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News in Surgical Oncology: future staging in primary cancer.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

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.
Moreover the authors speak about molecular techniques that can be applied to detection of micrometastasis. They cite reverse trascriptase-polymerase chain reaction ( RT-PCR), with high false-positive rates; and another PCR- based assay, mutant- allele-specific amplification (MASA) that is capable of detecting micrometastases in lymph nodes that are classified as histologically negative.
But the authors conclude that molecular technique should be reserved for blood samples or bone marrow aspirates.

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 ).
With regard to this aspect Tsuyoshi Etoh has performed a detection assay using CD45 immunomagnetic separation plus nested mutant allele specific amplification (MSA). The preliminary study demonstrates that the detection of circulating cancer cells in the tumor drainage blood by a new assay system may provide a predictor of recurrence and metastases of colorectal cancer ( 2 ).

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.
The authors rise important questions: the careful search for all nodes within the specimen, assignement of nodes to the correct level by the surgeon and pathologist and the thickness of sections and number of sections analysed.
Whether immunohistochemistry for upstaging of colorectal cancer has advantages over, or is equal to, reverse transcription-polymerase chain reaction (RT-PCR) analysis.
If sentinel lymph node techniques would prove to be applicable to colon cancer, this would permit an extensive analysis of one or two lymph 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.
The future lies with the molecular characterization of a patient's tumor in addition to the more accurate and sensitive staging of nodes at risk.
Some of the genes involved in tumor development and progression and their proteins are detectable only within the tumor cell. Others are produced and secreted by the tumor and therefore are detectable in serum. Some are produced by the host's normal tissue in direct response to tumor growth.
Possible applications of the determination of the complete molecular pattern are: the ultimate classification/staging of the tumor; assessing risk for failure and therefore, determining appropriateness of adjuvant therapies; providing monitors of therapeutic efficacy; and ultimately providing specific molecular targets for therapy (3, 4, 5 ).


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.

2) Tsuyoshi Etoh et al. Clinical significance of K ras mutations in intraoperative tumor drainage blood from patients with colorectal carcinoma. Annals of Surgical Oncology 2001, 8 (5); 407-412.

3) J E Niederhuber. The future for staging of primary tumors. Annals of Surgical Oncology, 8 (5): 384-385, 2001.

4) K Yasuda et al. Pattern of lymph node micrometastasis and prognosis of patients with colorectal cancer. Ann Surg Oncol 2001; 8: 300-4.

5) AI Sarela et al. Immunohistochemical detection of the anti- apoptosis protein, Survivin, predicts survival after curative resection of stage II colorectal carcinomas. Ann Surg Oncol 2001; 8: 305-10.

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