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Multicenter Analysis of Clinicopathologic Features of Intraductal Papillary Mucinous Tumor of the Pancreas: Is It Possible to Predict the Malignancy Before Surgery?

¹ Department of Surgery, Seoul National University Hospital, 28 Yongon-dong, Changno-gu, 110-744, Seoul, Korea
² Department of Radiology, Seoul National University, Seoul 110-744, Korea
³ Department of Pathology, Seoul National University, Seoul 110-744, Korea
⁴ Department of Surgery, Ulsan University, Seoul 138-736, Korea
⁵ Department of Surgery, Sungkyunkwan University, Seoul 135-710, Korea
⁶ Department of Surgery, Chonbuk National University, Jeonju 561-712, Korea
⁷ Department of Surgery, Yonsei University, Seoul 120-752, Korea
⁸ Department of Surgery, Korea University, Seoul 136-701, Korea
⁹ Department of Surgery, Hanyang University, Seoul 133-792, Korea
¹⁰ Department of Surgery, Ajou University, Suwon 442-721, Korea
¹¹ Department of Surgery, Yeungnam University, Daegu 705-717, Korea
¹² Department of Surgery, Chonnam National University, Gwangju 501-757, Korea

Correspondence: Address correspondence and reprint requests to: Sun-Whe Kim, MD, FACS; E-mail: sunkim{at}plaza.snu.ac.kr.

	ABSTRACT

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Background: Despite recently increasing numbers of reports on intraductal papillary mucinous tumors (IPMTs), difficulties still remain in terms of diagnosis, treatment, and prognosis. The purpose of this multicenter study was to evaluate the clinicopathologic features of IPMT in Korea and to suggest predictive criteria for malignancy in IPMT.

Methods: We retrospectively reviewed the clinicopathologic data of 208 patients who underwent operations for IPMT between 1993 and 2002 at 28 institutes in Korea.

Results: Of the 208 patients (mean age, 61 years), 147 were men and 61 were women. A total of 124 patients underwent pancreatoduodenectomy, 42 underwent distal pancreatectomy, 17 underwent total pancreatectomy, and 25 underwent limited pancreatic resection. There were 128 benign cases (adenoma, n = 62; borderline, n = 66) and 80 malignant cases (noninvasive, n = 29; invasive, n= 51). A significant difference in 5-year survival was observed between the benign and malignant groups (92.6% vs. 65.3%; P = .006). Of the six factors (age, location, duct dilatation, mural nodule, main duct type, and tumor size) that showed statistical differences by univariate analysis between the benign and malignant groups, three were significant by multivariate analysis—namely, mural nodule (P = .009), tumor size (P = .023), and a dilated duct size (P = .010).

Conclusions: A significant proportion of IPMTs are malignant, although the overall prognosis of IPMT is superior to that of ordinary pancreatic cancer. Radical surgery is recommended for IPMT with the predictors of malignancy: mural nodule, tumor size (30 mm), and dilated duct size (12 mm).

Key Words: Intraductal papillary mucinous tumor • Multicenter study • Multivariate study • Malignancy prediction

	INTRODUCTION

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Reports on intraductal papillary mucinous tumors (IPMTs), which were first reported in 1982 by Ohhashi et al.¹ as mucin-producing pancreatic cancers, have been increasing in the West and in Japan. IPMT is characterized by cystic dilation of the pancreatic ducts because of the large amount of mucin produced by papillary growing epithelium and mucin excretion through a patulous orifice of the papilla of Vater. Clinically, IPMT is a slowly growing tumor with a good prognosis, even if the tumor is malignant, as compared with the usual ductal adenocarcinoma. These pathologic features and clinical characteristics of IPMT have attracted the attention of clinicians.^2–4

Although clinical information has accumulated, most of these reports deal with limited numbers of patients and, thus, do not provide a high level of confidence in disease prognosis or suggest an accurate means of preoperative diagnosis or treatment selection. Thus, many problems remain to be solved in terms of when to treat, how to treat, and how to diagnose IPMT. The objectives of this study were to investigate the clinicopathologic features of IPMT in Korea and to identify the prognostic indicators of malignancy.

	PATIENTSAND METHODS

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Selection of Study Centers and Collection of Data
This study was retrospectively performed to collect data on IPMT cases between June 1993 and May 2002 throughout Korea. To obtain representative data, the study centers were confined to institutions such as university hospitals or those considered major hospitals in terms of hepatobiliary pancreatic surgery containing specialized gastrointestinal pathologists. Overall, 48 hepatobiliary pancreatic surgeons from 28 institutions participated. This study was approved by the Korean Association of Hepato-Biliary-Pancreatic Surgery, and the biostatistical center for study design and data analysis was sited at Seoul National University (Seoul, Korea).

We used standardized data forms, which contained fields for the clinical and pathologic characteristics of IPMT with survival data. Each experienced radiologist and pathologist in Seoul National University Hospital made out the standard protocols for radiological and pathologic readings. Primary radiological and pathologic review was performed at the site where the operation was performed according to the standard reading form, and these readings and matched radiological and pathologic digital images were returned to and confirmed by the radiologist and the pathologist, respectively, who made out the protocol.

We collected data from 223 IPMT patients who underwent surgical treatments. Of these, we excluded 15 cases because of a lack of clinicopathologic information or nonconformity with standard protocol (n = 13) or ambiguity in the pathologic diagnosis (n = 2). Thus, 208 patients who underwent surgery were eligible for this study. We analyzed the present state of surgical treatment of IPMT in Korea and the clinicopathologic features of IPMT to suggest factors that are predictive of malignancy.

Statistical Analysis
Data were stored in Excel (Microsoft Corp., Redmond, WA) and analyzed with SPSS 9.0 (SPSS Inc., Chicago, IL). Comparisons of nominal data were conducted with ² tests. Continuous variables were compared by using Student’s t-test. Parameters by univariate analysis with P values of <.05 were entered into a Cox proportional hazards regression model to identify independent predictive factors of malignancy. The significant values of quantitative criteria were transformed into binary categorical variables by using the mean value with its 95% confidence interval as a cutoff. Cumulative survival data were calculated by the Kaplan-Meier method and compared by using the log-rank test. Results are presented as means ±SEM. A two-sided P value of <.05 was considered significant.

	RESULTS

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Clinicopathologic Characteristics of IPMT
The IPMT patients consisted of 147 men and 61 women, with a mean age of 60.5 years (range, 30–81 years; Table 1). Tumor location was at the head of the pancreas in 127 cases (61.6%) and at the body and tail in 60 cases (28.8%); it was of the diffuse involved type in 10.1%. A total of 72.6% of the patients showed dilatation of the main pancreatic duct, and 65.3% showed branch duct dilatation. According to the reports, IPMT was classified as the main duct type, branch duct type, and combined type on the basis of radiological or pathologic features. When we classified the cases according to tumor ductal type,² 111 cases (53.4%) were of the main duct type, 79 cases (38.0%) were of the branch duct type, and 17 cases (8.2%) were of the combined type. A total of 116 cases (55.8%) had mural nodules (papillary projection: diameter 3 mm).⁵

Eleven (5.3%) of 208 patients had previous or concurrent neoplasms at other sites, including colon cancer (n = 3), stomach cancer (n = 3), hepatocellular carcinoma (n = 2), lymphoma (n = 1), and combined pancreatic ductal adenocarcinoma (n =2). Nine patients had adenoma or borderline IPMT. Two patients with colon cancer and pancreatic cancer had invasive IPMT.

Pathologic Diagnosis and Operations Performed
Table 2 lists the surgical procedures performed in relation to the definitive pathologic findings from surgical specimens. Pancreatoduodenectomy, including the pylorus-preserving procedure, was most often performed, and this was closely related to a high incidence of tumor in the pancreatic head. Organ preserving surgery—i.e., duodenum-preserving resection of the head of the pancreas (n = 7), segmental (median) pancreatectomy (n = 7), and pancreas head resection with segmental duodenectomy (n=1)—has increased recently, especially for benign lesions.

Of the patients who had recurrence, two patients had combined other neoplasms. A 72-year-old man who underwent pancreatoduodenectomy for invasive IPMT received an anterior resection for colon cancer 30 months later. Multiple liver metastases were detected 12 months after colectomy. This patient is alive at 46 months’ follow-up. The other 57-year-old man underwent pylorus-preserving pancreatoduodenectomy for invasive IPMT, and 1.8-cm pancreatic ductal adenocarcinoma (T1N0) was detected separately in a resected specimen. This patient remains alive at 21 months, although liver metastasis was detected 16 months after pancreatectomy.

No difference in the tumor recurrence rates after total pancreatectomy (3 of 8; 37.5%) and after partial pancreatectomy (14 of 43; 32.5%) was observed in cases of invasive IPMT (P = .785). Most recurrences were distant metastasis, regardless of resection margin involvement.

Survival and Disease-Free Survival After Surgery in IPMT
Figure 1 shows that the cumulative 1-, 3-, and 5- year survival rates for all 208 IPMT patients were 95.2%, 90.6%, and 78.5%, respectively. When we analyzed the survival data according to the pathologic diagnosis, we found a significant difference in the 5-year survival rates of adenoma (93.5%), borderline (91.4%), noninvasive (84.7%), and invasive (52.1%) IPMT (P = .003; Fig. 2).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Survival curve of intraductal papillary mucinous tumor patients.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Survival curve according to the pathologic diagnosis.

By grouping the IPMT patients into two groups, a significant difference was evident in the 5-year survival rates of benign (92.6%) and malignant (65.3%) IPMT (P = .006; Fig. 3). In this study, we could not find a survival difference according to the subtypes based on tumor location. The 5-year survival rates of main duct type, branch duct type, and combined type were 79.8%, 76.5%, and 80.0%, respectively (P = .728; Fig. 4). The 1-, 3-, and 5-year disease-free survival rates of all patients were 93.0%, 85.0%, and 67.2%, respectively, and the 5-year disease-free survival rates of adenoma, borderline, noninvasive, and invasive IPMT were 80.1%, 78.5%, 84.7%, and 36.9%, respectively (P = .001).

View larger version (14K): [in this window] [in a new window]   FIG. 3. Differences in the survival rates of patients with benign and malignant lesions.

View larger version (14K): [in this window] [in a new window]   FIG. 4. Survival curve according to the ductal type of intraductal papillary mucinous tumor.

Prognostic Indicators of Malignancy
To identify malignancy-predicting factors, we divided the patients into two groups: a benign group (adenoma or borderline) and a malignant group (noninvasive or invasive). Age, location of tumor, main duct dilatation, mural nodule, tumor ductal type, tumor size, and duct size were significantly different between these groups by univariate analysis (Table 4). Of these factors, mural nodule, tumor size, and duct size remained significant by multivariate analysis with the Cox proportional hazard model (Table 5). We set the diagnostic threshold of continuous variables (tumor size and duct size) within 95% of the confidence interval after error analysis (Fig. 5). According to this result, we identified three malignancy- predicting factors: mural nodule, tumor size 30 mm, and main duct size 12 mm.

View larger version (13K): [in this window] [in a new window]   FIG. 5. (a) Tumor and (b) duct size differences in benign and malignant lesions. CI, confidence interval.

	DISCUSSION

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However, IPMT has a pathologic spectrum that ranges from adenoma to invasive carcinoma, and most reports on IPMT have dealt with a small number of cases. This causes difficulties in terms of producing definite guidelines for the differential diagnosis of subtype, surgical standards, prognosis, and treatment modality.

The view that IPMT is a slow-growing tumor with a favorable prognosis has been changed because recent studies have reported a high rate of invasive carcinoma and poor prognosis in accordance with the accumulation of cases and long-term follow-up.^7–10 Malignant subtypes, such as invasive or noninvasive types, account for 50% to 72% of IPMT cases.

Because of the wide spectrum of IPMT, preoperative discrimination between benign and malignant IPMT is a prerequisite for accurate decision making on how and when to treat. Hara et al.¹¹ reported that the fish egg–like type with vascular images, the villous type, the vegetative type by peroral pancreatoscopy, and lesions protruding 4 mm by intraductal ultrasonography should be considered malignant. A combination of peroral pancreatoscopy and intraductal ultrasonography resulted in a considerably improved differential diagnosis of malignant and benign IPMT and was useful for determining an effective therapeutic approach.^11,12

Recently some reports have encouraged the establishment of molecular diagnosis by using K-ras, p53, p16(INK4A), Smad4, telomerase activity, and the expression of MUC1.^13–18 However, these techniques are not yet practically useful.

Many studies have been conducted on differentiating malignant from benign IPMT on the basis of clinical and diagnostic imaging findings. The frequently mentioned malignancy-predicting factors are main duct type, tumor size, and mural nodule presence. Sugiyama and Atomi² reported that tumors with mural nodules (86%) had a significantly higher incidence of carcinoma than tumors without nodules(37%). IPMT with a main pancreatic duct of 15 mm or a tumor diameter of 30 mm (branch duct type) showed a high prevalence of adenocarcinoma. Bernard et al.¹⁹ documented that main duct lesions and the presence of a mural nodule were important factors for predicting malignant IPMT. Yamaguchi et al.²⁰ reported that the presence of diabetes, large tumors (5 cm), marked dilatation of the main pancreatic duct (10 mm), main pancreatic duct type, and large mural nodules (10 mm) were strongly suggestive of malignancy.

After the introduction of the classification of IPMT according to the tumor ductal type,²¹ many studies have reported that the rates of malignancy are higher for the main duct type (67%–100%) than for the branch duct type (0%–47%). Therefore, most clinicians consider that the classification of main duct and branch duct type is very important in the differentiation of benign and malignant tumor. This classification of IPMT is easy to apply in the clinical situation. However, most of these reports are based on a small number of patients and univariate analysis, and, therefore, conclusions of a high malignancy rate for the main duct type should be treated as tentative. ^22–24

Another pitfall in this classification is the discrepancy between the dilated ductal segments and the actual presence of tumor cells.²¹ Kamisawa et al.²⁵ reported two autopsy cases of benign IPMT of the main pancreatic duct type in patients who were followed up for approximately 10 years. They suggested that the estimation of malignancy according to tumor location is not justified.

In this study, we also found that this classification in cases of malignancy has predictive value by univariate analysis. However, this was not sustained by multivariate analysis. We suggest three factors (mural nodule, tumor size 30 mm, and main duct size 12 mm) as predictors of malignancy. When we applied these criteria to IPMT patients, we obtained a 91% predictive value of malignancy in those who met the three criteria.

Selecting the optimal operation is another important problem in the management of IPMT. Various types of organ-preserving pancreatic surgery have been advocated recently.²⁶ Duodenum-preserving pancreatic head resection, pancreatic head resection with segmental duodenectomy, and spleen-preserving distal pancreatectomy are other surgical options for the treatment of benign IPMT. Our data show that these operations were introduced and are most actively performed in benign IPMT. However, when performing these operations, surgeons must consider the possibility of malignancy, and these limited operations should not be performed in cases with invasive IPMT. As shown by our data, approximately 15.7% of invasive IPMTs showed lymph node metastasis and poorer survival even after curative resection.

IPMT tends to spread along the pancreatic duct, and, therefore, sometimes it is not easy to obtain a tumor-free margin. For this reason, some have advocated total pancreatectomy in diffuse involved cases. Chari et al.²⁷ reported that the frequency of recurrence was similar after partial pancreatectomy (67%) and total pancreatectomy (62%) in invasive IPMT and that most often this is due to distant metastasis regardless of resection margin involvement. They suggested that completion pancreatectomy should be considered after local recurrence, especially in margin-positive noninvasive IPMT. In this study, we found that long-term survival is possible even if the tumor involves the resection margin in noninvasive IPMT. The tumor recurrence rate was 37.5% after total pancreatectomy and 32.5% after partial pancreatectomy in invasive IPMT, and most recurrences were due to distant metastasis; this supports Chari and associates’ suggestion. Therefore, total pancreatectomy should be reserved for the main duct type with diffuse involvement while bearing in mind the severe metabolic derangement involved and its lack of a preventive effect on distant metastasis. This recurrence pattern of invasive IPMT after surgical resection strongly requires systemic treatment. Further study is needed to establish chemotherapeutic effects on invasive IPMT.

It is interesting to note that the incidence of extrapancreatic neoplasms in IPMT patients was reported to be higher than that of the healthy population. Sugiyama and Atomi²⁸ reported that 20 (48%) of 42 patients with IPMT had a nonpancreatic neoplasm and that a colorectal neoplasm was the most frequent.

In this study, 11 (5.3%) of 208 patients had nonpancreatic neoplasms before (n = 4), at (n = 4), and after (n = 3) surgery for IPMT. The most frequent nonpancreatic neoplasms were colon (n = 3) and stomach (n = 3) cancer. Although more study is needed to obtain the population-based incidence of nonpancreatic neoplasms in IPMT, we strongly recommend systemic surveillance before and after surgery in patients with IPMT.

Despite the accumulation of data on IPMT, there are still many problems to be solved in terms of the management of IPMT. The peculiar characteristics of IPMT cause difficulty in describing and classifying, for example, how one measures the tumor size (two dimensionally or three-dimensionally), differentiates the IPMT from some type of pancreatic intraepithelial neoplasia, or deals with an infiltrating carcinoma arising in IPMT.^29,30 A worldwide consensus must be established as soon as possible.

In conclusion, mural nodule, tumor size (30 mm), and dilated duct size (12 mm) can be used as preoperative indicators of malignancy in IPMT. We also suggest that systemic and long-term surveillance is needed in patients with IPMT to detect recurrence and combined other neoplasms.

	ACKNOWLEDGMENTS

 
The authors thank Drs. Young Kook Yun (Kyungpook National University); Soon Chan Hong (Gyengsang National University); Koo Jeong Kang (Keimyung University); Kyong Woo Choi (National Medical Center); Yong Oon Yoo (Catholic University of Daegu); Jong Hun Park (Daegu Fatima Hospital); Young Hoon Kim (Dong-A University); Mun Sup Sim (Pusan National University); Hyung Chul Kim, Chang Ho Kim, and Man Kyu Chae (Soonchunhyang University); Hong Yong Kim and Young Gil Choi (Inje University); Kwon Mook Chae (Wonkwang University); Dong Wook Choi (Korea Cancer Center Hospital); Ho Seong Han (Ewha Women University); Seung Ik Ahn (Inha University); Kuk Hwan Kwon (National Health Insurance Corporation Ilsan Hospital); Jae Woon Choi (Chungbuk National University); Jong Riul Lee (Cheonju St. Mary’s Hospital); and Joo Seop Kim (Hallym University) for their cooperation in the conduction this study. They generously provided important clinicopathologic information about patients with IPMT.

Received for publication February 23, 2004. Accepted for publication October 5, 2004.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jang, J.-Y. Articles by Park, Y.-H. Search for Related Content PubMed PubMed Citation Articles by Jang, J.-Y. Articles by Park, Y.-H.