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RT-PCR Increases Detection of Submicroscopic Peritoneal Metastases in Gastric Cancer and Has Prognostic Significance

  • 2011 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Positive peritoneal cytology confers the same prognosis as clinical stage IV disease in gastric cancer. Conventional cytology examination, however, has low sensitivity. We hypothesize that real-time polymerase chain reaction (RT-PCR) may have increased sensitivity and provide more accurate staging information.

Methods

From February 2007 to April 2009, peritoneal lavage samples were collected prospectively from 156 patients with biopsy-proven gastric cancer undergoing staging laparoscopy. These washings were analyzed by both Papanicolaou staining and RT-PCR for the tumor marker carcinoembryonic antigen (CEA).

Results

Visible peritoneal disease was seen at laparoscopy in 38 patients (LAP+, 24%). Cytology was positive (CYT+) in 23 patients, while RT-PCR was positive (PCR+) in 30. The sensitivity of CYT for the detection of visible disease was 61% compared to 79% for PCR (P = 0.02). No visible peritoneal disease was seen at laparoscopy (LAP−) in 118 (76%) patients. Eight (7%) were CYT+, while 28 (24%) were PCR+. Predictors of PCR positivity included advanced-stage disease (T3–4 vs. T1–2 tumors) and poor pathologic features such as vascular or perineural invasion. Long-term follow-up demonstrated a worse survival of LAP−CYT−PCR+ (P = 0.0003) and LAP−CYT+PCR+ (P = 0.0004) compared to LAP−CYT−PCR− patients. There was no significant difference in survival between CYT−PCR+ and CYT+PCR+ patients. PCR positivity also predicted a higher likelihood of disease recurrence after resection. An R0 resection was performed in 85 LAP− patients (54%): only 1 (1%) was CYT+, while 13 (15%) were PCR+. Of this group, PCR+ demonstrated a worse survival than PCR− patients (P = 0.02). Further analysis showed that, in R0 resection, stage III/IV, CYT− subgroup, PCR+ was associated with a trend towards worse survival (P = 0.09) compared to PCR− patients.

Conclusion

RT-PCR for CEA increases the detection of subclinical peritoneal disease and is more sensitive than cytology. Predictors of positive PCR included advanced-stage disease, vascular invasion, and perineural invasion. PCR positivity was associated with increased disease recurrence and decreased survival. Further follow-up is required to determine if PCR positivity alone is an independent predictor of poor survival in gastric cancer.

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Authors and Affiliations

  1. Department of Surgery, Memorial Sloan–Kettering Cancer Center, 275 York Avenue, New York, NY, 10021, USA

    Joyce Wong, Kaitlyn Jane Kelly, Arjun Mittra, Mithat Gonen, Peter Allen, Yuman Fong & Daniel Coit

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  1. Joyce Wong
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  2. Kaitlyn Jane Kelly
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  7. Daniel Coit
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Correspondence to Daniel Coit.

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Discussant

Dr. R. Daniel Beauchamp (Nashville, TN, USA): One limitation of peritoneal cytology for staging of gastric cancer is that is has a relatively low sensitivity, and may be negative, even in the presence of visible peritoneal disease. This paper by Joyce Wong, Dan Coit, and colleagues from Memorial Sloan–Kettering Cancer Center examines the use of quantitative real-time RT-PCR analysis of the tumor marker carcinoembryonic antigen (CEA) as a more sensitive method to detect evidence of occult metastatic spread of within the peritoneal cavity in a group of patients with gastric adenocarcinoma. In addition, the presence of PCR positivity was associated with significantly worse survival as compared with PCR-negative patients, although PCR-positive status did not achieve statistical significance in cytologically negative patients. Interestingly, 39% of patients who had laparoscopically detectable peritoneal disease were cytologically negative and, of these, only 47% were PCR positive. Thus, my first two questions are the following: Did these PCR-negative tumors express CEA, and is there perhaps a more sensitive and specific gastric cancer cell biomarker or set of biomarkers that may be used? Secondly, since the peritoneal washings were done by laparoscopy, using this information for decisions to proceed with resection in the absence of visible implants would require awaiting these results and a second procedure. Have the authors begun to use this approach for decisions regarding resection, and can it be done with peritoneal lavage under local anesthesia?

Closing Discussant

Dr. Joyce Wong: Thank you for the discussion of our paper. Addressing your first question, we did also note that PCR for CEA was not positive in all or the vast majority of patients with positive cytology. While we do not have all the pathology data pertaining to CEA specifically, we presume that not all gastric cancers are CEA-expressing. We did examine a number of biomarkers prior to initiating this study, including CK20 and several of the MUC genes; however, CEA was the single most sensitive marker. We chose to independently examine RT-PCR for CEA, although it would be useful in the future to determine whether a panel of biomarkers may enhance disease detection. As to your second point, we performed staging laparoscopy as a separate procedure so that cytology results were available at the time of resection. Our institution considers patients with positive cytology as unresectable and will stratify those patients towards chemotherapy. Laparoscopy was performed with minimal morbidity. There has been some discussion revolving around how to perform peritoneal lavage without general anesthesia, although we currently do not routinely perform any other approach for obtaining peritoneal lavage.

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Wong, J., Kelly, K.J., Mittra, A. et al. RT-PCR Increases Detection of Submicroscopic Peritoneal Metastases in Gastric Cancer and Has Prognostic Significance. J Gastrointest Surg 16, 889–896 (2012). https://doi.org/10.1007/s11605-012-1845-2

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  • DOI: https://doi.org/10.1007/s11605-012-1845-2

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