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Figure.
Kaplan-Meier survival curves comparing intraductal papillary mucinous neoplasm in patients with (dashed lines) and without (solid lines) extrapancreatic malignancies.

Kaplan-Meier survival curves comparing intraductal papillary mucinous neoplasm in patients with (dashed lines) and without (solid lines) extrapancreatic malignancies.

Table 1. 
Clinicopathologic Features of 61 Resected Intraductal Papillary Mucinous Neoplasms
Clinicopathologic Features of 61 Resected Intraductal Papillary Mucinous Neoplasms
Table 2. 
Incidence of and Detection Time for Extrapancreatic Neoplasms Associated With Intraductal Papillary Mucinous Neoplasms
Incidence of and Detection Time for Extrapancreatic Neoplasms Associated With Intraductal Papillary Mucinous Neoplasms
Table 3. 
Comparison of Clinicopathologic Features in Patients With IPMN With and Without Extrapancreatic Neoplasms
Comparison of Clinicopathologic Features in Patients With IPMN With and Without Extrapancreatic Neoplasms
Table 4. 
Comparison of Clinicopathologic Features in Patients With IPMN With and Without Extrapancreatic Malignancies
Comparison of Clinicopathologic Features in Patients With IPMN With and Without Extrapancreatic Malignancies
Table 5. 
Comparison of Clinical Features and Extrapancreatic Neoplasms in Patients With IPMN and MCN and With IPMN and PDAC
Comparison of Clinical Features and Extrapancreatic Neoplasms in Patients With IPMN and MCN and With IPMN and PDAC
1.
Sohn  TAYeo  CJCameron  JL  et al.  Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004;239788- 799
PubMedArticle
2.
D'Angelica  MBrennan  MFSuriawinata  AA  et al.  Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004;239400- 408
PubMedArticle
3.
Adsay  NV The “new kid on the block”: intraductal papillary mucinous neoplasms of the pancreas: current concepts and controversies. Surgery 2003;133459- 463
PubMedArticle
4.
Traverso  LWPeralta  EARyan  JA  JrKozarek  RA Intraductal neoplasms of the pancreas. Am J Surg 1998;175426- 432
PubMedArticle
5.
Nakagohri  TKenmochi  TKainuma  O  et al.  Intraductal papillary mucinous tumors of the pancreas. Am J Surg 1999;178344- 347
PubMedArticle
6.
Salvia  RFernandez-del Castillo  CBassi  C  et al.  Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004;239678- 687
PubMedArticle
7.
Sugiyama  MAtomi  Y Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 1999;94470- 473
PubMedArticle
8.
Luttges  JZamboni  GLongnecker  DKloppel  G The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 2001;25942- 948
PubMedArticle
9.
Hruban  RHTakaori  KKlimstra  DS  et al.  An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28977- 987
PubMedArticle
10.
Takaori  KKobashi  YMatsusue  S  et al.  Clinicopathological features of pancreatic intraepithelial neoplasias and their relationship to intraductal papillary-mucinous tumors. J Hepatobiliary Pancreat Surg 2003;10125- 136
PubMedArticle
11.
Kitago  MUeda  MAiura  K  et al.  Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas. Int J Cancer 2004;110177- 182
PubMedArticle
12.
Kobari  MEgawa  SShibuya  K  et al.  Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg 1999;1341131- 1136
PubMedArticle
13.
Warren  SGates  O Multiple primary malignant tumors: a survey of the literature and a statistical study. Am J Cancer 1932;161358- 1414
14.
Dong  CHemminki  K Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers. Int J Cancer 2001;92883- 887
PubMedArticle
15.
Luciani  ABalducci  L Multiple primary malignancies. Semin Oncol 2004;31264- 273
PubMedArticle
16.
Maire  FHammel  PTerris  B  et al.  Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis. Gut 2002;51446- 449
PubMedArticle
17.
Z'graggen  KRivera  JACompton  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;226491- 498
PubMedArticle
18.
Uemura  KHiyama  EMurakami  Y  et al.  Comparative analysis of K-ras point mutation, telomerase activity, and p53 overexpression in pancreatic tumours. Oncol Rep 2003;10277- 283
PubMed
19.
Sessa  FSolcia  ECapella  C  et al.  Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch 1994;425357- 367
PubMedArticle
20.
Terada  TOhta  TNakanuma  Y Expression of oncogene products, anti-oncogene products and oncofetal antigens in intraductal papillary-mucinous neoplasm of the pancreas. Histopathology 1996;29355- 361
PubMedArticle
21.
Satoh  KSasano  HShimosegawa  T  et al.  An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer 1993;7251- 56
PubMedArticle
22.
Sato  NRosty  CJansen  M  et al.  STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001;1592017- 2022
PubMedArticle
Original Article
January 01, 2006

High Incidence of Extrapancreatic Neoplasms in Patients With Intraductal Papillary Mucinous Neoplasms

Arch Surg. 2006;141(1):51-56. doi:10.1001/archsurg.141.1.51
Abstract

Background  Intraductal papillary mucinous neoplasms (IPMNs) are associated with a high incidence of extrapancreatic neoplasms.

Design  Retrospective study.

Setting  Tertiary care referral center.

Patients  Sixty-one patients underwent surgical resection for IPMN between January 1, 1993, and June 30, 2004. Thirty-eight patients with mucinous cystic neoplasms and 50 patients with pancreatic ductal adenocarcinoma also were examined for development of extrapancreatic neoplasms.

Main Outcome Measures  The incidence and clinicopathological features of extrapancreatic neoplasms with IPMNs were compared with those with mucinous cystic neoplasm and pancreatic ductal adenocarcinoma.

Results  Of the 61 patients with IPMNs, 24 (39%) developed 26 extrapancreatic neoplasms, and 18 (30%) had extrapancreatic malignancies. Gastric adenocarcinoma (33%) and colorectal adenocarcinoma (17%) were the most common neoplasms in the 24 patients. During postoperative follow-up, 3 patients died of malignant IPMNs, 3 of associated malignancies, and 1 of a nonmalignancy-related cause. Comparisons of the clinicopathological features in patients with IPMNs with and without associated malignancies revealed no significant differences in age, sex, family history of malignancy, history of cigarette smoking or alcohol abuse, or type of IPMN. The incidence of extrapancreatic neoplasms in patients with IPMN was significantly higher than in those with other pancreatic diseases such as mucinous cystic neoplasm (8%) or pancreatic ductal adenocarcinoma (10%).

Conclusions  Frequently, IPMNs are associated with the development of extrapancreatic neoplasms. Considerable attention should be paid to the possible occurrence of other associated malignancies in patients with IPMNs, either concurrently or postoperatively. Further molecular studies may be necessary to elucidate the unusual association between IPMN and other primary neoplasms.

Intraductal papillary mucinous neoplasm (IPMN) is now a well-recognized entity in the pancreas and is being reported with increasing frequency.1,2 The tumor covers a broad histological spectrum, which ranges from adenoma to invasive carcinoma, and shows a variety of biological behaviors.3 Moreover, IPMNs are believed to progress slowly showing a spectrum of neoplastic transformations and are characterized by a more favorable prognosis than pancreatic ductal adenocarcinomas (PDACs), even in malignant cases.16

Another important feature of IPMN is that the tumor is associated with a high frequency of extrapancreatic neoplasms.2,7 Because of a favorable prognosis in patients with IPMN, these second primary neoplasms, especially malignant tumors, could be more important than IPMN in determining prognosis. These second primary neoplasms also offer an important insight into the cause of IPMNs and their associated malignancies, which may have a common carcinogenic process. In the present study, we evaluated the incidence of extrapancreatic neoplasms in patients with IPMN and analyzed clinicopathological features in these patients. The results obtained were compared with those for mucinous cystic neoplasm (MCN) and PDAC.

METHODS

Between January 1, 1993, and June 30, 2004, 61 patients underwent surgical resection for IPMN at our institution. Medical records were reviewed retrospectively for the following information: patient characteristics, perioperative clinical and laboratory data, operative management, pathology examination results, and postoperative course. History of a previous extrapancreatic neoplasm or the concurrent development of an extrapancreatic neoplasm was investigated thoroughly. Overall survival and follow-up information, including the postoperative development of neoplasms in other organs, was obtained by contacting the Cancer Registration and Biostatics Branch of the National Cancer Center Research Institute, Goyang-si, Gyeonggi-do, Korea, by direct patient contact, and by reviewing outpatient medical records. Perioperative mortality was defined as in-hospital death or death within 30 days after surgery, and a positive family history was defined as a history of malignancy among first-degree relatives.

Mean follow-up was 28.8 months and mean patient age was 62.4 years (Table 1). Sixty of the 61 IPMNs were classified as main duct (18 [30%]), branch duct (37 [61%]), or combined (5 [8%]). Of the 61 patients, 10 (16%) had adenomas, 34 (56%) had borderline adenomas, 6 (10%) had carcinoma in situ, and 11 (18%) had invasive carcinoma. No postoperative death occurred.

The incidence and clinicopathological features of extrapancreatic neoplasms in 38 patients with MCNs who underwent surgical resection at our institution between January 1, 1993, and June 30, 2004, and in 50 patients with PDAC who underwent surgical resection at our institution between January 1, 2000, and December 31, 2002, also were analyzed and compared with those of the patients with IPMN. One postoperative death occurred among the patients with MCN, for an overall perioperative mortality of 3%. Of the 38 MCNs, 21 (55%) were benign adenomas; 12 (32%), borderline; 3 (8%), noninvasive carcinoma; and 2 (5%), invasive carcinoma. No postoperative death occurred among the 50 patients with PDAC. Data were compared by using the χ2 and t tests. Cumulative survival data were calculated with the Kaplan-Meier method, and significance was accepted at the 5% level.

RESULTS

Of the 61 patients with IPMN, 24 (39%) developed 26 extrapancreatic neoplasms, and 18 (30%) had other extrapancreatic malignancies (Table 2). The stomach, colorectum, and thyroid gland were the organs most frequently involved in IPMN-associated neoplasms, which developed in 9, 6, and 3 patients, respectively. The most frequently associated extrapancreatic neoplasms were gastric adenocarcinoma in 8 patients (33%) and colorectal adenocarcinoma in 4 (17%). Of 26 extrapancreatic neoplasms, 8 were diagnosed 3.7 to 91.0 months (mean, 29.4) before the IPMN operation, 15 concurrently, and 3 at 9.5 to 44.2 months (mean, 23.3) postoperatively.

All associated neoplasms were proved pathologically and treated surgically or by means of colonoscopic removal, except a case of low-grade B-cell lymphoma and a case of thyroid adenoma, which were diagnosed at lymph node biopsy and fine-needle aspiration, respectively, and managed medically. In IPMN cases with concurrently associated extrapancreatic neoplasms, thyroid cancer and colon tubular adenoma were detected at physical examination and at an additional preoperative, but not routine, colonoscopic examination. In other cases, most IPMNs were detected secondarily at computed tomography during preoperative evaluation of concurrent gastrointestinal tumors.

During postoperative follow-up, 3 patients died of malignant IPMNs and 3 of associated malignancies (ie, colon cancer, common bile duct cancer, and lymphoma). Another patient died of a nonmalignancy-related cause. The 5-year disease-specific survival rates were 93.4% for all tumors, 100.0% for all noninvasive tumors (including adenoma, borderline, and carcinoma in situ lesions), and 68.2% for invasive cancers.

A comparison of clinicopathological features in patients with IPMN with and without associated extrapancreatic neoplasms revealed no significant differences in mean age, sex ratio, mean follow-up, family history of malignancy, family history of gastrointestinal malignancy, history of cigarette smoking or alcohol abuse, and type of IPMNs (Table 3). However, borderline lesions and distally located IPMNs were found more frequently in patients with extrapancreatic neoplasms. When patients were grouped according to the presence of associated extrapancreatic malignancies, no significant difference was observed in any characteristic except mean follow-up, which was significantly shorter in those with associated malignancies (Table 4). Of the 11 invasive IPMNs, 2 cases were included in the malignancy-associated group and 9 in the nonassociated group. Three patients died of extrapancreatic malignancies in the malignancy-associated group and 3 of malignant IPMNs in the nonassociated group. No statistical difference in survival rates was found between patients with IPMN with and without extrapancreatic malignancies (Figure).

The incidence of extrapancreatic neoplasms in patients with IPMN (39%) was significantly greater than in patients with MCN (8%) and PDAC (10%) (Table 5). Mean follow-up in patients with MCN was 40.2 months, which was not significantly different from that in patients with IPMN. No disease-specific mortality occurred among patients with MCN. Of the 38 patients with MCN, 3 (8%) developed 4 extrapancreatic neoplasms. One patient underwent total thyroidectomy for papillary thyroid adenocarcinoma 4 months before the MCN operation and developed pituitary adenoma 22 months postoperatively, which also was resected surgically. The other 2 patients had concurrently associated ovarian serous cystadenocarcinoma and gastrointestinal stromal tumor of the small bowel 15 months postoperatively, and both tumors were treated surgically. No significant difference in family history of malignancy was observed between patients with IPMN and those with MCN; however, mean age, sex ratio, and history of cigarette smoking or alcohol abuse were significantly different between these groups.

Mean postoperative follow-up in patients with PDAC was 17.1 months, which was significantly shorter than that in patients with IPMN; the all-disease specific survival rate 40 months postoperatively was 18.7% for patients with PDAC. Of the 50 patients with PDAC, 5 (10.0%) developed 5 extrapancreatic neoplasms: 2 stomach cancers, lung cancer, cervix cancer, and larynx cancer. All these malignancies were diagnosed and treated 13.8 to 153.0 months (mean, 69.6) preoperatively. No significant differences were observed between patients with PDAC and those with IPMN in terms of mean age, sex ratio, family history of malignancy, or history of smoking or alcohol abuse.

COMMENT

In recent years, IPMNs have been receiving more attention because of their favorable prognosis and pathogenesis, and because of their relationships with PDAC and its variants.8,9 The IPMN is believed to be an important precursor of invasive carcinoma of the pancreas and may progress through a hyperplasia-adenoma-carcinoma sequence.1012 However, the slowly progressing features and genetic changes involved in this progression are distinct from those of conventional ductal adenocarcinoma.

Another unique characteristic of IPMNs is their frequent association with other primary neoplasms. Sugiyama and Atomi7 reported a high incidence of nonpancreatic neoplasms (48%) and malignancies (36%) in 42 patients with IPMNs. Colorectal cancer (33.3%) and gastric cancer (26.7%) accounted for most of the associated malignancies in their study. Similarly, the incidence of IPMN-associated extrapancreatic neoplasms was 39% and that of malignancies was 30% among the 61 patients in our study. The actual incidence of associated benign tumors, such as thyroid adenoma and colon adenoma, could have been higher because these tumors were not evaluated comprehensively in patients with IPMN. Stomach cancer (8 [44%] of 18) and colorectal cancer (4 [22%] of 18) were most frequent in malignancy-associated cases, which may be related to the fact that in South Korea stomach cancer is the most frequent malignancy, and it is also the most commonly associated cancer in patients with multiple primary cancers.

According to the definition of Warren and Gates,13 multiple primary malignancies should meet the following criteria: each tumor must present a definite picture of malignancy, each must be distinct, and the possibility of metastases from each tumor must be excluded. In this regard, we excluded PDAC in evaluating IPMN-associated neoplasms and focused on the development of extrapancreatic neoplasms, even though the original concept of multiple primary malignancies cannot be applied exactly because nonmalignant IPMN cases were included. One patient with IPMN developed both PDAC and another extrapancreatic malignancy in the present study.

The increased occurrence of second primary cancers after an initial primary could be the result of intensive medical surveillance after the first diagnosis; exposure to cytotoxic agents because of chemotherapy or radiotherapy for the initial cancer; or environmental, hereditary, and immunological factors shared between the first and the second cancers.14

Accordingly, the high incidence of other primary tumors in patients with IPMN may be attributable to full staging evaluations for previous or concurrently associated malignancies. However, when IPMNs were compared with potentially or overtly malignant pancreatic diseases (ie, MCNs or PDACs), the incidences of associated previous and concurrent extrapancreatic malignancies in patients with IPMN were significantly higher. Thus, it seems that IPMNs differ somewhat from these tumors and that they are associated more frequently with other extrapancreatic malignancies.

After surgery, only 3 patients with IPMN, 2 with MCN, and none with PDAC developed additional neoplasms. The postoperative incidence of associated neoplasms with IPMN seemed to be not much higher than that in other groups. Even in patients with PDAC, the frequency of postoperative developments of other neoplasms may have been underestimated because postoperative follow-up was reduced due to a poor surgical outcome. However, postoperative-associated malignancies were identified only in patients with IPMN in this study, and there is a possibility that in some cases, IPMN was a precedent that happened to be found concurrently with another malignancy. In this context, it may be necessary to pay closer attention during follow-up to the possible development of associated neoplasms in patients known to have IPMN, although evaluations of more cases and longer follow-ups are needed to reach a definite conclusion.

In the present study, chemotherapy was performed for malignant IPMNs in 4 patients, and associated malignancies were resected at the same time as the IPMNs in 4 other patients. Radiotherapy was used for IPMN in 4 patients and for concurrent malignancies in 2 patients. However, no other primary neoplasm occurred postoperatively in patients who received chemotherapy or radiotherapy in either group.

Generally, the development of multiple primary malignancies can be explained by the inheritance of a predisposing genomic defect or field carcinogenesis, which means that organ systems that have developed a neoplasm are likely to develop multiple and independent neoplasms because all cells have been exposed to carcinogens to similar extents.15 The aging process is another cancer risk factor to consider because the longer a person lives, as long as the cancer risk is constant, the more likely it is that neoplasms will develop over time.

However, in the present study, no significant differences were found between the malignancy-associated group and the nonassociated group with respect to cancer risk factors, such as family history of malignancy, age, and history of cigarette smoking or alcohol abuse. Histologic classification and type and location of IPMN were also no different between groups. A comparison of patients with IPMN and those with MCN revealed that the general characteristics of the 2 groups were significantly different in age and sex, which was accompanied by a different history of cigarette smoking or alcohol abuse perhaps because of sociocultural dissimilarity between men and women. Thus, it may not be appropriate simply to compare the incidences of associated malignancies in these groups, even if the diseases have similar features. However, no differences were found between patients with IPMN and those with PDAC in terms of these factors, although the incidence of previous and concurrent extrapancreatic neoplasms was significantly higher in patients with IPMN.

Genetic or epigenetic changes associated with the progression of IPMNs may play a role in the development of other primary neoplasms, especially of gastrointestinal tract cancers. The carcinogenesis of IPMNs and colorectal adenomatous polyps are thought to be similar in that they follow a pattern of progression from adenoma to dysplasia and eventually to invasive cancer. In addition, they share common genetic alterations including K-ras mutations.11,16 Although the pathogenetic mechanisms involved in the progression of IPMNs have not been established entirely, genetic alterations such as point mutations in the K-ras oncogene,17,18 the overexpression of the HER-2/neu (c-erbB-2) gene,1921 and the inactivation of the STK11/LKB1 gene22 (a tumor-suppressor gene responsible for Peutz-Jeghers syndrome) have been reported.

It is likely that extrapancreatic malignancies in patients with IPMN have potential prognostic importance, even though we could not come to a definite conclusion because of limited case numbers and short follow-up. Although the survival rates were no different in the malignancy-associated group and the nonassociated group, the late portion of the survival curve of the malignancy-associated group was affected by extrapancreatic malignancies, which means that extrapancreatic malignancy, rather than malignant but docile IPMN itself, can determine long-term patient survival.

Results of the present study concur with those of earlier studies that found that IPMNs are associated with a high incidence of neoplasms in organs other than pancreas.7 Considerable attention should be paid to patients with IPMN for the possible occurrence of other cancers, especially gastrointestinal tract cancers, which can affect the long-term survival of the patients. Further molecular studies are necessary to elucidate the mechanism of extrapancreatic neoplasm development in patients with IPMN. We believe that IPMN offers an attractive model for investigating the cause of human carcinogenesis.

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Article Information

Correspondence: Sun-Whe Kim, MD, Department of Surgery, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea (sunkim@plaza.snu.ac.kr).

Accepted for Publication: April 5, 2005.

References
1.
Sohn  TAYeo  CJCameron  JL  et al.  Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004;239788- 799
PubMedArticle
2.
D'Angelica  MBrennan  MFSuriawinata  AA  et al.  Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004;239400- 408
PubMedArticle
3.
Adsay  NV The “new kid on the block”: intraductal papillary mucinous neoplasms of the pancreas: current concepts and controversies. Surgery 2003;133459- 463
PubMedArticle
4.
Traverso  LWPeralta  EARyan  JA  JrKozarek  RA Intraductal neoplasms of the pancreas. Am J Surg 1998;175426- 432
PubMedArticle
5.
Nakagohri  TKenmochi  TKainuma  O  et al.  Intraductal papillary mucinous tumors of the pancreas. Am J Surg 1999;178344- 347
PubMedArticle
6.
Salvia  RFernandez-del Castillo  CBassi  C  et al.  Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004;239678- 687
PubMedArticle
7.
Sugiyama  MAtomi  Y Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 1999;94470- 473
PubMedArticle
8.
Luttges  JZamboni  GLongnecker  DKloppel  G The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 2001;25942- 948
PubMedArticle
9.
Hruban  RHTakaori  KKlimstra  DS  et al.  An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28977- 987
PubMedArticle
10.
Takaori  KKobashi  YMatsusue  S  et al.  Clinicopathological features of pancreatic intraepithelial neoplasias and their relationship to intraductal papillary-mucinous tumors. J Hepatobiliary Pancreat Surg 2003;10125- 136
PubMedArticle
11.
Kitago  MUeda  MAiura  K  et al.  Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas. Int J Cancer 2004;110177- 182
PubMedArticle
12.
Kobari  MEgawa  SShibuya  K  et al.  Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg 1999;1341131- 1136
PubMedArticle
13.
Warren  SGates  O Multiple primary malignant tumors: a survey of the literature and a statistical study. Am J Cancer 1932;161358- 1414
14.
Dong  CHemminki  K Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers. Int J Cancer 2001;92883- 887
PubMedArticle
15.
Luciani  ABalducci  L Multiple primary malignancies. Semin Oncol 2004;31264- 273
PubMedArticle
16.
Maire  FHammel  PTerris  B  et al.  Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis. Gut 2002;51446- 449
PubMedArticle
17.
Z'graggen  KRivera  JACompton  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;226491- 498
PubMedArticle
18.
Uemura  KHiyama  EMurakami  Y  et al.  Comparative analysis of K-ras point mutation, telomerase activity, and p53 overexpression in pancreatic tumours. Oncol Rep 2003;10277- 283
PubMed
19.
Sessa  FSolcia  ECapella  C  et al.  Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch 1994;425357- 367
PubMedArticle
20.
Terada  TOhta  TNakanuma  Y Expression of oncogene products, anti-oncogene products and oncofetal antigens in intraductal papillary-mucinous neoplasm of the pancreas. Histopathology 1996;29355- 361
PubMedArticle
21.
Satoh  KSasano  HShimosegawa  T  et al.  An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer 1993;7251- 56
PubMedArticle
22.
Sato  NRosty  CJansen  M  et al.  STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001;1592017- 2022
PubMedArticle
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