Metastatic Alveolar Rhabdomyosarcoma with Increased Serum Creatine Kinase MB and Cardiac Troponin T and Normal Cardiac Troponin I

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 × 3.9 × 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. CK and LD isoenzyme electrophoretic fractionation. ND, usually not detected. CK and LD isoenzyme electrophoretic fractionation. ND, usually not detected. 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. We thank the technologists at the Ottawa Hospital for technical assistance.