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Letters |
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Department of Pathology, and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
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Division of Biochemistry, Department of Pathology, and Laboratory Medicine, Ottawa Hospital–General Campus, Ottawa, Ontario, Canada K1H 8L6
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Division of Biochemistry, Department of Pathology, and Laboratory Medicine, Ottawa Hospital–Civic Campus, Ottawa, Ontario, Canada K1Y 4E9
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Department of Biochemistry,, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa,, Ottawa, Ontario, Canada K1H 8M5
a Address correspondence to this author at: Division of Biochemistry, Department of Laboratory Medicine, Ottawa Hospital–Civic Campus, 1053 Carling Ave., Ottawa, Ontario, Canada K1Y 4E9. Fax 613-761-5361; e-mail jdonnelly{at}civich.ottawa.on.ca
To the Editor:
We describe a 53-year-old man with metastatic alveolar rhabdomyosarcoma who had a massively increased creatine kinase MB (CK-MB) mass and index. The CK-MB increase was initially interpreted as evidence of myocardial infarction (MI), but the CK-MB remained increased. The patient had increased serum concentrations of cardiac troponin T (cTnT) and normal cardiac troponin I (cTnI). We theorize that tumor anaplasia caused malignant myocytes to re-express CK-MB and cTnT isoforms. Rhabdomyosarcoma release of both CK-MB and cTnT has not been described previously.
Serum CK and lactate dehydrogenase (LD) activities were assayed at 37 °C with the Hitachi 911 automated analyzer [Boehringer Mannheim (BM)]. CK-MB mass was measured with the Access (Beckman Instruments) immunoenzymatic assay. Serum cTnT was evaluated using a second-generation Elecsys 1010 immunoassay (BM). Serum cTnI was analyzed using both the AxSYM (Abbott) microparticle enzyme immunoassay and the Opus Plus (Dade Behring) fluorogenic two-site immunoassay.
The patient presented to a community hospital with acute, bilateral leg
weakness. He had a 3-week history of worsening thoracic back pain and
lower extremity paresthesias, and 3 months earlier he had discovered a
subcutaneous mass of his left foot. Foot x-ray at that time was
unremarkable. The patient's neurologic examination revealed that lower
extremity motor power was decreased to 2+/5. He was unable to walk. His
deep tendon reflexes were diminished, and his plantar responses were
abnormal bilaterally. The patient was continent of urine but had anal
sphincter laxity. He had decreased sensation below the nipples. Spinal
cord compression was diagnosed. Computerized tomography scan
revealed a soft tissue mass that permeated the T2 vertebral body and
impinged on the spinal cord. A left foot mass was also confirmed, and
computerized tomography scan revealed a circumscribed soft tissue
tumor, measuring 4 x 3.9 x 3.8 cm that surrounded the
lateral fifth metatarsal. Core biopsies of both tumors revealed
similar, round-cell neoplasms that were confirmed to be alveolar
rhabdomyosarcomas by immunohistochemical and ultrastructural studies,
with positive staining for vimentin, desmin, and muscle-specific actin.
The patient underwent thoracic laminectomy. Postoperative neurologic
function was unchanged. The patient was treated with three cycles of
doxorubicin and cis-platinum and then with spinal
radiotherapy. Six months after his initial presentation, the left foot
mass began to grow rapidly. The foot tumor was treated with
radiotherapy, but within 1 month, the patient developed left inguinal
lymph node metastases and deep venous thrombosis. He was readmitted to
hospital where he developed an episode of atypical chest pain. An
electrocardiogram revealed only nonspecific T-wave abnormalities. His
serum CK was 336 U/L [reference interval (RI), 45–220 U/L]. His
CK-MB mass was 150 µg/L (RI, 0.0–5.0 µg/L) with a CK-MB index of
45 (RI, 0.0–2.0), a cTnT of 0.95 µg/L (RI, 0.00–0.10 µg/L), and a
cTnI of <0.5 µg/L on the Opus Plus (reference value, <0.5 µg/L)
and 1.2 µg/L on the AxSYM (RI, 0.0–2.0 µg/L). There was no
biochemical evidence of hepatic or renal failure. CK electrophoresis
revealed increases of all CK isoenzymes (Table 1
). Atypical CK variants were not present. A diagnosis of MI was
maintained until serum cardiac enzymes, measured 3 days later, showed
sustained increases. At this time, the patient had a CK of 334 U/L, a
CK-MB mass of 195 µg/L, a CK-MB index of 58, a cTnT of 0.80 µg/L,
and a cTnI of <0.5 µg/L (Opus Plus) and 0.8 µg/L (AxSYM). Serum LD
was increased to 570 U/L (RI, 95–195 U/L). Considering
the history of atypical chest pain, the equivocal electrocardiogram
changes, and the sustained and dramatically increased CK-MB mass
and index, a recent MI was considered unlikely. The aberrant cardiac
markers were thought to be secondary to tumor expression of CK-MB and
cTnT.
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The patient returned 2 weeks after discharge with new spinal cord
compression. Postradiotherapy analysis revealed a CK of 1364 U/L, LD of
1500 U/L, a CK-MB mass of 1047 µg/L, a CK-MB index of 77, a cTnT of
2.49 µg/L, and a cTnI of <0.5 µg/L (Opus Plus) and 1.1 µg/L
(AxSYM). LD electrophoresis revealed predominant increases of
LD1, LD2, and
LD3 (Table 1
). The
LD1-to-LD2 ratio was 0.44.
There were no further clinical episodes compatible with MI, nor did the
patient have congestive heart failure. The patient died 11 months after
his initial presentation. No postmortem examination was performed.
Rhabdomyolysis, Duchenne muscular dystrophy, polymyositis, viral myositis, and various other myopathies may cause false-positive CK-MB tests for MI (1). Malignancies have also been associated with increased serum CK-MB and CK-BB (1)(2)(3). Usually the pattern of CK-MB increases is sustained, with CK-MB indexes ranging from 40 to 60, beyond values usually observed with MI. Features consistent with CK-MB release from a non-cardiac source in our patient included a sustained increase of serum CK-MB mass that fluctuated little over a 3-day period, CK-MB indexes of 45 and 58, and a marked increase of serum CK-MB after radiotherapy. CK electrophoresis confirmed the absence of CK variants. The increase of all LD isoenzyme fractions is seen with neoplasms (4). Cardiospecific cTnI values remained within the RIs in two different immunoassays, effectively dismissing ongoing myocardial ischemia. In addition to CK-MB isoenzyme expression, our patient's rhabdomyosarcoma also likely expressed cTnT.
Rhabdomyosarcoma expression of both CK-MB and cTnT can be explained by tumor anaplasia and concurrent expression of fetal phenotypes. Certain tumors, in particular lung carcinomas, develop an ability to synthesize peptide hormones secondary to tumor anaplasia and altered gene expression (5). Maturing chick embryo skeletal muscle shows progression of CK isoenzyme content from CK-BB to CK-MB to CK-MM (6). Fetal human skeletal muscle is known to express cTnT isoforms (7). With skeletal muscle maturation, there is increased expression of skeletal TnT isoforms and concurrent down-regulation of cTnT isoforms (7)(8). Adult rat skeletal muscle has shown re-expression of cTnT isoforms after denervation injury (9). Re-expression of fetal genes is also thought to occur in the diseased skeletal muscle of Duchenne muscular dystrophy and polymyositis. The cTnI isoform, unlike cTnT, is not expressed by skeletal muscle at any point during muscle maturation, and therefore, diseased skeletal muscle shows a lack of cTnI expression (10).
Although our conclusions are speculative, the cTnT increases clearly were not associated with renal or congestive heart failure. The major limitation of our investigation was the lack of direct tumor analysis by either immunohistochemical or genetic techniques. Isoforms of cTnT have been identified in diseased skeletal muscle of chronic renal failure patients by Western blots and highly specific M7 and M11.7 monoclonal antibodies for cTnT (11)(12). These monoclonal antibodies are the same ones that are used in the BM second-generation cTnT immunoassay. Although cTnT isoform expression occurs in the skeletal muscle of chronic renal failure patients, it apparently does not produce false positives in second-generation BM cTnT tests because of differential detection of cTnT epitopes by M7 and M11.7 antibodies (11). The cTnT isoforms expressed in skeletal muscle neoplasms may have epitope combinations that produce false-positive cTnT tests, even with second-generation immunoassays. Haller et al. (13) were unable to demonstrate cTnT mRNA expression in skeletal muscle from five patients with end-stage renal failure. To our knowledge, no studies have investigated rhabdomyosarcomas at the mRNA level to determine their expression of troponins. Further rhabdomyosarcoma genetic studies are required to elucidate their protein expression. We theorize that rhabdomyosarcoma anaplasia leads to an immature skeletal muscle phenotype that may cause false-positive biochemical testing for MI, secondary to expression of CK-MB and cTnT.
Acknowledgments
We thank the technologists at the Ottawa Hospital for technical assistance.
References
The following articles in journals at HighWire Press have cited this article:
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  H. J. Fingert and M. L. Varterasian Cardiac safety, risk management, and oncology drug development. Clin. Cancer Res., June 15, 2006; 12(12): 3646 - 3647. [Full Text] [PDF]
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 D. Grandmougin, G. Fayad, C. Decoene, A. Pol, and H. Warembourg Total orthotopic heart transplantation for primary cardiac rhabdomyosarcoma: factors influencing long-term survival Ann. Thorac. Surg., May 1, 2001; 71(5): 1438 - 1441. [Abstract] [Full Text] [PDF]
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 S. Agewall Increases of Creatine Kinase MB and Cardiac Troponin T in Serum of a Patient with Uterine Leiomyosarcoma Clin. Chem., December 1, 2000; 46(12): 2016 - 2017. [Full Text] [PDF]
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S. Fredericks, P. O. Collinson, D. W. Holt, P. A. Isotalo, D. C. Greenway, and J. G. Donnelly Response to ""Increased Creatine Kinase MB and Cardiac Troponin T with Normal Cardiac Troponin I in Metastatic Alveolar Rhabdomyosarcoma"" • The authors of the Letter cited above reply: Clin. Chem., March 1, 2000; 46(3): 432 - 435. [Full Text] [PDF]
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