Laparoscopic Staging and Peritoneal Cytology

PANCREATIC CANCER

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LAPAROSCOPIC STAGING AND PERITONEAL CYTOLOGY Carlos FernBndez-del Castillo, MD, a n d Andrew L. Warshaw, MD

Two basic approaches prevail in the management of the patient with recently diagnosed pancreatic cancer. In one approach, all patients undergo surgical exploration soon after the clinical diagnosis has been established. In the other, a series of tests are carried out in an attempt preoperatively to stage the cancer, and tailored treatment is instituted based on these findings. The potential advantages of preoperative staging in pancreatic cancer are manifold: (1) further surgery is avoided in patients with advanced disease, (2) patients with resectable tumors are identified and transferred to specialized centers in which pancreatic resection can be carried out safely, (3) new treatment protocols that complement or extend surgery can be implemented in order to improve the poor long-term results after resection, and (4) radiation therapy is limited to patients without metastatic disease. If precise preoperative staging is desired, laparoscopy must be part of the protocol. Peritoneal and superficial liver metastases are the second most common sites of extranodal metastases in pancreatic cancer (following the liver) and are .~ these implants compresent in more than 50% of patients at a ~ t o p s yBecause monly measure only a few millimeters and thus are beyond the resolution power of CT or ultrasonography, they can be detected only by direct visualization at the time of laparotomy or laparoscopy. They are frequently multiple and can be located on the peritoneal surfaces of the liver, abdominal and pelvic wall, stomach and intestines, or omentum (Fig. 1). TECHNIQUE FOR LAPAROSCOPIC EXAMINATION IN PANCREATIC CANCER

Our preference is to perform laparoscopic examination under general anesthesia, although local anesthesia and intravenous sedation can be used. After adequate pneumoperitoneum is obtained, a large trocar and subsequently the camFrom the Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston. Massachusetts SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA

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Figure 1. Intra-abdominal spread in pancreatic cancer.

era are inserted, usually through an infraumbilical incision. Visual examination of the lower abdomen and pelvis is completed first. Peritoneal and omental metastases may be found in this location even in the absence of implants elsewhere. Free fluid is aspirated for cytologic evaluation. The laparoscope is then rotated to inspect the upper abdomen. Examination of the liver surfaces is particularly relevant. To inspect the undersurface of the liver adequately, a rod must be inserted through a second, smaller trocar (5 mm) in the right upper quadrant of the abdomen. Specimens of peritoneal or omental nodules can be taken for biopsy with forceps inserted through the second trocar. Implants in the liver are most easily sampled with a Tru-Cut needle inserted directly through the abdominal wall. Nodules smaller than 1 mm can be sampled accurately under direct vision. For samples on the pelvic peritoneum, another trocar in the lower midline is sometimes necessary for the biopsy forceps, although the cutting needle inserted percutaneously can be used. Enlarged lymph nodes can be sampled successfully with the cutting needle or by fine-needle aspiration. Laparoscopy also permits visualization of the body and tail of the pancreas by using either a supragastric approach (through the lesser omentum) or entering below the stomach (through the gastrocolic omentum or the mesocolon). This procedure, which also has been called pancreatoscopy, was first proposed by Meyer-Burglgand was further developed by Ishidan and Cuschieri et aL6Others have proposed a more extensive laparoscopic evaluation for staging pancreatic cancer, including examination of the hilus of the liver and mesenteric and celiac vessels4 and use of laparoscopic ultrasonography for detection of intraparenchyma1 liver metastases, vascular invasion, or lyrnphaden~pathy.','~ Cholangiography also can be performed at the time of laparoscopy, with injection of contrast agent transhepatically either into the gallbladder or into a dilated bile duct.6 Laparoscopic cholecystojejunostomy recently was described in patients with pancreatic cancer who at the time of laparoscopic staging are found and gastrojejunostomy is feasible as well. to be ~nresectable?~ It has been our practice to use laparoscopy to help stage pancreatic cancer because of its unique capacity to detect small peritoneal metastatic disease. We do not believe that direct visualization of the pancreatic tumor or involvement of the

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major vessels is necessary because a CT scan already has been obtained in most cases. Furthermore, the tumor can be biopsied percutaneously in most cases and perhaps should not be attempted in patients with potentially resectable tumors, as is discussed later. Diagnostic cholangiography is rarely needed by the time the patient is being staged. If any question exists about the diagnosis of pancreatic cancer or if relief of jaundice is required before surgery, endoscopic retrograde cholangiopancreatography (EPCP) and stenting are performed before staging. Furthermore, one of the attractive features of laparoscopy should be its simplicity, which makes it feasible in any hospital and thereby allows for triage of potentially resectable patients to specialized centers. RESULTS FROM CLINICAL STUDIES

The use of laparoscopy for staging in pancreatic cancer predates by many years the current surge of laparoscopic surgical procedures. As early as 1911, Bernheim2reported a patient with pancreatic cancer that was evaluated with "cystoscopy of the abdominal cavity" and proposed that this technique could be useful to identify patients who would not benefit from further surgery. Before the widespread availability of CT, laparoscopy was used extensively in Europe for the diagnosis and staging of various gastrointestinal cancers, including those of the p a n ~ r e a s . ~ , Results ~ , ' ~ , ~of ~ several published series that describe the use of diagThe table nostic laparoscopy in pancreatic cancer are found in Table 1.1,5,6,9,"~12~24,25 includes a more recent series of 114 patients staged by us over a 5-year period (April 1989-April 1994). The series published by Ivanov and Keranov12and the second one from Cuschieri5 both show prevalences of peritoneal and liver metastases identified by laparoscopy of 70% or more. This prevalence is much higher than the range of 35% to 43% previously described by us and reported by Ishida." This discrepancy is explained by our exclusion of patients with liver or other distant metastases already identified by CT or ultrasonography. These patients clearly derive no further benefit from laparoscopy, because they are not candidates for resection or radiation, and tissue for diagnosis can be obtained percutaneously with little morbidity. The series by Conlon et a14was not included in the table because it involves a variety of peripancreatic malignancies. In that study, the use of extended laparoscopic assessment allowed for identification of unresectability in 41 of 108 patients, in some cases because of liver or peritoneal metastases and in other cases because of vascular invasion or nodal meta~tases.~ Our experience from 1989 to 1994 shows that the prevalence of liver and peritoneal involvement identified by laparoscopy was 27 of 114 patients (23.6%). Table 1. DETECTION BY LAPAROSCOPY OF PERITONEAL AND LIVER METASTASES IN PANCREATIC CANCER Liver and Peritoneal Year of Publication Involvement (%) (No. of Patients) Reference Cuschieri5 Ishidall Warshaw et aIz5 Cuschieri et aI6 lvanov and Keranov12 Warshaw et aIz4 Bemelman et all Fernandez-del Castillo et a19

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Eleven of these patients had metastases to the liver surface, 3 to the peritoneum, 2 to the omentum, and 11 to more than one site. Metastases were 2.4 times more common in tumors of the body and tail of the pancreas (11/25, 44%) than in pancreatic head cancers (16/89, 17.9%)(P < 0.05). This observation is probably due to a relative delay in diagnosis of tumors of the distal pancreas, which remain "silent" in the absence of jaundice. The overall prevalence of intra-abdominal spread detected by laparoscopy is significantly less than that found by us in the period of 1982 to 1989, in which 35 of 86 patients (40.6%)had positive findings. No obvious explanation exists for this change, although several possibilities exist. One is that refinements in CT allow for identification of smaller liver and peritoneal metastases. However, if this were the case, we might expect to be performing fewer staging laparoscopies, whereas we actually perform almost twice as many. Another possibility is that we are seeing patients at an earlier stage of the disease, which could be true but seems unlikely inasmuch as the patient's recognition and reporting of symptoms has been and still is the index for diagnostic evaluation. Recent studies show that the delay until definitive diagnosis has only been reduced by a few weeks in the last decade.22A third explanation is that the biology of pancreatic cancer may be changing, something also suggested by the increased cure rate and 5-year survival rate being seen throughout the world in the past few years. Despite this relatively lower diagnostic yield, we still believe that laparoscopy should form an integral part of the staging of patients with pancreatic cancer as a way to optimize resources and avoid unnecessary surgery (Fig. 2). Of the 27 patients with metastases in our recent series none underwent further surgery. Those patients with jaundice (which comprised 60%)received palliative treatment with endoscopic or percutaneous techniques or both. Of the 87 patients without visible intra-abdominal spread, 42 were found to have vascular invasion by angiography and were offered radiation therapy. This treatment was ultimately undertaken by 35. Forty patients underwent exploratory surgery with the intent of

114 patients

27 patients with metastases underwent no further surgery

87 patients without metastatic spread

40 patients with negative angiographic findings explored for resection

30 resected (75%)

42 patients had positive angiographic findings demonstrating vascularinvasion

35 radiated

Figure 2. Outcome of 114 laparoscopies in patients with pancreatic cancer without evidence of spread by CT.

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resection, which was accomplished in 30 (resectability of 75%). Two of the remaining 10 patients had evidence of peritoneal spread that had been missed by laparoscopy. These results indicate a sensitivity of 93% for the procedure, similar to our previous experience. The specificity is 100%because in all cases the diagnosis of metastatic carcinoma was based on histologic evidence from biopsies at the time of laparoscopy and not on the visual impression alone (which can be in error). The current trend for more aggressive multimodality treatments in which radiation and chemotherapy precede resection underscores even more the necessity to exclude metastatic disease, because the morbidity, costs, and time commitment required by this approach are not negligible. Other institutions share this belief and include laparoscopy in their protocols before including patients for neoadjuvant therapy In our current staging scheme for patients with presumptive pancreatic cancer, we use spiral CT as an initial test. If this study demonstrates on absence of metastases, we proceed with laparoscopy in all patients with tumors of the pancreatic body and tail and in patients with pancreatic head tumors larger than 2 cm, because in smaller lesions the likelihood of metastases is low. The information obtained by spiral CT and its curvilinear and three-dimensional reconstructions makes the use of angiography obsolete in most cases.

PERITONEAL CYTOLOGY

Pancreatic cancer implants on the serosal surfaces are presumably the result of transperitoneal seeding from the primary tumor. To investigate the prevalence of malignant cells within the peritoneal cavity in patients with small, apparently contained tumors, we performed peritoneal washings in 40 patients with early .~~ were perpancreatic cancer (i.e., localized by CT and a n g i ~ g r a p h y )Washings formed during laparoscopy or laparotomy by instilling 100 mL of normal saline into the subhepatic space, allowing it to disperse in the peritoneal cavity by tilting the operating table and agitating the abdominal wall, and then aspirating under direct vision. Cytologic smears and cell blocks prepared from centrifuged specimens were used and examined for the presence of malignant cells using strict criteria for malignancy in order to avoid potential confusion with reactive mesothelial or inflammatory cells. Malignant cells were found in 12 of those first 40 patients (30%) (Fig. 3). A disturbing finding of the study was that positive cytologic results were significantly increased in patients who had undergone percutaneous needle biopsy earlier compared with those who had not (75%versus 19%).This finding is consistent with observations made by other investigators of rapid intra-abdominal spread ~ , ~cautions ~ against and implantation after tumor manipulation and b i o p ~ y land the use of preoperative biopsy in potentially resectable patients. The likelihood of resectability was higher in patients with negative cytologic findings (13 of 25) compared with patients with positive malignant cells (1of lo), a fact that was also reflected in a significantly better survival. In another report of a small series of patients, peritoneal cytology was positive preoperatively in two of seven patients who had undergone a previous percutaneous biopsy with fine-needle aspiration and was negative in all eight patients without prior biopsy.29Although our more recent experience9and that of others16,17 has failed to confirm a statistically significant increased risk of peritoneal dissemination with needle biopsy, the phenomenon does exist. We therefore continue to recommend that whenever histologic diagnosis is mandatory (e.g., if the patient

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a

Figure 3. Malignant cells obtained through peritoneal wash~ngsat the time of laparoscopy.

is to enter a protocol of intensive preoperative radiation and chemotherapy), the biopsy be guided transduodenally by endoscopic ultrasonography. In our experience of 1989 to 1994, peritoneal cytology was positive in only 16 of 94 patients (17%).9A positive peritoneal cytology had a close correlation with the presence of liver or peritoneal implants (10/22 with metastases vs 6/72 without, P < 0.001). Although most of the cytologies are seen in conjunction with visible metastases, 38% of positive cases occur without other evidence of spread, and this group still amounts to 8% of all resection candidates. This lower overall prevalence in recent years may be in agreement with the lower prevalence of other positive laparoscopic findings, or may be the result of a more limited use of preoperative biopsy of pancreatic tumors. In an attempt to enhance the detection of malignant cells and therefore the yield of peritoneal cytology, we recently measured Ki-ras mutations in peritoneal washings obtained at laparoscopy or laparotomy in 24 subjects with pancreatic cancer.20Conventional cytologic analysis detected micrometastases in 3 of 24 cases (12%),whereas radiolabeled polymerase chain reaction (PCR)-basedKi-ras codon 12 mutational analysis was positive in only 2 of 24 (a%),which were also positive by morphologic criteria. In a different approach, we used immunocytochemistry, with monoclonal antibodies against carcinoembryonic antigen (CEA), CA 19-9, LEUMI, and 872.3. In a series of 33 patients, morphology alone detected four patients with micrometastases (12%), whereas immunocytochemistry confirmed the diagnosis of malignancy in these four patients and identified five more (27%), suggesting that this technique may expand the value of peritoneal cytology in the staging of pancreatic cancer. To further investigate the significance of peritoneal cytology, we examined the outcomes of 32 consecutive patients with positive (i.e., malignant) cytology by either morphologic or immunocytochemical criteria. Seventeen patients had visible metastases at the time of laparoscopy or laparotomy and 15 did not. Of the 15

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patients without visible metastases, 2 were resected, 3 were treated with intraoperative radiation, and 8 received external beam radiation and 5-fluorouracil. In comparison, 9 of 17 patients with metastases received no further treatment, and the remaining 8 patients underwent palliative chemotherapy or radiation. The survival curves overlap, and the median survival is not significantly different (7.8 months for the group with visible metastases, and 8.6 months for the one without visible lesions, P = 0.9), indicating that the presence of micrometastases has the same meaning as visible metastases and that local treatment that aims at tumor control has no benefit when malignant cells are found in peritoneal washings. Only three other studies have evaluated peritoneal washings in pancreatic cancer. In one, Martin and Goellner18describe the presence of malignant peritoneal cells in 22% of 20 pancreatic cancer patients. They also describe a better prognosis for patients with negative washings. The second study found malignant cells in 3 The third study of 36 patients (8%), all of whom had peritoneal carcin~matosis.'~ also Aught evidence of metastatic spread by immunocytologic methods rather than conventional morphology. Using a panel of monoclonal antibodies directed against tumor-associated antigens CEA, CA 19-9, Ra96, and c-54-0, Juhl et all4 found intraperitoneal micrometastatic cells after peritoneal lavage in 58% of 32 pancreatic cancer patients who underwent surgical exploration. The significance of this finding is not clear, particularly because micrometastases also were sought in the bone marrow and were found to be present in 58% of patients. The incidence of metastatic dissemination when both sites are combined was 72%. Of the 11 patients in this group who underwent resection 5 had tumor cells in the bone marrow or the peritoneal cavity or both, but their outcome was not described in the study. CONCLUSIONS

Laparoscopy is a valuable adjunct in the staging of pancreatic cancer. This study allows identification of implants in a significant number of patients with tumors of the body and tail of the pancreas and, to a lesser extent, in those of the pancreatic head. Peritoneal washings obtained at the time of laparoscopy detect micrometastases in many patients who otherwise have no evidence of metastatic spread and portend advanced disease that does not benefit from aggressive local treatment. References 1. Bemelman WA, de Wit LTh, van Delden OM, et al: Diagnostic laparoscopy combined with laparoscopic ultrasonography in staging of cancer of the pancreatic head region. Br J Surg 825320-824,1995 2. Bernheim BM: Organoscopy: Cystoscopy of the abdominal cavity. Ann Surg 53:764-767, 1911 A

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A

A

3. Chissov VI, Maksimov IA, Vinogradov AL: Laparoscopy in the diagnosis of gastric carcinoma spread. Khirurgiia (Mosk) 11:13,1981 4. Conlon KC, Dougherty E, Klimstra DS, et al: The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg 223:134-140,1996 5. Cuschieri A: Laparoscopy for pancreatic cancer: Does it benefit the patient? Eur J Surg Oncol14:4144,1988 6. Cuschieri A, Hall AW, Clark J: Value of laparoscopy in the diagnosis and management of pancreatic carcinoma. Gut 19:672-677,1978 7. Dagnini G, Caldironi MW, Marin G, et al: Laparoscopy in abdominal staging of esophageal carcinoma: Report of 369 cases. Gastrointest Endosc 32:400-402,1986

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8. Fernbndez-del Castillo C, Warshaw AL: Peritoneal metastases in pancreatic carcinoma. Hepatogastroenterology 40:430432,1993 9. Ferntindez-del Castillo C, Rattner DW, Warshaw AL: Further experience with laparoscopy and peritoneal cytology in staging for pancreatic cancer. Br J Surg 82:1127-1129, 1995 10. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al: Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 167:104-113,1994 11. Ishida H: Peritoneoscopy and pancreas biopsy in the diagnosis of pancreatic diseases. Gastrointest Endosc 29:211-218,1983 12. Ivanov S, Keranov S. Laparoscopic assessment of the operability of pancreatic cancer. Khirurgiia (Sofiia) 4212-14, 1989 13. John TG, Greig JD, Carter DC, et al: Carcinoma of the pancreatic head and periampullary region: Tumor staging with laparoscopy and laparoscopic ultrasonography. Ann Surg 221:156-164,1995 14. Juhl H, ~ t r i i eM, l Wroblewski A, et al: Immunocytological detection of micrometastatic cells: Comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastric, colorectal and pancreatic cancer patients. Int J Cancer 57:l-6,1994 15. Kriplani AK, Kapur BM: Laparoscopy for preoperative staging and assessment of operability in gastric carcinoma. Gastrointest Endosc 37:441443, 1991 16. Leach SD, Rose JA, Lowy AM, et al: Significance of peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreatic head. Surgery 118:472-478,1995 17. Lei S, Kini J, Kim K, et al: Pancreatic cancer: Cytologic study of peritoneal washings. Arch Surg 129:639-642,1994 18. Martin JK Jr, Goellner JR: Abdominal fluid cytology in patients with gastrointestinal malignancies. Mayo Clin Proc 61:467471,1986 19. Meyer-Burg J: The inspection, palpation and biopsy for the pancreas. Endoscopy 499, 1972 20. Rall CJ, Rivera JA, Centeno BA, et al: Peritoneal exfoliative cytology and Ki-ras mutational analysis in patients with pancreatic adenocarcinoma. Cancer Lett 97:203-211,1995 21. Shirni S, Banting S, Cuschieri A: Laparoscopy in the management of pancreatic cancer: Endoscopic cholecystojejunostomyfor advanced disease. Br J Surg 79:317-319,1992 22. Singh SM, Longmire WP, Reber HA: Surgical palliation for pancreatic cancer: The UCLA experience. Ann Surg 212:132-139, 1990 23. Warshaw AL: Implications of peritoneal cytology for staging of early pancreatic cancer. Am J Surg 161:26-30,1991 24. Warshaw AL, Gu Z-y, Wittenberg J, et al: Preoperative staging and assessment of resectability of pancreatic cancer. Arch Surg 125:230-233,1990 25. Warshaw AL, Tepper JE, Shipley WU: Laparoscopy in the staging and planning of therapy for pancreatic cancer. Am J Surg 151:76-80,1986 26. Watt I, Stewart I, Anderson D, et al: Laparoscopy, ultrasound and computed tomography in cancer of the oesophagus and gastric cardia: A prospective comparison for detecting intra-abdominal metastases. Br J Surg 76:1036-1039,1989 27. Weiss SM, Skibber JM, Mohiuddin M, et al: Rapid intra-abdominal spread of pancreatic cancer. Arch Surg 120:415416,1985 28. Yeung RS, Weese JL, Hoffman JP, et al: Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma: A phase I1 study. Cancer 72:2124-2133,1993 29. Zerbi A, Balzano G, Bottura R, et al: Reliability of pancreatic cancer staging classifications. Int J Pancreatol15:13-18,1994

Address reprint requests to Carlos Fernbndez-del Castillo, MD Massachusetts General Hospital ACC/464 15 Parkman Street Boston, MA 02114