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Gastric cancer and micrometastases:second updating

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

December 2001.     Review Article.

To previous article about micrometastases
To the first updating
To the third updating
To the fourth updating

Although great progress has been made in surgical oncology in recent decades, early metastatic spread significantly reduces survival rates. Molecular research has identified numerous proteins that influence the metastastic potential of tumor cells.
The conditions necessary for the growth of epithelial cells in sites such as bone marrow are still unknown. The factors determining tumor cell dormancy ( the interval between initial dissemination of tumor cells and clinical appearance of metastases) are also unclear.
Cytokeratins (CK) are integral components of the cytoskeleton of epithelial cells, and they are reliably expressed by tumor cells. CK can be clearly identified in individual carcinoma cells by means of specific monoclonal antibodies. Although the prognostic significance of immunocytochemical assays has been confirmed in prospective clinical studies, the techniques used in these studies differ considerably in terms of reproducibility. It is therefore necessary to define critical variables of the immunocytochemical assays and to introduce standardization that will allow a reproducible and more precise determination of the cancer cell count.
In contrast to immunohistochemistry, molecular markers allow analysis of the entire lymph node in one reaction, thus reducing the time needed for screening. Recent preliminary studies of a small number of patients with colorectal cancer demonstrated an increase in the detection of lymph node micrometastases using reverse transcription-polymerase chain reaction ( RT-PCR) assays for carcinoembryonic antigen (CEA) or CK20 messenger RNAs (mRNAs). The presence of lymph node micrometastases was significantly correlated to reduced overall survival. However because the detection of these markers is based on molecular methods using amplification of mRNA, the specificity might be reduced by illegitimate expression of the respective marker gene from normal lymph node cells ( 1 ).

Y Okada et al assessed 435 LNs from 28 patients with gastric carcinoma who underwent gastrectomy with lymphadenectomy using the multiple marker RT-PCR assay in addition to histologic examination.
Carcinoembryonic antigen ( CEA ), cytokeratin-20 ( CK-20 ), and MAGE-3 gene markers were used in this assay. LNs were scored positive for metastases if at least one marker was positive. The presence of LN micrometastases also was verified by immunohostochemistry in histologically negative and RT-PCR positive LNs.
RT-PCR assay for the detection of occult tumor cells currently is limited by gene markers and identification of markers associated with specific tumors or with malignant diseases in general. Therefore any attempt to modify this assay to optimize its sensitivity and specificity must take into consideration these important issues. Rather than increasing PCR sensitivity ( with the risk of false positive results ) the authors applied an alternative approach to improve the sensitivity and specificity of the assays: the development of a multiple marker RT-PCR assay in which more than one marker is expressed in micrometastases positive lymph nodes.
Currently the authors cannot confirm that a single tumor cell can always multiply to form a nest of tumor cells. Thus the clinical significance of positive lymph nodes by RT-PCR assays remains unclear. However early reports suggest that patients with lymph nodes that are positive on RT-PCR but negative on histopathologic analysis have a poor prognosis compared with patients who have RT-PCR negative lymph nodes, although further studies definitively are required to confirm these findings ( 2 ).

Hong Jo Choi et al. try to assess the incidence of micrometastases of lymph nodes in patients with early gastric cancer invading the submucosal layer and to investigate the correlation between nodal micrometastases and malignancy potential to determine whether micrometastases of lymph nodes have prognostic significance, by use of an anticytokeratin immunohistochemical technique.
As many as 2,5% ( 57 of 2272 ) of lymph nodes and 31,8% of patients with submucosal gastric carcinoma showed micrometastases in the regional nodes, thus confirming that this is a common phenomenon in gastric carcinoma.
Only a few studies have been performed to evaluate the prognostic significance of lymph node micrometastases in submucosal gastric carcinoma. Cai et al found that the presence of cytokeratin-positive cells in lymph nodes from submucosal gastric carcinoma patients correlated with significantly worse prognosis and that cytokeratin immunohistochemistry may make it possible to identify patients with a higher risk of recurrence after removal of a submucosal gastric carcinoma. Maehara et al reported that the survival time of the cytokeratin-positive group was significantly shorter than that of the cytokeratin negative group in patients with early gastric cancer who died of recurrence.
In the Hong Jo Choi analysis of retrospective data, however, patients with lymph node micrometastases found in their resected specimen did not show a worse prognosis than patients in whom such findings were not identified. Moreover no relationship was seen with age, sex, gross tumor type, or blood vessel invasion, although a weak association was found beteween micrometastases and tumor size, and lymphatic vessel invasion. Thus it is concluded that immunohistochemical detection of lymph node micrometastases does not offer a significant benefit over conventional pathologic staging with E&E staining in stratifying patients for planning appropriate adjuvant therapy and for prognostic grouping in diverse clinical settings ( 3, 4, 5 ).

On the contrary Caj et al in a recent article ( 2001 ) riaffirm that tumors with micrometastases of only a single or a few scattered cancer cells in the lymph node may already have potential metastastic activity, and these micrometastases may have the same consequence as clustered cancer cells in the lymph node, i.e., a reduced patient survival rate. Multivariate analysis showed that loss of expression of E cad was an independent risk factor for these micrometastases with only single or scattered cancer cells in the lymph nodes.
They suggest an endoscopic mucosal resection ( EMR ) or laparoscopic wedge resection without lymphadenectomy for an m-cancer of less than 1.0 cm superficial diameter, because lymph node involvement is extremely rare in this tumors; a limited perigastric lymph node dissection can be performed for an m-cancer that is 1.0 to 2.0 cm in diameter, because these tumors rarely metastasize to the extra-perigastric lymph nodes; a radical D2 lymphadenectomy is needed for an m-cancer that is more than 2.0 cm in diameter, and for all sm-cancers, because these tumors have the potential for extraperigastric lymph node involvement. Preoperative E-cadherin immunostaining and determination of histology from an endoscopic biopsy sample may be helpful for the prediction of lymph node involvement ( 6 ).


1) Klaus Pantel, Stefan B Hosch. Molecular profiling of micrometastatic cancer cells. Annals of Surgical Oncology 2001, 8 (9S): 18-21.

2) Y Okada et al. Genetic detection of lymph node micrometastases in patients with gastric carcinoma by multiple-marker reverse trancriptase-polymerase chain reaction assay. Cancer 2001; 92: 2056-64.

3) Hong Jo Choi et al. Occurrence and prognostic implications of micrometastases in lymph nodes from patients with submucosal gastric carcinoma. Annals of Surgical Oncology 2002, 9 ( 1 ): 13-19.

4) J Cai et al. Micrometastasis in lymph nodes and microinvasion of the muscularis propria in primary lesions of submucosal gastric cancer. Surgery 1999: 126:32-9.

5) Y Maehara et al. Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence. Surgery 1996; 119: 397-402.

6) J Cai et al. Significant correlation between micrometastases in the lymph nodes and reduced expression od E cadherin in early gastric cancer. Gastric Cancer 2001, 4: 66-74.

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