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Blog aimed at residents in surgery
 URL :  www.surgical-oncology.net             e mail surgoncnet@gmail.com
Peritoneal cytology in staging of gastric cancer.

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



December 2001.     Review Article.         To the updating

In Japan the 5 year survival of patients with serosa exposed gastric cancer is reported as 30 %. Peritoneal seeding is one of the common patterns of recurrence in SE gastric cancer. The etiology of peritoneal dissemination is yet to be fully understood; however the presence of peritoneal free cancer cells appears to be one of the main factors in its development.
In the Suzuki's study the mean age of patients with positive cytology findings is significantly younger than that of those with negative cytology findings.
A correlation is observed between the tumor size and positive cytology findings, as the mean size of the positive cytology tumors is significantly larger than that of the negative cytology findings.
Cytology is positive in 6,9% of cases without macroscopic peritoneal dissemination and in 42% of those with peritoneal dissemination.
When the tumor invasion is limited to the mucosal or submucosal layer, positive cytology is absent; however when the invasion includes the muscolaris propria, subserosal layer, serosal surface and adjacent structures, the rate of positive cytology is 5,9%, 9,8%, 27,3% and 21,4% respectively.
The frequency of positive cytology findings is clearly higher in undifferentiated type as compared to that of the differentiated type.
The grade of lymphatic invasion is more closely correlated with the rate of positive cytology than that of venous invasion.
The authors conclude that the survival curve of patients with positive cytology findings are worse than that of all patients in each stage, thus indicating that a positive cytology finding results in a poorer prognosis of one stage or more. The degree of difference in prognosis between positive and negative cytology findings is suggested to be about one stage.
Administration of anticancer drug during surgery seems reasonable when the rapid results of cytology are positive, since the accuracy of rapid result of cytology has been proven from this study and positive cytology has been revealed as a sensitive predictor for the development of peritoneal recurrence. At present intraperitoneal administrations of anticancer drugs and placement of intraperitoneal catheters for postoperative chemotherapy in curative case with positive cytology are being performed in Suzuki's institute ( 1 ).

In a large retrospective study multivariate analysis indicates that intraoperative cytological findings is an indipendent prognostic factor for survival, and is the most important factor for predicting peritoneal recurrence. Serum concentrations of carcinoembryonic antigen and carbohydrate antigen 19-9 is significantly higher in patients with positive cytology. These results indicates that more abundant intra-abdominal cancer cells might produce both elevated levels of tumor markers and higher rates of cytological positivity, as well as a poor prognosis ( 2 ).

Less than one-third of patients with advanced gastric cancer have positive peritoneal citology at the time of operation. This is significantly fewer cases than the proportion which might be expected to die with peritoneal metastatic recurrent disease: historically up to 80%. This underdetection may be due to the insensitivity of the sampling technique, or it may be that the process of surgical resection itself encourages the dissemination of malignant cells.
Addition of serosal brush citology ( by slightly sweeping the serosa overlying the tumor with a sterilized brush in the preresection phase) and imprinting citology (after resection the specimen is handed to an assistant and slides coated with poly-L-lysine are pressed against the serosa overlying the tumor and immediately fixed ) to conventional peritoneal lavage significantly increases the yeld of free malignant peritoneal cells.
The post resection peritoneal sampling is associated with a low yeld of malignant cells. Probably the considerable increase in the numbers of polymorphonuclear cells and mesothelial cells ( which change in appearance from regular, monotonous cells to bizarre, heterogeneous, multinucleated cells ) after surgery may swamp any malignant cells remaining in the abdominal cavity, making their detection more difficult. In addition malignant cells rapidly adhere to either normal or denuded peritoneum. Surgical insult may contribute to this process by triggering the fibrin cascade which enmeshes malignant cells and facilitates their implantation ( 3 ).

Nekarda and colleagues affirm that the sensitivity for the detection of malignant cells in effusions can be increased by a factor of two to three using immunocitology. Using immunocitology they find Free Peritoneal Tumor Cells to have a strong negative indipendent impact in patients who had a complete resection of their gastric carcinoma, with an impact similar to the presence of distant nodal metastases (pM1 lymph). A particularly important finding of the study in this regard lies in the detection of FPTC and its attendant poor prognosis in 19% of patients without histological serosal involvement by tumor. In some FPTC-positive cases, a so called occult peritoneal carcinosis is present , perhaps represented in the study by the subgroup of FPT C-positive patients who died in the first post-operative year and had a very high risk for the development of peritoneal carcinosis. In other cases, FPTC seems to carry a risk of distant metastatic disease similar to the impact of isolated tumor cells in the bone marrow.
The authors conclude that the detection of FPTC might form an important component of preoperative staging, especially when the option of neoadjuvant therapy is to be considered ( 4 ).

Nobutsugu Abe et al. reaffirm that the sensitivity of cytologic examination of peritoneal washes has been reported to be relatively low, ranging from 22% to 30% in gastric carcinoma involving the serosa, as approximately 50% of patients with serosal invasion are known to develop peritoneal recurrence even if curative resection is performed. Recently several investigators have demonstrated that molecular techniques using highly sensitive reverse transcriptase-polymerase chain reaction may serve as a useful method for the detection of free cancer cells (for example the Reverse transcriptase-PCR-rT-PCR- probing of the cellular content of peritoneal lavage fluid for the mRNA encoding the CEA protein was recently introduced as a novel method for detection of free tumor cells). These molecular diagnostic techniques are, however, time-consuming and relatively laborious compared with conventional cytodiagnostic methods, and are, therefore, considered to be practically of limited value. One possible way of circumventing these problems could be the measurement of the carcinoembryonic antigen (CEA) level in peritoneal washes.
The presence of CEA in the peritoneal cavity at the time of gastrectomy positively correlates with lower survival rates of patients with gastric cancer. It is conceivable that the local production of CEA by cancer cells present in the peritoneal cavity is the most important factor determining pCEA level. If this is the case, then the pCEA level may be determined by such factors as the number of cells present in the peritoneal cavity or the CEA-producing ability of the carcinoma cells present.
The authors find in the present study, however, that pCEA positivity correlates with sCEA level. The CEA protein produced may be taken up into the systemic circulation resulting in an increased sCEA level followed by exudation into the peritoneal cavity from the circulation, thereby increasing the pCEA level. On the other hand, an increased sCEA level could be the result of an increased CEA production in the peritoneal cavity, which in turn results in the increase of both sCEA and pCEA level. Consistent with the latter view, sCEA level has been positively correlated with positive cytologic examination in the peritoneal cavity.
Comparison of the sensitivity for predicting peritoneal recurrence between determining pCEA levels and conventional cytologic examination in this study reveales that the former method (93.6%) is far more sensitive than cytologic examination (42.9%). The authors further demonstrates by multivariate analysis that pCEA is a statistically significant independent prognostic factor for the survival of patients with gastric cancer.
The measurement of pCEA levels could be carried out within a few hours; hence this method provides surgeons with prognostic information intraoperatively. If high levels of pCEA, for example, were obtained, then an aggressive intraoperative therapy such as intraperitoneal chemotherapy could be performed to prevent peritoneal recurrence. Although intraoperative adjuvant therapy is still not widely accepted as a standard therapy, intraperitoneal chemotherapy applied as a prophylactic measure has been reported to significantly improve the survival of patients with serosal invasion but without macroscopic dissemination. Such an adjuvant therapy for pCEA-positive patients at an early stage of the disease might improve the overall prognosis of gastric cancer ( 5 ).

Recently, laparoscopy has emerged as a staging modality that is more sensitive and specific in staging gastric cancer than preoperative imaging modalities. Peritoneal lavage cytology during diagnostic laparoscopy has also been demonstrated to be useful for identifying free cancer cells in the intraperitoneal cavity. Such a view may support the idea that determination of the pCEA level could also be applicable to laparoscopic staging of gastric cancer. This method can be of great value in identifying patients who will benefit from neoadjuvant chemotherapy ( 5, 6, 7 ).

Although histopathological diagnosis is extremely useful for the definitive as well as the supportive diagnosis of gastric cancer in clinical practice, it is limited in certain respects. Over the past 15 years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. These abnormalities, which include telomerase activation, genetic instability, and abnormalities in oncogenes, tumor suppressor genes, cell-cycle regulators, cell adhesion molecules, and DNA repair genes, could be effective markers in the molecular diagnosis of gastric cancer. It is possible that the molecular analysis of these alterations in histopathology specimens may overcome deficiencies in diagnoses that depend only on histomorphology, and, consequently, we may be able to improve the differential diagnosis of cancer, obtain information on the grade of malignancy, and identify patients at high risk of developing multiple primary cancers. In the near future, genetic analysis by means of DNA microarray may become routine in the diagnosis of gastric cancer. Genetic analysis of histopathology specimens may make clear the characteristics of individual cancers; indicating the common and specific features of molecular pathogenesis that may be directly connected with gene therapy or molecular-targeted therapy. By analyzing the relationship between single-nucleotide polymorphisms and cancer susceptibility, we will be able to obtain information on cancer prevention from histopathology samples ( 8, 9, 10 ).

References

1) Takao Suzuki et al. Peritoneal lavage cytology findings as prognostic factor for gastric cancer. Seminars Surg Oncol 1999; 17:103-107.

2) Etsuro Bando et al. Intraoperative lavage for cytological examination in 1297 patients with gastric carcinoma. Am J Surg 1999; 178: 256-262.

3) N Hayes et al. Peritoneal citology in the surgical evaluation of gastric carcinoma. British Journal Cancer 1999, 79( ), 520-524.

4) H Nekarda et al. Immunocytochemically detected free peritoneal tumour cells (FPTC) are a strong prognostic factor in gastric carcinoma. British Journal of Cancer, 1999 79 (3/4), 611-619.

5) Nobutsugu Abe, Takashi Watanabe, Hiroshi Toda, Hiromichi Machida, Kazufumi Suzuki, Tadahiko Masaki, Toshiyuki Mori, Masanori Sugiyama, Yutaka Atomi and Yuzo Nakaya. Prognostic significance of carcinoembryonic antigen levels in peritoneal washes in patients with gastric cancer.The American Journal of Surgery 181 (2001) 356-361.

6) U. Ribeiro, J.J. Gama-Rodrigues, A.V. Safatle-Ribeiro et al., Prognostic significance of intraperitoneal free cancer cells obtained by laparoscopic peritoneal lavage in patients with gastric cancer. J Gastrointest Surg 2 (1998), pp. 244-249.

7) U. Ribeiro, J.J. Gama-Rodrigues, B. Biteman et al., Value of peritoneal lavage cytology during laparoscopic staging of patients with gastric cancer. Surg Laparosc Endosc 8 (1998), pp. 132-135.

8) Wataru Yasui , Naohide Oue , Hiroki Kuniyasu , Reiko Ito, Eiichi Tahara , Hiroshi Yokozaki . Review article: Molecular diagnosis of gastric cancer: present and future. Gastric Cancer Volume 4 Issue 3 (2001) pp 113-121.

9) Karl-Friedrich Becker,Gisela Keller and Heinz Hoefler. The use of molecular biology in diagnosis and prognosis of gastric cancer. Surgical Oncology 9 ( 2000 ), 5-11.

10) Ettore Seregni, et al. Diagnostic and prognostic tumor markers in the gastrointestinal tract. Seminars in Surgical Oncology 2001; 20:147-166.

11) N Mori et al. detection of telomerase activity in peritoneal lavage fluid from patients with gastric cancer using immunomagnetic beads. British Journal of Cancer, ( 2000 ), 83 (8), 1026-1032.



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