho Shinkeigaku 1988;28:55-61. 13. Kakulas BA, Adams RD, editors. Diseases of muscle. 4th rev. ed. Philadelphia: Harper & Row, 1985. 14. Manchul LA, Jin A, Pritchard KI, Tenebaum J, Boyd NF, Lee P, et al. The frequency of malignant neoplasms in patients with polymyositis-dermatomyositis. Arch Intern Med 1985; 145:1835-9. 15. Masi AT, Hochberg MC. Temporal association of polymyositisdermatomyositis with malignancy: methodologic and clinical considerations. Mt Sinai J Med 1988;55:471-8. 16. Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis, a populationbased study. N Engl J Med 1992;326:363-7. 17. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis: observations in 40 patients. Brain 1989; 112:727-47.

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