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Pancreatic Cancer in Patients With Pancreatic Cystic Lesions: A Prospective Study in 197 Patients
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:1265–1270
Pancreatic Cancer in Patients With Pancreatic Cystic Lesions: A Prospective Study in 197 Patients MINORU TADA,* TAKAO KAWABE,‡ MASATOSHI ARIZUMI,* OSAMU TOGAWA,* SABURO MATSUBARA,* NATSUYO YAMAMOTO,* YOSUKE NAKAI,* NAOKI SASAHIRA,* KENJI HIRANO,* TAKESHI TSUJINO,* KEISUKE TATEISHI,* HIROYUKI ISAYAMA,* NOBUO TODA,* HARUHIKO YOSHIDA,* and MASAO OMATA* *Department of Gastroenterology and ‡Department of Endoscopy and Endoscopic Surgery, University of Tokyo, Tokyo, Japan
See CME exam on page 1188. Background & Aims: K-ras mutation is frequently detected in pancreatic juice of patients with pancreatic small cystic lesions, as well as those with pancreatic cancer. Those cystic lesions are often found by chance with modern radiologic imaging modalities. In this study, we prospectively examined the prognosis of patients with pancreatic cystic lesions, focusing on pancreatic cancer development. Methods: A total of 197 patients with pancreatic cystic lesions, 80 with intraductal papillary mucinous neoplasm (IPMN) and 117 with non-IPMN cysts, were followed up for 3.8 years on average. Blood tests and imaging diagnosis were performed twice a year. The observed incidence of pancreatic cancer was compared with the expected incidence calculated on the basis of age- and gender-matched mortality of pancreatic cancer in the general Japanese population. Results: Pancreatic cancer developed in 7 patients during the observation period (0.95% per year), infiltrating ductal carcinoma in 5 and intraductal papillary mucinous carcinoma in 2. Three of the ductal cancer cases had pancreatic non-IPMN cyst as preexisting lesion. At least 2 of the carcinomas arose in regions remote from preexisting lesions. The observed incidence of pancreatic cancer was 22.5 times higher (95% confidence interval, 11.0 – 45.3) than expected mortality from this cancer among general population. Conclusions: Patients with pancreatic cystic lesions are at a considerably high risk for pancreatic cancer, with a standardized incidence rate of 22.5. Cancer might develop in regions remote from the preexisting cystic lesion, suggesting diffuse pathologic changes predisposing to malignant transformation in the entire pancreas harboring cystic lesions.
P
ancreatic cancer is one of the malignancies with extremely poor prognosis,1–3 with its mortality being nearly identical to its incidence rate. Moreover, we have little knowledge regarding precursor lesions or high-risk groups for this cancer. Thus, the majority of patients are found at advanced stages with symptoms such as obstructive jaundice, obstinate abdominal pain, and body weight loss. Early diagnosis of pancreatic cancer is a challenging issue requiring urgent attention. Recently, a variety of novel imaging modalities including noninvasive ones have enabled us to find small cystic lesions in the pancreas quite by chance. Most of these lesions are different from malignant cystic neoplasms or pancreatitis-related pseudocysts.4,5 Some of them have been designated as intraductal papil-
lary mucinous neoplasm (IPMN) characterized by enhanced mucus secretion. Others appear as “simple” cysts on diagnostic imaging. Pancreatic cancer has K-ras mutation with the highest frequency among human cancers. Interestingly, the mutation is found not only in pancreatic ductal carcinoma but also in IPMN.6 –11 We previously reported that pancreatic juice contains a large amount of mutated K-ras gene in patients with pancreatic cancer or IPMN.12–15 Interestingly, the mutation was also found in the pancreatic juice of the pancreas harboring apparently simple cysts. IPMN is a benign or low-grade malignant neoplasm characterized by a dilated main pancreatic duct, patulous ampullary orifice, and mucus secretion. This neoplasm occasionally contains invasive foci and becomes invasive cancer. The excessive mucus secretion leads to the dilation of secondary or more proximal pancreatic ducts, which might appear as cystic lesions in the pancreas.16 –21 When the mucus secretion remains moderate, IPMN might not be distinguishable from simple cysts. The data on K-ras mutation suggest that IPMN and cysts are, in fact, related lesions. Thus, we developed the hypothesis that incidentally detected cysts might develop into IPMN and in turn eventually into invasive cancer. In the present study, we evaluated the prognosis of patients with cystic lesions, IPMN and non-IPMN cysts, of the pancreas by prospective follow-up, focusing on pancreatic cancer development.
Patients and Methods Patients Cystic lesions in the pancreas were detected in 259 consecutive patients at the Department of Gastroenterology of Tokyo University Hospital between 1995–2004. These lesions were detected by imaging modalities such as abdominal ultrasonography (US), computed tomography (CT), endoscopic ultrasonography (EUS), and magnetic resonance cholangiopanAbbreviations used in this paper: AVSJ, annual vital statistics of Japan; CI, confidence interval; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; IPMC, intraductal papillary mucinous carcinoma; IPMN, intraductal papillary mucinous neoplasm of the pancreas; MCT, mucinous cystadenoma; MRCP, magnetic resonance cholangiopancreatography; SIR, standardized incidence ratio; US, ultrasonography. © 2006 by the American Gastroenterological Association (AGA) Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.07.013
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creatography (MRCP). We then evaluated them by CT with injection of contrast material, EUS, and MRCP for differential diagnosis of cystic lesions and for possible existence of pancreatic malignancy. Endoscopic retrograde cholangiopancreatography (ERCP) was performed if needed. We also performed blood tests including pancreatic enzymes and tumor markers such as CA19-9, carcinoembryonic antigen, and Dupan-2 for diagnostic assistance. Cystic lesion with characteristic appearance of unilocular cystic mass with septa was diagnosed as mucinous cystadenoma (MCT), and that with microcystic appearance was diagnosed as serous cystadenoma. We recommended resection for IPMN that met criteria of predictive factors for malignancy as described in the next section and all MCTs. The following 62 cases diagnosed as typical pseudocyst or cystic tumor of the pancreas by imaging techniques and clinical signs or resected without follow-up were excluded: 21 patients with pseudocyst associated with pancreatitis, 5 with possibly serous cystadenoma, 1 with MCT for resection, 1 with large retention cyst for resection that was suspected of MCT, 18 with IPMN undergoing surgery, and 16 patients followed for less than 1 year. The remaining 197 patients were included in the present study (Table 1). They were essentially asymptomatic and were found incidentally. One hundred thirty-two cases were found by chance during follow-up of nonpancreatic diseases (29 with chronic liver diseases, 12 with biliary stones, 9 with hepatocellular carcinoma, 9 with diabetes mellitus, as well as with numerous other diseases), 48 during medical checkups, and 17 during assessment of gastrointestinal disease after complaining of ambiguous abdominal discomfort. The initial imaging modality of detection of cystic lesions was US in 107, CT in 65, MRCP in 24, and EUS in 1.
Nature of Cystic Lesions Cystic lesions in the pancreas are sometimes a reflection of IPMN, which is characterized by dilatation of the main and/or secondary pancreatic ducts as a result of accumulation of mucinous secretion, especially in branched-type IPMN. Mucus secretion from papilla into the duodenum and/or a dilated pancreatic duct with or without filling defects observed during ERCP is a typical characteristic indicative of IPMN.16 –21 However, there has been no clear definition of IPMN in terms of the diameter of main pancreatic duct dilatation when there is no sign of mucinous secretion. In addition, it is unclear whether to make the definition of IPMN when small cystic lesions are observed without dilatation of the main pancreatic duct. Therefore, cystic lesions were defined as IPMN when one of the following characteristic features was observed: thick mucus secretion from the papilla of Vater into the duodenum, faint and mobile filling defect in the pancreatic duct during ERCP that is not identified by other imaging such as EUS, which
suggested presence of mucus production, or cystic lesion with a dilated main pancreatic duct wider than 3 mm. In cases of IPMN, surgery was proposed when the following features, reportedly predictive factors for malignancy, were observed: mural nodules clearly existing within the wall of cystic lesions, diameter of the main pancreatic duct larger than 7 mm, diameter of a cystic lesion larger than 40 mm,19,20 or malignant cells identified in pancreatic juice by cytology. Surgery was also selected when the patients had been suffering from pancreatitis. For these reasons, 18 of 20 meeting these criteria were resected without follow-up, and these 18 cases were excluded as described in the section on patients.
Follow-up One hundred ninety-seven patients with cystic lesions (117 cases of pancreatic cyst and 80 cases of IPMN) were followed up as outpatients at least twice a year with blood tests including tumor markers such as CA19-9, carcinoembryonic antigen, and Dupan-2, and imaging diagnostic modalities including abdominal US, CT scan, MRCP, and EUS were performed if needed.
Expected Pancreatic Cancer Development in General Japanese Population Age-gender–specific mortality rates and pancreatic cancer death rates are described in Vital Statistics of Japan, Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labor and Welfare, 2003. With these data, the expected number of pancreatic cancer deaths was calculated when age-gender–matched 197 Japanese were followed for the same period. In brief, the expected risk of a general Japanese subject Ci gender-age–matched to a patient Xi was evaluated as follows. When the age of Ci at inclusion was Ai1 and the annual mortality rates of pancreatic cancer death/all causes were Mpi1/Mai1, the expected number of pancreatic cancer deaths for the first year, ni1, was Mpi1. For next year, the expected number, ni2, was calculated as (1 ⫺ Mai1) ⫻ Mpi2. In a uniform manner, nij was as (1 ⫺ Mai(j-1)) ⫻ Mpij. The expected number for Ci (Ni) was n,m i⫽1,j⫽1 ni,j When the follow-up period was between m ⫺ 1 and m years, nim was corrected by interpolation technique. Then, the total expected number for the age-gender–matched Japanese 197 general population was calculated as i⫽1 Ni. The expected pancreatic cancer death rates were also estimated by using the expected numbers calculated above. We considered the expected number of pancreatic cancer deaths to be the expected number of pancreatic cancer developments because this cancer has devastatingly poor prognosis.1–3 The expected pancreatic cancer death rate was also considered to be the expected incidence of pancreatic cancer.
兺
兺
Table 1. Patients’ Profiles for Follow-Up
Age (y) Sex (female/male) Size of cyst (mm) No. of cysts (1/2–4/⬎5) Follow-up period (mo)
All patients (n ⫽ 197)
IPMN (n ⫽ 80)
Pancreatic cyst (n ⫽ 117)
24–87 (average, 65) 95/102 3–60 (average, 18) 114/48/35 12–115 (average, 45)
50–87 (average, 67) 26/54 5–60 (average, 22) 49/23/8 12–100 (average, 48)
24–87 (average, 65) 69/48 3–60 (average, 15) 65/25/27 12–115 (average, 43)
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Table 2. Characteristics of the 7 Patients With Pancreatic Cyst Who Were Found to Have Pancreatic Carcinoma During Follow-Up Data at entry
Patient no.
Age (y)/sex
Diagnosis
Maximum size of cyst (mm)
1
77/M
IPMN
10
1
Body
GAT(3⫹)
2
68/F
Cyst
8
2
Body
(⫺)
3 4 5
71/M 76/M 84/M
IPMN IPMN Cyst
15 40 10
2 1 ⬎10
GAT(1⫹) (⫺) (⫺)
6
71/M
IPMN
11
⬎10
7
75/M
Cyst
20
1
Body Head Head, body, tail Head, body, tail Head
No. of cysts
Location of cyst
K-ras
N/A N/A
Type of malignancy
Period (mo)
Ductal adenocarcinoma Ductal adenocarcinoma IPMC IPMC Ductal adenocarcinoma Ductal adenocarcinoma Ductal adenocarcinoma
14 60 51 61 42 45 20
Diagnostic clue CT, tumor marker US, tumor marker MRCP US Ileus Abdominal pain CT, tumor marker
GAT, represents a mutated nucleotide sequence of K-ras codon 12 from wild-type sequence of GGT; NA, not available.
Analysis of K-ras Mutation Pancreatic juice was collected during endoscopic retrograde cholangiopancreatography (ERCP), and it was used for both cytologic diagnosis and quantitative analysis of mutant K-ras gene as previously described.14,15,22 Informed consent for ERCP and analysis of ras gene mutation in pancreatic juice was obtained from all patients.
Statistical Analysis All statistical analyses were performed with SAS software release 8.2 (SAS Institute Inc, Cary, NC). Continuous variables were compared with either unpaired Student t test (parametric) or Mann-Whitney U test (nonparametric). Frequency distribution was compared with Fisher exact test or the 2 test. The odds ratios for developing pancreatic cancer were calculated by unconditional logistic regression. A P value ⬍.05 was considered statistically significant.23 The standardized incidence ratio (SIR) was calculated as the ratio of the observed to the expected number of incidences of pancreatic cancer. Standard error and 95% confidence interval (CI) of SIR were estimated by assuming the Poisson distribution, and changes in morbidity of the study cohort from the general population were considered significant if CI did not include unity.24
Results Patients One hundred ninety-seven patients were prospectively followed (Table 1). They consisted of 95 women and 102 men, with a mean age of 65 years (range, 24 – 87 years).
Characteristics of Cystic Lesions The maximum size of cystic lesions was 18 mm on average (range, 3– 60 mm). The numbers of cysts were 1 in 114 patients, 2– 4 in 48, and 5 or more (multiple) in 35 patients. The patients were categorized into 80 with IPMN and 117 with pancreatic cyst (Table 1). There were tendencies that more men,
larger diameter of cystic lesions, and a lower number of cystic lesions were found in cases with IPMN.
Development of Pancreatic Neoplasms Pancreatic cancer developed in 7 patients during follow-up (Table 2). Six were confirmed by pathology (resected specimens in 4 cases and cytology in 2 cases). The remaining one was diagnosed by imaging modalities and an unfavorable clinical course. They consisted of 1 woman and 6 men, with a mean age of 72.1 years (range, 68 – 84 years) at the diagnosis of cancer. Pancreatic cancer was diagnosed between 14 and 61 months (42 on average) after the diagnosis of cystic lesions. Ductal pancreatic carcinoma developed in 5 patients. Tumors were smaller than 2 cm in diameter in 2 patients, arising in apparently different sites from the cystic lesions (Figure 1). This was confirmed by pathologic examination of the resected specimens. In addition, no malignant cells were found in the epithelium of these cystic lesions. In another patient, ductal pancreatic carcinoma developed around the preexisting cystic lesions. The other 2 patients were diagnosed as having stage 4 pancreatic cancer, and tumor size was too large for evaluating any locational relationship between the carcinoma and cystic lesion. All 3 patients without resection exhibited rapid progression and died of pancreatic cancer within 8 months after diagnosis. Intraductal papillary mucinous carcinoma (IPMC), as a well-known type of malignant transformation of IPMN, developed in 2 patients.18,25 In these cases, malignant epithelium was observed mainly in the wall of the cystic lesion. Diagnostic clues for the development of malignancy of patients without symptoms were tumor markers in 3 cases and imaging modalities in 5 cases (2 by US, 2 by CT, 1 by MRCP), respectively. One patient had a mucinous cystadenoma and underwent surgery because of the increased size of the cystic lesion. There were no pancreatic cysts that increased its size with signs of mucous secretion or accompanied dilatation of the pancreatic duct, as we defined as IPMN in this study. Eight patients died of disorders other than pancreas-related ones.
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Figure 1. Infiltrating carcinoma found in a case of pancreatic cyst. (A) MRCP findings at the diagnosis of pancreatic cyst. Cystic lesion, diameter of 8 mm, was seen in the body of the pancreas. (B) MRCP findings when cancer was found. Invasive carcinoma developed distal to the cystic lesion after 60 months. There were no malignant cells between these lesions. (C) CT findings when cancer was found. Spaceoccupying lesion as a feature of conventional ductal carcinoma was seen.
Incidence of Pancreatic Cancer The incidence of pancreatic cancer was calculated as 0.948% per year. In contrast, the expected incidence death in the general Japanese population corrected by age and gender is 0.0423% per year. The standardized morbidity ratio was calculated to be 22.5 (95% CI; 11.0 – 45.3) (Table 3, Figure 2).
Characteristics of Patients Developing Pancreatic Cancer Prior characteristics of the patients developing pancreatic cancer were as follows. Maximum average size of cystic lesions was 18 mm (range, 8 – 40 mm). The number of cysts was 1 in 3 patients, 2 in 2, and multiple in 2 patients. No significant differences were found in gender, presence of main pancreatic duct dilatation (more than 3 mm), the number, size, and location of cystic lesions between patients developing pancreatic cancer and the other patients except in age by Cox proportional hazard model analysis (Table 4).
Analysis of Ras Gene in Pancreatic Juice
Figure 2.
Incidence of pancreatic cancer was compared with a matched case-control group. Closed circles represent the expected incidence of pancreatic cancer death in age-gender–matched general population.
gene, as defined in our previous reports,14,15 were detected in 39 patients (38%), 15 (15%), and 48 (47%, including 39 patients without detection), respectively. Among 7 patients with pancreatic cancer during follow-up, 1 patient each had a high and an intermediate amount of mutant K-ras gene, respectively. Mutant K-ras gene was not detected in 3 patients, and pancreatic juice was not available in the remaining 2 (Table 2). No significant differences were observed in the incidence of pancreatic cancer development between patients with high amount of mutant K-ras gene and the others by log rank test (P ⫽ .594).
Table 4. Factors for Developing Cancer by Cox Proportional Hazard Model
Mutant ras gene in pancreatic juice was analyzed in 102 patients. High, intermediate, and low amounts of mutant ras Table 3. Development of Pancreatic Cancer Present series No. of patients Male/female Age (y) Follow-up (y) No. of pancreatic cancers Annual incidence SIR aExpected
197 102/95 65.4 ⫾ 10.2 3.73 ⫾ 1.83 7 0.95% (0.46%–1.91%) 22.5 (11.0–45.3)
Expected value
0.31a 0.04%b
number and bexpected annual incidence of pancreatic cancer deaths in age-gender–matched general population.
Age (y) Gender Male Female Pancreatic duct dilatation ⫹ ⫺ Size of cyst (mm) No. of cysts Single Multiple Location of cysts Body, tail Head
Hazard ratio (95% confidence interval)
P value
1.12 (1.01–1.25)
.032
1.0 0.17 (0.02–1.49)
.109
1.0 0.44 (0.07–2.63) 0.94 (0.85–1.04)
.368 .244
1.0 1.30 (0.22–7.62)
.772
1.0 0.78 (0.12–5.12)
.792
October 2006
Discussion In the present study, we followed up 197 patients with incidentally detected cystic lesions, both IPMN and cysts, in the pancreas and subsequently found pancreatic cancer development in 7 patients during an observation period of 3.8 years, an annual incidence rate of 0.95%. The precise age-specific and gender-specific incidence rates of pancreatic cancer in the general Japanese population are not known, but they can be approximated by the specific mortality rates described in the Annual Vital Statistics of Japan (AVSJ), considering the high fatality and short survival time of cancer. The observed incidence of pancreatic cancer was 22.5 times higher than the expected incidence thus calculated (n ⫽ 0.311; annual rate, 0.04%). The ratio of 22.5 indicates the SIR. CIs can be calculated for SIR by assuming the Poisson distribution, and the result, 11.0 – 45.3, does not include unity, indicating that the incidence of pancreatic cancer was statistically significantly higher among the patients with cystic lesions. Pseudocyst and serous/mucinous cystadenoma are apparently of different nature in the points of view of pathologic/clinical features and K-ras mutation.12–15 Thus, we excluded these cases from follow-up. It might be argued that the cystic lesions were concomitants of pancreatic cancer that was present but undetectable at the time of entry. However, if this were the case, cancer would have been detected within a short period of time, and thereafter the incidence rate would have declined. However, pancreatic cancer continued to develop after up to 5 years of observation (Figure 2), indicating that carcinogenesis was subsequent to the formation of cystic lesions. Most cysts in the pancreas used to be considered as pseudocysts.5,26 However, recent studies have indicated that a substantial proportion of those lesions are lined with epithelium of possibly neoplastic nature.4,5 Thus, these “true” cysts might constitute a spectrum of neoplasms with IPMN and IPMC. Our initial hypothesis was that the cyst itself might develop into IPMN and eventually into IPMC. In fact, it is often difficult to distinguish between a cyst and IPMN if enhanced mucus secretion is not apparent. Although we adopted a criterion of main pancreatic duct dilatation wider than 3 mm for IPMN, this cutoff dimension was rather arbitrary. Therefore, non-IPMN cysts might constitute a wide spectrum of cystic lesions including IPMN without typical characteristics. Fine-needle aspiration (FNA) and/or cyst fluid analysis could lead to more precise diagnosis of the cystic lesions.27 However, we did not use these modalities because seeding of malignant cells was reported in cases of EUS-FNA for pancreatic cystic lesions.28,29 Contrary to our hypothesis, 5 of 7 patients developing pancreatic cancer had common-type ductal cancer, whereas the remaining 2 with previous IPMN developed IPMC. Moreover, 3 of the 5 patients with ductal cancer had non-IPMN cysts, and the other 2 had IPMN. It appears from these observations that both cysts and IPMN have a similar malignant potential for pancreatic ductal cancer. The follow-up period might be too short to evaluate development of the cyst to IPMN. However, no development of IPMC whose carcinoma derived from the original cystic lesion in cyst group in contrast to IPMN group might reflect some different nature of cystic lesions concerning malignant alternative pathway between these groups. Further accumulation of development of pancreatic malignancies will be needed to confirm these observations.
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In this study, 2 cases of ductal cancer occurred in regions remote from the preexisting cystic lesions. In 2 other cases, the distance between the cancers and original lesions could not be determined because they were at a far advanced stage when detected. Thus, not only the cystic lesion itself but also the entire pancreas might be at high risk of carcinogenesis. Although IPMN is considered to be a less invasive neoplasm,25,30,31 it sometimes shows an aggressive nature accompanied by extrapancreatic spread. Invasive pancreatic ductal cancer is occasionally found remotely from IPMN32 or in the remnant pancreas several years after excision of IPMN.30 We confirmed in this study that the presence of IPMN indicates a risk of ductal cancer over the entire pancreas. Moreover, we also showed that the presence of non-IPMN cysts indicates a similar risk of ductal cancer. The mechanism of the malignant potential in the pancreas harboring cystic lesions is not clear. However, the presence of K-ras mutation in pancreatic juice of patients with IPMN or cysts, as confirmed in our study,14,15 might suggest a common background. Moreover, it was reported that mutant K-ras was detected in pancreatic juice samples 18 – 40 months before the development of infiltrating cancer,33 and also that pancreatic intraepithelial neoplasm bearing multiple genetic changes, including K-ras mutation,34 had been identified 1.5–10 years before the development of infiltrating adenocarcinoma of the pancreas.35 These data might suggest that some preneoplastic changes had already occurred in the pancreas harboring cystic lesions, which were impossible to detect even with modern radiologic diagnostic methods. The presence of mutant K-ras in pancreatic juice at a high level might reflect a widespread neoplastic “field defect” in the entire pancreas with cysts or IPMN. Additional studies will be needed to identify possible precursor lesions in the pancreas containing K-ras mutation. We analyzed the baseline clinical features of patients who subsequently developed pancreatic cancer to identify additional risk factors. Although mutant K-ras in the pancreatic juice seemed to be promising, it was not found to be significant, possibly because of the small total number of patients who developed cancer. No factors were found significant as predictors for pancreatic cancer by multivariate analysis. Further studies will be needed to distinguish a higher-risk subgroup among patients with pancreatic cyst lesions. Early diagnosis of pancreatic ductal cancer is still difficult. In fact, in our series, 2 cases of pancreatic cancer were diagnosed at advanced stage despite close follow-up in the current study. Obviously, the higher-risk group needs to be identified and receive more extensive follow-up. In conclusion, patients with pancreatic cystic lesions, not only IPMN but also simple cysts, are at an increased risk of pancreatic cancer, including ductal cancer. These patients should be carefully monitored so as to detect the development of cancer as early as possible. References 1. Warshaw AL, Castillo CF. Pancreatic carcinoma. N Engl J Med 1992;326:455– 465. 2. Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet 1997; 349:485– 489. 3. Carpelan-Holmstrom M, Nordling S, Pukkala E, et al. Does anyone survive pancreatic ductal adenocarcinoma?: a nationwide study re-evaluating the data from the Finnish cancer registry. Gut 2005; 54:385–387.
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4. Fernandez-del Castillo C, Targarona J, Thayer SP, et al. Incidental pancreatic cysts. Arch Surg 2003;138:427– 434. 5. Klöppel G, Kosmahl M. Cystic lesions and neoplasms of the pancreas. Pancreatology 2001;1:648 – 655. 6. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549 –554. 7. Tada M, Yokosuka O, Omata M, et al. Analysis of ras gene mutation in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing. Cancer 1990;66:930 –935. 8. Tada M, Omata M, Ohto M. Clinical applications of ras gene mutation for diagnosis of pancreatic adenocarcinoma. Gastroenterology 1991;100:233–238. 9. Tada M, Omata M, Ohto M. Ras gene mutation in intraductal papillary neoplasms of the pancreas: analysis in five cases. Cancer 1991;67:634 – 637. 10. Hoshi T, Imai M, Ogawa K. Frequent K-ras mutations and absence of p53 mutations in mucin-producing tumors of the pancreas. J Surg Oncol 1994;55:84 –91. 11. Z’graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 1997;226:491– 498. 12. Tada M, Omata M, Kawai S, et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 1993;53:2472–2474. 13. Tada M. Ki-ras mutations in chronic pancreatitis: which relevance? Gastroenterology 1996;111:566 –567. 14. Tateishi K, Tada M, Yamagata M, et al. High proportion of mutant K-ras gene in pancreatic juice of patients with pancreatic cystic lesions. Gut 1999;45:737–740. 15. Tada M, Tateishi K, Kawabe T, et al. Quantity of mutant K-ras gene in pancreatic secretions for diagnosis of pancreatic carcinoma with different assays: analysis of 100 patients. Clin Chim Acta 2002;324:105–111. 16. Loftus EV, Olivares-Pakzad BA, Batts KP, et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Gastroenterology 1996;110: 1909 –1918. 17. Azar C, de Stadt JV, Rickaert F, et al. Intraductal papillary mucinous tumors of the pancreas: clinical and therapeutic issues in 32 patients. Gut 1996;39:457– 464. 18. Solcia E, Capella A, Klöppel G, eds. Intraductal papillary-mucinous tumor. In: Tumors of the pancreas. Bethesda, MD: Armed Forces Institute of Pathology, 1995:53– 64. 19. Sugiyama M, Izumisato Y, Abe N, et al. Predictive factors for malignancy in intraductal papillary-mucinous tumors of the pancreas. Br J Surg 2003;90:1244 –1249. 20. Irie H, Yoshitomi K, Aibe H, et al. Natural history of pancreatic intraductal papillary mucinous tumor of branch duct type: follow-up study by magnetic resonance cholangiopancreatography. J Comput Assist Tomogr 2004;28:117–122. 21. Shimizu Y, Yasui K, Morimoto T, et al. Case of intraductal papillary mucinous tumor (noninvasive adenocarcinoma) of the pan-
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Address requests for reprints to: Minoru Tada, MD, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan 113-8655. e-mail: [email protected]; fax: 81-3-3814-0021. The authors acknowledge Dr Masatoshi Makuuchi for surgical resection, Drs Kuni Ohtomo and Masaaki Akahane for radiologic imaging diagnosis, and Dr Masashi Fukayama for pathologic diagnosis.
Pancreatic Cancer in Patients With Pancreatic Cystic Lesions: A Prospective Study in 197 Patients MINORU TADA,* TAKAO KAWABE,‡ MASATOSHI ARIZUMI,* OSAMU TOGAWA,* SABURO MATSUBARA,* NATSUYO YAMAMOTO,* YOSUKE NAKAI,* NAOKI SASAHIRA,* KENJI HIRANO,* TAKESHI TSUJINO,* KEISUKE TATEISHI,* HIROYUKI ISAYAMA,* NOBUO TODA,* HARUHIKO YOSHIDA,* and MASAO OMATA* *Department of Gastroenterology and ‡Department of Endoscopy and Endoscopic Surgery, University of Tokyo, Tokyo, Japan
See CME exam on page 1188. Background & Aims: K-ras mutation is frequently detected in pancreatic juice of patients with pancreatic small cystic lesions, as well as those with pancreatic cancer. Those cystic lesions are often found by chance with modern radiologic imaging modalities. In this study, we prospectively examined the prognosis of patients with pancreatic cystic lesions, focusing on pancreatic cancer development. Methods: A total of 197 patients with pancreatic cystic lesions, 80 with intraductal papillary mucinous neoplasm (IPMN) and 117 with non-IPMN cysts, were followed up for 3.8 years on average. Blood tests and imaging diagnosis were performed twice a year. The observed incidence of pancreatic cancer was compared with the expected incidence calculated on the basis of age- and gender-matched mortality of pancreatic cancer in the general Japanese population. Results: Pancreatic cancer developed in 7 patients during the observation period (0.95% per year), infiltrating ductal carcinoma in 5 and intraductal papillary mucinous carcinoma in 2. Three of the ductal cancer cases had pancreatic non-IPMN cyst as preexisting lesion. At least 2 of the carcinomas arose in regions remote from preexisting lesions. The observed incidence of pancreatic cancer was 22.5 times higher (95% confidence interval, 11.0 – 45.3) than expected mortality from this cancer among general population. Conclusions: Patients with pancreatic cystic lesions are at a considerably high risk for pancreatic cancer, with a standardized incidence rate of 22.5. Cancer might develop in regions remote from the preexisting cystic lesion, suggesting diffuse pathologic changes predisposing to malignant transformation in the entire pancreas harboring cystic lesions.
P
ancreatic cancer is one of the malignancies with extremely poor prognosis,1–3 with its mortality being nearly identical to its incidence rate. Moreover, we have little knowledge regarding precursor lesions or high-risk groups for this cancer. Thus, the majority of patients are found at advanced stages with symptoms such as obstructive jaundice, obstinate abdominal pain, and body weight loss. Early diagnosis of pancreatic cancer is a challenging issue requiring urgent attention. Recently, a variety of novel imaging modalities including noninvasive ones have enabled us to find small cystic lesions in the pancreas quite by chance. Most of these lesions are different from malignant cystic neoplasms or pancreatitis-related pseudocysts.4,5 Some of them have been designated as intraductal papil-
lary mucinous neoplasm (IPMN) characterized by enhanced mucus secretion. Others appear as “simple” cysts on diagnostic imaging. Pancreatic cancer has K-ras mutation with the highest frequency among human cancers. Interestingly, the mutation is found not only in pancreatic ductal carcinoma but also in IPMN.6 –11 We previously reported that pancreatic juice contains a large amount of mutated K-ras gene in patients with pancreatic cancer or IPMN.12–15 Interestingly, the mutation was also found in the pancreatic juice of the pancreas harboring apparently simple cysts. IPMN is a benign or low-grade malignant neoplasm characterized by a dilated main pancreatic duct, patulous ampullary orifice, and mucus secretion. This neoplasm occasionally contains invasive foci and becomes invasive cancer. The excessive mucus secretion leads to the dilation of secondary or more proximal pancreatic ducts, which might appear as cystic lesions in the pancreas.16 –21 When the mucus secretion remains moderate, IPMN might not be distinguishable from simple cysts. The data on K-ras mutation suggest that IPMN and cysts are, in fact, related lesions. Thus, we developed the hypothesis that incidentally detected cysts might develop into IPMN and in turn eventually into invasive cancer. In the present study, we evaluated the prognosis of patients with cystic lesions, IPMN and non-IPMN cysts, of the pancreas by prospective follow-up, focusing on pancreatic cancer development.
Patients and Methods Patients Cystic lesions in the pancreas were detected in 259 consecutive patients at the Department of Gastroenterology of Tokyo University Hospital between 1995–2004. These lesions were detected by imaging modalities such as abdominal ultrasonography (US), computed tomography (CT), endoscopic ultrasonography (EUS), and magnetic resonance cholangiopanAbbreviations used in this paper: AVSJ, annual vital statistics of Japan; CI, confidence interval; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; IPMC, intraductal papillary mucinous carcinoma; IPMN, intraductal papillary mucinous neoplasm of the pancreas; MCT, mucinous cystadenoma; MRCP, magnetic resonance cholangiopancreatography; SIR, standardized incidence ratio; US, ultrasonography. © 2006 by the American Gastroenterological Association (AGA) Institute 1542-3565/06/$32.00 doi:10.1016/j.cgh.2006.07.013
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creatography (MRCP). We then evaluated them by CT with injection of contrast material, EUS, and MRCP for differential diagnosis of cystic lesions and for possible existence of pancreatic malignancy. Endoscopic retrograde cholangiopancreatography (ERCP) was performed if needed. We also performed blood tests including pancreatic enzymes and tumor markers such as CA19-9, carcinoembryonic antigen, and Dupan-2 for diagnostic assistance. Cystic lesion with characteristic appearance of unilocular cystic mass with septa was diagnosed as mucinous cystadenoma (MCT), and that with microcystic appearance was diagnosed as serous cystadenoma. We recommended resection for IPMN that met criteria of predictive factors for malignancy as described in the next section and all MCTs. The following 62 cases diagnosed as typical pseudocyst or cystic tumor of the pancreas by imaging techniques and clinical signs or resected without follow-up were excluded: 21 patients with pseudocyst associated with pancreatitis, 5 with possibly serous cystadenoma, 1 with MCT for resection, 1 with large retention cyst for resection that was suspected of MCT, 18 with IPMN undergoing surgery, and 16 patients followed for less than 1 year. The remaining 197 patients were included in the present study (Table 1). They were essentially asymptomatic and were found incidentally. One hundred thirty-two cases were found by chance during follow-up of nonpancreatic diseases (29 with chronic liver diseases, 12 with biliary stones, 9 with hepatocellular carcinoma, 9 with diabetes mellitus, as well as with numerous other diseases), 48 during medical checkups, and 17 during assessment of gastrointestinal disease after complaining of ambiguous abdominal discomfort. The initial imaging modality of detection of cystic lesions was US in 107, CT in 65, MRCP in 24, and EUS in 1.
Nature of Cystic Lesions Cystic lesions in the pancreas are sometimes a reflection of IPMN, which is characterized by dilatation of the main and/or secondary pancreatic ducts as a result of accumulation of mucinous secretion, especially in branched-type IPMN. Mucus secretion from papilla into the duodenum and/or a dilated pancreatic duct with or without filling defects observed during ERCP is a typical characteristic indicative of IPMN.16 –21 However, there has been no clear definition of IPMN in terms of the diameter of main pancreatic duct dilatation when there is no sign of mucinous secretion. In addition, it is unclear whether to make the definition of IPMN when small cystic lesions are observed without dilatation of the main pancreatic duct. Therefore, cystic lesions were defined as IPMN when one of the following characteristic features was observed: thick mucus secretion from the papilla of Vater into the duodenum, faint and mobile filling defect in the pancreatic duct during ERCP that is not identified by other imaging such as EUS, which
suggested presence of mucus production, or cystic lesion with a dilated main pancreatic duct wider than 3 mm. In cases of IPMN, surgery was proposed when the following features, reportedly predictive factors for malignancy, were observed: mural nodules clearly existing within the wall of cystic lesions, diameter of the main pancreatic duct larger than 7 mm, diameter of a cystic lesion larger than 40 mm,19,20 or malignant cells identified in pancreatic juice by cytology. Surgery was also selected when the patients had been suffering from pancreatitis. For these reasons, 18 of 20 meeting these criteria were resected without follow-up, and these 18 cases were excluded as described in the section on patients.
Follow-up One hundred ninety-seven patients with cystic lesions (117 cases of pancreatic cyst and 80 cases of IPMN) were followed up as outpatients at least twice a year with blood tests including tumor markers such as CA19-9, carcinoembryonic antigen, and Dupan-2, and imaging diagnostic modalities including abdominal US, CT scan, MRCP, and EUS were performed if needed.
Expected Pancreatic Cancer Development in General Japanese Population Age-gender–specific mortality rates and pancreatic cancer death rates are described in Vital Statistics of Japan, Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labor and Welfare, 2003. With these data, the expected number of pancreatic cancer deaths was calculated when age-gender–matched 197 Japanese were followed for the same period. In brief, the expected risk of a general Japanese subject Ci gender-age–matched to a patient Xi was evaluated as follows. When the age of Ci at inclusion was Ai1 and the annual mortality rates of pancreatic cancer death/all causes were Mpi1/Mai1, the expected number of pancreatic cancer deaths for the first year, ni1, was Mpi1. For next year, the expected number, ni2, was calculated as (1 ⫺ Mai1) ⫻ Mpi2. In a uniform manner, nij was as (1 ⫺ Mai(j-1)) ⫻ Mpij. The expected number for Ci (Ni) was n,m i⫽1,j⫽1 ni,j When the follow-up period was between m ⫺ 1 and m years, nim was corrected by interpolation technique. Then, the total expected number for the age-gender–matched Japanese 197 general population was calculated as i⫽1 Ni. The expected pancreatic cancer death rates were also estimated by using the expected numbers calculated above. We considered the expected number of pancreatic cancer deaths to be the expected number of pancreatic cancer developments because this cancer has devastatingly poor prognosis.1–3 The expected pancreatic cancer death rate was also considered to be the expected incidence of pancreatic cancer.
兺
兺
Table 1. Patients’ Profiles for Follow-Up
Age (y) Sex (female/male) Size of cyst (mm) No. of cysts (1/2–4/⬎5) Follow-up period (mo)
All patients (n ⫽ 197)
IPMN (n ⫽ 80)
Pancreatic cyst (n ⫽ 117)
24–87 (average, 65) 95/102 3–60 (average, 18) 114/48/35 12–115 (average, 45)
50–87 (average, 67) 26/54 5–60 (average, 22) 49/23/8 12–100 (average, 48)
24–87 (average, 65) 69/48 3–60 (average, 15) 65/25/27 12–115 (average, 43)
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Table 2. Characteristics of the 7 Patients With Pancreatic Cyst Who Were Found to Have Pancreatic Carcinoma During Follow-Up Data at entry
Patient no.
Age (y)/sex
Diagnosis
Maximum size of cyst (mm)
1
77/M
IPMN
10
1
Body
GAT(3⫹)
2
68/F
Cyst
8
2
Body
(⫺)
3 4 5
71/M 76/M 84/M
IPMN IPMN Cyst
15 40 10
2 1 ⬎10
GAT(1⫹) (⫺) (⫺)
6
71/M
IPMN
11
⬎10
7
75/M
Cyst
20
1
Body Head Head, body, tail Head, body, tail Head
No. of cysts
Location of cyst
K-ras
N/A N/A
Type of malignancy
Period (mo)
Ductal adenocarcinoma Ductal adenocarcinoma IPMC IPMC Ductal adenocarcinoma Ductal adenocarcinoma Ductal adenocarcinoma
14 60 51 61 42 45 20
Diagnostic clue CT, tumor marker US, tumor marker MRCP US Ileus Abdominal pain CT, tumor marker
GAT, represents a mutated nucleotide sequence of K-ras codon 12 from wild-type sequence of GGT; NA, not available.
Analysis of K-ras Mutation Pancreatic juice was collected during endoscopic retrograde cholangiopancreatography (ERCP), and it was used for both cytologic diagnosis and quantitative analysis of mutant K-ras gene as previously described.14,15,22 Informed consent for ERCP and analysis of ras gene mutation in pancreatic juice was obtained from all patients.
Statistical Analysis All statistical analyses were performed with SAS software release 8.2 (SAS Institute Inc, Cary, NC). Continuous variables were compared with either unpaired Student t test (parametric) or Mann-Whitney U test (nonparametric). Frequency distribution was compared with Fisher exact test or the 2 test. The odds ratios for developing pancreatic cancer were calculated by unconditional logistic regression. A P value ⬍.05 was considered statistically significant.23 The standardized incidence ratio (SIR) was calculated as the ratio of the observed to the expected number of incidences of pancreatic cancer. Standard error and 95% confidence interval (CI) of SIR were estimated by assuming the Poisson distribution, and changes in morbidity of the study cohort from the general population were considered significant if CI did not include unity.24
Results Patients One hundred ninety-seven patients were prospectively followed (Table 1). They consisted of 95 women and 102 men, with a mean age of 65 years (range, 24 – 87 years).
Characteristics of Cystic Lesions The maximum size of cystic lesions was 18 mm on average (range, 3– 60 mm). The numbers of cysts were 1 in 114 patients, 2– 4 in 48, and 5 or more (multiple) in 35 patients. The patients were categorized into 80 with IPMN and 117 with pancreatic cyst (Table 1). There were tendencies that more men,
larger diameter of cystic lesions, and a lower number of cystic lesions were found in cases with IPMN.
Development of Pancreatic Neoplasms Pancreatic cancer developed in 7 patients during follow-up (Table 2). Six were confirmed by pathology (resected specimens in 4 cases and cytology in 2 cases). The remaining one was diagnosed by imaging modalities and an unfavorable clinical course. They consisted of 1 woman and 6 men, with a mean age of 72.1 years (range, 68 – 84 years) at the diagnosis of cancer. Pancreatic cancer was diagnosed between 14 and 61 months (42 on average) after the diagnosis of cystic lesions. Ductal pancreatic carcinoma developed in 5 patients. Tumors were smaller than 2 cm in diameter in 2 patients, arising in apparently different sites from the cystic lesions (Figure 1). This was confirmed by pathologic examination of the resected specimens. In addition, no malignant cells were found in the epithelium of these cystic lesions. In another patient, ductal pancreatic carcinoma developed around the preexisting cystic lesions. The other 2 patients were diagnosed as having stage 4 pancreatic cancer, and tumor size was too large for evaluating any locational relationship between the carcinoma and cystic lesion. All 3 patients without resection exhibited rapid progression and died of pancreatic cancer within 8 months after diagnosis. Intraductal papillary mucinous carcinoma (IPMC), as a well-known type of malignant transformation of IPMN, developed in 2 patients.18,25 In these cases, malignant epithelium was observed mainly in the wall of the cystic lesion. Diagnostic clues for the development of malignancy of patients without symptoms were tumor markers in 3 cases and imaging modalities in 5 cases (2 by US, 2 by CT, 1 by MRCP), respectively. One patient had a mucinous cystadenoma and underwent surgery because of the increased size of the cystic lesion. There were no pancreatic cysts that increased its size with signs of mucous secretion or accompanied dilatation of the pancreatic duct, as we defined as IPMN in this study. Eight patients died of disorders other than pancreas-related ones.
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Figure 1. Infiltrating carcinoma found in a case of pancreatic cyst. (A) MRCP findings at the diagnosis of pancreatic cyst. Cystic lesion, diameter of 8 mm, was seen in the body of the pancreas. (B) MRCP findings when cancer was found. Invasive carcinoma developed distal to the cystic lesion after 60 months. There were no malignant cells between these lesions. (C) CT findings when cancer was found. Spaceoccupying lesion as a feature of conventional ductal carcinoma was seen.
Incidence of Pancreatic Cancer The incidence of pancreatic cancer was calculated as 0.948% per year. In contrast, the expected incidence death in the general Japanese population corrected by age and gender is 0.0423% per year. The standardized morbidity ratio was calculated to be 22.5 (95% CI; 11.0 – 45.3) (Table 3, Figure 2).
Characteristics of Patients Developing Pancreatic Cancer Prior characteristics of the patients developing pancreatic cancer were as follows. Maximum average size of cystic lesions was 18 mm (range, 8 – 40 mm). The number of cysts was 1 in 3 patients, 2 in 2, and multiple in 2 patients. No significant differences were found in gender, presence of main pancreatic duct dilatation (more than 3 mm), the number, size, and location of cystic lesions between patients developing pancreatic cancer and the other patients except in age by Cox proportional hazard model analysis (Table 4).
Analysis of Ras Gene in Pancreatic Juice
Figure 2.
Incidence of pancreatic cancer was compared with a matched case-control group. Closed circles represent the expected incidence of pancreatic cancer death in age-gender–matched general population.
gene, as defined in our previous reports,14,15 were detected in 39 patients (38%), 15 (15%), and 48 (47%, including 39 patients without detection), respectively. Among 7 patients with pancreatic cancer during follow-up, 1 patient each had a high and an intermediate amount of mutant K-ras gene, respectively. Mutant K-ras gene was not detected in 3 patients, and pancreatic juice was not available in the remaining 2 (Table 2). No significant differences were observed in the incidence of pancreatic cancer development between patients with high amount of mutant K-ras gene and the others by log rank test (P ⫽ .594).
Table 4. Factors for Developing Cancer by Cox Proportional Hazard Model
Mutant ras gene in pancreatic juice was analyzed in 102 patients. High, intermediate, and low amounts of mutant ras Table 3. Development of Pancreatic Cancer Present series No. of patients Male/female Age (y) Follow-up (y) No. of pancreatic cancers Annual incidence SIR aExpected
197 102/95 65.4 ⫾ 10.2 3.73 ⫾ 1.83 7 0.95% (0.46%–1.91%) 22.5 (11.0–45.3)
Expected value
0.31a 0.04%b
number and bexpected annual incidence of pancreatic cancer deaths in age-gender–matched general population.
Age (y) Gender Male Female Pancreatic duct dilatation ⫹ ⫺ Size of cyst (mm) No. of cysts Single Multiple Location of cysts Body, tail Head
Hazard ratio (95% confidence interval)
P value
1.12 (1.01–1.25)
.032
1.0 0.17 (0.02–1.49)
.109
1.0 0.44 (0.07–2.63) 0.94 (0.85–1.04)
.368 .244
1.0 1.30 (0.22–7.62)
.772
1.0 0.78 (0.12–5.12)
.792
October 2006
Discussion In the present study, we followed up 197 patients with incidentally detected cystic lesions, both IPMN and cysts, in the pancreas and subsequently found pancreatic cancer development in 7 patients during an observation period of 3.8 years, an annual incidence rate of 0.95%. The precise age-specific and gender-specific incidence rates of pancreatic cancer in the general Japanese population are not known, but they can be approximated by the specific mortality rates described in the Annual Vital Statistics of Japan (AVSJ), considering the high fatality and short survival time of cancer. The observed incidence of pancreatic cancer was 22.5 times higher than the expected incidence thus calculated (n ⫽ 0.311; annual rate, 0.04%). The ratio of 22.5 indicates the SIR. CIs can be calculated for SIR by assuming the Poisson distribution, and the result, 11.0 – 45.3, does not include unity, indicating that the incidence of pancreatic cancer was statistically significantly higher among the patients with cystic lesions. Pseudocyst and serous/mucinous cystadenoma are apparently of different nature in the points of view of pathologic/clinical features and K-ras mutation.12–15 Thus, we excluded these cases from follow-up. It might be argued that the cystic lesions were concomitants of pancreatic cancer that was present but undetectable at the time of entry. However, if this were the case, cancer would have been detected within a short period of time, and thereafter the incidence rate would have declined. However, pancreatic cancer continued to develop after up to 5 years of observation (Figure 2), indicating that carcinogenesis was subsequent to the formation of cystic lesions. Most cysts in the pancreas used to be considered as pseudocysts.5,26 However, recent studies have indicated that a substantial proportion of those lesions are lined with epithelium of possibly neoplastic nature.4,5 Thus, these “true” cysts might constitute a spectrum of neoplasms with IPMN and IPMC. Our initial hypothesis was that the cyst itself might develop into IPMN and eventually into IPMC. In fact, it is often difficult to distinguish between a cyst and IPMN if enhanced mucus secretion is not apparent. Although we adopted a criterion of main pancreatic duct dilatation wider than 3 mm for IPMN, this cutoff dimension was rather arbitrary. Therefore, non-IPMN cysts might constitute a wide spectrum of cystic lesions including IPMN without typical characteristics. Fine-needle aspiration (FNA) and/or cyst fluid analysis could lead to more precise diagnosis of the cystic lesions.27 However, we did not use these modalities because seeding of malignant cells was reported in cases of EUS-FNA for pancreatic cystic lesions.28,29 Contrary to our hypothesis, 5 of 7 patients developing pancreatic cancer had common-type ductal cancer, whereas the remaining 2 with previous IPMN developed IPMC. Moreover, 3 of the 5 patients with ductal cancer had non-IPMN cysts, and the other 2 had IPMN. It appears from these observations that both cysts and IPMN have a similar malignant potential for pancreatic ductal cancer. The follow-up period might be too short to evaluate development of the cyst to IPMN. However, no development of IPMC whose carcinoma derived from the original cystic lesion in cyst group in contrast to IPMN group might reflect some different nature of cystic lesions concerning malignant alternative pathway between these groups. Further accumulation of development of pancreatic malignancies will be needed to confirm these observations.
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In this study, 2 cases of ductal cancer occurred in regions remote from the preexisting cystic lesions. In 2 other cases, the distance between the cancers and original lesions could not be determined because they were at a far advanced stage when detected. Thus, not only the cystic lesion itself but also the entire pancreas might be at high risk of carcinogenesis. Although IPMN is considered to be a less invasive neoplasm,25,30,31 it sometimes shows an aggressive nature accompanied by extrapancreatic spread. Invasive pancreatic ductal cancer is occasionally found remotely from IPMN32 or in the remnant pancreas several years after excision of IPMN.30 We confirmed in this study that the presence of IPMN indicates a risk of ductal cancer over the entire pancreas. Moreover, we also showed that the presence of non-IPMN cysts indicates a similar risk of ductal cancer. The mechanism of the malignant potential in the pancreas harboring cystic lesions is not clear. However, the presence of K-ras mutation in pancreatic juice of patients with IPMN or cysts, as confirmed in our study,14,15 might suggest a common background. Moreover, it was reported that mutant K-ras was detected in pancreatic juice samples 18 – 40 months before the development of infiltrating cancer,33 and also that pancreatic intraepithelial neoplasm bearing multiple genetic changes, including K-ras mutation,34 had been identified 1.5–10 years before the development of infiltrating adenocarcinoma of the pancreas.35 These data might suggest that some preneoplastic changes had already occurred in the pancreas harboring cystic lesions, which were impossible to detect even with modern radiologic diagnostic methods. The presence of mutant K-ras in pancreatic juice at a high level might reflect a widespread neoplastic “field defect” in the entire pancreas with cysts or IPMN. Additional studies will be needed to identify possible precursor lesions in the pancreas containing K-ras mutation. We analyzed the baseline clinical features of patients who subsequently developed pancreatic cancer to identify additional risk factors. Although mutant K-ras in the pancreatic juice seemed to be promising, it was not found to be significant, possibly because of the small total number of patients who developed cancer. No factors were found significant as predictors for pancreatic cancer by multivariate analysis. Further studies will be needed to distinguish a higher-risk subgroup among patients with pancreatic cyst lesions. Early diagnosis of pancreatic ductal cancer is still difficult. In fact, in our series, 2 cases of pancreatic cancer were diagnosed at advanced stage despite close follow-up in the current study. Obviously, the higher-risk group needs to be identified and receive more extensive follow-up. In conclusion, patients with pancreatic cystic lesions, not only IPMN but also simple cysts, are at an increased risk of pancreatic cancer, including ductal cancer. These patients should be carefully monitored so as to detect the development of cancer as early as possible. References 1. Warshaw AL, Castillo CF. Pancreatic carcinoma. N Engl J Med 1992;326:455– 465. 2. Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet 1997; 349:485– 489. 3. Carpelan-Holmstrom M, Nordling S, Pukkala E, et al. Does anyone survive pancreatic ductal adenocarcinoma?: a nationwide study re-evaluating the data from the Finnish cancer registry. Gut 2005; 54:385–387.
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4. Fernandez-del Castillo C, Targarona J, Thayer SP, et al. Incidental pancreatic cysts. Arch Surg 2003;138:427– 434. 5. Klöppel G, Kosmahl M. Cystic lesions and neoplasms of the pancreas. Pancreatology 2001;1:648 – 655. 6. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549 –554. 7. Tada M, Yokosuka O, Omata M, et al. Analysis of ras gene mutation in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing. Cancer 1990;66:930 –935. 8. Tada M, Omata M, Ohto M. Clinical applications of ras gene mutation for diagnosis of pancreatic adenocarcinoma. Gastroenterology 1991;100:233–238. 9. Tada M, Omata M, Ohto M. Ras gene mutation in intraductal papillary neoplasms of the pancreas: analysis in five cases. Cancer 1991;67:634 – 637. 10. Hoshi T, Imai M, Ogawa K. Frequent K-ras mutations and absence of p53 mutations in mucin-producing tumors of the pancreas. J Surg Oncol 1994;55:84 –91. 11. Z’graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 1997;226:491– 498. 12. Tada M, Omata M, Kawai S, et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 1993;53:2472–2474. 13. Tada M. Ki-ras mutations in chronic pancreatitis: which relevance? Gastroenterology 1996;111:566 –567. 14. Tateishi K, Tada M, Yamagata M, et al. High proportion of mutant K-ras gene in pancreatic juice of patients with pancreatic cystic lesions. Gut 1999;45:737–740. 15. Tada M, Tateishi K, Kawabe T, et al. Quantity of mutant K-ras gene in pancreatic secretions for diagnosis of pancreatic carcinoma with different assays: analysis of 100 patients. Clin Chim Acta 2002;324:105–111. 16. Loftus EV, Olivares-Pakzad BA, Batts KP, et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Gastroenterology 1996;110: 1909 –1918. 17. Azar C, de Stadt JV, Rickaert F, et al. Intraductal papillary mucinous tumors of the pancreas: clinical and therapeutic issues in 32 patients. Gut 1996;39:457– 464. 18. Solcia E, Capella A, Klöppel G, eds. Intraductal papillary-mucinous tumor. In: Tumors of the pancreas. Bethesda, MD: Armed Forces Institute of Pathology, 1995:53– 64. 19. Sugiyama M, Izumisato Y, Abe N, et al. Predictive factors for malignancy in intraductal papillary-mucinous tumors of the pancreas. Br J Surg 2003;90:1244 –1249. 20. Irie H, Yoshitomi K, Aibe H, et al. Natural history of pancreatic intraductal papillary mucinous tumor of branch duct type: follow-up study by magnetic resonance cholangiopancreatography. J Comput Assist Tomogr 2004;28:117–122. 21. Shimizu Y, Yasui K, Morimoto T, et al. Case of intraductal papillary mucinous tumor (noninvasive adenocarcinoma) of the pan-
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Address requests for reprints to: Minoru Tada, MD, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan 113-8655. e-mail: [email protected]; fax: 81-3-3814-0021. The authors acknowledge Dr Masatoshi Makuuchi for surgical resection, Drs Kuni Ohtomo and Masaaki Akahane for radiologic imaging diagnosis, and Dr Masashi Fukayama for pathologic diagnosis.