Intraductal Papillary Mucinous Neoplasm: Clinical Surveillance and Management Decisions Joanna Y. Chin, MD, PhD,* Martha B. Pitman, MD,† and Theodore S. Hong, MD* Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a relatively rare cystic neoplasm. Although most IPMNs appear to be benign and may be managed by surveillance, all IPMNs are considered premalignant lesions with malignant potential. As such, current efforts are focused on identifying those neoplasms that are at high risk for malignancy to optimize treatment strategy and outcome. IPMNs with invasive carcinoma have clinical outcomes that approach those of conventional pancreatic ductal adenocarcinoma. Management guidelines recommend surgical resection for IPMNs with high-risk imaging or cytologic features. The role of adjuvant therapy is unclear, and we review the evidence for chemoradiation here. Some studies suggest adjuvant chemoradiation may have the greatest impact in malignant IPMNs with adverse histologic features, that is, lymph node metastasis at the time of diagnosis or positive surgical margins. As more IPMNs are recognized and treated, more evidence will accumulate to guide clinicians regarding appropriate use of radiotherapy in the management of IPMN. Semin Radiat Oncol 24:77-84 C 2014 Elsevier Inc. All rights reserved.
Introduction
V
arious names have been used to describe intraductal papillary mucinous neoplasms (IPMNs) since Ohashi1 published 4 cases of mucinous neoplasms of the pancreas leading to ectasia of the pancreatic duct system in 1982. In 1996, the World Health Organization (WHO) classified cystic mucinproducing pancreatic neoplasms under intraductal papillary mucinous tumor (renamed neoplasm in 2006) and mucinous cystic neoplasm (MCN). IPMNs are defined as mucinproducing cystic pancreatic neoplasms with intraductal papillary projections of tall columnar epithelium, without subepithelial ovarian-type stroma, which distinguishes them from MCNs. Originally thought to be a rare tumor, IPMNs are now recognized to be more frequent entities based on autopsy and surgical series and currently constitute approximately 20%50% of resected cystic pancreatic tumors.2-4 Likely, some of the
*
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. †Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. The authors declare no conflict of interest. Address reprint requests to Theodore S. Hong, MD, Department of Radiation Oncology, Massachusetts General Hospital, Cox Building-3, 100 Blossom St, Boston, MA 02114. E-mail: [email protected]
1053-4296/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semradonc.2013.11.005
apparent increase in IPMN incidence is because of increased incidental detection on imaging.5 It is estimated that at least 2% of the general population have pancreatic cysts, with a strong correlation to age; for example, in patients older than 80 years, 8.7% of patients had pancreatic cysts in an institutional series.6 Using magnetic resonance imaging (MRI), the prevalence of pancreatic cysts has been estimated to be as high as 13.5%.7 IPMNs range from premalignant intraductal lesions to malignant neoplasms with invasive carcinoma. Indeed, 20%50% of resected IPMNs have an invasive component. Although 10-year disease-specific survival for resected, noninvasive IPMNs is greater than 95%, invasive cancers have a 5-year overall survival of 36%-70%.8-11 Overall, patients with invasive IPMN appear to present at an earlier stage than those with classic pancreatic ductal adenocarcinoma, and this is likely a reflection of the natural history of the disease, in which larger cystic lesions may be apparent on imaging or cause clinical symptoms that prompt imaging.8,12 In a series of resected IPMNs at the Massachusetts General Hospital (MGH), 30% of patients with invasive IPMN presented with nodal involvement compared with approximately 70% in patients with classic pancreatic ductal adenocarcinoma.4 Similarly, in a surgical series from Johns Hopkins University, 64% of patients presented with stage II disease.8 Although overall mortality for resected invasive IPMN is better 77
J.Y. Chin, M.B. Pitman, and T.S. Hong
78 than in conventional pancreatic ductal carcinoma (hazard ratio [HR] ¼ 0.58, 95% CI: 0.39-0.86), it appears that among nodepositive patients, there is no significant difference between clinical outcomes in invasive IPMN and ductal adenocarcinoma (HR ¼ 0.89, 95% CI: 0.52-1.50).13 Therefore, at least some of the improved outcomes observed in IPMN compared with conventional adenocarcinoma may be because of earlier stage at presentation; that is, smaller size and a decreased incidence of nodal involvement.
Classification Location IPMNs are classified preoperatively by imaging according to the pancreatic ducts involved: the main duct (MD-IPMN), the branch ducts (BD-IPMN), or both (mixed or combined type). Identifying the type of IPMN has implications on prognosis and, therefore, management, as MD-IPMNs have a higher risk of malignancy. MD-IPMN typically leads to marked dilation that can often be seen by computed tomography (CT) imaging or by magnetic resonance cholangiopancreatography (MRCP). More invasive techniques, such as endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreatography (ERCP) with or without balloon catheter, intraductal ultrasound, and peroral pancreatoscopy, can also be used to assess MD involvement (discussed later). BD-IPMNs typically involve only 1 part of the pancreas but are multifocal in up to 30% of patients. The risk of malignancy in BD-IPMN is stratified by imaging features and the results of cytologic analysis of the cyst fluid.14 Imaging that demonstrates both a markedly dilated MD and BD cysts is classified as combined-type IPMNs.
Histopathologic Classification Histologic subtyping of IPMNs is a paramount step in prognostication. IPMNs can be subclassified into intestinal, pancreatobiliary, oncocytic, and gastric subtypes by morphologic patterns based on histology and mucin expression by immunohistochemical analysis. MD-IPMNs are typically intestinal-type and rarely pancreatobiliary and oncocytic subtypes, whereas BD-IPMNs are most commonly gastric subtype. Invasive carcinomas arising in pancreatobiliary subtypes have a particularly poor prognosis and are associated with high invasive rates (90.2%), high recurrence rates (70.7% even after R0 resection), and 5-year survival rates (35.6%) approaching that of conventional pancreatic ductal adenocarcinoma.15 The best prognosis is associated with invasive carcinomas arising from the intestinal subtype of IPMN because these are usually mucinous (colloid) carcinomas in contrast to the tubular carcinomas that generally arise from the other subtypes. In a surgical series at MGH, tubular histology was associated with higher rates of perineural invasion and a trend toward higher rates of advanced tumor stage and lymph node involvement compared with colloid and oncocytic tumors.13 In fact, the prognosis of tumors with tubular histology approached that of conventional ductal adenocarcinoma in this surgical series.
The degree of dysplasia, graded histologically, is also correlated with prognosis. In a review of 136 resected IPMNs at Johns Hopkins, the 5-year overall survival of patients with invasive IPMN was 43% compared with 77% for patients with noninvasive IPMNs.10 Approximately 20%-30% of all resected IPMNs demonstrated invasion.8,16,17 Most series of surgically resected IPMNs show increased rates of malignancy in MDIPMN compared with BD-IPMN, although there is some ambiguity in the literature regarding rates of invasive disease, as histology nomenclature has shifted in the last 2 decades. Typically, 50%-90% of MD-IPMNs are identified histologically as malignant (high-grade dysplasia, also known as carcinoma in situ or invasion), with approximately half to two-thirds of those cases appearing to be invasive. In contrast, BD-IPMNs demonstrate such high-grade features in 20%-40% of cases.18-20 Even in noninvasive IPMNs, there is a 10% recurrence rate following partial pancreatic resection with negative margins, suggesting the insidious nature of IPMNs; in contrast, MCNs are solitary cysts and do not recur after complete resection. The trajectory from noninvasive, premalignant IPMN to invasive, malignant transformation is not clear. It is generally believed to occur over 5-7 years although there are scant data to support this.10,21 In a retrospective series, which attempted to understand the natural progression of IPMNs, it was estimated that 63% of MD-IPMNs progressed to high-grade dysplasia or invasive carcinoma within 5 years.21 In contrast, it was estimated that 10%-40% of BD-IPMNs progressed over 5 years, with invasive carcinoma developing in approximately 20% of those patients over 10 years.22 This uncertainty is complicated because of the difficulty in distinguishing between noninvasive and invasive IPMNs in the preoperative setting. In a recent retrospective series, invasive IPMN was diagnosed correctly in 68% of patients who underwent preoperative biopsies. Furthermore, 20% of patients with noninvasive disease seen on resection were initially misdiagnosed with invasive IPMN.23 However, the management goal should be to resect IPMN with high-grade (premalignant) dysplasia, as this offers the patient the best prognosis. Using imaging characteristics coupled with cytologic analysis of the cells shed into the cyst fluid offers the best diagnostic tests to detect IPMNs at this stage and before high-risk imaging features that generally correlate with invasive disease.24
Prognostic Features Prognostic factors for malignancy include higher stage,12 nodal metastases,12,16,25,26 vascular invasion,16,25 positive surgical margins,10,27 perineural invasion,12,16 histology subtype,13,15 and recently, size of mural nodules.28 For example, in a Surveillance, Epidemiology, and End Results (SEER) analysis, lymph node–positive patients with resected IMPN showed a 5year overall survival rate of 12% compared with 42% in nodenegative patients.23
Molecular Pathogenesis There has been a significant amount of research conducted on the pathogenesis of IPMN in the past 2 decades, with the goal of identifying a sufficiently specific molecular marker for high-
Intraductal papillary mucinous neoplasm grade premalignant neoplasms, for example, identification of premalignant intraductal lesions before invasion and malignant transformation.29 To date, however, no molecular alterations have met this goal to qualify as a clinically useful test for preoperative diagnosis and treatment. Currently, KRAS and GNAS mutations are exclusively being used in molecular tests of aspirated cyst fluid. KRAS codes for a guanosine triphosphate–binding protein, which becomes upregulated from point mutations primarily on codon 12, thus affecting many different downstream intracellular signaling cascades. KRAS is a commonly mutated gene in pancreatic cancer, including IPMNs.30 In fact, the very high frequency of KRAS mutations in IPMNs suggests that this mutation is a near-essential event for the development of this neoplasm. In addition, the frequency of KRAS mutations increases with grade, with distinct mutations noted in different parts of multiple BD-IPMNs as well as different parts of combined-type IPMNs, findings that support the hypothesis that IPMNs are multicentric tumors.31 A study of cellular clonality and KRAS mutations also suggests that IPMNs arise from polyclonal epithelia, which are replaced with monoclonal cells as transformation occurs along the adenoma-carcinoma spectrum.32 Unfortunately, KRAS mutations are present in both premalignant and malignant tumors, and thus, analysis of these mutations does not provide a specific molecular marker for determining the grade of premalignant tumors or distinguishing high-grade dysplastic tumors from invasive tumors.30 GNAS is an oncogene that becomes mutated on codon 201 early during the development of IPMNs.33 This mutation appears to be unique to IPMN, designating it a molecular marker that distinguishes it from serous cystadenoma (SCA) and MCN, which are very important preoperative distinctions that affect patient management. SCA are benign tumors that do not need resection unless symptomatic or large,34 and all MCNs are resected regardless of grade because of the ease of the usual distal pancreatectomy relative to the stress and cost of life-long follow-up of a typical middle-aged woman affected by this neoplasm. Like KRAS, however, GNAS mutations do not distinguish the grade of an IPMN or the noninvasive from invasive neoplasms. RNF43, a gene encoding for a protein with intrinsic ubiquitin ligase activity on chromosome 17, has recently been noted to be inactivated in mucinous cysts (both IPMN and MCN) compared with nonmucinous cysts (SCA and solid pseudopapillary neoplasms). Therefore, it is an effective preoperative marker in some instances, particularly for the distinction between macrocystic SCA and mucinous cysts, which are difficult to distinguish by imaging studies.35 Mutation in TP53, a gene encoding for a tumor suppressor protein that affects the expression of many genes including those involved in cell cycle arrest, DNA repair, and apoptosis has been shown to be associated with IPMNs with high-grade dysplasia, but the detection of this mutated gene is insufficiently sensitive and specific to make it a useful preoperative marker for surgical management.30,36,37 Although the genetic deletion of SMAD4/DPC4 in the region of chromosome 18q is considered an early genetic change in conventional pancreatic ductal carcinoma and thus a useful marker for
79 distinguishing benign from malignant ductal epithelium by immunohistochemical staining,38 it is a gene that is retained in IPMN regardless of grade. Consequently, it is suggested that the inactivation of this gene is a late event in the development of malignant IPMNs.39 Other genetic mutations have been implicated in the development of IPMN. Sonic Hedgehog is a gene involved in the differentiation of gastric epithelia of human adults, which is misexpressed in pancreatic adenocarcinoma and intraepithelial neoplasia, as well as in the early development of IPMN.40 The CDKN2A-p16-MTS1 gene pathway associated with cyclindependent kinase inhibition has been shown to be inactivated in IPMNs with both low-grade and high-grade dysplasia.36 Hypermethylation of genes associated with cell cycle control (including p16, p73 and, APC genes), DNA repair (MGMT and hMLH1), and cell adhesion (E-cadherin) are more often found in malignant, invasive IPMNs compared with premalignant, noninvasive tumors.41,42 Although the study of molecular pathways in the pathogenesis of IPMNs is fruitful, none of the information thus far can replace the sensitivity and specificity of cytologic analysis of the cyst fluid for the detection of highgrade epithelial atypia as a marker for at least high-grade dysplasia.43
Preoperative Diagnosis and Management Imaging Cystic pancreatic lesions, including IPMNs, are found on imaging that is often performed for unrelated reasons. The location and degree of duct dilation can be seen on CT and, in our institution, a dedicated pancreatic protocol is used for improved detection of ductal abnormalities (Fig. 1). Mucinous globules are often seen and may appear as filling defects in the duct system. Serial sectioning of the entire pancreas by CT is useful for determining the full extent of the disease. Staging should include imaging of the chest and liver, the most common sites of distant metastases for invasive disease. High-risk features of an IPMN on imaging include MD involvement, main pancreatic duct dilation 410 mm, the presence of mural nodules, and dilation of the biliary tree. MRCP may sometimes be helpful in visualizing ductal communication with the cyst, though thin-slice CT and multiplanar reconstructions can often provide similar information as MRCP. However, MRCP offers improved morphologic detection of small (o3 cm) lesions and of small mural nodules. When CT or MRCP or both are equivocal or when confirmation of malignancy is required before surgery, EUS can be of high diagnostic value, with a 92% accuracy in differentiating IPMN from other cystic pancreatic lesions,44 though this is operator dependent. With endoscopy, mucus can be seen in one-third of patients exuding from a bulging papilla of Vater when the MD is involved. EUS is also useful in showing internal septae, mural nodules, solid masses, vascular invasion, lymph node involvement, and wall thickness.44,45
J.Y. Chin, M.B. Pitman, and T.S. Hong
80
Figure 1 Axial CT of a patient with an IPMN in the pancreatic head (A, solid arrow) causing mild ductal dilatation (B). CT angiography (C) can be useful in determining lesion location and resectability. IPMNs typically appear cystic and fluid filled compared with conventional pancreatic ductal adenocarcinoma (D, open arrow), which appear denser and more solid on CT imaging. Panels (A-C) are of the same patient; (B) A coronal CT reconstruction showing the pancreatic duct. (D) A coronal CT of a different patient.
EUS has the additional advantage of being able to obtain cyst fluid for cytology analysis or a biopsy specimen or both. ERCP often reveals a dilated main pancreatic duct, with or without mucinous globules, mural nodules, or areas of invasion. ERCP is also useful in determining ductal communication and confirming the diagnosis of IPMN as MCNs do not typically communicate with the ductal system. The presence of mucin or papillary tumor growth or both may preclude full visualization of the ductal system during ERCP, even with the aid of a contrast agent. It should be noted that despite available sophisticated imaging, IPMN type has been misclassified in 20%-40% of reported surgical series. A series from Germany determined that 58.9% of preoperative classifications turned out to be correct on final histology, with most misclassifications being BD-IPMNs preoperatively in whom MD components were identified postoperatively.46 Similarly, in a surgical series of presumed BD-IPMN based on preoperative workup, 20% were found to have MD involvement,47 indicating the difficulty of classification.
dysplastic IPMN.48 CEA is the most reliable and accurate marker of a mucinous cyst; other tumor markers such as CA 15-3, CA 19-9, CA 125, and CA 72.4 do not offer more diagnostic value than CEA alone.49,50 Amylase has less diagnostic value than CEA on a routine basis, and although high amylase levels are noted in IPMN, consistent with communication with the pancreatic ductal system, amylase levels do not distinguish between IPMN and MCN because some MCNs also demonstrate high amylase levels.50 Unfortunately, CEA level is not a reliable marker to distinguish benign from invasive disease. Cytology can provide important diagnostic information. Although the finding of a “positive” (ie, diagnostically malignant) cytology requires both adequate quantity and quality of viable cells for analysis, the category of “high-grade atypia” may also be useful in risk assessment (Fig. 2). This latter category includes aggregates of cells and small clusters or crowded, molded cells and single epithelial cells showing an increased nuclear-to-cytoplasmic ratio, irregular nuclear membranes, or abnormal chromatin pattern with or without visible intracytoplasmic mucin.
Cyst Fluid Analysis Cyst fluid analysis includes testing for mucin, carcinoembryonic antigen (CEA), and amylase. Mucin and CEA are found in mucinous neoplasms. Relatively higher levels of MUC2 and MUC4 have been reported in cyst fluid of
Molecular Markers Molecular markers KRAS and GNAS are useful in supporting classification of a cyst as mucinous, as not all mucinous cysts have an elevated CEA. However, these markers cannot
Intraductal papillary mucinous neoplasm
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Figure 2 Cytology of an IPMN with invasive carcinoma (A). Compared with the cytology of the typical conventional ductal adenocarcinoma (B), adenocarcinoma arising in an IPMN is often less overt and obvious on cytology. The cluster of cells (A) shows high-grade atypia similar to what is seen in premalignant IPMN with high-grade dysplasia. The extracellular mucin on the right and the necrotic cyst debris on the center-left position can be noted. In contrast, FNAs of solid mass lesions produce cellular smears composed of cell groups in variable quantity as illustrated in (B). The overt malignant features illustrated include very large cells, high nuclear-to-cytoplasmic ratio, large nuclei with coarse chromatin, irregular nuclear membranes, prominent nucleoli, and mitotic activity, which make the cytologic diagnosis of adenocarcinoma straight forward even on scantily cellular smears.
distinguish between low-grade and high-grade dysplasia, and in addition, 4% of IPMNs have neither mutation.51 Approximately 50%-80% of IPMNs also have point mutations in p53. Loss of heterozygosity of p16 is rarer in IPMNs than in classic pancreatic ductal adenocarcinomas, though a series reported that invasive IPMNs had a higher p16 mutation rate than benign IPMNs.52 Other genetic changes implicated in the pathogenesis of invasive IPMN are increased expression of cyclooxygenase-2, matrix metalloproteinase-7, proliferating cell nuclear antigen, and vascular endothelial growth factor; upregulation of mesothelin; increased telomerase activity; and increased levels of the tumor suppressor gene SMAD4.53 Recently, several groups have demonstrated differential expression of microRNAs in invasive IPMN.54-56 Two of these, mir-155 and mir-21, were originally identified in pancreatic adenocarcinomas. Interestingly, multiple groups have shown that the levels of both mir-155 and mir-21 were correlated with invasiveness; that is, these microRNAs are upregulated in invasive disease relative to noninvasive disease and in noninvasive disease relative to normal pancreatic tissue. If validated, they may prove to be useful as biomarkers, particularly if they are also found in pancreatic cyst fluid that can be used in preoperative decision making.
Management The management guidelines for IPMN outlined by the 2005 and 2012 International Consensus Guidelines recommend resection of lesions that are at high risk for malignancy and for symptomatic management.14 Before the 1990s, surgical resection was recommended for all mucin-producing pancreatic neoplasms. The 2012 guidelines of multidisciplinary experts recognized the different propensities for malignancy of MD and mixed type IPMNs compared with the lower malignant potential of the BD-IPMN subtypes. Therefore, oncologic resection is recommended for MD-IPMN regardless of size and location in the pancreas (ie, head or tail), preferably with
lymphadenectomy, in patients with a reasonable life expectancy and in whom resection can be achieved safely. An attempt is made to achieve negative surgical margins, and positive surgical margins warrant re-resection. In contrast, there appears to be a subset of BD-IPMNs in which clinical surveillance may be indicated, given the low likelihood of malignancy. The 2012 guidelines indicate resection for BD-IPMNs based on the presence of worrisome features (cysts Z3 cm, thickened cyst walls, nonenhanced mural nodules, MD size 5-9 mm, or an abrupt change in MD caliber associated with distal pancreatic atrophy and lymphadenopathy), high-risk stigmata (MD 410 mm and an enhanced solid component), and suspicious or positive cytology.14 However, even in the absence of mural nodules, invasive IPMNs have been reported in up to 15% of BD-IPMNs in some surgical series,18,19,46 indicating that the identification of benign disease can be difficult. Another series of asymptomatic patients with pancreatic cysts less than 3 cm in size, with no identifiable malignancy risks on imaging, demonstrated a 3.3% occult malignancy rate.57 Finally, invasive disease was identified in 10.5% of patients with BD-IPMNs who were initially surveilled at a large referral center. Overall, 57% of the initially surveilled group ultimately had resection with a median of 40 months of follow-up, primarily for radiographic or endoscopic changes (55%), followed by concern of premalignant condition and suspicious cytology.58 A recent report suggests that invasive BD-IPMNs have unfavorable clinical outcomes compared with invasive MD-IPMNs,53 although the underlying biology of this observation is unclear. Furthermore, it is not clear that preoperative “worrisome features” carry equal weighting when evaluating the malignant potential of a cyst. In a recent meta-analysis, cyst size in particular was considered to be a significant risk factor for malignancy (OR ¼ 62.4; 95% CI: 30.8-126.3), whereas presence of mural nodule (OR ¼ 9.3; 95% CI: 5.3-16.1), pancreatic duct dilation (OR ¼ 7.27; 95% CI: 3.0-17.4), and
82 symptoms (OR ¼ 1.6; 95% CI: 1.0-2.6) were weaker predictors for malignancy.59 Therefore, further studies on malignancy risk are needed to more carefully design algorithms for management. Total pancreatectomy is not routinely recommended because of the significant complication rate and potential mortality associated with the procedure, as well as long-term side effects. It is estimated that 2.8% of all patients with IPMN in a surgical series from Memorial Sloan-Kettering Cancer Center developed carcinoma in a region remote from the initially identified cyst.58 However, in several surgical series, total pancreatectomy was not associated with lower recurrence rates compared with partial resection,60,61 thus suggesting that any benefit to resecting potential microscopic disease at either the surgical margins or at metachronous sites is offset by the significant increase in morbidity. Similarly, it is controversial whether re-resection is warranted for benign IPMNs, as there are case reports of malignant transformation of recurrent IPMN in the remnant pancreas following resection of noninvasive IPMN with negative surgical margins.10,62 Some speculate that these apparent recurrences actually occurred in the setting of undiagnosed multifocal disease. Therefore, in cases of multifocal disease, the surgeon may choose to excise the dominant lesion and follow less-concerning lesions with surveillance imaging.10
Role of Radiotherapy Determining the optimal strategy following resection for invasive IPMN is subject to discussion, as is adjuvant therapy for pancreatic carcinomas in general. Because of the relative rarity of the disease, there is no randomized evidence regarding adjuvant therapy in malignant (invasive) IPMN. Most commonly, clinicians extend results from trials of pancreatic ductal adenocarcinoma to the management of invasive IPMNs, which may not be applicable. Complicating the discussion, is the relatively sparse data comparing, stage for stage, ductal adenocarcinoma arising from an IPMN with “classic” pancreatic adenocarcinoma arising from intraepithelial neoplasia.63,64 It is now increasingly recognized that invasive IPMN is distinct from classic pancreatic adenocarcinoma, and therefore, extrapolation from those data may not be justified. There are some retrospective, institutional data regarding adjuvant radiation in invasive disease arising in the setting of IPMN. In a series at MGH, 44 patients who had resection for invasive disease were observed with a median follow-up of 19 months.12 Of these patients, 61% had resection alone, whereas 39% had concurrent chemoradiation. The median radiation dose was 50.4 Gy, and most (65%) patients received concurrent infusional 5-fluorouracil. Overall, 5 patients had additional 4-6 months of adjuvant chemotherapy. In this study, patients who received adjuvant chemoradiation therapy (CRT) were more likely to be at a higher stage (P ¼ 0.035) and have positive nodes (P ¼ 0.024) compared with patients undergoing resection alone. Overall, as a group, patients receiving adjuvant CRT had no overall survival benefit compared with patients undergoing resection alone; however, when stratified
J.Y. Chin, M.B. Pitman, and T.S. Hong for node-positive disease, cancer-specific survival and overall survival were improved in the adjuvant group (cancer-specific survival, HR ¼ 0.10; 95% CI: 0.018-0.59 and overall survival, HR ¼ 0.13; 95% CI: 0.029-0.56). However, it is likely that some patients were not able to receive adjuvant therapy because of disease progression, and therefore, this survivor bias may overestimate the benefit of adjuvant radiation. Interestingly, node-positive patients who completed adjuvant CRT had a survival benefit of 16.5 months compared with patients undergoing resection alone (median survival 3.3 months). It is unclear whether this relatively long median survival time following adjuvant therapy is because of intrinsic biology or the treatment itself or both. Similar results were seen in a series of 70 patients who were evaluated following resection for invasive carcinoma arising from IPMN.8 All but one of these patients had stage I-II disease; 59 were in the head of the pancreas and 11 were in the distal pancreas. The median survival of the patients was 28 months, with a 5-year overall survival of 45%, consistent with other series of invasive IPMN. Of the 70 patients, 40 received adjuvant therapy and were more likely to have positive surgical margins, involved nodes, stage II-III disease, and perineural invasion. Negative prognostic factors for outcome included lymph node involvement, margin positivity, and poor, anaplastic, or undifferentiated tumors. Although the overall survival was not different whether the patients received adjuvant treatment, the authors identified subgroups of patients with improved survival following adjuvant CRT compared with resection alone, that is, patients with positive lymph nodes (relative risk ¼ 0.43; P ¼ 0.047) or with positive margins (P ¼ 0.042). Finally, adjuvant treatment was not found to confer a survival benefit in patients with resected invasive IPMN in a retrospective series from Indiana University and the Mayo Clinic.16 In agreement with the studies mentioned earlier, those patients receiving adjuvant treatment (37 of 98 patients with resected invasive IPMN) tended to have larger size tumors, positive nodes, and positive surgical margins. Perhaps not surprisingly, given the selection bias of patients receiving adjuvant treatment, patients receiving adjuvant treatment had an overall detriment in 5-year survival (22% vs 26%; P ¼ 0.002) compared with patients with resection alone. When matched for stage, the overall survival was similar regardless of adjuvant therapy. It is noteworthy that of all patients with resected invasive IPMN 45 (46%) recurred, and there was no association between receiving adjuvant treatment and developing recurrence. The 19 recurrences treated by chemotherapy (2 with concurrent radiation) did not have a survival benefit compared with patients who received no further treatment following recurrence, indicating ineffective salvage options following recurrence. According to a SEER analysis of 972 patients with resected IPMN during 1998-2007, 31.8% were identified as having received adjuvant radiation.23 Because of the nature of the SEER database, there is no information on margin status, on radiation dose, or on the use of concurrent or adjuvant chemotherapy. In this SEER analysis, median survival did not differ between patients who received adjuvant radiation
Intraductal papillary mucinous neoplasm and patients who received resection alone (23.5 months in both groups; P ¼ 0.23). In subgroup analysis, however, there appears to be cause-specific survival benefit to adjuvant radiation in patients with positive nodes, particularly in T3T4 patients. Taken together, these studies do not support broad application of adjuvant treatment for all resected IPMN. However, there is some evidence for the use of adjuvant chemoradiation in a select group of patients; that is, patients with lymph node involvement, positive surgical margins, or concerning histopathologic subtypes. Although randomized evidence will be difficult to efficiently achieve, cautious interpretation of observational studies will help us further refine management of this growing cohort of patients.
Summary Recommendations IPMNs are relatively new entities that are recognized with increasing frequency. Because of the limited number of cases, prospective clinical trials to identify optimal treatment would be difficult to achieve. Therefore, we are dependent on retrospective studies that have only recently been using similar guidelines regarding classification and histologic grading. In addition, surgical resection techniques, including whether lymph node dissections are performed, may vary across institutions, limiting accurate comparison of surgical complications, morbidities, and recurrence rates. As the field gains more experience with identifying lesions based on presurgical characteristics, such as symptoms, imaging, and cyst fluid analysis, there will be improved delineation of those lesions that are at high risk for malignancy, that is, those that warrant resection, while avoiding unnecessary surgeries in those patients in whom lesions can be safely observed. Furthermore, the benefit of adjuvant therapy is as yet unknown, as adjuvant therapy has only been applied in selected patients with perhaps worse baseline features. Ongoing careful study and discussion are needed to identify the patients whom adjuvant radiation would benefit.
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83 8. Swartz MJ, Hsu CC, Pawlik TM: Adjuvant chemoradiotherapy after pancreatic resection for invasive carcinoma associated with intraductal papillary mucinous neoplasm of the pancreas. Int J Radiat Oncol Biol Phys 76:839-844, 2010 9. Salvia R, Fernandez-del Castillo C, Bassi C: Main-duct intraductal papillary mucinous neoplasms of the pancreas: Clinical predictors of malignancy and long-term survival following resection. Ann Surg 239:678-685, 2004 [discussion 685-677] 10. Sohn TA, Yeo CJ, Cameron JL: Intraductal papillary mucinous neoplasms of the pancreas: An updated experience. Ann Surg 239:788-797, 2004 [discussion 797-789] 11. Chari ST, Yadav D, Smyrk TC: Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas. Gastroenterology 123:1500-1507, 2002 12. Alexander BM, Fernandez-Del Castillo C, Ryan DP: Intraductal papillary mucinous adenocarcinoma of the pancreas: Clinical outcomes, prognostic factors, and the role of adjuvant therapy. Gastrointest Cancer Res 4:116-121, 2011 13. Mino-Kenudson M, Fernandez-del Castillo C, Baba Y: Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. Gut 60:1712-1720, 2011 14. Tanaka M, Fernandez-del Castillo C, Adsay V: International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12:183-197, 2012 15. Distler M, Kersting S, Niedergethmann M: Pathohistological subtype predicts survival in patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg 258:324-330, 2013 16. Turrini O, Waters JA, Schnelldorfer T: Invasive intraductal papillary mucinous neoplasm: Predictors of survival and role of adjuvant therapy. HPB (Oxford) 12:447-455, 2010 17. Azar C, Van de Stadt J, Rickaert F: Intraductal papillary mucinous tumours of the pancreas. Clinical and therapeutic issues in 32 patients. Gut 39:457-464, 1996 18. Schmidt CM, White PB, Waters JA: Intraductal papillary mucinous neoplasms: Predictors of malignant and invasive pathology. Ann Surg 246:644-651, 2007 [discussion 651-644] 19. Jang JY, Kim SW, Lee SE: Treatment guidelines for branch duct type intraductal papillary mucinous neoplasms of the pancreas: When can we operate or observe? Ann Surg Oncol 15:199-205, 2008 20. Sawai Y, Yamao K, Bhatia V: Development of pancreatic cancers during long-term follow-up of side-branch intraductal papillary mucinous neoplasms. Endoscopy 42:1077-1084, 2010 21. Levy P, Jouannaud V, O'Toole D: Natural history of intraductal papillary mucinous tumors of the pancreas: Actuarial risk of malignancy. Clin Gastroenterol Hepatol 4:460-468, 2006 22. Spinelli KS, Fromwiller TE, Daniel RA: Cystic pancreatic neoplasms: Observe or operate. Ann Surg 239:651-657, 2004 [discussion 657-659] 23. Worni M, Akushevich I, Gloor B: Adjuvant radiotherapy in the treatment of invasive intraductal papillary mucinous neoplasm of the pancreas: An analysis of the surveillance, epidemiology, and end results registry. Ann Surg Oncol 19:1316-1323, 2012 24. Pitman MB, Yaeger KA, Brugge WR: Prospective analysis of atypical epithelial cells as a high-risk cytologic feature for malignancy in pancreatic cysts. Cancer Cytopathol 121:29-36, 2013 25. D'Angelica M, Brennan MF, Suriawinata AA: Intraductal papillary mucinous neoplasms of the pancreas: An analysis of clinicopathologic features and outcome. Ann Surg 239:400-408, 2004 26. Salvia R, Partelli S, Crippa S: Intraductal papillary mucinous neoplasms of the pancreas with multifocal involvement of branch ducts. Am J Surg 198:709-714, 2009 27. Turrini O, Schmidt CM, Pitt HA: Side-branch intraductal papillary mucinous neoplasms of the pancreatic head/uncinate: Resection or enucleation? HPB (Oxford) 13:126-131, 2011 28. Shimizu Y, Yamaue H, Maguchi H: Predictors of malignancy in intraductal papillary mucinous neoplasm of the pancreas: Analysis of 310 pancreatic resection patients at multiple high-volume centers. Pancreas 42:883-888, 2013 29. Thosani N, Dasari CS, Bhutani MS: Molecular pathogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreas 39:1129-1133, 2010
84 30. Satoh K, Shimosegawa T, Moriizumi S: K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas. Pancreas 12:362-368, 1996 31. Kitago M, Ueda M, Aiura K: Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas. Int J Cancer 110:177-182, 2004 32. Yoshizawa K, Nagai H, Sakurai S: Clonality and K-ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas. Virchows Arch 441:437-443, 2002 33. Wu J, Matthaei H, Maitra A: Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 3:92ra66, 2011 34. Tseng JF, Warshaw AL, Sahani DV: Serous cystadenoma of the pancreas: Tumor growth rates and recommendations for treatment. Ann Surg 242:413-419, 2005 [discussion 419-421] 35. Wu J, Jiao Y, Dal Molin M: Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitindependent pathways. Proc Natl Acad Sci U S A 108:21188-21193, 2011 36. Furukawa T, Fujisaki R, Yoshida Y: Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Mod Pathol 18:1034-1042, 2005 37. Sessa F, Solcia E, Capella C: 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 425:357-367, 1994 38. Tang ZH, Zou SQ, Hao YH: The relationship between loss expression of DPC4/Smad4 gene and carcinogenesis of pancreatobiliary carcinoma. Hepatobiliary Pancreat Dis Int 1:624-629, 2002 39. Iacobuzio-Donahue CA, Wilentz RE, Argani P: Dpc4 protein in mucinous cystic neoplasms of the pancreas: Frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24:1544-1548, 2000 40. Ohuchida K, Mizumoto K, Fujita H: Sonic Hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: Clinical implications of mRNA levels in pancreatic juice. J Pathol 210:42-48, 2006 41. Sato N, Goggins M: The role of epigenetic alterations in pancreatic cancer. J Hepatobiliary Pancreat Surg 13:286-295, 2006 42. House MG, Guo M, Iacobuzio-Donahue C: Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Carcinogenesis 24:193-198, 2003 43. Genevay M, Mino-Kenudson M, Yaeger K: Cytology adds value to imaging studies for risk assessment of malignancy in pancreatic mucinous cysts. Ann Surg 254:977-983, 2011 44. Kubo H, Chijiiwa Y, Akahoshi K: Intraductal papillary-mucinous tumors of the pancreas: Differential diagnosis between benign and malignant tumors by endoscopic ultrasonography. Am J Gastroenterol 96: 1429-1434, 2001 45. Sahani DV, Lin DJ, Venkatesan AM: Multidisciplinary approach to diagnosis and management of intraductal papillary mucinous neoplasms of the pancreas. Clin Gastroenterol Hepatol 7:259-269, 2009 46. Fritz S, Klauss M, Bergmann F: Small (Sendai negative) branch-duct IPMNs: Not harmless. Ann Surg 256:313-320, 2012
J.Y. Chin, M.B. Pitman, and T.S. Hong 47. Correa-Gallego C, Ferrone CR, Thayer SP: Incidental pancreatic cysts: Do we really know what we are watching? Pancreatology 10:144-150, 2010 48. Maker AV, Katabi N, Gonen M: Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas. Ann Surg Oncol 18:199-206, 2011 49. Brugge WR, Lewandrowski K, Lee-Lewandrowski E: Diagnosis of pancreatic cystic neoplasms: A report of the cooperative pancreatic cyst study. Gastroenterology 126:1330-1336, 2004 50. Cizginer S, Turner BG, Bilge AR: Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas 40:1024-1028, 2011 51. Pitman MB: Revised international consensus guidelines for the management of patients with mucinous cysts. Cancer Cytopathol 120:361-365, 2012 52. Schonleben F, Allendorf JD, Qiu W: Mutational analyses of multiple oncogenic pathways in intraductal papillary mucinous neoplasms of the pancreas. Pancreas 36:168-172, 2008 53. Okabayashi T, Shima Y, Kosaki T: Invasive carcinoma derived from branch duct-type IPMN may be a more aggressive neoplasm than that derived from main duct-type IPMN. Oncol Lett 5:1819-1825, 2013 54. Habbe N, Koorstra JB, Mendell JT: MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 8:340-346, 2009 55. Nakahara O, Takamori H, Iwatsuki M: Carcinogenesis of intraductal papillary mucinous neoplasm of the pancreas: Loss of microRNA-101 promotes overexpression of histone methyltransferase EZH2. Ann Surg Oncol 19(suppl 3):S565-S571, 2012 56. Lubezky N, Loewenstein S, Ben-Haim M: MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas. Surgery 153:663-672, 2013 57. Lee CJ, Scheiman J, Anderson MA: Risk of malignancy in resected cystic tumors of the pancreas o or ¼3 cm in size: Is it safe to observe asymptomatic patients? A multi-institutional report. J Gastrointest Surg 12:234-242, 2008 58. Lafemina J, Katabi N, Klimstra D: Malignant progression in IPMN: A cohort analysis of patients initially selected for resection or observation. Ann Surg Oncol 20:440-447, 2013 59. Anand N, Sampath K, Wu BU: Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: A metaanalysis. Clin Gastroenterol Hepatol 11:913-921, 2013 60. Jang JY, Kim SW, Ahn YJ: Multicenter analysis of clinicopathologic features of intraductal papillary mucinous tumor of the pancreas: Is it possible to predict the malignancy before surgery? Ann Surg Oncol 12:124-132, 2005 61. Maire F, Hammel P, Terris B: Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma. Gut 51:717-722, 2002 62. Schnelldorfer T, Sarr MG, Nagorney DM: Experience with 208 resections for intraductal papillary mucinous neoplasm of the pancreas. Arch Surg 143:639-646, 2008 [discussion 646] 63. Poultsides GA, Reddy S, Cameron JL: Histopathologic basis for the favorable survival after resection of intraductal papillary mucinous neoplasm-associated invasive adenocarcinoma of the pancreas. Ann Surg 251:470-476, 2010 64. Lewis R, Drebin JA, Callery MP: A contemporary analysis of survival for resected pancreatic ductal adenocarcinoma. HPB (Oxford) 15:49-60, 2013
Introduction
V
arious names have been used to describe intraductal papillary mucinous neoplasms (IPMNs) since Ohashi1 published 4 cases of mucinous neoplasms of the pancreas leading to ectasia of the pancreatic duct system in 1982. In 1996, the World Health Organization (WHO) classified cystic mucinproducing pancreatic neoplasms under intraductal papillary mucinous tumor (renamed neoplasm in 2006) and mucinous cystic neoplasm (MCN). IPMNs are defined as mucinproducing cystic pancreatic neoplasms with intraductal papillary projections of tall columnar epithelium, without subepithelial ovarian-type stroma, which distinguishes them from MCNs. Originally thought to be a rare tumor, IPMNs are now recognized to be more frequent entities based on autopsy and surgical series and currently constitute approximately 20%50% of resected cystic pancreatic tumors.2-4 Likely, some of the
*
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. †Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. The authors declare no conflict of interest. Address reprint requests to Theodore S. Hong, MD, Department of Radiation Oncology, Massachusetts General Hospital, Cox Building-3, 100 Blossom St, Boston, MA 02114. E-mail: [email protected]
1053-4296/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semradonc.2013.11.005
apparent increase in IPMN incidence is because of increased incidental detection on imaging.5 It is estimated that at least 2% of the general population have pancreatic cysts, with a strong correlation to age; for example, in patients older than 80 years, 8.7% of patients had pancreatic cysts in an institutional series.6 Using magnetic resonance imaging (MRI), the prevalence of pancreatic cysts has been estimated to be as high as 13.5%.7 IPMNs range from premalignant intraductal lesions to malignant neoplasms with invasive carcinoma. Indeed, 20%50% of resected IPMNs have an invasive component. Although 10-year disease-specific survival for resected, noninvasive IPMNs is greater than 95%, invasive cancers have a 5-year overall survival of 36%-70%.8-11 Overall, patients with invasive IPMN appear to present at an earlier stage than those with classic pancreatic ductal adenocarcinoma, and this is likely a reflection of the natural history of the disease, in which larger cystic lesions may be apparent on imaging or cause clinical symptoms that prompt imaging.8,12 In a series of resected IPMNs at the Massachusetts General Hospital (MGH), 30% of patients with invasive IPMN presented with nodal involvement compared with approximately 70% in patients with classic pancreatic ductal adenocarcinoma.4 Similarly, in a surgical series from Johns Hopkins University, 64% of patients presented with stage II disease.8 Although overall mortality for resected invasive IPMN is better 77
J.Y. Chin, M.B. Pitman, and T.S. Hong
78 than in conventional pancreatic ductal carcinoma (hazard ratio [HR] ¼ 0.58, 95% CI: 0.39-0.86), it appears that among nodepositive patients, there is no significant difference between clinical outcomes in invasive IPMN and ductal adenocarcinoma (HR ¼ 0.89, 95% CI: 0.52-1.50).13 Therefore, at least some of the improved outcomes observed in IPMN compared with conventional adenocarcinoma may be because of earlier stage at presentation; that is, smaller size and a decreased incidence of nodal involvement.
Classification Location IPMNs are classified preoperatively by imaging according to the pancreatic ducts involved: the main duct (MD-IPMN), the branch ducts (BD-IPMN), or both (mixed or combined type). Identifying the type of IPMN has implications on prognosis and, therefore, management, as MD-IPMNs have a higher risk of malignancy. MD-IPMN typically leads to marked dilation that can often be seen by computed tomography (CT) imaging or by magnetic resonance cholangiopancreatography (MRCP). More invasive techniques, such as endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreatography (ERCP) with or without balloon catheter, intraductal ultrasound, and peroral pancreatoscopy, can also be used to assess MD involvement (discussed later). BD-IPMNs typically involve only 1 part of the pancreas but are multifocal in up to 30% of patients. The risk of malignancy in BD-IPMN is stratified by imaging features and the results of cytologic analysis of the cyst fluid.14 Imaging that demonstrates both a markedly dilated MD and BD cysts is classified as combined-type IPMNs.
Histopathologic Classification Histologic subtyping of IPMNs is a paramount step in prognostication. IPMNs can be subclassified into intestinal, pancreatobiliary, oncocytic, and gastric subtypes by morphologic patterns based on histology and mucin expression by immunohistochemical analysis. MD-IPMNs are typically intestinal-type and rarely pancreatobiliary and oncocytic subtypes, whereas BD-IPMNs are most commonly gastric subtype. Invasive carcinomas arising in pancreatobiliary subtypes have a particularly poor prognosis and are associated with high invasive rates (90.2%), high recurrence rates (70.7% even after R0 resection), and 5-year survival rates (35.6%) approaching that of conventional pancreatic ductal adenocarcinoma.15 The best prognosis is associated with invasive carcinomas arising from the intestinal subtype of IPMN because these are usually mucinous (colloid) carcinomas in contrast to the tubular carcinomas that generally arise from the other subtypes. In a surgical series at MGH, tubular histology was associated with higher rates of perineural invasion and a trend toward higher rates of advanced tumor stage and lymph node involvement compared with colloid and oncocytic tumors.13 In fact, the prognosis of tumors with tubular histology approached that of conventional ductal adenocarcinoma in this surgical series.
The degree of dysplasia, graded histologically, is also correlated with prognosis. In a review of 136 resected IPMNs at Johns Hopkins, the 5-year overall survival of patients with invasive IPMN was 43% compared with 77% for patients with noninvasive IPMNs.10 Approximately 20%-30% of all resected IPMNs demonstrated invasion.8,16,17 Most series of surgically resected IPMNs show increased rates of malignancy in MDIPMN compared with BD-IPMN, although there is some ambiguity in the literature regarding rates of invasive disease, as histology nomenclature has shifted in the last 2 decades. Typically, 50%-90% of MD-IPMNs are identified histologically as malignant (high-grade dysplasia, also known as carcinoma in situ or invasion), with approximately half to two-thirds of those cases appearing to be invasive. In contrast, BD-IPMNs demonstrate such high-grade features in 20%-40% of cases.18-20 Even in noninvasive IPMNs, there is a 10% recurrence rate following partial pancreatic resection with negative margins, suggesting the insidious nature of IPMNs; in contrast, MCNs are solitary cysts and do not recur after complete resection. The trajectory from noninvasive, premalignant IPMN to invasive, malignant transformation is not clear. It is generally believed to occur over 5-7 years although there are scant data to support this.10,21 In a retrospective series, which attempted to understand the natural progression of IPMNs, it was estimated that 63% of MD-IPMNs progressed to high-grade dysplasia or invasive carcinoma within 5 years.21 In contrast, it was estimated that 10%-40% of BD-IPMNs progressed over 5 years, with invasive carcinoma developing in approximately 20% of those patients over 10 years.22 This uncertainty is complicated because of the difficulty in distinguishing between noninvasive and invasive IPMNs in the preoperative setting. In a recent retrospective series, invasive IPMN was diagnosed correctly in 68% of patients who underwent preoperative biopsies. Furthermore, 20% of patients with noninvasive disease seen on resection were initially misdiagnosed with invasive IPMN.23 However, the management goal should be to resect IPMN with high-grade (premalignant) dysplasia, as this offers the patient the best prognosis. Using imaging characteristics coupled with cytologic analysis of the cells shed into the cyst fluid offers the best diagnostic tests to detect IPMNs at this stage and before high-risk imaging features that generally correlate with invasive disease.24
Prognostic Features Prognostic factors for malignancy include higher stage,12 nodal metastases,12,16,25,26 vascular invasion,16,25 positive surgical margins,10,27 perineural invasion,12,16 histology subtype,13,15 and recently, size of mural nodules.28 For example, in a Surveillance, Epidemiology, and End Results (SEER) analysis, lymph node–positive patients with resected IMPN showed a 5year overall survival rate of 12% compared with 42% in nodenegative patients.23
Molecular Pathogenesis There has been a significant amount of research conducted on the pathogenesis of IPMN in the past 2 decades, with the goal of identifying a sufficiently specific molecular marker for high-
Intraductal papillary mucinous neoplasm grade premalignant neoplasms, for example, identification of premalignant intraductal lesions before invasion and malignant transformation.29 To date, however, no molecular alterations have met this goal to qualify as a clinically useful test for preoperative diagnosis and treatment. Currently, KRAS and GNAS mutations are exclusively being used in molecular tests of aspirated cyst fluid. KRAS codes for a guanosine triphosphate–binding protein, which becomes upregulated from point mutations primarily on codon 12, thus affecting many different downstream intracellular signaling cascades. KRAS is a commonly mutated gene in pancreatic cancer, including IPMNs.30 In fact, the very high frequency of KRAS mutations in IPMNs suggests that this mutation is a near-essential event for the development of this neoplasm. In addition, the frequency of KRAS mutations increases with grade, with distinct mutations noted in different parts of multiple BD-IPMNs as well as different parts of combined-type IPMNs, findings that support the hypothesis that IPMNs are multicentric tumors.31 A study of cellular clonality and KRAS mutations also suggests that IPMNs arise from polyclonal epithelia, which are replaced with monoclonal cells as transformation occurs along the adenoma-carcinoma spectrum.32 Unfortunately, KRAS mutations are present in both premalignant and malignant tumors, and thus, analysis of these mutations does not provide a specific molecular marker for determining the grade of premalignant tumors or distinguishing high-grade dysplastic tumors from invasive tumors.30 GNAS is an oncogene that becomes mutated on codon 201 early during the development of IPMNs.33 This mutation appears to be unique to IPMN, designating it a molecular marker that distinguishes it from serous cystadenoma (SCA) and MCN, which are very important preoperative distinctions that affect patient management. SCA are benign tumors that do not need resection unless symptomatic or large,34 and all MCNs are resected regardless of grade because of the ease of the usual distal pancreatectomy relative to the stress and cost of life-long follow-up of a typical middle-aged woman affected by this neoplasm. Like KRAS, however, GNAS mutations do not distinguish the grade of an IPMN or the noninvasive from invasive neoplasms. RNF43, a gene encoding for a protein with intrinsic ubiquitin ligase activity on chromosome 17, has recently been noted to be inactivated in mucinous cysts (both IPMN and MCN) compared with nonmucinous cysts (SCA and solid pseudopapillary neoplasms). Therefore, it is an effective preoperative marker in some instances, particularly for the distinction between macrocystic SCA and mucinous cysts, which are difficult to distinguish by imaging studies.35 Mutation in TP53, a gene encoding for a tumor suppressor protein that affects the expression of many genes including those involved in cell cycle arrest, DNA repair, and apoptosis has been shown to be associated with IPMNs with high-grade dysplasia, but the detection of this mutated gene is insufficiently sensitive and specific to make it a useful preoperative marker for surgical management.30,36,37 Although the genetic deletion of SMAD4/DPC4 in the region of chromosome 18q is considered an early genetic change in conventional pancreatic ductal carcinoma and thus a useful marker for
79 distinguishing benign from malignant ductal epithelium by immunohistochemical staining,38 it is a gene that is retained in IPMN regardless of grade. Consequently, it is suggested that the inactivation of this gene is a late event in the development of malignant IPMNs.39 Other genetic mutations have been implicated in the development of IPMN. Sonic Hedgehog is a gene involved in the differentiation of gastric epithelia of human adults, which is misexpressed in pancreatic adenocarcinoma and intraepithelial neoplasia, as well as in the early development of IPMN.40 The CDKN2A-p16-MTS1 gene pathway associated with cyclindependent kinase inhibition has been shown to be inactivated in IPMNs with both low-grade and high-grade dysplasia.36 Hypermethylation of genes associated with cell cycle control (including p16, p73 and, APC genes), DNA repair (MGMT and hMLH1), and cell adhesion (E-cadherin) are more often found in malignant, invasive IPMNs compared with premalignant, noninvasive tumors.41,42 Although the study of molecular pathways in the pathogenesis of IPMNs is fruitful, none of the information thus far can replace the sensitivity and specificity of cytologic analysis of the cyst fluid for the detection of highgrade epithelial atypia as a marker for at least high-grade dysplasia.43
Preoperative Diagnosis and Management Imaging Cystic pancreatic lesions, including IPMNs, are found on imaging that is often performed for unrelated reasons. The location and degree of duct dilation can be seen on CT and, in our institution, a dedicated pancreatic protocol is used for improved detection of ductal abnormalities (Fig. 1). Mucinous globules are often seen and may appear as filling defects in the duct system. Serial sectioning of the entire pancreas by CT is useful for determining the full extent of the disease. Staging should include imaging of the chest and liver, the most common sites of distant metastases for invasive disease. High-risk features of an IPMN on imaging include MD involvement, main pancreatic duct dilation 410 mm, the presence of mural nodules, and dilation of the biliary tree. MRCP may sometimes be helpful in visualizing ductal communication with the cyst, though thin-slice CT and multiplanar reconstructions can often provide similar information as MRCP. However, MRCP offers improved morphologic detection of small (o3 cm) lesions and of small mural nodules. When CT or MRCP or both are equivocal or when confirmation of malignancy is required before surgery, EUS can be of high diagnostic value, with a 92% accuracy in differentiating IPMN from other cystic pancreatic lesions,44 though this is operator dependent. With endoscopy, mucus can be seen in one-third of patients exuding from a bulging papilla of Vater when the MD is involved. EUS is also useful in showing internal septae, mural nodules, solid masses, vascular invasion, lymph node involvement, and wall thickness.44,45
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Figure 1 Axial CT of a patient with an IPMN in the pancreatic head (A, solid arrow) causing mild ductal dilatation (B). CT angiography (C) can be useful in determining lesion location and resectability. IPMNs typically appear cystic and fluid filled compared with conventional pancreatic ductal adenocarcinoma (D, open arrow), which appear denser and more solid on CT imaging. Panels (A-C) are of the same patient; (B) A coronal CT reconstruction showing the pancreatic duct. (D) A coronal CT of a different patient.
EUS has the additional advantage of being able to obtain cyst fluid for cytology analysis or a biopsy specimen or both. ERCP often reveals a dilated main pancreatic duct, with or without mucinous globules, mural nodules, or areas of invasion. ERCP is also useful in determining ductal communication and confirming the diagnosis of IPMN as MCNs do not typically communicate with the ductal system. The presence of mucin or papillary tumor growth or both may preclude full visualization of the ductal system during ERCP, even with the aid of a contrast agent. It should be noted that despite available sophisticated imaging, IPMN type has been misclassified in 20%-40% of reported surgical series. A series from Germany determined that 58.9% of preoperative classifications turned out to be correct on final histology, with most misclassifications being BD-IPMNs preoperatively in whom MD components were identified postoperatively.46 Similarly, in a surgical series of presumed BD-IPMN based on preoperative workup, 20% were found to have MD involvement,47 indicating the difficulty of classification.
dysplastic IPMN.48 CEA is the most reliable and accurate marker of a mucinous cyst; other tumor markers such as CA 15-3, CA 19-9, CA 125, and CA 72.4 do not offer more diagnostic value than CEA alone.49,50 Amylase has less diagnostic value than CEA on a routine basis, and although high amylase levels are noted in IPMN, consistent with communication with the pancreatic ductal system, amylase levels do not distinguish between IPMN and MCN because some MCNs also demonstrate high amylase levels.50 Unfortunately, CEA level is not a reliable marker to distinguish benign from invasive disease. Cytology can provide important diagnostic information. Although the finding of a “positive” (ie, diagnostically malignant) cytology requires both adequate quantity and quality of viable cells for analysis, the category of “high-grade atypia” may also be useful in risk assessment (Fig. 2). This latter category includes aggregates of cells and small clusters or crowded, molded cells and single epithelial cells showing an increased nuclear-to-cytoplasmic ratio, irregular nuclear membranes, or abnormal chromatin pattern with or without visible intracytoplasmic mucin.
Cyst Fluid Analysis Cyst fluid analysis includes testing for mucin, carcinoembryonic antigen (CEA), and amylase. Mucin and CEA are found in mucinous neoplasms. Relatively higher levels of MUC2 and MUC4 have been reported in cyst fluid of
Molecular Markers Molecular markers KRAS and GNAS are useful in supporting classification of a cyst as mucinous, as not all mucinous cysts have an elevated CEA. However, these markers cannot
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Figure 2 Cytology of an IPMN with invasive carcinoma (A). Compared with the cytology of the typical conventional ductal adenocarcinoma (B), adenocarcinoma arising in an IPMN is often less overt and obvious on cytology. The cluster of cells (A) shows high-grade atypia similar to what is seen in premalignant IPMN with high-grade dysplasia. The extracellular mucin on the right and the necrotic cyst debris on the center-left position can be noted. In contrast, FNAs of solid mass lesions produce cellular smears composed of cell groups in variable quantity as illustrated in (B). The overt malignant features illustrated include very large cells, high nuclear-to-cytoplasmic ratio, large nuclei with coarse chromatin, irregular nuclear membranes, prominent nucleoli, and mitotic activity, which make the cytologic diagnosis of adenocarcinoma straight forward even on scantily cellular smears.
distinguish between low-grade and high-grade dysplasia, and in addition, 4% of IPMNs have neither mutation.51 Approximately 50%-80% of IPMNs also have point mutations in p53. Loss of heterozygosity of p16 is rarer in IPMNs than in classic pancreatic ductal adenocarcinomas, though a series reported that invasive IPMNs had a higher p16 mutation rate than benign IPMNs.52 Other genetic changes implicated in the pathogenesis of invasive IPMN are increased expression of cyclooxygenase-2, matrix metalloproteinase-7, proliferating cell nuclear antigen, and vascular endothelial growth factor; upregulation of mesothelin; increased telomerase activity; and increased levels of the tumor suppressor gene SMAD4.53 Recently, several groups have demonstrated differential expression of microRNAs in invasive IPMN.54-56 Two of these, mir-155 and mir-21, were originally identified in pancreatic adenocarcinomas. Interestingly, multiple groups have shown that the levels of both mir-155 and mir-21 were correlated with invasiveness; that is, these microRNAs are upregulated in invasive disease relative to noninvasive disease and in noninvasive disease relative to normal pancreatic tissue. If validated, they may prove to be useful as biomarkers, particularly if they are also found in pancreatic cyst fluid that can be used in preoperative decision making.
Management The management guidelines for IPMN outlined by the 2005 and 2012 International Consensus Guidelines recommend resection of lesions that are at high risk for malignancy and for symptomatic management.14 Before the 1990s, surgical resection was recommended for all mucin-producing pancreatic neoplasms. The 2012 guidelines of multidisciplinary experts recognized the different propensities for malignancy of MD and mixed type IPMNs compared with the lower malignant potential of the BD-IPMN subtypes. Therefore, oncologic resection is recommended for MD-IPMN regardless of size and location in the pancreas (ie, head or tail), preferably with
lymphadenectomy, in patients with a reasonable life expectancy and in whom resection can be achieved safely. An attempt is made to achieve negative surgical margins, and positive surgical margins warrant re-resection. In contrast, there appears to be a subset of BD-IPMNs in which clinical surveillance may be indicated, given the low likelihood of malignancy. The 2012 guidelines indicate resection for BD-IPMNs based on the presence of worrisome features (cysts Z3 cm, thickened cyst walls, nonenhanced mural nodules, MD size 5-9 mm, or an abrupt change in MD caliber associated with distal pancreatic atrophy and lymphadenopathy), high-risk stigmata (MD 410 mm and an enhanced solid component), and suspicious or positive cytology.14 However, even in the absence of mural nodules, invasive IPMNs have been reported in up to 15% of BD-IPMNs in some surgical series,18,19,46 indicating that the identification of benign disease can be difficult. Another series of asymptomatic patients with pancreatic cysts less than 3 cm in size, with no identifiable malignancy risks on imaging, demonstrated a 3.3% occult malignancy rate.57 Finally, invasive disease was identified in 10.5% of patients with BD-IPMNs who were initially surveilled at a large referral center. Overall, 57% of the initially surveilled group ultimately had resection with a median of 40 months of follow-up, primarily for radiographic or endoscopic changes (55%), followed by concern of premalignant condition and suspicious cytology.58 A recent report suggests that invasive BD-IPMNs have unfavorable clinical outcomes compared with invasive MD-IPMNs,53 although the underlying biology of this observation is unclear. Furthermore, it is not clear that preoperative “worrisome features” carry equal weighting when evaluating the malignant potential of a cyst. In a recent meta-analysis, cyst size in particular was considered to be a significant risk factor for malignancy (OR ¼ 62.4; 95% CI: 30.8-126.3), whereas presence of mural nodule (OR ¼ 9.3; 95% CI: 5.3-16.1), pancreatic duct dilation (OR ¼ 7.27; 95% CI: 3.0-17.4), and
82 symptoms (OR ¼ 1.6; 95% CI: 1.0-2.6) were weaker predictors for malignancy.59 Therefore, further studies on malignancy risk are needed to more carefully design algorithms for management. Total pancreatectomy is not routinely recommended because of the significant complication rate and potential mortality associated with the procedure, as well as long-term side effects. It is estimated that 2.8% of all patients with IPMN in a surgical series from Memorial Sloan-Kettering Cancer Center developed carcinoma in a region remote from the initially identified cyst.58 However, in several surgical series, total pancreatectomy was not associated with lower recurrence rates compared with partial resection,60,61 thus suggesting that any benefit to resecting potential microscopic disease at either the surgical margins or at metachronous sites is offset by the significant increase in morbidity. Similarly, it is controversial whether re-resection is warranted for benign IPMNs, as there are case reports of malignant transformation of recurrent IPMN in the remnant pancreas following resection of noninvasive IPMN with negative surgical margins.10,62 Some speculate that these apparent recurrences actually occurred in the setting of undiagnosed multifocal disease. Therefore, in cases of multifocal disease, the surgeon may choose to excise the dominant lesion and follow less-concerning lesions with surveillance imaging.10
Role of Radiotherapy Determining the optimal strategy following resection for invasive IPMN is subject to discussion, as is adjuvant therapy for pancreatic carcinomas in general. Because of the relative rarity of the disease, there is no randomized evidence regarding adjuvant therapy in malignant (invasive) IPMN. Most commonly, clinicians extend results from trials of pancreatic ductal adenocarcinoma to the management of invasive IPMNs, which may not be applicable. Complicating the discussion, is the relatively sparse data comparing, stage for stage, ductal adenocarcinoma arising from an IPMN with “classic” pancreatic adenocarcinoma arising from intraepithelial neoplasia.63,64 It is now increasingly recognized that invasive IPMN is distinct from classic pancreatic adenocarcinoma, and therefore, extrapolation from those data may not be justified. There are some retrospective, institutional data regarding adjuvant radiation in invasive disease arising in the setting of IPMN. In a series at MGH, 44 patients who had resection for invasive disease were observed with a median follow-up of 19 months.12 Of these patients, 61% had resection alone, whereas 39% had concurrent chemoradiation. The median radiation dose was 50.4 Gy, and most (65%) patients received concurrent infusional 5-fluorouracil. Overall, 5 patients had additional 4-6 months of adjuvant chemotherapy. In this study, patients who received adjuvant chemoradiation therapy (CRT) were more likely to be at a higher stage (P ¼ 0.035) and have positive nodes (P ¼ 0.024) compared with patients undergoing resection alone. Overall, as a group, patients receiving adjuvant CRT had no overall survival benefit compared with patients undergoing resection alone; however, when stratified
J.Y. Chin, M.B. Pitman, and T.S. Hong for node-positive disease, cancer-specific survival and overall survival were improved in the adjuvant group (cancer-specific survival, HR ¼ 0.10; 95% CI: 0.018-0.59 and overall survival, HR ¼ 0.13; 95% CI: 0.029-0.56). However, it is likely that some patients were not able to receive adjuvant therapy because of disease progression, and therefore, this survivor bias may overestimate the benefit of adjuvant radiation. Interestingly, node-positive patients who completed adjuvant CRT had a survival benefit of 16.5 months compared with patients undergoing resection alone (median survival 3.3 months). It is unclear whether this relatively long median survival time following adjuvant therapy is because of intrinsic biology or the treatment itself or both. Similar results were seen in a series of 70 patients who were evaluated following resection for invasive carcinoma arising from IPMN.8 All but one of these patients had stage I-II disease; 59 were in the head of the pancreas and 11 were in the distal pancreas. The median survival of the patients was 28 months, with a 5-year overall survival of 45%, consistent with other series of invasive IPMN. Of the 70 patients, 40 received adjuvant therapy and were more likely to have positive surgical margins, involved nodes, stage II-III disease, and perineural invasion. Negative prognostic factors for outcome included lymph node involvement, margin positivity, and poor, anaplastic, or undifferentiated tumors. Although the overall survival was not different whether the patients received adjuvant treatment, the authors identified subgroups of patients with improved survival following adjuvant CRT compared with resection alone, that is, patients with positive lymph nodes (relative risk ¼ 0.43; P ¼ 0.047) or with positive margins (P ¼ 0.042). Finally, adjuvant treatment was not found to confer a survival benefit in patients with resected invasive IPMN in a retrospective series from Indiana University and the Mayo Clinic.16 In agreement with the studies mentioned earlier, those patients receiving adjuvant treatment (37 of 98 patients with resected invasive IPMN) tended to have larger size tumors, positive nodes, and positive surgical margins. Perhaps not surprisingly, given the selection bias of patients receiving adjuvant treatment, patients receiving adjuvant treatment had an overall detriment in 5-year survival (22% vs 26%; P ¼ 0.002) compared with patients with resection alone. When matched for stage, the overall survival was similar regardless of adjuvant therapy. It is noteworthy that of all patients with resected invasive IPMN 45 (46%) recurred, and there was no association between receiving adjuvant treatment and developing recurrence. The 19 recurrences treated by chemotherapy (2 with concurrent radiation) did not have a survival benefit compared with patients who received no further treatment following recurrence, indicating ineffective salvage options following recurrence. According to a SEER analysis of 972 patients with resected IPMN during 1998-2007, 31.8% were identified as having received adjuvant radiation.23 Because of the nature of the SEER database, there is no information on margin status, on radiation dose, or on the use of concurrent or adjuvant chemotherapy. In this SEER analysis, median survival did not differ between patients who received adjuvant radiation
Intraductal papillary mucinous neoplasm and patients who received resection alone (23.5 months in both groups; P ¼ 0.23). In subgroup analysis, however, there appears to be cause-specific survival benefit to adjuvant radiation in patients with positive nodes, particularly in T3T4 patients. Taken together, these studies do not support broad application of adjuvant treatment for all resected IPMN. However, there is some evidence for the use of adjuvant chemoradiation in a select group of patients; that is, patients with lymph node involvement, positive surgical margins, or concerning histopathologic subtypes. Although randomized evidence will be difficult to efficiently achieve, cautious interpretation of observational studies will help us further refine management of this growing cohort of patients.
Summary Recommendations IPMNs are relatively new entities that are recognized with increasing frequency. Because of the limited number of cases, prospective clinical trials to identify optimal treatment would be difficult to achieve. Therefore, we are dependent on retrospective studies that have only recently been using similar guidelines regarding classification and histologic grading. In addition, surgical resection techniques, including whether lymph node dissections are performed, may vary across institutions, limiting accurate comparison of surgical complications, morbidities, and recurrence rates. As the field gains more experience with identifying lesions based on presurgical characteristics, such as symptoms, imaging, and cyst fluid analysis, there will be improved delineation of those lesions that are at high risk for malignancy, that is, those that warrant resection, while avoiding unnecessary surgeries in those patients in whom lesions can be safely observed. Furthermore, the benefit of adjuvant therapy is as yet unknown, as adjuvant therapy has only been applied in selected patients with perhaps worse baseline features. Ongoing careful study and discussion are needed to identify the patients whom adjuvant radiation would benefit.
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