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Gastric cancer and micrometastases:third updating

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

May 2002.     Review Article.

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

Despite the progress made in recent decades, the prognosis of patients with solid cancer is still limited by metastatic relapse, which indicates an early tumor cell spread at the time of or before surgical resection.
If examination for occult tumor cell spread would be incorporated into future clinical trials for the evaluation of cancer treatments, individually tailored adjuvant therapy seems possible for those patients with proven residual disease. This approach might represent a substantial advance in oncologic treatment.
The availability of a surrogate marker for monitoring the effectiveness of a treatment would be of great value for the evaluation and development of new adjuvant therapies. A promising approach to achieve this goal might be the periodic examination of bone marrow and peripheral blood during therapy for the incidence of disseminated tumor cells. Recent longitudinal studies have shown that immunologic or molecular monitoring of disseminated cells in patients is possible. Long-term observations are still required to evaluate the reduction in disseminated tumor cells after therapy and its correlation with an improved prognosis ( 1 ).
The Kabashima's review concentrates on the clinicopathologic studies and molecular biologic studies of intramucosal gastric carcinomas (IMGCs) with lymph node metastasis that have been published to date.
In general, IMGCs with lymph node metastasis have been commonly reported to be large lesions, poorly differentiated adenocarcinoma, and associated with peptic ulcer, in comparison with IMGCs without lymph node metastasis. But the malignant potential of the carcinoma cells cannot been evaluated by a clinicopathologic study with the use of hematoxylin and eosin staining. It may be unavoidable that minimal operation is widely accepted for the treatment of IMGCs. It may be more essential to establish the staging by both clinicopathologic and molecular biologic examinations to rule out the presence of IMGCs with lymph node metastasis.
Regarding genetic studies or molecular biologic studies, only DNA distribution pattern, proliferative cell nuclear antigen and the monoclonal antibody Ki-67, or matrix metalloproteinases 2 and 9 have been investigated in IMGCs with lymph node metastasis ( 2 ).

To date, there is still controversy over the importance of MM in patients with gastric carcinoma. A few investigations have employed immunostaining for the detection of MM in patients with early gastric carcinoma (EGC) and advanced gastric carcinoma (AGC).
In patients with EGC, LNM was uncommon, and Lee at al. found only 13 positive lymph nodes. However, there were 28 lymph nodes that contained MM in patients with EGC. In all 28 lymph nodes, only 1 or 2 scattered tumor cells were identified in the cortex and subcapsular sinus. This suggested that conventional H&E staining frequently fails to show LNM in patients with EGC and that immunohistochemical staining for MM should be done. MM may be a significant prognostic factor in patients with EGC. Patients with EGC showed an overwhelmingly greater frequency of MM compared with patients who had LNM (28 lymph nodes vs. 13 lymph nodes, respectively). In patients with AGC, this was reversed (159 lymph nodes vs. 596 lymph nodes, respectively).
In summary the survival analysis in their study revealed that MM had a significantly adverse effect on postoperative survival. The effect of MM was most pronounced in Stage I, although the number of patients was small. The effect of MM was more important in patients who were negative for LNM compared with patients who were positive for LNM. After compensating for the effect of stage, MM still was an independent poor prognostic factor for survival. Thus, the authors strongly advocate the careful examination for MM in specimens from patients with gastric carcinoma, preferably employing a sensitive method of immunohistochemical staining for broad-spectrum cytokeratins ( 3 ).
Histologic type by Lauren classification was not associated with the frequency of LNM or MM. Other studies have indicated that MM was more frequent in the diffuse type compared with the intestinal type of gastric carcinoma ( 3, 4 ).
On the other hand Morgagni et al. found that MM detected by immunohistochemistry was of no prognostic relevance ( 5 ).

Matsumoto et al. demonstrated the relationship between LMM and clinicopathologic factors, especially in pT1 tumor. The mapping of LMM may prove useful for selecting the optimal treatment.
The purposes of their study were to examine lymph node micrometastasis (LMM) by reverse transcriptase-polymerase chain reaction (RT-PCR) method, and clarify the initial nodes involved by metastatic disease according to tumor location.
They examined 312 lymph nodes obtained from 50 patients with node-negative gastric carcinoma. RT-PCR and immunohistochemistry were performed.
The number of patients and LMM detected by RT-PCR was 14 and 17 and by immunohistochemistry was 7 and 8, respectively. RT-PCR was a more sensitive method than immunohistochemistry. LMM by RT-PCR correlated with depth of tumor invasion and lymphatic invasion.
Regarding pT1 tumor, 9 patients with LMM had tumors that were of the macroscopically depressed type and 2 cm or more in diameter. According to a Tsujitani report, endoscopic mucosal resection has been used to treat early gastric carcinoma with differentiated elevated tumors less than 2 cm in diameter and differentiated depressed tumors less than 1 cm in diameter.
According to the lymphatic map, right pericardial lymph nodes and lymph nodes along the lesser curvature were the initial nodes involved in the upper third of the stomach. Right pericardial lymph nodes, lymph nodes along the lesser curvature, and infrapyloric nodes were more important initial metastatic sites in the middle third of the stomach, and lymph nodes along the lesser curvature and infrapyloric nodes in the lower third.
All patients had LMM in perigastric nodes or No. 7 LN. LMMs detected by RT-PCR are believed to represent the earliest stage of metastatic disease. When we plan to perform minimal invasive operation such as laparoscopic gastrectomy, perigastric nodes and No. 7 LN should be dissected according to tumor location ( 6, 7 ).

Admittedly, there are still several problems related to the molecular diagnostic techniques when applied for clinical decision making. First, the techniques are time-consuming and relatively laborious. Second, the results of PCR assays lack reproducibility. However, recent advances in PCR technology have allowed a significant reduction of the time required for amplification and detection of specific messenger RNAs. The LightCycler format can also quantify cancer-specific mRNAs with real-time monitoring of PCR products, and the results are more reproducible and reliable. With this technique, Nakanishi et al first developed a rapid assay (intraoperative) for detection of lymph node micrometastasis and applied this method to esophagus cancer surgery. At present, the whole procedure takes 2.5 hours from the tissue sampling to completion of the test, although this duration limits the introduction of our method to long operations such as esophageal cancer. Further developments in molecular biology should shorten the assay time, allowing the PCR assay to be widely used during cancer surgery.
One of the recent topics in surgery is the introduction of sentinel node navigation surgery to decide on limited surgery such as exclusion of lymphadenectomy. However, the clinical application of this technique requires accurate intraoperative detection of metastasis of lymph nodes. This genetic diagnostic system may enhance the spread of the use of sentinel node navigation surgery and provide patients with cancer with more effective surgical treatment in the future ( 8 ).

Preoperative assessment of the presence of lymph node metastases and the depth of wall invasion is critical for determining appropriate therapies for early gastric cancer. Several conventional clinicopathological factors, such as tumor staging, lymphatic vessel invasion and penetrating type , are known to correlate with lymph node metastases. However these factors cannot be used for predicting lymph node metastases at the preoperative stage.
Since lymph node metastases are present in only 3-5% of mucosal tumors, but in 10-25% of submucosal tumors, it is also important to assess invasion depth before operation in early gastric cancer. Endoscopic ultrasonography is particularly useful for assessing the depth of invasion. However it cannot differentiate precisely between intramucosal and submucosal cancer, because the presence of limited infiltration into the submucosa. Therefore biological markers that accurately assess the depth of tumour invasion into the submucosa could facilitate detection of submucosal cancer and improve selection of treatment.
The cadherin-catenin complex, which consists of E-cadherin and alfa, beta, and gamma catenin has been implicated in cell adesion and mantainance of normal tissue architecture. E cadherin interacts at a conserved cytoplasmatic domain with the cytoskeleton via associated cytoplasmatic molecules, alfa, beta and gamma catenin. Loss of function in any one of these components is believed to result in loss of cell-cell adhesion and contribute to neoplasia.
Tanaka et al affirms that abnormal E cadherin expression is a possible marker of submucosal invasion in differentiated- type early gastric cancer and absent beta catenin staining could be used as a predictor of lymph node metastases in both types (differentiated and undifferentiated types tumours ) ( 10 ).


1) Jakob R. Izbicki, Klaus Pantel, Stefan B. Hosch. Micrometastasis in solid epithelial tumors: Impact on surgical oncology. Surgery, January 2002, Part 1 , Volume 131, Number 1, pp 1-5.

2) Akira Kabashima, Yoshihiko Maehara, Tadashi Koga, Yoshihiro Kakeji, Keizo Sugimachi. The biologic features of intramucosal gastric carcinoma with lymph node metastasis. Surgery 2002;131:S71-7.

3) Eungseok Lee, Yangseok Chae, Insun Kim, Jongsang Choi, Bomwoo Yeom, , Anthony S.-Y. Leong. Prognostic relevance of immunohistochemically detected lymph node micrometastasis in patients with gastric carcinoma. Cancer 2002;94:2867-73.

4) Ishida K, Katsuyama T, Sugiyama A, Kawasaki S. Immunohistochemical evaluation of lymph node micrometastases from gastric carcinomas. Cancer. 1997; 79: 1069-1076.

5) Morgagni P, Saragoni L, Folli S, et al. Lymph node micrometastases in patients with early gastric cancer: experience with 139 patients. Ann Surg Oncol. 2001; 8: 170-174.

6) Masataka Matsumoto, Shoji Natsugoe, Sumiya Ishigami, Saburo Nakashima, Akihiro Nakajo, Futoshi Miyazono, Shuichi Hokita, Sonshin Takao, Yoshito Eizuru, Takashi Aikou. Lymph node micrometastasis and lymphatic mapping determined by reverse transcriptase-polymerase chain reaction in pN0 gastric carcinoma. Surgery 2002;131:630-5.

7) Tsujitani S, Oka S, Saito H, Kondo A, Ikeguchi M, Maeta M, et al. Less invasive surgery for early gastric cancer based on the low probability of lymph node metastasis. Surgery 1999; 125:148-54.

8) Setsuko Yoshioka, Yoshiyuki Fujiwara, Yurika Sugita Yoshihiro Okada, Masahiko Yano, Shigeyuki Tamura, Takushi Yasuda, Shuji Takiguchi, Hitoshi Shiozaki, Morito Monden. Real-time rapid reverse transcriptase-polymerase chain reaction for intraoperative diagnosis of lymph node micrometastasis: Clinical application for cervical lymph node dissection in esophageal cancers. Surgery 2002;132:34-40.

9) Nakanishi H, Kodera Y, Yamamura Y, Ito S, Kato T, Ezaki T, et al. Rapid quantitative detection of carcinoembryonic antigen-expressing free tumor cells in the peritoneal cavity of gastric-cancer patients with real-time RT-PCR on the LightCycler. Int J Cancer (Red Oncol) 2000;89:411-7.

10) M Tanaka, Y Kitajiama, G Edakuni, S Sato and K Miyazaki. Abnormal expression of E-cadherin and Beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. BJS 2002, 89, 236-244.

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