Molecular staging individualizing cancer management

Abstract

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, approximately 30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy.

Figure 1. Identification of occult tumor metastases in lymph nodes employing marker-specific quantitative RT-PCR

At the time of colectomy, regional lymph nodes are harvested from tumor-associated mesenteric structures for staging. In the canonical paradigm, these lymph nodes are formalin-fixed and paraffin-embedded and thin sections are reviewed by standard histopathology to identify metastatic tumors cells. This approach is associated with limitations in sampling, in which only a small portion of the available tissue is subject to review. Also, there is a limitation in sensitivity, in which the pathologist can reliably identify only one tumor cell in 200 normal cells in a lymph node specimen. Together, these limitations result in under-staging of patients, in which lymph nodes apparently free of disease by standard histopathology (pN0) actually harbor occult metastases [pN0(mol+)]. One approach to identify lymph nodes harboring occult metastases that escape detection by the standard paradigm is to couple a sensitive and specific tumor marker, like GCC, to a powerful amplification technology, like RT-PCR. This molecular approach overcomes the sampling limitation of standard histopathology, since mRNA from the entire available specimen is extracted and sampled for expression of the tumor-associated marker. Moreover, RT-PCR is exquisitely sensitive and can detect one tumor cell in one million normal cells, unlike standard histopathology.