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

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

Min-Gew Choi, MD; Sun-Whe Kim, MD; Sung-Sik Han, MD; Jin-Young Jang, MD; Yong-Hyun Park, MD

Background: Intraductal papillary mucinous neo- (33%) and colorectal adenocarcinoma (17%) were the plasms (IPMNs) are associated with a high incidence of most common neoplasms in the 24 patients. During post- extrapancreatic neoplasms. operative follow-up, 3 patients died of malignant IPMNs, 3 of associated malignancies, and 1 of a nonmalignancy- Design: Retrospective study. related cause. Comparisons of the clinicopathological features in patients with IPMNs with and without associ- Setting: Tertiary care referral center. ated malignancies revealed no significant differences in age, sex, family history of malignancy, history of ciga- Patients: Sixty-one patients underwent surgical resec- rette smoking or alcohol abuse, or type of IPMN. The in- tion for IPMN between January 1, 1993, and June 30, cidence of extrapancreatic neoplasms in patients with 2004. Thirty-eight patients with mucinous cystic neo- IPMN was significantly higher than in those with other plasms and 50 patients with pancreatic ductal adenocar- pancreatic diseases such as mucinous cystic neoplasm cinoma also were examined for development of extra- (8%) or pancreatic ductal adenocarcinoma (10%). pancreatic neoplasms. Conclusions: Frequently, IPMNs are associated with the Main Outcome Measures: The incidence and clini- development of extrapancreatic neoplasms. Consider- copathological features of extrapancreatic neoplasms with able attention should be paid to the possible occurrence IPMNs were compared with those with mucinous cystic of other associated malignancies in patients with IPMNs, neoplasm and pancreatic ductal adenocarcinoma. either concurrently or postoperatively. Further molecular studies may be necessary to elucidate the unusual as- Results: Of the 61 patients with IPMNs, 24 (39%) de- sociation between IPMN and other primary neoplasms. veloped 26 extrapancreatic neoplasms, and 18 (30%) had extrapancreatic malignancies. Gastric adenocarcinoma Arch Surg. 2006;141:51-56

NTRADUCTAL PAPILLARY MUCI- cause of a favorable prognosis in patients nous neoplasm (IPMN) is now a with IPMN, these second primary neo- well-recognized entity in the pan- plasms, especially malignant tumors, could creas and is being reported with in- be more important than IPMN in deter- creasing frequency.1,2 The tumor mining prognosis. These second primary coversI a broad histological spectrum, which neoplasms also offer an important insight ranges from adenoma to invasive carci- into the cause of IPMNs and their associ- noma, and shows a variety of biological be- ated malignancies, which may have a com- haviors.3 Moreover, IPMNs are believed to mon carcinogenic process. In the present progress slowly showing a spectrum of neo- study, we evaluated the incidence of extra- plastic transformations and are character- pancreatic neoplasms in patients with IPMN ized by a more favorable prognosis than and analyzed clinicopathological features pancreatic ductal adenocarcinomas in these patients. The results obtained were (PDACs), even in malignant cases.1-6 compared with those for mucinous cystic neoplasm (MCN) and PDAC. See Invited Critique at end of article METHODS Author Affiliations: Between January 1, 1993, and June 30, 2004, Department of Surgery, Seoul Another important feature of IPMN is 61 patients underwent surgical resection for National University College of that the tumor is associated with a high fre- IPMN at our institution. Medical records were Medicine, Seoul, South Korea. quency of extrapancreatic neoplasms.2,7 Be- reviewed retrospectively for the following in-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 RESULTS Table 1. Clinicopathologic Features of 61 Resected Intraductal Papillary Mucinous Neoplasms Of the 61 patients with IPMN, 24 (39%) developed 26 Characteristic Result extrapancreatic neoplasms, and 18 (30%) had other ex- Follow-up, mo, mean ± SD 28.8 ± 27.3 trapancreatic malignancies (Table 2). The stomach, Age, y, mean ± SD 62.4 ± 7.4 colorectum, and thyroid gland were the organs most fre- Sex ratio (male:female) 1.7:1 Sex, No. (%) quently involved in IPMN-associated neoplasms, which Male 38 (62) developed in 9, 6, and 3 patients, respectively. The most Female 23 (38) frequently associated extrapancreatic neoplasms were gas- Type of intraductal papillary mucinous tric adenocarcinoma in 8 patients (33%) and colorectal neoplasm, No. (%) adenocarcinoma in 4 (17%). Of 26 extrapancreatic neo- Main duct 18 (30)* plasms, 8 were diagnosed 3.7 to 91.0 months (mean, 29.4) Branch duct 37 (61)* Combined 5 (8)* before the IPMN operation, 15 concurrently, and 3 at 9.5 Not classified 1 (2) to 44.2 months (mean, 23.3) postoperatively. Location, No. (%) All associated neoplasms were proved pathologically Head 28 (46) and treated surgically or by means of colonoscopic re- Head and body 1 (2) moval, except a case of low-grade B-cell lymphoma and Body 16 (26) a case of thyroid adenoma, which were diagnosed at lymph Body and tail 9 (15) node biopsy and fine-needle aspiration, respectively, and Tail 5 (8) Entire 2 (3) managed medically. In IPMN cases with concurrently as- Histologic classification, No. (%) sociated extrapancreatic neoplasms, thyroid cancer and Adenoma 10 (16) colon tubular adenoma were detected at physical exami- Borderline adenoma 34 (56) nation and at an additional preoperative, but not rou- Carcinoma in situ 6 (10) tine, colonoscopic examination. In other cases, most Invasive carcinoma 11 (18) IPMNs were detected secondarily at computed tomography during preoperative evaluation of concurrent gas- *Percentage of those classified. trointestinal tumors. During postoperative follow-up, 3 patients died of ma- formation: patient characteristics, perioperative clinical and labo- lignant IPMNs and 3 of associated malignancies (ie, co- ratory data, operative management, pathology examination lon cancer, common bile duct cancer, and lymphoma). results, and postoperative course. History of a previous extra- Another patient died of a nonmalignancy-related cause. pancreatic neoplasm or the concurrent development of an ex- The 5-year disease-specific survival rates were 93.4% for trapancreatic neoplasm was investigated thoroughly. Overall all tumors, 100.0% for all noninvasive tumors (includ- survival and follow-up information, including the postopera- ing adenoma, borderline, and carcinoma in situ le- tive development of neoplasms in other organs, was obtained sions), and 68.2% for invasive cancers. by contacting the Cancer Registration and Biostatics Branch of A comparison of clinicopathological features in pa- the National Cancer Center Research Institute, Goyang-si, Gyeonggi-do, Korea, by direct patient contact, and by review- tients with IPMN with and without associated extrapan- ing outpatient medical records. Perioperative mortality was de- creatic neoplasms revealed no significant differences in fined as in-hospital death or death within 30 days after sur- mean age, sex ratio, mean follow-up, family history of gery, and a positive family history was defined as a history of malignancy, family history of gastrointestinal malig- malignancy among first-degree relatives. nancy, history of cigarette smoking or alcohol abuse, and Mean follow-up was 28.8 months and mean patient age was type of IPMNs (Table 3). However, borderline lesions 62.4 years (Table 1). Sixty of the 61 IPMNs were classified as and distally located IPMNs were found more frequently main duct (18 [30%]), branch duct (37 [61%]), or combined in patients with extrapancreatic neoplasms. When pa- (5 [8%]). Of the 61 patients, 10 (16%) had adenomas, 34 tients were grouped according to the presence of asso- (56%) had borderline adenomas, 6 (10%) had carcinoma in ciated extrapancreatic malignancies, no significant dif- situ, and 11 (18%) had invasive carcinoma. No postoperative death occurred. ference was observed in any characteristic except mean The incidence and clinicopathological features of extrapan- follow-up, which was significantly shorter in those with creatic neoplasms in 38 patients with MCNs who underwent associated malignancies (Table 4). Of the 11 invasive surgical resection at our institution between January 1, 1993, IPMNs, 2 cases were included in the malignancy-asso- and June 30, 2004, and in 50 patients with PDAC who under- ciated group and 9 in the nonassociated group. Three pa- went surgical resection at our institution between January 1, tients died of extrapancreatic malignancies in the malig- 2000, and December 31, 2002, also were analyzed and com- nancy-associated group and 3 of malignant IPMNs in the pared with those of the patients with IPMN. One postopera- nonassociated group. No statistical difference in sur- tive death occurred among the patients with MCN, for an over- vival rates was found between patients with IPMN with all perioperative mortality of 3%. Of the 38 MCNs, 21 (55%) and without extrapancreatic malignancies (Figure). were benign adenomas; 12 (32%), borderline; 3 (8%), noninvasive carcinoma; and 2 (5%), invasive carcinoma. No postop- The incidence of extrapancreatic neoplasms in pa- erative death occurred among the 50 patients with PDAC. Data tients with IPMN (39%) was significantly greater than in were compared by using the ␹2 and t tests. Cumulative sur- patients with MCN (8%) and PDAC (10%) (Table 5). vival data were calculated with the Kaplan-Meier method, and Mean follow-up in patients with MCN was 40.2 months, significance was accepted at the 5% level. which was not significantly different from that in patients

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Incidence of and Detection Time for Extrapancreatic Neoplasms Associated With Intraductal Papillary Mucinous Neoplasms

Neoplasm Preoperative Concurrent Postoperative Total Malignant Stomach cancer 2 6 0 8 Colorectal cancer 1 2 1 4 Common bile duct cancer 0 2 0 2 Lymphoma* 0112 Gallbladder cancer 1 0 0 1 Thyroid cancer 0 1 0 1 Benign Colon tubular adenoma 0 2 0 2 Thyroid adenoma 2 0 0 2 Stomach tubular adenoma 1 0 0 1 Gastrointestinal stromal tumor 0 1 0 1 Ovarian mucinous cystadenoma 0 0 1 1 Meningioma 1 0 0 1 Total No. of neoplasms† 8 15 3 26 Total No. of malignancies 4 12 2 18 Total No. of patients with neoplasms 7 14 3 24 Total No. of patients with malignancy 4 12 2 18

*One is B-cell lymphoma and the other is B-cell lymphoma of the mucosa-associated lymphoid tissue type in the terminal ileum. †Two patients had more than 1 extrapancreatic neoplasm: 1 had stomach cancer and colon tubular adenoma, and the other had colon cancer and thyroid adenoma.

Table 3. Comparison of Clinicopathologic Features Table 4. Comparison of Clinicopathologic Features in Patients With IPMN With and Without in Patients With IPMN With and Without Extrapancreatic Neoplasms Extrapancreatic Malignancies

With Without With Without Neoplasm Neoplasm P Malignancy Malignancy P Characteristic (n = 24) (n = 37) Value Characteristic (n = 18) (n = 43) Value Age, y, mean ± SD Age, y, mean ± SD At operation 64.0 ± 8.1 61.4 ± 6.7 .17 At operation 64.2 ± 8.4 61.7 ± 6.9 .22 At end of follow-up 65.8 ± 8.1 64.2 ± 6.4 .37 At end of follow-up 65.8 ± 8.5 64.4 ± 6.5 .51 Sex (male/female), No. 14/10 24/13 .61 Sex (male/female), No. 13/5 25/18 .30 Follow-up, mo, mean ± SD 21.9 ± 16.4 33.3 ± 31.9 .07 Follow-up, mo, mean ± SD 18.5 ± 14.2 33.1 ± 30.3 .01 Family history of malignancy, 6/23 (26) 6/33 (18) .52 Family history of malignancy, 5/17 (29) 7/39 (18) .48 No. (%)* No. (%)* Family history of gastrointestinal 3/23 (13) 2/33 (6) .39 Family history of gastrointestinal 2/17 (12) 3/39 (8) .63 malignancy, No. (%)* malignancy, No. (%)* Smoking, No. (%)* 11/23 (48) 14/30 (47) .93 Smoking, No. (%)* 9/18 (50) 16/35 (46) .77 Alcohol, No. (%)* 9/23 (39) 10/30 (33) .66 Alcohol, No. (%)* 8/18 (44) 11/35 (31) .35 Histologic classification of IPMN, .02 Histologic classification of IPMN, .30 No. (%) No. (%) Benign 2 (8) 8 (22) Benign 2 (11) 8 (19) Borderline 19 (79) 15 (40) Borderline 13 (72) 21 (49) Cancer 3 (12) 14 (38) Cancer 3 (17) 14 (33) Type of IPMN, No. (%)† .20 Type of IPMN, No. (%)† .15 Main duct 4 (17) 14 (38) Main duct 3 (18) 15 (35) Branch duct 16 (70) 21 (57) Branch duct 11 (65) 26 (60) Combined 3 (13) 2 (5) Combined 3 (18) 2 (5) Location of IPMN, No. (%)‡ .01 Location of IPMN, No. (%)‡ .30 Proximal (head, head and 7 (29) 22 (63) Proximal (head or 7 (39) 22 (54) body lesions) head and body lesions) Distal (body and/or tail 17 (71) 13 (37) Distal (body and/or tail 11 (61) 19 (46) lesions) lesions)

Abbreviation: IPMN, intraductal papillary mucinous neoplasm. Abbreviation: IPMN, intraductal papillary mucinous neoplasm. *Patients with unavailable data were excluded. *Patients with unavailable data were excluded. †The patient without a classified IPMN type was excluded from the †The patient without a classified IPMN type was excluded from the analysis. analysis. ‡Cases in which the tumor occupied the entire pancreas were excluded. ‡Cases in which the tumor occupied the entire pancreas were excluded.

with IPMN. No disease-specific mortality occurred among derwent total thyroidectomy for papillary thyroid adeno- patients with MCN. Of the 38 patients with MCN, 3 (8%) carcinoma 4 months before the MCN operation and de- developed 4 extrapancreatic neoplasms. One patient un- veloped pituitary adenoma 22 months postoperatively,

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 39% and that of malignancies was 30% among the 61 pa- 1.0 tients in our study. The actual incidence of associated be- n = 43 nign tumors, such as thyroid adenoma and colon ad-

0.8 enoma, could have been higher because these tumors were not evaluated comprehensively in patients with IPMN. Stomach cancer (8 [44%] of 18) and colorectal cancer 0.6 (4 [22%] of 18) were most frequent in malignancy- associated cases, which may be related to the fact that in 0.4 South Korea stomach cancer is the most frequent malig- n = 18 nancy, and it is also the most commonly associated can- Cumulative Survival Rate cer in patients with multiple primary cancers. 0.2 According to the definition of Warren and Gates,13 mul- P = .13 tiple primary malignancies should meet the following cri- teria: each tumor must present a definite picture of ma- 0123624 48 60 lignancy, each must be distinct, and the possibility of Time, mo metastases from each tumor must be excluded. In this re- gard, we excluded PDAC in evaluating IPMN-associated Figure. Kaplan-Meier survival curves comparing intraductal papillary neoplasms and focused on the development of extrapan- mucinous neoplasm in patients with (dashed lines) and without (solid lines) extrapancreatic malignancies. creatic neoplasms, even though the original concept of multiple primary malignancies cannot be applied exactly because nonmalignant IPMN cases were included. One patient which also was resected surgically. The other 2 patients had with IPMN developed both PDAC and another extrapan- concurrently associated ovarian serous cystadenocarci- creatic malignancy in the present study. noma and gastrointestinal stromal tumor of the small bowel The increased occurrence of second primary cancers 15 months postoperatively, and both tumors were treated after an initial primary could be the result of intensive surgically. No significant difference in family history of ma- medical surveillance after the first diagnosis; exposure lignancy was observed between patients with IPMN and to cytotoxic agents because of chemotherapy or radio- those with MCN; however, mean age, sex ratio, and his- therapy for the initial cancer; or environmental, heredi- tory of cigarette smoking or alcohol abuse were signifi- tary, and immunological factors shared between the first cantly different between these groups. and the second cancers.14 Meanpostoperativefollow-upinpatientswithPDACwas Accordingly, the high incidence of other primary tu- 17.1 months, which was significantly shorter than that in mors in patients with IPMN may be attributable to full patients with IPMN; the all-disease specific survival rate 40 staging evaluations for previous or concurrently associ- months postoperatively was 18.7% for patients with PDAC. ated malignancies. However, when IPMNs were com- Of the 50 patients with PDAC, 5 (10.0%) developed 5 ex- pared with potentially or overtly malignant pancreatic trapancreatic neoplasms: 2 stomach cancers, lung cancer, diseases (ie, MCNs or PDACs), the incidences of asso- cervixcancer,andlarynxcancer.Allthesemalignancieswere ciated previous and concurrent extrapancreatic malig- diagnosed and treated 13.8to153.0 months (mean, 69.6) nancies in patients with IPMN were significantly higher. preoperatively. No significant differences were observed be- Thus, it seems that IPMNs differ somewhat from these tween patients with PDAC and those with IPMN in terms tumors and that they are associated more frequently with of mean age, sex ratio, family history of malignancy, or his- other extrapancreatic malignancies. tory of smoking or alcohol abuse. After surgery, only 3 patients with IPMN, 2 with MCN, and none with PDAC developed additional neoplasms. COMMENT The postoperative incidence of associated neoplasms with IPMN seemed to be not much higher than that in other In recent years, IPMNs have been receiving more atten- groups. Even in patients with PDAC, the frequency of tion because of their favorable prognosis and pathogen- postoperative developments of other neoplasms may have esis, and because of their relationships with PDAC and been underestimated because postoperative follow-up was its variants.8,9 The IPMN is believed to be an important reduced due to a poor surgical outcome. However, post- precursor of invasive carcinoma of the pancreas and may operative-associated malignancies were identified only progress through a hyperplasia-adenoma-carcinoma se- in patients with IPMN in this study, and there is a pos- quence.10-12 However, the slowly progressing features and sibility that in some cases, IPMN was a precedent that genetic changes involved in this progression are distinct happened to be found concurrently with another malig- from those of conventional ductal adenocarcinoma. nancy. In this context, it may be necessary to pay closer Another unique characteristic of IPMNs is their fre- attention during follow-up to the possible development quent association with other primary neoplasms. Sugi- of associated neoplasms in patients known to have IPMN, yama and Atomi7 reported a high incidence of nonpan- although evaluations of more cases and longer follow- creatic neoplasms (48%) and malignancies (36%) in 42 ups are needed to reach a definite conclusion. patients with IPMNs. Colorectal cancer (33.3%) and gas- In the present study, chemotherapy was performed for tric cancer (26.7%) accounted for most of the associ- malignant IPMNs in 4 patients, and associated malig- ated malignancies in their study. Similarly, the inci- nancies were resected at the same time as the IPMNs in dence of IPMN-associated extrapancreatic neoplasms was 4 other patients. Radiotherapy was used for IPMN in 4

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 5. Comparison of Clinical Features and Extrapancreatic Neoplasms in Patients With IPMN and MCN and With IPMN and PDAC

P Value* IPMN MCN PDAC Characteristic (n = 61) (n = 38) (n = 50) vs MCN vs PDAC Age, y, mean ± SD At operation 62.4 ± 7.4 47.6 ± 13.6 61.1 ± 9.9 Ͻ.001 .44 At end of follow-up 64.8 ± 7.1 50.9 ± 13.9 62.5 ± 10.0 Ͻ.001 .18 Sex (male/female), No. 38/23 0/38 31/19 Ͻ.001 .98 Follow-up, mo, mean ± SD 28.8 ± 27.3 40.2 ± 32.3 17.1 ± 9.6 .06 .003 Family history of malignancy, No. (%)† 12/56 (21) 5/27 (18) 5/32 (16) .76 .51 Smoking, No. (%)† 25/53 (47) 0/28 (0) 21/41 (51) Ͻ.001 .70 Alcohol, No. (%)† 19/53 (36) 4/29 (14) 17/41 (42) .03 .58 No. (%) of patients with n (%) 24 (39) 3 (8) 5 (10) .001 Ͻ.001 Preoperative‡ 8/26 (31) 1/4 (25) 5/5 (100) At the time of operation‡ 15/26 (58) 1/4 (25) 0/5 (0) Postoperative‡ 3/26 (12) 2/4 (50) 0/5 (0) No. (%) of patients with malignancies 18 (30) 2 (5) 5 (10) .003 .01 Preoperative 4 (22) 1 (50) 5 (100) At the time of operation 12 (67) 1 (50) 0 Postoperative 2 (11) 0 0 No. (%) of patients with postoperative work-ups§ 57 (93) 34 (90) 48 (96) .48 .69 Computed tomography 43 (70) 25 (66) 48 (96) .62 .001 Abdominal ultrasonography 45 (74) 28 (74) 39 (78) .99 .61 Gastrofibroscopy 10 (16) 3 (8) 14 (28) .36 .14 Colonoscopy 4 (7) 0 4 (8) .30 Ͼ.99

Abbreviations: IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; PDAC, pancreatic ductal adenocarcinoma. *Data represent the results of a statistical comparison between patients with IPMN and MCN and between patients IPMN and PDAC. †Patients with unavailable data were excluded. ‡Some IPMN and MCN patients had more than 1 extrapancreatic neoplasm. §The number of patients who underwent at least 1 of the listed workups.

patients and for concurrent malignancies in 2 patients. factors, although the incidence of previous and concur- However, no other primary neoplasm occurred postop- rent extrapancreatic neoplasms was significantly higher eratively in patients who received chemotherapy or ra- in patients with IPMN. diotherapy in either group. Genetic or epigenetic changes associated with the pro- Generally, the development of multiple primary ma- gression of IPMNs may play a role in the development of lignancies can be explained by the inheritance of a pre- other primary neoplasms, especially of gastrointestinal tract disposing genomic defect or field carcinogenesis, which cancers. The carcinogenesis of IPMNs and colorectal ad- means that organ systems that have developed a neo- enomatous polyps are thought to be similar in that they plasm are likely to develop multiple and independent neo- follow a pattern of progression from adenoma to dyspla- plasms because all cells have been exposed to carcino- sia and eventually to invasive cancer. In addition, they share gens to similar extents.15 The aging process is another common genetic alterations including K-ras muta- cancer risk factor to consider because the longer a per- tions.11,16 Although the pathogenetic mechanisms in- son lives, as long as the cancer risk is constant, the more volved in the progression of IPMNs have not been estab- likely it is that neoplasms will develop over time. lished entirely, genetic alterations such as point mutations However, in the present study, no significant differ- in the K-ras oncogene,17,18 the overexpression of the HER- ences were found between the malignancy-associated 2/neu (c-erbB-2) gene,19-21 and the inactivation of the STK11/ group and the nonassociated group with respect to can- LKB1 gene22 (a tumor-suppressor gene responsible for cer risk factors, such as family history of malignancy, age, Peutz-Jeghers syndrome) have been reported. and history of cigarette smoking or alcohol abuse. His- It is likely that extrapancreatic malignancies in pa- tologic classification and type and location of IPMN were tients with IPMN have potential prognostic impor- also no different between groups. A comparison of pa- tance, even though we could not come to a definite tients with IPMN and those with MCN revealed that the conclusion because of limited case numbers and short general characteristics of the 2 groups were signifi- follow-up. Although the survival rates were no different cantly different in age and sex, which was accompanied in the malignancy-associated group and the nonassoci- by a different history of cigarette smoking or alcohol abuse ated group, the late portion of the survival curve of the perhaps because of sociocultural dissimilarity between malignancy-associated group was affected by extrapan- men and women. Thus, it may not be appropriate sim- creatic malignancies, which means that extrapancreatic ply to compare the incidences of associated malignan- malignancy, rather than malignant but docile IPMN it- cies in these groups, even if the diseases have similar fea- self, can determine long-term patient survival. tures. However, no differences were found between Results of the present study concur with those of ear- patients with IPMN and those with PDAC in terms of these lier studies that found that IPMNs are associated with a

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 high incidence of neoplasms in organs other than pan- cin expression pattern distinguishes different types of intraductal papillary mu- 7 cinous neoplasms of the pancreas and determines their relationship to muci- creas. Considerable attention should be paid to patients nous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol. 2001; with IPMN for the possible occurrence of other cancers, 25:942-948. especially gastrointestinal tract cancers, which can affect 9. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary muci- the long-term survival of the patients. Further molecular nous neoplasms. Am J Surg Pathol. 2004;28:977-987. studies are necessary to elucidate the mechanism of ex- 10. Takaori K, Kobashi Y, Matsusue S, et al. 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STK11/LKB1 Peutz-Jeghers gene inactivation Am J Gastroenterol. 1999;94:470-473. in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol. 2001; 8. Luttges J, Zamboni G, Longnecker D, Kloppel G. The immunohistochemical mu- 159:2017-2022.

Invited Critique

n recent years, there have been an increasing number of studies evaluating outcome in patients with IPMN. As noted by the I authors, some of these studies have suggested an increased risk of extrapancreatic neoplasms in patients with IPMN. The potential bias in reporting these findings, however, is that patients previously diagnosed with other malignancies are subject to closer surveillance, including a higher number of physician visits and imaging tests, which may increase the likelihood that they are subsequently diagnosed as having IPMN. In addition, because we now understand the significant chance for recur- rence of IPMN in the pancreas (up to 23% at 32 months’ median follow-up in a recent series by D’Angelica et al1 at Memorial Sloan-Kettering), postoperative patients with a new diagnosis of IPMN are closely followed up postoperatively with imaging tests, which may increase the likelihood of discovering other extrapancreatic malignancies. Because of this, it is difficult to sort out the meaning behind what might appear to be a high risk of extrapancreatic neoplasms in patients with IPMN. Although the authors attempt to reduce this bias by comparing IPMN patients with patients with MCN or PDAC, new biases arise in that comparison. This includes the shorter follow-up period in patients with PDAC due to their poor overall survival, and the markedly younger age for MCN patients compared with IPMN patients in the authors’ series. In addition, there is no standard algorithm for follow-up for any of these patients, including the interval and type of imaging tests obtained. Thus, it is difficult to directly compare these patients. That being said, it is certainly worth further investigating the potential that some undefined environmental influence or genetic change may influence the development of both IPMN and other neoplasms. The authors’ data reveals a markedly el- evated rate (nearly 40%) of extrapancreatic neoplasms developing in patients with IPMN. Because we do not understand the inciting events leading to IPMN, these findings warrant further scientific investigation, including evaluation of the molecular changes associated with IPMN, with the caveat that inherent biases will make retrospective comparisons difficult to interpret.

Sharon Weber, MD Correspondence: Dr Weber, Section of Surgical Oncology, Department of Surgery, University of Wisconsin Hospital, 600 Highland Ave, K4/764 CSC, Madison, WI 53792.

1. D’Angelica M, Brennan MF, Suriawinata AA, Klimstra D, Conlon KC. Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg. 2004;239:400-408.

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