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July 2001. Review Article.
Kell et al in a review article published in the British Journal of Surgery stress that the concept of micrometastases has resulted in a paradigm shift in the staging of epithelial tumours and our overall understanding of malignant processes.
In fact the most important prognostic determinant in cancer is the identification of disseminated tumor burden (metastases). Micrometastases are microscopic (smaller than 2 mm) deposits of malignant cells that are segregated spatially from the primary tumour and depend on neovascular formation (angiogenesis) to propagate. Strategies against angiogenesis may provide novel therapies to induce and maintain micrometastatic dormancy. In fact the challenge now is to incorporate this knowledge into management strategies.
In the immediate future, identification, sampling and even culture of micrometatases should permit assessment of chemotherapeutic sensitivity before the initiation of adjuvant therapy. By opening a window on the cancer process, bone marrow micrometastases offer an ongoing measurement of response to systemic therapy. Neoadjuvant and postoperative cytotoxic therapies may be employed initially, but perioperative manipulations of angiogenesis and host immunity are attractive alternatives.
Detection of micrometatses in regional lymph nodes and / or bone marrow confers a poor prognosis in epithelial cancers. The prognostic significance of nodal and / or bone marrow micrometatses has been established in several malignancies.
Immunohistochemical techniques combined with serial sectioning offer the best accuracy for detection of nodal micrometastasis.
The concept of sentinel node biopsy combined with serial sectioning and dedicated screening for micrometastases may improve staging procedures. In fact sentinel lymph node biopsy facilitates detailed pathological examination for micrometastatic deposits because of the small tissue volume: the node is divided into multiple sections that are submitted to rigorous examination.
The bone marrow cavity provides an accessible space not normally contaminated with epithelial cells; its native cells are mesenchymal in origin and easily distinguished form malignant epithelial cells by immunocytochemistry, flow cytometry and molecular techniques(RT-PCR) and enzyme linked immunosorbent assay (ELISA). Whether these occult deposits of metastatic cells have biological significance or if they reflect the behaviour of the primary tumor remains to be determined.
There is little known about the prognostic significance of tumour cells in the circulating blood stream. Molecular techniques such MASA have been used to detect the relatively small number of cells found in pheripheral blood
( 1 ).
In an editorial J E Niederhuber points out two articles in the May issue of Annals of Surgical Oncology that addressed the importance of obtaining more prognostic information concerning resected colorectal carcinoma.
The first article by Yasuda and collegues studies the significance of lymph node micrometastases and upstaging the patient's tumor using immunohistochemistry. Of the conventional histopathologic staging parameters, the presence of micrometastases is a significant predictor of failure in patients with Dukes B colorectal cancer, when four or more nodes are involved or when micrometastases are found in N2 or higher level nodes.
In the second article Guillou and collegues define a gene and its protein termed Survivin selectively expressed in tumor cells, that should be included as a molecular marker of prognosis in colorectal cancer.
1) MR Kell, DC Winter, GC O'Sullivan, F Shanahan and Hp Redmond. Biological behaviour and clinical implications of micrometastases. British Journal of Surgery 2000, 87, 1629-1639.
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