Intraoperative irrigation cytology of the remnant pancreas to detect remnant distinct pancreatic ductal adenocarcinoma in patients with intraductal papillary mucinous neoplasm undergoing partial pancreatectomy Yasuhisa Mori, MD, PhD,a Takao Ohtsuka, MD, PhD,a Koji Tamura, MD,a Noboru Ideno, MD,a Teppei Aso, MD,a Hiroshi Kono, MD,a Yosuke Nagayoshi, MD,a Junji Ueda, MD, PhD,a Shunichi Takahata, MD, PhD,a Shinichi Aishima, MD, PhD,b Fumihiko Ookubo, CT,b Yoshinao Oda, MD, PhD,b and Masao Tanaka, MD, PhD,a Fukuoka, Japan
Background. Patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas may have concomitant distinct pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and usefulness of intraoperative irrigation cytology of the remnant pancreas (IICP) during pancreatectomy to detect remnant distinct PDAC in patients with IPMN. Methods. The records of all 48 patients with IPMN who underwent IICP during partial pancreatectomy at our institution from April 2007 to March 2012 were reviewed retrospectively. After division of the pancreas, a 4-French tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and fluid for cytologic examination was obtained by saline irrigation through the tube. If the third IICP was positive, patients underwent additional pancreatic resection. Clinical and pathologic outcomes were evaluated. Results. The third IICP was positive in 5 patients. Postoperative pathologic examination showed that these patients all had remnant distinct PDAC in the additionally resected specimen, which was not detectable on preoperative imaging examination or on intraoperative macroscopic examination, ultrasonography, or palpation. This PDAC was stage 0 in 4 patients and stage III in 1 patient. No procedure-related complications were observed. One patient developed peritoneal metastasis after 10 months, 1 developed liver metastasis after 20 months, and 1 developed PDAC in the remnant pancreas after 24 months. Conclusion. IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging or intraoperative examination. (Surgery 2014;155:67-73.) From the Department of Surgery and Oncology,a and the Department of Anatomic Pathology,b Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM (IPMN) of the pancreas was first reported by Ohashi et al1 in Accepted for publication June 28, 2013. Reprint requests: Masao Tanaka, MD, PhD, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.06.059
1982. Since then, improved imaging techniques and increased clinician awareness have increased the frequency of diagnosis.2 International consensus guidelines established in 20063 and revised in 20124 defined appropriate management. Histologic findings range from low-grade dysplasia to invasive ductal carcinoma, but progression to carcinoma is generally slow5-7 and the prognosis is therefore favorable. In contrast, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor. Early diagnosis can improve prognosis, SURGERY 67
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but early PDAC is generally asymptomatic and difficult to detect on imaging examinations, and the majority of patients present with advanced disease. The reported prevalence of PDAC in patients with IPMN, including both synchronous and metachronous lesions, is 4.4–9.9%,8-15 indicating that patients with IPMN have an increased risk of PDAC. Because of the increased risk of PDAC, we performed intraoperative irrigation cytology of the remnant pancreas (IICP) during some partial pancreatectomy procedures in patients with IPMN. From April 2007 to November 2010, IICP was performed at the discretion of the surgeon. Postoperative pathologic examination found that 13 of the 37 patients (35%) who did not undergo IICP during this period had malignant IPMN or unexpected distinct PDAC in the resected specimen despite negative preoperative cytology. We also previously reported a patient with IPMN who had concomitant multifocal PDAC that was not detectable on preoperative imaging examinations.16 We therefore changed our policy, and from December 2010 we performed IICP during partial pancreatectomy in patients with IPMN whenever feasible, aiming to detect remnant, distinct PDAC. Such a protocol has not previously been reported. This study evaluated the safety of our IICP technique and its usefulness for the detection of previously undetected, concomitant remnant PDAC. PATIENTS AND METHODS Study population. This study was performed according to the principles of the Declaration of Helsinki. Written informed consent for pancreatic surgery including IICP was obtained from all subjects. We reviewed retrospectively the records of all 93 patients with a preoperative diagnosis of possible IPMN who underwent initial partial pancreatectomy at our institution from April 2007 to March 2012. The indications for operative treatment of IPMN were according to the international consensus guidelines, including all cases of main duct IPMN (MD-IPMN), and branch duct IPMN (BD-IPMN) with abdominal pain, jaundice, pancreatitis, mural nodule, or positive cytology.3,4 The study group also included patients with IPMN who did not have any predictors of malignant transformation, but who underwent operations for other reasons, such as PDAC or carcinoma of the duodenal papilla. Among the 73 patients who underwent surgery before December 2010, IICP was performed in 36 patients, at the discretion of the surgeon. Among the 20 patients who underwent surgery from December 2010 to March 2012, IICP was performed in all 12 patients who underwent open
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surgery, irrespective of preoperative cytology findings (positive in 7 patients, negative in 5 patients). IICP was not performed in patients who underwent laparoscopic operations. From December 2010, open operations were performed in all patients with positive preoperative cytology, in patients with MD-IPMN who had a mural nodule, and in patients with BD-IPMN who had $2 of the following: (1) Cyst $30 mm in diameter, (2) mural nodule, and (3) history of acute pancreatitis.17 All 48 patients who underwent IICP were enrolled in this study (29 males, 19 females; mean age, 69 years; range, 38– 86). Four surgeons performed IICP during the study period. Preoperative imaging and pancreatic juice collection. All patients underwent preoperative magnetic resonance imaging (MRI)/cholangiopancreatography and computed tomography (CT). IPMN was defined as MD-IPMN or BDIPMN based on the findings of these examinations.3,4 BD-IPMN was defined as IPMN exclusively involving the branch ducts, with grape-like collections of small cysts. MD-IPMN was defined as IPMN with a dilated main pancreatic duct, without grape-like collections. If both grape-like collections and dilation of the main duct were observed, but there were no findings indicating main duct involvement (such mural nodules in the main duct), the dilated duct was considered to be caused by mucin hypersecretion from BD-IPMN and the lesion was classified as BD-IPMN. Mixed-type IPMN was classified as MD-IPMN. Because early stage PDAC cannot easily be detected by CT or MRI, all patients underwent preoperative ERP for pancreatic juice collection for cytologic examination, which was successful in 46 of the 48 patients. Percutaneous, endoscopic, and intraductal ultrasonography were performed when indicated.11,17,18 Cytologic examination. Pancreatic fluid samples were centrifuged at 3,200 rpm for 5 minutes. Sediment smear slides were fixed in 95% ethyl alcohol and polyethylene glycol and stained by the Papanicolaou technique. Two cytologists classified the samples according to the degree of structural and cytologic atypia: Class I, no atypical cells; class II, atypical cells but no evidence of malignancy; class III, atypical cells inconclusive for malignancy (Fig 1, A); class IV, strongly suggestive of malignancy (Fig 1, B); and class V, conclusive for malignancy (Fig 1, C). Class IV and V results were considered positive. Operative procedures and IICP. The pancreas was cut near the superior mesenteric artery or vein, and planned pancreatoduodenectomy or distal pancreatectomy (DP) was performed.19-21 After
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Fig 1. Representative microscopic findings of cells collected by intraoperative irrigation cytology of the remnant pancreas. A, Class III, atypical cells inconclusive for malignancy. B, Class IV, strongly suggestive of malignancy. C, Class V, conclusive for malignancy.
Fig 2. Intraoperative irrigation cytology of the remnant pancreas. A 4-French polyvinyl tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and saline was gently irrigated through the tube with a syringe to obtain fluid for cytologic analysis.
division of the pancreas, a 4-French polyvinyl tube (Atom Medical, Saitama, Japan) was inserted into the main pancreatic duct of the remnant pancreas from the cut edge and advanced about 2 cm. Saline (1–2 mL) was gently irrigated through the tube with a syringe to obtain fluid for cytologic examination (Fig 2). This irrigation was performed 3 times, with an assistant suctioning any pancreatic fluid that leaked into the abdominal cavity to prevent dissemination of cancer. Intraoperative frozen section examination of the surgical margin was also performed. Visual inspection, palpation, and intraoperative ultrasonography of the remnant pancreas were performed to help determine the optimal resection line and to detect any signs of tumor. The IICP samples were graded as for the preoperative pancreatic fluid samples. If the third IICP was positive, additional pancreatic resection was performed. When feasible, this additional resection removed only an additional 2–4 cm of the pancreas. If additional resection after proximal pancreatectomy would leave only a minimal
volume of the pancreatic tail, total pancreatectomy was performed. Additional resection after DP is more difficult than after proximal pancreatectomy.4 If additional resection of 2–4 cm was not feasible after DP, total pancreatectomy was performed. Additional resection was also performed if frozen section examination showed high-grade dysplasia or invasive carcinoma at the cut margin, but not if it showed low- or intermediate-grade dysplasia at the cut margin, in accordance with the international consensus guidelines (2012).4 IICP and frozen section examinations were repeated after each additional resection. Additional resections were performed until both these examinations had negative findings. Pathologic examination. Surgical specimens were fixed in 10% formalin, cut into 5-mm thick slices, and stained with hematoxylin and eosin. Pathologic diagnosis classified IPMN according to the World Health Organization 2010 classification as low-, intermediate-, or high-grade dysplasia, or associated invasive carcinoma. IPMN lesions had histologic characteristics that were distinct from pancreatic intraepithelial neoplasia.22 If >1 IPMN was resected, the greatest pathologic grade was recorded. Concomitant distinct PDAC was defined as a lesion that was separate from the IPMN, with no transition area from the IPMN to the PDAC. Staging of PDAC was according to the Japanese General Rules for pancreatic cancer.23 Stage 0 PDAC was defined as pancreatic intraepithelial neoplasia-3, but not IPMN with high-grade dysplasia. RESULTS Tumor classifications, and IICP and pathologic findings. The preoperative classification of IPMN was BD-IPMN in 40 patients and MD-IPMN in 8 patients. Thirteen of the 48 patients (10 with
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BD-IPMN and 3 with MD-IPMN) had class III, IV, or V results on the first IICP sample (Table I). Five of these 13 patients had positive (class IV or V) findings on the third IICP sample (3 patients with BD-IPMN and 2 with MD-IPMN) and underwent additional resection. The pathologic examination findings of the 48 resected specimens are shown in Table II. Preoperative pancreatic juice cytology and IICP findings. Table III shows the relationships between preoperative pancreatic juice cytology and IICP. One of the 33 patients (3%) with negative preoperative cytology and 4 of the 13 patients (31%) with positive preoperative cytology had positive IICP. The 9 patients with positive preoperative cytology and negative IICP all had malignant IPMN or distinct PDAC in the resected specimen. Tumors in patients who underwent additional resection. All 5 patients who underwent additional resection had malignant lesions in the additionally resected specimens. These lesions were not detectable on preoperative imaging examinations or on intraoperative macroscopic examination, ultrasonography, or palpation. Fig 3 shows the locations of IPMN and distinct PDAC in these patients. Patients 4, 6, and 7 eventually underwent total pancreatectomy (Table I). Patient 4 underwent proximal pancreatectomy for invasive PDAC in the pancreatic head. After positive IICP, total pancreatectomy was performed because an irregular stricture of the main pancreatic duct in the pancreatic tail had been detected on preoperative ERP. Patient 6 underwent DP for invasive PDAC and BD-IPMN in the pancreatic body and tail. After positive IICP, total pancreatectomy was performed because the cut surface was already close to the gastroduodenal artery. Patient 7 underwent proximal pancreatectomy for MD-IPMN in the pancreatic head. This patient initially underwent additional resection of 2 cm of the remnant pancreas. Repeat IICP after the additional resection was positive, and total pancreatectomy was eventually performed. Patient 10, who had a preoperative diagnosis of BD-IPMN, and patient 12, who had a preoperative diagnosis of MD-IPMN, underwent additional resection of only 2–4 cm of the remnant distal pancreas. Intraoperative frozen section results reported a positive surgical margin only in patient 7, showing IPMN with high-grade dysplasia. The frozen section results were reported simultaneously with the IICP results. Pathologic examination revealed noninvasive PDAC (stage 0) in the additionally resected pancreas in patients 4, 7, 10, and 12; and invasive PDAC with regional lymph node metastasis on the posterior surface of the
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pancreatic head (stage III) in patient 6. All previously undetected lesions in the additionally resected specimens were distinct PDAC that was separate from IPMN. Follow-up. No IICP-related complications, such as postoperative pancreatitis, bleeding, or perforation of the pancreatic duct or periductal pancreatic parenchyma were observed. Patients with invasive IPMN or PDAC on pathologic examination were followed up every 3 months after surgery with CT and MRI. Patients with only noninvasive IPMN on pathologic examination were followed up every 6 months. During the mean follow-up period of 20 months (range, 1–50), recurrence was detected in 3 patients. Patient 6, who had positive IICP findings and stage III PDAC in the additionally resected pancreas, developed peritoneal metastasis after 10 months but no liver metastasis, and died of this disease. One patient with negative IICP findings (class II) and IPMN with high-grade dysplasia in the resected specimen developed PDAC in the remnant pancreas that was detected 24 months postoperatively. Another patient with negative IICP findings who had invasive IPMN in the resected specimen died of liver metastasis that was detected 20 months postoperatively, without tumor recurrence in the remnant pancreas. The remaining 45 patients were alive without evidence of recurrence at the last follow-up. DISCUSSION The results of this study show that IICP during partial pancreatectomy in patients with IPMN can detect remnant distinct PDAC that cannot be detected by preoperative imaging or by intraoperative macroscopic examination, ultrasonography, or palpation. It is important to consider the possibility of concomitant distinct PDAC in patients with IPMN, and make an effort to avoid leaving PDAC in the remnant pancreas after partial pancreatectomy. ERP is not routinely performed before pancreatectomy because it has a high morbidity rate. However, early stage PDAC is not easily detected by CT, MRI, or endoscopic ultrasonography,16,24-26 and we now routinely perform ERP before partial pancreatectomy in patients with IPMN. Eguchi et al27 screened patients with IPMN undergoing partial pancreatectomy by intraoperative frozen section histology and pancreatic juice cytology from each pancreatic segment (head, body, and tail), and reported that 13 of 43 patients (42%) required additional pancreatic resection. Lavage fluid from a specific section of the pancreatic duct has previously been reported to be useful
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Table I. Details of the 13 patients with class III, IV, or V results for the first intraoperative irrigation cytology of the remnant pancreas (IICP) IICP
1 2 3 4 5 6 7 8 9 10 11 12 13
Pathologic diagnosis
1st
2nd
3rd
Frozen section histology of surgical margin
BD-IPMN (Ph, IGD) BD-IPMN (Pb, HGD) BD-IPMN (Pb, associated IC) BD-IPMN (Pt, LGD) + PDAC (Ph) + PDAC (Pt) BD-IPMN (Pt*) + PDAC (Ph) BD-IPMN (Ph, IGD + Pt, IGD) + PDAC (Ph + Pb + Pt) MD-IPMN (Ph, HGD) + PDAC (Pt) BD-IPMN (Ph, HGD) BD-IPMN (Ph, associated IC) BD-IPMN (Ph, IGD + Pb, IGD + Pt, IGD) + PDAC (Pb) MD-IPMN (Ph, IGD) MD-IPMN (Ph, HGD + Pb, HGD) + PDAC (Pt) BD-IPMN (Ph, associated IC)
IV III III V III V IV III III IV III V III
III II II V II V IV III II IV II V III
II II II V II V IV II II IV II V II
+
Proposed procedure
Performed procedure
PPPD PPPD PPPD PPPD PPPD DP PD PPPD PPPD PPPD PPPD PPPD PPPD
PPPD PPPD PPPD TP PPPD TP TP PPPD PPPD PPPDy PPPD PPPDy PPPD
*The pathologic type of IPMN could not be determined because the IPMN was not resected. ySecond additional resection was performed. BD-IPMN, Branch duct intraductal papillary mucinous neoplasm; DP, distal pancreatectomy; HGD, high-grade dysplasia; IC, invasive carcinoma; IGD, intermediate-grade dysplasia; LGD, low-grade dysplasia; MD-IPMN, main duct intraductal papillary mucinous neoplasm; Pb, pancreatic body; PDAC, pancreatic ductal adenocarcinoma; Ph, pancreatic head; PPPD, pylorus-preserving pancreatoduodenectomy; Pt, pancreatic tail; TP, total pancreatectomy.
Table II. Pathologic diagnoses of the 48 resected specimens Pathologic diagnosis IPMN LGD IGD HGD Associated IC PDACy Ampullary cancery Total
No. of patients* 1 20 11 8 7 1 48
(0) (2) (2) (0) (1) (0) (5)
*The numbers in parentheses indicate the numbers of patients with previously undetected PDAC in additionally resected specimens. yThe pathologic type of IPMN could not be determined because the IPMN was not resected. HGD, High-grade dysplasia; IC, invasive carcinoma; IGD, intermediategrade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PDAC, pancreatic ductal adenocarcinoma.
for diagnosing the precise location of PDAC.25,28,29 In our IICP procedure, the surgeon inserts the catheter directly into the main pancreatic duct and uses saline irrigation to collect ductal epithelial cells. This procedure is easy to perform, even for the first time. We collected 3 samples after each resection, to avoid false-positive results caused by cancer cells that may have migrated from the resected portion into the remnant pancreas. Our results show that repeat IICP procedures found the same or lower grade of atypia, but
Table III. Comparisons between cytologic findings from preoperative pancreatic juice collection by endoscopic retrograde pancreatography (ERP) and intraoperative irrigation cytology of the remnant pancreas (IICP) IICP
ERP Negative Positive Unsuccessful Total
Negative
Positive
Total
32 9 2 43
1 4 0 5
33 13 2 48
never an increased grade of atypia, compared with earlier procedures (Table I). IICP was not performed for the initially resected segment of the pancreas, because this would not have changed our decisions regarding either resection of tumors with a clear indication for surgery, or additional resection after IICP of the remnant pancreas. All patients with positive IICP had previously undetected distinct PDAC in the remnant pancreas, and one of these patients had negative preoperative pancreatic juice cytology. Four of these 5 patients had early stage PDAC, and early detection may therefore have improved their prognosis. IICP carries a risk of complications such as postoperative pancreatitis, bleeding, or perforation
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Fig 3. Locations of intraductal papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC) in 5 patients with positive findings on intraoperative irrigation cytology of the remnant pancreas.
of the pancreatic duct. There were no procedurerelated complications in this series. One patient developed PDAC in the remnant pancreas 24 months postoperatively despite negative IICP. It is likely that this represents a false-negative IICP result, and indicates that it may not be completely safe to rely on negative IICP findings. Because the IICP procedure is operator dependent and the cytopathologic evaluation is observer dependent, the reliability of this technique may also vary among institutions. One patient with positive IICP developed peritoneal metastasis after 10 months. It is not known whether leakage of pancreatic fluid during IICP caused the peritoneal dissemination. The risk of missing PDAC that is detectable only by IICP must be balanced against the risk of complications, and surgeons should take great care to avoid peritoneal dissemination. IICP was not performed during laparoscopic pancreatectomy, because it was considered to be too difficult. Laparoscopic pancreatectomy is now widely performed, which may limit the ability to perform IICP in patients with IPMN. It is unclear whether the patient with invasive PDAC of the pancreatic head benefitted from additional resection of noninvasive PDAC in the remnant pancreas. However, additional resection was warranted because it was not possible to determine the histologic grade of the lesion in the remnant pancreas at the time of surgery. The limitations of this study include its retrospective, single-center design and small number of subjects, which limits the ability to analyze the safety and usefulness of IICP. There was also a
potential selection bias, both before December 2010 when IICP was performed at the discretion of the surgeon, and from December 2010 when IICP was performed only in patients selected for open operation. Although the results indicate that IICP may be a useful method for detection of early stage PDAC, they do not show that it is completely safe to rely on negative IICP findings. The significance of negative IICP findings needs to be further evaluated in the future. Controlled, randomized studies with larger patient populations are needed to further evaluate this technique, and to compare the outcomes after IICP with other techniques such as intraoperative ultrasonography. In conclusion, IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging findings or by intraoperative macroscopic examination, ultrasonography, or palpation. Routine IICP in patients with IPMN undergoing open partial pancreatectomy may contribute to early detection of concomitant PDAC and improved prognosis, even if preoperative pancreatic juice cytology is negative.
REFERENCES 1. Ohashi K, Murakami Y, Takekoshi T. Four cases of ‘‘mucinproducing’’ cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc 1982;20:348-51. 2. Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555-8.
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3. Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17-32. 4. Tanaka M, Fernandez-Del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97. 5. Ball CG, Howard TJ. Natural history of intraductal papillary mucinous neoplasia: how much do we really know? World J Gastrointest Surg 2010;2:368-72. 6. Levy P, Jouannaud V, O’Toole D, Couvelard A, Vullierme MP, Palazzo L, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol 2006;4:460-8. 7. Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004;239:788-97. 8. Yamaguchi K, Ohuchida J, Ohtsuka T, Nakano K, Tanaka M. Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology 2002;2:484-90. 9. Ingkakul T, Sadakari Y, Ienaga J, Satoh N, Takahata S, Tanaka M. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 2010;251:70-5. 10. Kanno A, Satoh K, Hirota M, Hamada S, Umino J, Itoh H, et al. Prediction of invasive carcinoma in branch type intraductal papillary mucinous neoplasms of the pancreas. J Gastroenterol 2010;45:952-9. 11. Ohtsuka T, Kono H, Tanabe R, Nagayoshi Y, Mori Y, Sadakari Y, et al. Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas. Am J Surg 2012;204:44-8. 12. Tanaka M. Controversies in the management of pancreatic IPMN. Nat Rev Gastroenterol Hepatol 2011;8:56-60. 13. Tanno S, Nakano Y, Sugiyama Y, Nakamura K, Sasajima J, Koizumi K, et al. Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. Pancreatology 2010;10:173-8. 14. Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 2008;57:1561-5. 15. Tanaka M. Important clues to the diagnosis of pancreatic cancer. Rocz Akad Med Bialymst 2005;50:69-72. 16. Mori Y, Ohtsuka T, Tsutsumi K, Yasui T, Sadakari Y, Ueda J, et al. Multifocal pancreatic ductal adenocarcinomas concomitant with intraductal papillary mucinous neoplasms of the pancreas detected by intraoperative pancreatic juice cytology. A case report. JOP 2010;11:389-92.
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17. Ohtsuka T, Kono H, Nagayoshi Y, Mori Y, Tsutsumi K, Sadakari Y, et al. An increase in the number of predictive factors augments the likelihood of malignancy in branch duct intraductal papillary mucinous neoplasm of the pancreas. Surgery 2012;151:76-83. 18. Sadakari Y, Ienaga J, Kobayashi K, Miyasaka Y, Takahata S, Nakamura M, et al. Cyst size indicates malignant transformation in branch duct intraductal papillary mucinous neoplasm of the pancreas without mural nodules. Pancreas 2010;39:232-6. 19. Ohtsuka T, Yamaguchi K, Chijiiwa K, Tanaka M. Effect of gastrointestinal reconstruction on quality of life and nutritional status after pylorus-preserving pancreatoduodenectomy. Dig Dis Sci 2002;47:1241-7. 20. Takahata S, Ohtsuka T, Nabae T, Matsunaga H, Yokohata K, Yamaguchi K, et al. Comparison of recovery of gastric phase III motility and gastric juice output after different types of gastrointestinal reconstruction following pylorus-preserving pancreatoduodenectomy. J Gastroenterol 2002;37:596-603. 21. Kawamoto M, Konomi H, Kobayashi K, Shimizu S, Yamaguchi K, Tanaka M. Type of gastrointestinal reconstruction affects postoperative recovery after pancreatic head resection. J Hepatobiliary Pancreat Surg 2006;13:336-43. 22. Adsay V, Kloppel G, Fukushima N. Intraductal papillary mucinous neoplasms of the pancreas. World Health Organization classification of tumors of the digestive system. Lyon, France: IARC Press; 2010:304-13. 23. Japan Pancreas Society. Classification of pancreatic carcinomaRevised in English. 2nd ed. Tokyo: Kanehara; 2002. 24. Inoue K, Ohuchida J, Ohtsuka T, Nabae T, Yokohata K, Ogawa Y, et al. Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography. Gastrointest Endosc 2003;58:510-5. 25. Tanaka M, Yokohata K, Konomi H, Yamaguchi K, Chijiiwa K, Ohta M. Segmental balloon cytology for preoperative localization of in situ pancreatic cancer. Gastrointest Endosc 1997;46:447-9. 26. Yamaguchi K, Nakamura M, Shirahane K, Kawamoto M, Konomi H, Ohta M, et al. Pancreatic juice cytology in IPMN of the pancreas. Pancreatology 2005;5:416-21. 27. Eguchi H, Ishikawa O, Ohigashi H, Sasaki Y, Yamada T, Nakaizumi A, et al. Role of intraoperative cytology combined with histology in detecting continuous and skip type intraductal cancer existence for intraductal papillary mucinous carcinoma of the pancreas. Cancer 2006;107:2567-75. 28. Ishikawa O, Imaoka S, Ohigashi H, Nakaizumi A, Uehara H, Wada A, et al. A new method of intraoperative cytodiagnosis for more precisely locating the occult neoplasms of the pancreas. Surgery 1992;111:294-300. 29. Imamura T, Koyama R, Okuda C, Takeuchi K, Matsuda M, Hashimoto M, et al. Effectiveness of cytodiagnosis with pancreatic duct lavage fluid for pancreatic ductal carcinoma: new sampling technique. Dig Endosc 2006;51:84-90.
Background. Patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas may have concomitant distinct pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and usefulness of intraoperative irrigation cytology of the remnant pancreas (IICP) during pancreatectomy to detect remnant distinct PDAC in patients with IPMN. Methods. The records of all 48 patients with IPMN who underwent IICP during partial pancreatectomy at our institution from April 2007 to March 2012 were reviewed retrospectively. After division of the pancreas, a 4-French tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and fluid for cytologic examination was obtained by saline irrigation through the tube. If the third IICP was positive, patients underwent additional pancreatic resection. Clinical and pathologic outcomes were evaluated. Results. The third IICP was positive in 5 patients. Postoperative pathologic examination showed that these patients all had remnant distinct PDAC in the additionally resected specimen, which was not detectable on preoperative imaging examination or on intraoperative macroscopic examination, ultrasonography, or palpation. This PDAC was stage 0 in 4 patients and stage III in 1 patient. No procedure-related complications were observed. One patient developed peritoneal metastasis after 10 months, 1 developed liver metastasis after 20 months, and 1 developed PDAC in the remnant pancreas after 24 months. Conclusion. IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging or intraoperative examination. (Surgery 2014;155:67-73.) From the Department of Surgery and Oncology,a and the Department of Anatomic Pathology,b Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM (IPMN) of the pancreas was first reported by Ohashi et al1 in Accepted for publication June 28, 2013. Reprint requests: Masao Tanaka, MD, PhD, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.06.059
1982. Since then, improved imaging techniques and increased clinician awareness have increased the frequency of diagnosis.2 International consensus guidelines established in 20063 and revised in 20124 defined appropriate management. Histologic findings range from low-grade dysplasia to invasive ductal carcinoma, but progression to carcinoma is generally slow5-7 and the prognosis is therefore favorable. In contrast, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor. Early diagnosis can improve prognosis, SURGERY 67
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but early PDAC is generally asymptomatic and difficult to detect on imaging examinations, and the majority of patients present with advanced disease. The reported prevalence of PDAC in patients with IPMN, including both synchronous and metachronous lesions, is 4.4–9.9%,8-15 indicating that patients with IPMN have an increased risk of PDAC. Because of the increased risk of PDAC, we performed intraoperative irrigation cytology of the remnant pancreas (IICP) during some partial pancreatectomy procedures in patients with IPMN. From April 2007 to November 2010, IICP was performed at the discretion of the surgeon. Postoperative pathologic examination found that 13 of the 37 patients (35%) who did not undergo IICP during this period had malignant IPMN or unexpected distinct PDAC in the resected specimen despite negative preoperative cytology. We also previously reported a patient with IPMN who had concomitant multifocal PDAC that was not detectable on preoperative imaging examinations.16 We therefore changed our policy, and from December 2010 we performed IICP during partial pancreatectomy in patients with IPMN whenever feasible, aiming to detect remnant, distinct PDAC. Such a protocol has not previously been reported. This study evaluated the safety of our IICP technique and its usefulness for the detection of previously undetected, concomitant remnant PDAC. PATIENTS AND METHODS Study population. This study was performed according to the principles of the Declaration of Helsinki. Written informed consent for pancreatic surgery including IICP was obtained from all subjects. We reviewed retrospectively the records of all 93 patients with a preoperative diagnosis of possible IPMN who underwent initial partial pancreatectomy at our institution from April 2007 to March 2012. The indications for operative treatment of IPMN were according to the international consensus guidelines, including all cases of main duct IPMN (MD-IPMN), and branch duct IPMN (BD-IPMN) with abdominal pain, jaundice, pancreatitis, mural nodule, or positive cytology.3,4 The study group also included patients with IPMN who did not have any predictors of malignant transformation, but who underwent operations for other reasons, such as PDAC or carcinoma of the duodenal papilla. Among the 73 patients who underwent surgery before December 2010, IICP was performed in 36 patients, at the discretion of the surgeon. Among the 20 patients who underwent surgery from December 2010 to March 2012, IICP was performed in all 12 patients who underwent open
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surgery, irrespective of preoperative cytology findings (positive in 7 patients, negative in 5 patients). IICP was not performed in patients who underwent laparoscopic operations. From December 2010, open operations were performed in all patients with positive preoperative cytology, in patients with MD-IPMN who had a mural nodule, and in patients with BD-IPMN who had $2 of the following: (1) Cyst $30 mm in diameter, (2) mural nodule, and (3) history of acute pancreatitis.17 All 48 patients who underwent IICP were enrolled in this study (29 males, 19 females; mean age, 69 years; range, 38– 86). Four surgeons performed IICP during the study period. Preoperative imaging and pancreatic juice collection. All patients underwent preoperative magnetic resonance imaging (MRI)/cholangiopancreatography and computed tomography (CT). IPMN was defined as MD-IPMN or BDIPMN based on the findings of these examinations.3,4 BD-IPMN was defined as IPMN exclusively involving the branch ducts, with grape-like collections of small cysts. MD-IPMN was defined as IPMN with a dilated main pancreatic duct, without grape-like collections. If both grape-like collections and dilation of the main duct were observed, but there were no findings indicating main duct involvement (such mural nodules in the main duct), the dilated duct was considered to be caused by mucin hypersecretion from BD-IPMN and the lesion was classified as BD-IPMN. Mixed-type IPMN was classified as MD-IPMN. Because early stage PDAC cannot easily be detected by CT or MRI, all patients underwent preoperative ERP for pancreatic juice collection for cytologic examination, which was successful in 46 of the 48 patients. Percutaneous, endoscopic, and intraductal ultrasonography were performed when indicated.11,17,18 Cytologic examination. Pancreatic fluid samples were centrifuged at 3,200 rpm for 5 minutes. Sediment smear slides were fixed in 95% ethyl alcohol and polyethylene glycol and stained by the Papanicolaou technique. Two cytologists classified the samples according to the degree of structural and cytologic atypia: Class I, no atypical cells; class II, atypical cells but no evidence of malignancy; class III, atypical cells inconclusive for malignancy (Fig 1, A); class IV, strongly suggestive of malignancy (Fig 1, B); and class V, conclusive for malignancy (Fig 1, C). Class IV and V results were considered positive. Operative procedures and IICP. The pancreas was cut near the superior mesenteric artery or vein, and planned pancreatoduodenectomy or distal pancreatectomy (DP) was performed.19-21 After
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Fig 1. Representative microscopic findings of cells collected by intraoperative irrigation cytology of the remnant pancreas. A, Class III, atypical cells inconclusive for malignancy. B, Class IV, strongly suggestive of malignancy. C, Class V, conclusive for malignancy.
Fig 2. Intraoperative irrigation cytology of the remnant pancreas. A 4-French polyvinyl tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and saline was gently irrigated through the tube with a syringe to obtain fluid for cytologic analysis.
division of the pancreas, a 4-French polyvinyl tube (Atom Medical, Saitama, Japan) was inserted into the main pancreatic duct of the remnant pancreas from the cut edge and advanced about 2 cm. Saline (1–2 mL) was gently irrigated through the tube with a syringe to obtain fluid for cytologic examination (Fig 2). This irrigation was performed 3 times, with an assistant suctioning any pancreatic fluid that leaked into the abdominal cavity to prevent dissemination of cancer. Intraoperative frozen section examination of the surgical margin was also performed. Visual inspection, palpation, and intraoperative ultrasonography of the remnant pancreas were performed to help determine the optimal resection line and to detect any signs of tumor. The IICP samples were graded as for the preoperative pancreatic fluid samples. If the third IICP was positive, additional pancreatic resection was performed. When feasible, this additional resection removed only an additional 2–4 cm of the pancreas. If additional resection after proximal pancreatectomy would leave only a minimal
volume of the pancreatic tail, total pancreatectomy was performed. Additional resection after DP is more difficult than after proximal pancreatectomy.4 If additional resection of 2–4 cm was not feasible after DP, total pancreatectomy was performed. Additional resection was also performed if frozen section examination showed high-grade dysplasia or invasive carcinoma at the cut margin, but not if it showed low- or intermediate-grade dysplasia at the cut margin, in accordance with the international consensus guidelines (2012).4 IICP and frozen section examinations were repeated after each additional resection. Additional resections were performed until both these examinations had negative findings. Pathologic examination. Surgical specimens were fixed in 10% formalin, cut into 5-mm thick slices, and stained with hematoxylin and eosin. Pathologic diagnosis classified IPMN according to the World Health Organization 2010 classification as low-, intermediate-, or high-grade dysplasia, or associated invasive carcinoma. IPMN lesions had histologic characteristics that were distinct from pancreatic intraepithelial neoplasia.22 If >1 IPMN was resected, the greatest pathologic grade was recorded. Concomitant distinct PDAC was defined as a lesion that was separate from the IPMN, with no transition area from the IPMN to the PDAC. Staging of PDAC was according to the Japanese General Rules for pancreatic cancer.23 Stage 0 PDAC was defined as pancreatic intraepithelial neoplasia-3, but not IPMN with high-grade dysplasia. RESULTS Tumor classifications, and IICP and pathologic findings. The preoperative classification of IPMN was BD-IPMN in 40 patients and MD-IPMN in 8 patients. Thirteen of the 48 patients (10 with
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BD-IPMN and 3 with MD-IPMN) had class III, IV, or V results on the first IICP sample (Table I). Five of these 13 patients had positive (class IV or V) findings on the third IICP sample (3 patients with BD-IPMN and 2 with MD-IPMN) and underwent additional resection. The pathologic examination findings of the 48 resected specimens are shown in Table II. Preoperative pancreatic juice cytology and IICP findings. Table III shows the relationships between preoperative pancreatic juice cytology and IICP. One of the 33 patients (3%) with negative preoperative cytology and 4 of the 13 patients (31%) with positive preoperative cytology had positive IICP. The 9 patients with positive preoperative cytology and negative IICP all had malignant IPMN or distinct PDAC in the resected specimen. Tumors in patients who underwent additional resection. All 5 patients who underwent additional resection had malignant lesions in the additionally resected specimens. These lesions were not detectable on preoperative imaging examinations or on intraoperative macroscopic examination, ultrasonography, or palpation. Fig 3 shows the locations of IPMN and distinct PDAC in these patients. Patients 4, 6, and 7 eventually underwent total pancreatectomy (Table I). Patient 4 underwent proximal pancreatectomy for invasive PDAC in the pancreatic head. After positive IICP, total pancreatectomy was performed because an irregular stricture of the main pancreatic duct in the pancreatic tail had been detected on preoperative ERP. Patient 6 underwent DP for invasive PDAC and BD-IPMN in the pancreatic body and tail. After positive IICP, total pancreatectomy was performed because the cut surface was already close to the gastroduodenal artery. Patient 7 underwent proximal pancreatectomy for MD-IPMN in the pancreatic head. This patient initially underwent additional resection of 2 cm of the remnant pancreas. Repeat IICP after the additional resection was positive, and total pancreatectomy was eventually performed. Patient 10, who had a preoperative diagnosis of BD-IPMN, and patient 12, who had a preoperative diagnosis of MD-IPMN, underwent additional resection of only 2–4 cm of the remnant distal pancreas. Intraoperative frozen section results reported a positive surgical margin only in patient 7, showing IPMN with high-grade dysplasia. The frozen section results were reported simultaneously with the IICP results. Pathologic examination revealed noninvasive PDAC (stage 0) in the additionally resected pancreas in patients 4, 7, 10, and 12; and invasive PDAC with regional lymph node metastasis on the posterior surface of the
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pancreatic head (stage III) in patient 6. All previously undetected lesions in the additionally resected specimens were distinct PDAC that was separate from IPMN. Follow-up. No IICP-related complications, such as postoperative pancreatitis, bleeding, or perforation of the pancreatic duct or periductal pancreatic parenchyma were observed. Patients with invasive IPMN or PDAC on pathologic examination were followed up every 3 months after surgery with CT and MRI. Patients with only noninvasive IPMN on pathologic examination were followed up every 6 months. During the mean follow-up period of 20 months (range, 1–50), recurrence was detected in 3 patients. Patient 6, who had positive IICP findings and stage III PDAC in the additionally resected pancreas, developed peritoneal metastasis after 10 months but no liver metastasis, and died of this disease. One patient with negative IICP findings (class II) and IPMN with high-grade dysplasia in the resected specimen developed PDAC in the remnant pancreas that was detected 24 months postoperatively. Another patient with negative IICP findings who had invasive IPMN in the resected specimen died of liver metastasis that was detected 20 months postoperatively, without tumor recurrence in the remnant pancreas. The remaining 45 patients were alive without evidence of recurrence at the last follow-up. DISCUSSION The results of this study show that IICP during partial pancreatectomy in patients with IPMN can detect remnant distinct PDAC that cannot be detected by preoperative imaging or by intraoperative macroscopic examination, ultrasonography, or palpation. It is important to consider the possibility of concomitant distinct PDAC in patients with IPMN, and make an effort to avoid leaving PDAC in the remnant pancreas after partial pancreatectomy. ERP is not routinely performed before pancreatectomy because it has a high morbidity rate. However, early stage PDAC is not easily detected by CT, MRI, or endoscopic ultrasonography,16,24-26 and we now routinely perform ERP before partial pancreatectomy in patients with IPMN. Eguchi et al27 screened patients with IPMN undergoing partial pancreatectomy by intraoperative frozen section histology and pancreatic juice cytology from each pancreatic segment (head, body, and tail), and reported that 13 of 43 patients (42%) required additional pancreatic resection. Lavage fluid from a specific section of the pancreatic duct has previously been reported to be useful
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Table I. Details of the 13 patients with class III, IV, or V results for the first intraoperative irrigation cytology of the remnant pancreas (IICP) IICP
1 2 3 4 5 6 7 8 9 10 11 12 13
Pathologic diagnosis
1st
2nd
3rd
Frozen section histology of surgical margin
BD-IPMN (Ph, IGD) BD-IPMN (Pb, HGD) BD-IPMN (Pb, associated IC) BD-IPMN (Pt, LGD) + PDAC (Ph) + PDAC (Pt) BD-IPMN (Pt*) + PDAC (Ph) BD-IPMN (Ph, IGD + Pt, IGD) + PDAC (Ph + Pb + Pt) MD-IPMN (Ph, HGD) + PDAC (Pt) BD-IPMN (Ph, HGD) BD-IPMN (Ph, associated IC) BD-IPMN (Ph, IGD + Pb, IGD + Pt, IGD) + PDAC (Pb) MD-IPMN (Ph, IGD) MD-IPMN (Ph, HGD + Pb, HGD) + PDAC (Pt) BD-IPMN (Ph, associated IC)
IV III III V III V IV III III IV III V III
III II II V II V IV III II IV II V III
II II II V II V IV II II IV II V II
+
Proposed procedure
Performed procedure
PPPD PPPD PPPD PPPD PPPD DP PD PPPD PPPD PPPD PPPD PPPD PPPD
PPPD PPPD PPPD TP PPPD TP TP PPPD PPPD PPPDy PPPD PPPDy PPPD
*The pathologic type of IPMN could not be determined because the IPMN was not resected. ySecond additional resection was performed. BD-IPMN, Branch duct intraductal papillary mucinous neoplasm; DP, distal pancreatectomy; HGD, high-grade dysplasia; IC, invasive carcinoma; IGD, intermediate-grade dysplasia; LGD, low-grade dysplasia; MD-IPMN, main duct intraductal papillary mucinous neoplasm; Pb, pancreatic body; PDAC, pancreatic ductal adenocarcinoma; Ph, pancreatic head; PPPD, pylorus-preserving pancreatoduodenectomy; Pt, pancreatic tail; TP, total pancreatectomy.
Table II. Pathologic diagnoses of the 48 resected specimens Pathologic diagnosis IPMN LGD IGD HGD Associated IC PDACy Ampullary cancery Total
No. of patients* 1 20 11 8 7 1 48
(0) (2) (2) (0) (1) (0) (5)
*The numbers in parentheses indicate the numbers of patients with previously undetected PDAC in additionally resected specimens. yThe pathologic type of IPMN could not be determined because the IPMN was not resected. HGD, High-grade dysplasia; IC, invasive carcinoma; IGD, intermediategrade dysplasia; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; PDAC, pancreatic ductal adenocarcinoma.
for diagnosing the precise location of PDAC.25,28,29 In our IICP procedure, the surgeon inserts the catheter directly into the main pancreatic duct and uses saline irrigation to collect ductal epithelial cells. This procedure is easy to perform, even for the first time. We collected 3 samples after each resection, to avoid false-positive results caused by cancer cells that may have migrated from the resected portion into the remnant pancreas. Our results show that repeat IICP procedures found the same or lower grade of atypia, but
Table III. Comparisons between cytologic findings from preoperative pancreatic juice collection by endoscopic retrograde pancreatography (ERP) and intraoperative irrigation cytology of the remnant pancreas (IICP) IICP
ERP Negative Positive Unsuccessful Total
Negative
Positive
Total
32 9 2 43
1 4 0 5
33 13 2 48
never an increased grade of atypia, compared with earlier procedures (Table I). IICP was not performed for the initially resected segment of the pancreas, because this would not have changed our decisions regarding either resection of tumors with a clear indication for surgery, or additional resection after IICP of the remnant pancreas. All patients with positive IICP had previously undetected distinct PDAC in the remnant pancreas, and one of these patients had negative preoperative pancreatic juice cytology. Four of these 5 patients had early stage PDAC, and early detection may therefore have improved their prognosis. IICP carries a risk of complications such as postoperative pancreatitis, bleeding, or perforation
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Fig 3. Locations of intraductal papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC) in 5 patients with positive findings on intraoperative irrigation cytology of the remnant pancreas.
of the pancreatic duct. There were no procedurerelated complications in this series. One patient developed PDAC in the remnant pancreas 24 months postoperatively despite negative IICP. It is likely that this represents a false-negative IICP result, and indicates that it may not be completely safe to rely on negative IICP findings. Because the IICP procedure is operator dependent and the cytopathologic evaluation is observer dependent, the reliability of this technique may also vary among institutions. One patient with positive IICP developed peritoneal metastasis after 10 months. It is not known whether leakage of pancreatic fluid during IICP caused the peritoneal dissemination. The risk of missing PDAC that is detectable only by IICP must be balanced against the risk of complications, and surgeons should take great care to avoid peritoneal dissemination. IICP was not performed during laparoscopic pancreatectomy, because it was considered to be too difficult. Laparoscopic pancreatectomy is now widely performed, which may limit the ability to perform IICP in patients with IPMN. It is unclear whether the patient with invasive PDAC of the pancreatic head benefitted from additional resection of noninvasive PDAC in the remnant pancreas. However, additional resection was warranted because it was not possible to determine the histologic grade of the lesion in the remnant pancreas at the time of surgery. The limitations of this study include its retrospective, single-center design and small number of subjects, which limits the ability to analyze the safety and usefulness of IICP. There was also a
potential selection bias, both before December 2010 when IICP was performed at the discretion of the surgeon, and from December 2010 when IICP was performed only in patients selected for open operation. Although the results indicate that IICP may be a useful method for detection of early stage PDAC, they do not show that it is completely safe to rely on negative IICP findings. The significance of negative IICP findings needs to be further evaluated in the future. Controlled, randomized studies with larger patient populations are needed to further evaluate this technique, and to compare the outcomes after IICP with other techniques such as intraoperative ultrasonography. In conclusion, IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging findings or by intraoperative macroscopic examination, ultrasonography, or palpation. Routine IICP in patients with IPMN undergoing open partial pancreatectomy may contribute to early detection of concomitant PDAC and improved prognosis, even if preoperative pancreatic juice cytology is negative.
REFERENCES 1. Ohashi K, Murakami Y, Takekoshi T. Four cases of ‘‘mucinproducing’’ cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc 1982;20:348-51. 2. Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555-8.
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3. Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17-32. 4. Tanaka M, Fernandez-Del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97. 5. Ball CG, Howard TJ. Natural history of intraductal papillary mucinous neoplasia: how much do we really know? World J Gastrointest Surg 2010;2:368-72. 6. Levy P, Jouannaud V, O’Toole D, Couvelard A, Vullierme MP, Palazzo L, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol 2006;4:460-8. 7. Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004;239:788-97. 8. Yamaguchi K, Ohuchida J, Ohtsuka T, Nakano K, Tanaka M. Intraductal papillary-mucinous tumor of the pancreas concomitant with ductal carcinoma of the pancreas. Pancreatology 2002;2:484-90. 9. Ingkakul T, Sadakari Y, Ienaga J, Satoh N, Takahata S, Tanaka M. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 2010;251:70-5. 10. Kanno A, Satoh K, Hirota M, Hamada S, Umino J, Itoh H, et al. Prediction of invasive carcinoma in branch type intraductal papillary mucinous neoplasms of the pancreas. J Gastroenterol 2010;45:952-9. 11. Ohtsuka T, Kono H, Tanabe R, Nagayoshi Y, Mori Y, Sadakari Y, et al. Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas. Am J Surg 2012;204:44-8. 12. Tanaka M. Controversies in the management of pancreatic IPMN. Nat Rev Gastroenterol Hepatol 2011;8:56-60. 13. Tanno S, Nakano Y, Sugiyama Y, Nakamura K, Sasajima J, Koizumi K, et al. Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. Pancreatology 2010;10:173-8. 14. Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 2008;57:1561-5. 15. Tanaka M. Important clues to the diagnosis of pancreatic cancer. Rocz Akad Med Bialymst 2005;50:69-72. 16. Mori Y, Ohtsuka T, Tsutsumi K, Yasui T, Sadakari Y, Ueda J, et al. Multifocal pancreatic ductal adenocarcinomas concomitant with intraductal papillary mucinous neoplasms of the pancreas detected by intraoperative pancreatic juice cytology. A case report. JOP 2010;11:389-92.
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17. Ohtsuka T, Kono H, Nagayoshi Y, Mori Y, Tsutsumi K, Sadakari Y, et al. An increase in the number of predictive factors augments the likelihood of malignancy in branch duct intraductal papillary mucinous neoplasm of the pancreas. Surgery 2012;151:76-83. 18. Sadakari Y, Ienaga J, Kobayashi K, Miyasaka Y, Takahata S, Nakamura M, et al. Cyst size indicates malignant transformation in branch duct intraductal papillary mucinous neoplasm of the pancreas without mural nodules. Pancreas 2010;39:232-6. 19. Ohtsuka T, Yamaguchi K, Chijiiwa K, Tanaka M. Effect of gastrointestinal reconstruction on quality of life and nutritional status after pylorus-preserving pancreatoduodenectomy. Dig Dis Sci 2002;47:1241-7. 20. Takahata S, Ohtsuka T, Nabae T, Matsunaga H, Yokohata K, Yamaguchi K, et al. Comparison of recovery of gastric phase III motility and gastric juice output after different types of gastrointestinal reconstruction following pylorus-preserving pancreatoduodenectomy. J Gastroenterol 2002;37:596-603. 21. Kawamoto M, Konomi H, Kobayashi K, Shimizu S, Yamaguchi K, Tanaka M. Type of gastrointestinal reconstruction affects postoperative recovery after pancreatic head resection. J Hepatobiliary Pancreat Surg 2006;13:336-43. 22. Adsay V, Kloppel G, Fukushima N. Intraductal papillary mucinous neoplasms of the pancreas. World Health Organization classification of tumors of the digestive system. Lyon, France: IARC Press; 2010:304-13. 23. Japan Pancreas Society. Classification of pancreatic carcinomaRevised in English. 2nd ed. Tokyo: Kanehara; 2002. 24. Inoue K, Ohuchida J, Ohtsuka T, Nabae T, Yokohata K, Ogawa Y, et al. Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography. Gastrointest Endosc 2003;58:510-5. 25. Tanaka M, Yokohata K, Konomi H, Yamaguchi K, Chijiiwa K, Ohta M. Segmental balloon cytology for preoperative localization of in situ pancreatic cancer. Gastrointest Endosc 1997;46:447-9. 26. Yamaguchi K, Nakamura M, Shirahane K, Kawamoto M, Konomi H, Ohta M, et al. Pancreatic juice cytology in IPMN of the pancreas. Pancreatology 2005;5:416-21. 27. Eguchi H, Ishikawa O, Ohigashi H, Sasaki Y, Yamada T, Nakaizumi A, et al. Role of intraoperative cytology combined with histology in detecting continuous and skip type intraductal cancer existence for intraductal papillary mucinous carcinoma of the pancreas. Cancer 2006;107:2567-75. 28. Ishikawa O, Imaoka S, Ohigashi H, Nakaizumi A, Uehara H, Wada A, et al. A new method of intraoperative cytodiagnosis for more precisely locating the occult neoplasms of the pancreas. Surgery 1992;111:294-300. 29. Imamura T, Koyama R, Okuda C, Takeuchi K, Matsuda M, Hashimoto M, et al. Effectiveness of cytodiagnosis with pancreatic duct lavage fluid for pancreatic ductal carcinoma: new sampling technique. Dig Endosc 2006;51:84-90.
