Clin J Gastroenterol (2009) 2:365–370 DOI 10.1007/s12328-009-0116-6

CLINICAL REVIEW

Risk of additional pancreatic cancer in patients with branch duct intraductal papillary-mucinous neoplasm Satoshi Tanno • Takeshi Obara • Kazuya Koizumi Yasuhiro Nakano • Manabu Osanai • Yusuke Mizukami • Yutaka Kohgo



Received: 18 September 2009 / Accepted: 24 September 2009 / Published online: 30 October 2009 Ó Springer 2009

Abstract Branch duct intraductal papillary-mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency. Although BD-IPMN outcomes are generally good, pancreatic ductal adenocarcinoma (PDA) is found distant from the original BD-IPMN in about 3.3–9.2% of cases. These reports raise the question of whether a possible association exists between BD-IPMN and PDA. Recent findings from follow-up studies suggest that pancreases with BD-IPMNs have a high risk of developing additional pancreatic cancer, with standardized incidence ratios (SIRs) of 15.8- to 26-fold. These studies suggest that special attention should be paid to BD-IPMN patients who are C70 years. Furthermore, molecular evidence supports the hypothesis that field cancerization causing multiple primary neoplastic lesions exists in pancreases harboring IPMNs. Although more extensive studies are required to clarify the magnitude of this increased risk, clinicians should pay close attention to the development of PDA in patients with BD-IPMN, as well as to changes in BD-IPMN lesions. Keywords IPMN  Branch duct  Pancreatic cancer  Risk factor  Follow-up

S. Tanno (&) Department of General Medicine, Asahikawa Medical College, 2-1-1-1 East Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan e-mail: [email protected] T. Obara  K. Koizumi  Y. Nakano  M. Osanai  Y. Mizukami  Y. Kohgo Department of Gastroenterology and Hematology/Oncology, Asahikawa Medical College, Asahikawa, Japan

Abbreviations IPMN Intraductal papillary-mucinous neoplasm PDA Pancreatic ductal adenocarcinoma PanIN Pancreatic intraepithelial neoplasia

Introduction Intraductal papillary-mucinous neoplasm of the pancreas (IPMN) is a relatively new tumor entity that is characterized by intraductal papillary growths of neoplastic and mucin-producing columnar cells [1–8]. In the past, these tumors have been reported under various names, such as papillary carcinoma, ductectatic mucinous cystadenoma, and mucin-producing tumor. IPMNs show variable degrees of mucin secretion, cystic dilatation, and cytoarchitectural atypia. Compared to pancreatic ductal adenocarcinoma (PDA), IPMN is a slow-growing tumor that has a favorable prognosis following surgical resection [4, 6, 7]. IPMNs can be subdivided into main duct (MD-IPMN) and branch duct (BD-IPMN) types depending on whether the lesion is located in the main pancreatic duct or the side branch [9, 10]. Several studies have suggested that approximately 57–92% of patients with MD-IPMNs and 6–46% of patients with BD-IPMNs present with malignant lesions [11–16]. Current consensus guidelines recommend nonsurgical management of low-risk BD-IPMNs for asymptomatic patients with tumors \30 mm in size without mural nodules and without main duct dilation ([6 mm) [17]. In contrast, it is widely recommended that patients with MD-IPMN undergo surgical resection at the time of diagnosis. As BD-IPMNs are thus considered to be less aggressive than MD-IPMNs, proper classification of

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IPMNs has substantial value in determining the management strategy for this tumor type. BD-IPMN has been increasingly recognized and is now being diagnosed with increasing frequency as a result of recent improvements in imaging techniques and increased clinician awareness [18]. Many BD-IPMN patients are elderly and asymptomatic. Recent follow-up studies of patients with BD-IPMN suggest that the vast majority of BD-IPMNs, particularly the above-mentioned low-risk BDIPMNs, remain unchanged over time [8, 19]. Although BDIPMN outcomes are generally good, PDA is found at distant sites from the original BD-IPMN lesion in approximately 3.3–9.2% of cases [20–22]. There have also been reports of PDA developing in the remnant pancreas several years after resection of a BD-IPMN [20, 23]. Furthermore, small BDIPMNs may be incidentally detected in pancreases resected from PDA patients [24]. Consequently, these reports raise the question of whether BD-IPMN patients may be at high risk for additional pancreatic cancer. Although these studies suggest a possible association between BD-IPMN and PDA, little is known about the incidence and clinical features of PDA development in patients with BD-IPMN. This review describes recent findings about the incidence and clinical characteristics of PDA development in patients with BD-IPMN and discusses the possible mechanisms underlying the development of PDA in BD-IPMN patients.

PDA in patients with BD-IPMN Incidence of PDA in patients with BD-IPMN Of 60 resected IPMNs, Sohn et al. [20] identified PDA in the remnant pancreas in 2 patients (3.3%) (Table 1). Yamaguchi et al. [22] observed PDA in 7 (9.2%) of 76 patients with BD-IPMN. In their report, five of the seven PDAs were synchronously detected at the time of BDIPMN diagnosis; the remaining two were metachronously

Table 1 Incidence of PDA in patients with BD-IPMN Study

Year

Incidence of PDA in patients with BD-IPMN (%)

Sohn et al. [20]

2001

2/60 (3.3)

Yamaguchi et al. [22]

2002

7a/76 (9.2)

Kobayashi et al. [25]

2005

3/47 (6.4)

Tanno et al. [26]

2009

9/168 (5.4)

PDA Pancreatic ductal adenocarcinoma, BD-IPMN branch duct intraductal papillary-mucinous neoplasm of the pancreas a

Including 2 in situ carcinoma

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identified as histologically noninvasive ductal adenocarcinomas in the remnant pancreas after surgical resection of the BD-IPMN lesion. Kobayashi et al. [25] reported that PDA developed in 3 (6.4%) of 47 patients with BD-IPMN. In our study that reviewed a series of 168 consecutive patients with BD-IPMN, PDA developed in 9 (5.4%) cases [26]. In contrast to the study by Yamaguchi et al., our analysis did not include patients with in situ carcinoma; all 9 PDAs were histologically invasive ductal adenocarcinomas, thus resulting in an incidence (3.3–6.4%) lower than that reported by Yamaguchi et al. [22]. It should be noted that when the 2 in situ carcinoma cases are excluded, the incidence of invasive carcinoma in the report by Yamaguchi et al. is 6.6% (5 of 76), which is consistent with our data. An important finding from these studies is that all PDAs developed in regions distinct from the original BD-IPMN lesion. This suggests that none of the PDAs could have been prevented by limited surgery of the BD-IPMN. Particular attention should therefore be given to the development of PDA throughout the entire pancreas, as well as to changes in the original BD-IPMN lesion, if the pancreas harbors BD-IPMN. It is essential to continue careful follow-up of patients who remain capable of developing PDA. Risk of PDA development in patients with BD-IPMN Recent studies in Japan have reported standardized incidence ratios (SIRs) of PDA development in patients with BD-IPMN compared to the expected mortality from this cancer among the general population (Table 2) [21, 27, 28]. Tada et al. [21] reported a follow-up study in which PDAs developed in 5 (2.5%) of the 197 patients with cystic pancreatic lesions, including 80 BD-IPMN patients. Among these 80 BD-IPMN patients, 2 PDAs (2.5%) developed during the follow-up period (14–45 months). Although the SIR of PDA in BD-IPMN patients was not described, these investigators reported an SIR of 22.5 (95%

Table 2 SIR of PDA development during follow-up of patients with BD-IPMN Study

Year Incidence of PDA development (%)

SIR of PDA development

Tada et al. [21]

2006 3/80 (2.5)

22.5a (95% CI; 11.0–45.3)

Uehara et al. 2008 5/60 (8.3) [28]

26.0 (95% CI; 3.0–48.0)

Tanno et al. [27]

15.8 (95% CI; 4.3–40.4)

2009 4/89 (4.5)

SIR Standardized incidence ratio a

SIR of PDA in 197 patients with pancreatic cysts including 80 BDIPMN lesions

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CI; 11.0–45.3) in 197 patients with cystic pancreatic lesions. Uehara et al. [28] reported that PDA distinct from the original IPMN developed in 5 (8.3%) of 60 BD-IPMN patients during follow-up (18–112 months), and the SIR of PDA development was 26 (95%; CI 3–48). In our study, we reported that 4 (4.5%) PDAs distant from the original IPMN developed in 89 BD-IPMN patients during followup (37–92 months), and the SIR of PDA development in BD-IPMN patients was 15.8 (95% CI; 4.3–40.4) [27]. These follow-up studies strongly indicate that patients with BD-IPMNs have a high risk of developing PDA, with SIR findings of 15.8- to 26-fold. Although more extensive studies are required to clarify the magnitude of this increased risk, clinicians should pay close attention to the development of PDA in patients with BD-IPMN, as well as to changes in BD-IPMN lesions. The international consensus guidelines for IPMN indicate that the follow-up interval can be lengthened after 2 years if no changes are observed [17]. However, the results of the studies described above suggest that the interval should not be lengthened even if no changes are observed for C2 years, thereby emphasizing the importance of long-term surveillance of the entire pancreas in patients with BD-IPMN. Clinical characteristics of BD-IPMN patients who develop PDA Identification of the clinical characteristics of BD-IPMN patients at high risk for developing PDA would help enrich the pool of newly diagnosed or follow-up BD-IPMN patients. Tada et al. [21] reported a significant difference in age, but not in gender or cyst location and size, between patients who did and did not develop PDA. Uehara et al. [28] reported that BD-IPMN patients [70 years old developed ductal carcinoma significantly more frequently than younger patients. In our study, the incidence of PDA was significantly higher in patients C70 years (SIR 16.7; 95% CI 3.4–48.7) and in females (SIR 22.5; 95% CI 2.7– 81.1) [27]. We found no significant differences in cyst size or location between patients with and without PDA. Interestingly, none of the BD-IPMN patients with PDA had symptoms, mural nodules, or a cyst size [30 mm, as is necessary to indicate resection in accordance with the criteria described by the international consensus guidelines [17]. These studies suggest that special attention should be paid to BD-IPMN patients who are C70 years and/or female. More extensive analysis is required to clarify the characteristics of BD-IPMN patients at high risk for developing PDA. Since PDA can potentially develop even in patients with BD-IPMN with a low risk of progressing to invasive cancer, careful follow-up with periodic surveillance is crucial for all BD-IPMN patients.

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Possible mechanisms underlying the development of PDA in pancreases with BD-IPMN Pancreatic intraepithelial neoplasia (PanIN) The mechanisms underlying the development of PDA in pancreases with BD-IPMN are not clear. However, pancreatic intraepithelial neoplasia (PanIN) lesions may play a crucial role in the pathogenesis of PDA in patients with BD-IPMN. PanIN lesions, particularly PanIN-2 and -3, are widely believed to represent putative precursors of PDA [29–31]. PanIN lesions have been reported to be found extensively in the ducts of resected pancreases harboring IPMN [29, 32, 33]. PanIN lesions that are more dysplastic than the concomitant IPMN may also be detected in ducts distant from the IPMN. These reports suggest that the development of PDA may be the result of progression of dysplastic PanIN lesions that exist in the ducts of pancreases harboring BD-IPMNs. PanIN lesions are also frequently found in the ducts of whole pancreases resected for PDA [34]. A considerably high incidence of multicentric, pancreatic PanIN lesions has been documented in a series of total pancreatectomies of PDA patients [35]. Furthermore, multifocal carcinomas of the pancreas have been found in 32% of 47 patients with PDA. Thus, multicentric and metachronous development of carcinomas potentially occurs in pancreases with PDA as well as those with BD-IPMN [30, 33, 34]. In contrast to the extremely poor prognosis of PDA, BD-IPMN is associated with a favorable prognosis; thus, the progression of PanIN lesions that are more dysplastic than the concomitant BDIPMN may precede the progression of BD-IPMN to carcinoma over time. K-ras codon 12 mutations in pancreases with IPMN Another source of PDA development in pancreases harboring BD-IPMN is K-ras aberrations that occur early in the development of PanIN lesions identified in ducts distant from the original IPMN [32, 36]. The K-ras oncogene (chromosome 12p) is activated by point mutations in codons 12 (most common), 13, and 61 in approximately 90% of PDAs [37]. K-ras codon 12 mutations occur in approximately 13–83% of PanINs [36, 38–45]. Recent studies have demonstrated a high prevalence of PanINs harboring K-ras codon 12 mutations in patients with PDA [45, 46] and chronic pancreatitis [39]. Likewise, K-ras mutations are found in 30–100% of IPMNs [38–43]. A stepwise increase in the frequency of K-ras codon 12 mutations has been reported to be correlated with the stage of neoplastic evolution to carcinoma [36]. Furthermore, K-ras mutations in PanINs have been frequently identified in patients with an otherwise disease-free pancreas [40,

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44]. Thus, K-ras mutations occur very early in PanIN, which is regarded as a precursor lesion of pancreatic cancer [39, 40, 45–47]. K-ras mutations and other genetic and chromosomal changes are shared between PDA and IPMN. This similar ‘‘soil’’ may be the progenitor of either type of neoplasm, supporting the hypothesis that the two lesions may be more likely to arise in the same pancreas. In a mouse model with an endogenous K-ras mutation, the full spectrum of human pancreatic carcinogenesis was recapitulated with murine PanIN lesions progressing to PDA [48]. A recent report using another mouse model demonstrated that concomitant pancreatic activation of K-ras and transforming growth factor-alpha results in PanIN lesions and cystic papillary neoplasms reminiscent of human IPMN, and that these lesions progress to invasive cancer [49]. Such animal studies have the potential to provide insight into the mechanisms underlying the risk of PDA in human pancreases harboring BD-IPMNs. Field cancerization in pancreases with IPMNs Tumor clonality is directly relevant to tumorigenesis. Neoplastic tissues are believed to be comprised of a monoclonal cell population. However, some neoplasms, such as colon adenoma in patients with familial adenomatous polyposis [50], pancreatic endocrine tumors [51], and fibroadenoma of the breast [52], appear to be polyclonal in origin. Because K-ras mutations represent a very early event in PanIN development, K-ras mutation status can be used as a marker of field cancerization and clonality in the development of IPMNs as well as in PDA. Multiple, different PanINs in the same pancreas with distinct K-ras mutations would represent multicentric and independent lesions suggestive of field cancerization in which carcinogenic insults result in the independent transformation of different epithelial cells [53]. Recent studies have reported the identification of multiple distinct K-ras codon 12 mutations among different PanINs in 47–50% of patients with PDA [45, 46], and 6–12% of patients with PDA have been reported to have multiple, distinct mutations [46, 54]. These data support the notion of field cancerization, which is compatible with multiple, independent, transforming events in each lesion of a single pancreas. By evaluating multiple samples microdissected from various lesions of different histologic grades, Z’graggen et al. [36] demonstrated a stepwise increase in the incidence of K-ras mutations during the evolution of IPMN. In a recent study in which extensive multiple sampling from PanIN and IPMN was performed, Matsubayashi et al. [45] demonstrated the presence of K-ras mutations in 11 (92%) of 12 patients with IPMNs and multiple K-ras mutations in 5 (45%) of 11 patients with PanIN. Izawa et al. reported

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that mutation of K-ras is a very early event in the adenoma–carcinoma evolution of IPMN and that the incidence of K-ras mutations increases with pathologic atypia [32]. In their study, K-ras mutations were found in adenomas in 62% of patients with IPMNs, 65% of whom had multiple, distinct mutations in different lesions. These results provide molecular evidence for field cancerization in pancreases bearing IPMNs and suggest that patients with IPMN are at risk for synchronous and/or metachronous multiple tumors before and after surgery [36, 55, 56]. Multifocal occurrence of IPMN An important clinicopathologic feature of IPMN is that multifocal occurrence of IPMN has been observed in the same pancreas [12, 16, 55, 56]. The incidence of tumor multifocality of IPMN ranges from 9.8 to 32% [12, 16, 55, 56], and recurrences after surgical resection have been reported [16, 55, 56]. A study of IPMNs treated with total pancreatectomy showed multifocal discontinuous sites of dysplasia within the pancreatic ducts [57]. These observations further support the hypothesis that field cancerization causing multiple primary neoplastic lesions exists in pancreases harboring IPMNs [32].

Discrimination between invasive carcinoma derived from BD-IPMN and independent carcinoma arising within a BD-IPMN It may occasionally be difficult to distinguish carcinoma derived from BD-IPMN versus an independent carcinoma arising within a BD-IPMN if PDA develops immediately adjacent to the BD-IPMN lesion. Invasive carcinoma may also be diagnosed at a time when the pre-existing IPMN may have been obliterated and be undetectable. Two histological types of invasive carcinomas derived from IPMN exist: mucinous type and tubular type [58]. Patients with mucinous carcinoma arising in BD-IPMN lesions have a substantially better prognosis than patients with tubular carcinomas [1, 59, 60]. Precise discrimination between invasive carcinoma derived from BD-IPMN and independent carcinoma arising within a BD-IPMN lesion is important to facilitate proper evaluation of the risk of PDA development in pancreases with BD-IPMNs.

Summary Recent findings from follow-up studies suggest that patients with BD-IPMNs are at high risk for the development of PDA. Clinicians should pay close attention to the development of PDA in patients with BD-IPMN, as well as

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to changes in BD-IPMN lesions. Since PDA can potentially develop even in patients with low-risk BD-IPMN, careful follow-up with periodic surveillance is crucial for all BDIPMN patients. We recommend that follow-up intervals should not be lengthened, even if no changes are observed for C2 years. This review emphasizes the importance of long-term, careful surveillance of the entire pancreas in patients with BD-IPMN. Conflict of interest statement

No conflicts of interest exist.

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Risk of additional pancreatic cancer in patients with branch duct intraductal papillary-mucinous neoplasm.

Branch duct intraductal papillary-mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency. Although BD-IPMN outcome...
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