Subclinical myopathy in patients affected with newly diagnosed colorectal cancer at clinical onset of disease: evidence from skeletal muscle biopsies

Abstract

Objective: To evaluate skeletal muscle biopsy from asymptomatic patients affected with newly diagnosed colorectal cancer and to identify pathological features which may be indicative of tumor-associated muscle disorders, potentially leading to cachexia.

Methods: Patients affected with newly diagnosed colorectal cancer at clinical onset of disease underwent biopsy of the rectus abdominis muscle during elective laparoscopic tumor resection, before chemotherapeutic treatment. Morphometric analyses, ATPase histochemistry and immunohistochemical studies using antibodies directed to N-CAM and to MHC-emb, two sound makers of muscle denervation and injury-induced muscle regeneration, were performed on intraoperative muscle biopsies from ten patients. Muscle biopsies from rectus abdominis of seven subjects affected with non-neoplastic condition, which underwent laparoscopic surgery, were used as controls.

Results: In patients' biopsies, we observed a surprisingly high percentage of myofibers with internalized or central nuclei compared to controls (9·15 ± 8·9 versus 0·6 ± 0·9, p<0.0003). In addition, in the 30% of patients, small myofibers expressing the MHC-emb have been identified (0·4 ± 0·5 positive fibers/mm²), while in 50% of patients, larger fibers positive for N-CAM have also been detected (0·7 ± 1·1 positive fibers/mm²), suggesting that investigated muscle biopsies exhibit other evidence of muscle fiber injury/regeneration and/or denervation. Among the 10,000 analysed myofibers in control biopsies, no MHC-emband N-CAM-positive muscle fibers have been detected. Thus, patients affected with newly diagnosed colorectal cancer at clinical onset of disease display early signs of a subclinical myopathy.

Discussion: Factors and mechanisms of this cancer-associated myopathy are yet unknown. The facts that the great majority of the abnormally nucleated myofibers are of the fast type and that regenerating myofibers are present, suggest a myogenic response to the colorectal cancer and not to the laparoscopic modalities of the biopsy harvesting. Follow-up of the patients will elucidate the clinical relevance of our observation, and further studies investigating the molecular mechanism underlying this early cancer-associated myopathy will hopefully provide some pathogenetic clues leading to the identification of potential specific targets for therapeutic intervention to prevent tumor cachexia.

Keywords:

• CACHEXIA
• CENTRALIZED NUCLEI MYOPATHY
• COLORECTAL CANCER
• SKELETAL MUSCLE
• RECTUS ABDOMINIS