Surgical Research Review

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Surgery

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Detection of gastric cancer peritonealmetastases by peritoneal lavage:Current limitations and futureperspectivesJoyce Wong, MD,a and Daniel Coit, MD,b Tampa, FL, and New York, NY

From the Department of Surgery at Moffitt Cancer Center,a Tampa, FL; and Memorial Sloan-Kettering CancerCenter,b New York, NY

LONG-TERM SURVIVAL for most abdominal gastrointes-tinal malignancies is predicated upon stage, basedupon the tumor-node-metastasis (TNM) classifica-tion that includes tumor size or depth, nodal sta-tus, and presence of distant metastasis. Surgicalresection remains the mainstay of treatment andthe only possibility for cure for locoregional dis-ease. The evaluation of the extent of disease inthe peritoneal cavity remains critical in the deter-mination of appropriateness of surgical resection.Unlike ovarian cancer, where surgical debulkingoffers palliation and improved survival, the pres-ence of peritoneal metastases indicates stage IVdisease and is a contraindication for aggressive sur-gical resection in most gastrointestinal malignan-cies. Addressing each of these malignancies isbeyond the scope of this review. As such, we willconcentrate on gastric cancer as a model of perito-neal metastases in gastrointestinal cancer.

THE ROLE OF DIAGNOSTIC LAPAROSCOPY

Determination of whether a patient with gastriccarcinoma is a candidate for surgical resectionremains challenging, despite high-quality preoper-ative imaging. Staging laparoscopy before resec-tion allows for the detection of visiblesubradiologic disease and the collection of perito-neal lavage for cytology, with minimal morbidity,

d for publication March 22, 2012.

requests: Joyce Wong, MD, Department of Surgery, Mof-cer Center, 12902 Magnolia Drive, Tampa, FL 33612.joyce.wong@moffitt.org.

2012;152:1-4.

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often being performed as an outpatient proce-dure. Staging laparoscopy has clearly proven to bea clinically relevant tool in the preoperative stagingof patients. Up to one-third of patients consideredresectable after preoperative assessment with en-doscopy, endoscopic ultrasound, and multidetec-tor computed tomographic (CT) imaging havevisible peritoneal disease at the time of laparos-copy.1 Up to 30% of patients who have undergonelaparoscopy will not undergo any further operativeintervention, and as many as 10% of patientswould avoid a futile laparotomy and longer dura-tion of hospital stay had they undergone laparos-copy instead of direct laparotomy.2 Thesepatients should instead be directed towards moreappropriate palliative systemic treatment.

Staging laparoscopy, however, is underused inthe United States, only being performed in 8% ofgastric carcinoma patients according to an analysisof the Surveillance, Epidemiology and End Results(SEER) population-based cancer registry.2 CurrentNational Comprehensive Care Network (NCCN)guidelines recommend considering staging lapa-roscopy in patients with locoregional disease; how-ever, this has not been widely incorporated as aroutine part of the pretreatment staging evalua-tion. While there is still considerable reliance onpretreatment imaging, multidetector CT and posi-tron emission tomography (PET) scans have a lowsensitivity for detection of low-volume, clinicallyrelevant disease in the peritoneal cavity.

PERITONEAL CYTOLOGY

The analysis of peritoneal cytology is also anessential component of pretreatment staging. Thenatural history of patients with positive peritoneal

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cytology (PPC) mimics stage IV disease, as evi-denced by radiologic or visible metastatic disease.3

PPC has been shown to be a strong independentpredictor of worse outcome, even after R0 resec-tion.3 While the incidence of PPC varies in the lit-erature, Bentrem et al3 found up to 12% ofpatients with advanced (T4a, Nany, or TanyN$1) gas-tric cancer and 6% with <T4a tumors had PPC atlaparoscopy.3 The seventh edition of the AmericanJoint Committee on Cancer Staging designatesPPC as M1 disease.4 These patients most likelywill not benefit from aggressive surgical resection,and it is our practice to offer these patients pallia-tive systemic chemotherapy.

Surgical intervention for the prevention of po-tential future complications is also generally un-warranted in patients with PPC.5 In a series bySarela et al5 among gastric cancer patients withM1 disease visualized at laparoscopy, half ulti-mately required an intervention for palliationand 12% required palliative laparotomy, but only1% required gastrectomy for perforation. Gastrec-tomy in patients with PPC is unlikely to be ofbenefit unless performed to palliate intractablesymptoms.

Studies of neoadjuvant chemotherapy andresection in patients with PPC as the only evidenceof stage IV disease have found a median survival ofonly 12 months from resection and no 3-yearsurvivors.6 Aggressive resection to negative marginsin these patients is only anecdotally associated withlong-term survival. Mezhir et al7 found a mediansurvival of 2.5 years with clearance of PPC, as eval-uated by repeat laparoscopy after chemotherapy,compared to 1.4 years in those patients with persis-tence of positive cytology (P = .0003). However, sur-gical resection after the clearance of PPC was notassociated with any improvement in disease-specific survival. The median survival was similarbetween patients with clearance of PPC undergo-ing resection and those without resection.7 There-fore, the role of surgery after the clearance of PPCremains to be defined. It is our strategy to rou-tinely perform diagnostic laparoscopy with assess-ment of peritoneal cytology on all gastric cancerpatients as part of their pretreatment stagingevaluation.

MOLECULAR DETECTION

Peritoneal cytology is currently assessed viaPapanicolau staining and assessment by a cytopa-thologist. Conventional cytology, however, is posi-tive in only 59% of patients with visible peritonealdisease.8 There may still be a need for more sensi-tive methods of disease detection. Numerous

studies have attempted to define the yield and clin-ical utility of molecular analysis of peritoneal la-vage fluid.

Polymerase chain reaction (PCR) detection oftumor markers in peritoneal lavage fluid hasbeen studied as a potential method to improvedetection of peritoneal tumor cells in patients withgastric cancer. PCR is a laboratory technique thatallows for the exponential amplification of DNA,thereby increasing the sensitivity of gene detectionand identifying minute amounts of DNA. Deter-mination of what constitutes a positive result hasvaried widely, from ratio of gene mRNA to back-ground housekeeping gene mRNA9 to gene cycleamplification number.10

PCR evaluation of carcinoembryonic antigen(CEA) mRNA in peritoneal fluid has shown in-creased sensitivity for the detection of diseasecompared to cytology, and has also been shownto be associated with poor survival, similar to PPC.Kodera et al9 found significantly worse overall andrecurrence-free survival of CEA PCR+ patients com-pared to PCR� patients, independent of cytology.Our experience with PCR detection of CEAmRNA in peritoneal fluid also confirmed PCR tobe more sensitive than cytology, with positivePCR correlating with advanced stage disease. Wealso observed a significantly worse survival ofcytology-negative, PCR+ patients compared tocytology-negative, PCR� patients both overall andin a subset of patients that underwent R0 resec-tion. PCR appears to increase the yield of patientswith presumably micrometastatic disease, but theclinical sensitivity for disease behavior has yet tobe defined. To date, no study has shown PCR tobe a predictor of survival that is independent of cy-tology and tumor stage.

Tumor markers other than CEA have also beenevaluated, because not all gastric tumors are CEA-expressing.11 The Japanese, in particular, haveevaluated CK20, matrix metalloproteinase-7, andtelomerase expression, and have found similar re-sults with earlier time-to-recurrence and worseoverall survival. While CEA seems to be the mostsensitive tumor marker evaluated to date, it is un-clear whether this should be the sole marker tostudy in detection of gastric cancer cells in theperitoneal cavity. Multimarker PCR may prove tobe more clinically useful in capturing an ex-panded genetic profile, although this has yet tobe studied.

LIMITATIONS TO MOLECULAR DETECTION

The lack of a uniform definition of positive PCRstatus and uncertainty about the association of

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positive PCR with clinically relevant outcomesindependent of currently validated prognostic in-dices both remain significant limitations to thewidespread clinical use of this technology.Whether positive status is defined as gene ampli-fication cycle number or absolute mRNA quantifi-cation will impact which patients are classified aspositive. Unfortunately, this is the biggest chal-lenge when applying a more sensitive technique,such as PCR, to the detection of subclinical met-astatic disease. With conventional cytology, a pos-itive result is clearly associated with a very pooroutcome. The clinically relevant threshold has notyet been defined for PCR detection of peritonealmetastases. With the development of rapid PCRtechnology, the ability to use PCR as a means ofquickly and efficiently evaluating the peritonealcavity is being realized. A need for standardizingPCR classification is therefore necessary.

A significant number of patients with visibleperitoneal metastases have false-negative peritonealcytology. Evaluating peritoneal cytology with amoresensitive technique, such as PCR, offers a muchhigher yield of disease detection. A concern ofusing PCR in a staging algorithm, however, is thefalse-positive rate of detection. PPC has been shownto indicate a poor outcome, even in patients withearly-stage disease. Positive PCR in a similar groupof early-stage disease patients has an undefinedclinical relevance. Longer prospective follow-uptimes are needed in order to determine the bestthreshold and true predictive role of PCR, in areproducible manner, in both early stage andlocally advanced cancers. Overinterpreting the clin-ical significance of a false-positive PCR could lead toeither overtreatment with chemotherapy, or worse,not offering potentially curative resection.

Determination of which genes to evaluate mustalso be defined. With personalized cancer carebecoming more popular and feasible, the analysisof individual tumors may provide insight intowhich tumors markers are expressed and may bethe most sensitive for detection of disease. Micro-array analysis of gastric tumors may help in iden-tifying a panel of tumor markers that offer themost prognostic information.

FUTURE PERSPECTIVES

Currently, staging laparosopy with peritoneal cy-tology analysis remains the standard technique todelineate extent of disease beyond what conven-tional imaging reveals. PCR has emerged as aninnovative research tool with an as yet unknownclinical role. Other modalities, such as immunocyto-chemistry, targeted immunofluorescent antibodies,

and virally-mediated fluorescence, have all recentlybeen proposed as alternatives to PCR in theidentification of tumor cells. It is unclear at thistime what the prognostic significance and clinicalrelevance of detection is using these methods.

In conclusion, the pretreatment evaluation ofpatients with gastric cancer has undergone tre-mendous change in the last decade. The use ofendoscopy, endoscopic ultrasound, multidetectorCT, and PET-CT to stage disease has beensupplemented by staging diagnostic laparoscopywith peritoneal cytology analysis. Despite therecent inclusion of PPC into the staging criteriaof gastric cancer as M1 disease, routine laparo-scopic evaluation of the peritoneum and perito-neal cytology is infrequently performed. Staginglaparoscopy should be performed before surgicalresection, because a significant percentage ofpatients will require no further operative inter-vention and avoid the morbidity associated withlaparotomy.

Clearly, cytology has a clinically predictive rolein gastric cancer, and tools to molecularly charac-terize peritoneal cytology are now available.A standardized definition of positive PCR isneeded, and additional studies are necessary tocorrelate positive PCR cytology with clinical out-come and validate those findings independent oftumor stage. With evidence showing the highsensitivity of PCR, the molecular characterizationof peritoneal lavage fluid may be a reality in futurecancer staging.

REFERENCES

1. Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparos-copy in the management of gastric adenocarcinoma. AnnSurg 1997;225:262-7.

2. Karanicolas PJ, Elkin EB, Jacks LM, et al. Staging laparos-copy in the management of gastric cancer: a population-based analysis. J Am Coll Surg 2011;213:644-51.

3. Bentrem D, Wilton A, Mazumdar M, et al. The value of per-itoneal cytology as a preoperative predictor in patients withgastric carcinoma undergoing curative resection. Ann SurgOncol 2004;12:1-7.

4. Edge SB, Byrd DR, Compton CC, et al. American Joint Com-mittee on Cancer (AJCC) Cancer Staging Manual. 7th ed.Chicago: Springer; 2010.

5. Sarela AI, Miner TJ, Karpeh MS, et al. Clinical outcomeswith laparoscopic stage M1, unresected gastric adenocarci-noma. Ann Surg 2006;243:189-95.

6. Gold JS, Jaques DP, Bentrem DJ, et al. Outcome of pa-tients with known metastatic gastric cancer undergoing re-section with therapeutic intent. Ann Surg Oncol 2007;14:365-72.

7. Mezhir JJ, Shah MA, Jacks LM, et al. Positive peritoneal cy-tology in patients with gastric cancer: natural history andoutcome of 291 patients. Ann Surg Oncol 2010;17:3173-80.

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8. Burke EC, Karpeh MS, Conlon KC, et al. Peritoneal lavagecytology in gastric cancer: an independent predictor of out-come. Ann Surg Oncol 1998;5:411-5.

9. Kodera Y, Nakanishi H, Ito S, et al. Quantitative detection ofdisseminated free cancer cells in peritoneal washes withreal-time reverse transcriptase-polymerase chain reaction:A sensitive predictor of outcome for patients with gastriccarcinoma. Ann Surg 2002;235:499-506.

10. Moore Dalal K, Woo Y, Kelly K, et al. Detection of microme-tastases in peritoneal washings of gastric cancer patients bythe reverse transcriptase polymerase chain reaction. GastricCancer 2008;11:206-13.

11. Fujiwara Y, Doki Y, Taniguchi H, et al. Genetic detection offree cancer cells in peritoneal cavity of the patient with gas-tric cancer: Present status and future perspectives. GastricCancer 2007;10:197-204.