In the past, these lesions were variably referred to as mucinous ductal ectasia, intraductal papillomatosis, intraductal adenoma or adenomatosis, intraductal mucin-secreting tumor, and intraductal papillary mucinous tumor. However, the earliest report of this “new” lesion is attributed to Ohashi and Maruyama and was published in the Japanese literature in 1982.68 This report described four malignant lesions associated with the main pancreatic duct and characterized the now well-described copious amounts of mucus that distend and emanate from the ductal system. The authors noted the comparatively better survival of these patients compared to those with classic invasive ductal adenocarcinoma of the pancreas. While many subsequent authors have helped to further characterize the subtleties of IPMN, these initial observations accurately depict typical cases.
In 1996, the WHO first formally recognized IPMN as a distinct entity, establishing criteria for the pathological diagnosis of these lesions.41 Characteristic features include a tall, columnar epithelium with marked mucin production, and cystic transformation of either the main pancreatic duct or one of its side branches (Fig. 58-8). More recent versions of these diagnostic criteria have allowed the stratification of noninvasive IPMNs based on their degree of dysplastic change, and the clear separation of noninvasive IPMN from IPMN with an associated invasive carcinoma.
Histologically, IPMNs are characterized by intraductal proliferation of mucinous cells which form papillae. Secretion of mucin leads to dilatation of the pancreatic ducts (Fig. 58-9). Lesions may be localized, multicentric, or rarely involve the entire ductal system. The proliferation of mucinous cells may involve the main pancreatic duct (main duct type), or be confined to the branch ducts (branch duct type) or show a pattern spanning both areas in a combined type. Three different morphologic patterns of IPMN can be seen.69 Most branch duct type IPMN demonstrate papillae lined by tall columnar cells with basally oriented nuclei and abundant pale mucin. This pattern is also prevalent in the nonpapillary areas of main duct type IPMN and appears similar to the gastric mucosa. Scattered goblet cells are present and stain for MUC2. This pattern is called the gastric-foveolar type. Most main duct type IPMN closely resemble colonic villous adenomas and show molecular characteristics of intestinal differentiation, such that the cells express CDX2 and MUC2.70 These are classified as villous-intestinal type. Their papillae are also positive for MUC5AC. Cancers arising in these IPMN are typically colloid carcinomas (Fig. 58-10). Colloid carcinomas also express CDX2 and MUC2, but not MUC1. A small proportion of IPMN is more complex and lined by cuboidal cells which do not express MUC2 or CDX2. This form is referred to as the pancreatobiliary type. Invasive cancers associated with the pancreatobiliary morphology are usually tubular, with structure similar to ductal adenocarcinoma. The invasive component expresses MUC1, but not MUC2. While both the villous-intestinal and the pancreatobiliary types may be found alongside the gastric-foveolar type, it is however, uncommon to identify both the villous-intestinal and pancreatobiliary type of papillae in the same IPMN.69
Gross photograph of a distal pancreatectomy specimen from a patient with an IPMN with carcinoma in situ. Characteristic features include the mass in direct communication with a markedly dilated main pancreatic duct.
Photomicrograph of a colloid carcinoma within an IPMN. Note the largely acellular nature of these cancers and their abundant mucus production.
IPMNs demonstrate a progressive precursor model of carcinogenesis similar to that seen in colon cancer.71 Tall mucin-producing columnar epithelial cells that remain well differentiated characterize IPMN adenoma (low-grade dysplasia). Little or no dysplasia is present in these lesions. IPMN borderline lesions (moderate grade dysplasia) are described as lesions with moderate epithelial dysplasia, characterized by moderate loss of polarity, changes in nuclear morphology, and pseudopapillary formation (Fig. 58-11). IPMNs with carcinoma-in situ have severe dysplastic changes. These lesions may be papillary or micropapillary, and severely dysplastic lesions may lose the ability to secrete mucin. IPMNs are pathologically similar to pancreatic intraepithelial neoplasia (PanIN). IPMNs, like PanIN, are intraductal lesions that may demonstrate a range of cellular atypia and malignant transformation. However, IPMNs may be distinguished based on their gross visibility and involvement of large ducts. PanIN should be considered a microscopic finding involving ducts less than 5 mm in diameter, while IPMNs are macroscopic findings.72 In addition, IPMNs often express the mucin MUC2, while PanINs usually express MUC1.
Photomicrograph of an IPMN with borderline features. Characteristic features include the tall columnar cells lining the papillary projections of the tumor, moderate dysplastic changes of the epithelium, and varied nuclear morphology.
IPMNs appear also to have distinct molecular events contributing to the clinical and pathological behavior that further distinguish them from lesions in the PanIN–ductal adenocarcinoma sequence. Iacobuzio-Donahue and associates described the intact (normal) expression of the tumor-suppressor gene Dpc4 in the intraductal components of 79 IPMN.73 In contrast, Dpc4 inactivation has been shown to be relatively specific for pancreatic adenocarcinoma, and its persistence in both noninvasive and invasive IPMNs argues that these lesions may arise through a pathway that is distinct from the PanIN–ductal adenocarcinoma. IPMNs also appear to have a significantly lower rate of K-ras and p53 mutations, lesions that are common in ductal adenocarcinoma.74 Fritz and coworkers recently demonstrated that loss of chromosome 5q, 6q, and 11q was significantly higher in IPMN with high-grade dysplasia or invasion compared with ductal adenocarcinoma.75 These data and others suggest that IPMNs are unique pancreatic neoplasms, with a pathogenesis that is distinct from that of the PanIN–ductal adenocarcinoma sequence.
The biologic behavior of IPMNs parallels their classification according to their distribution within the pancreatic ductal system. Main duct type and combined main duct and branch duct type lesions are more likely to present with symptoms, while strictly branch duct type IPMNs are more frequently detected as asymptomatic cystic neoplasms on cross-sectional imaging.76 Pancreatitis is seen more commonly in main duct type IPMN, possibly related to mucous plugging of the ampulla. In a combined experience of the Massachusetts General Hospital and the University of Verona reported by Salvia and colleagues, acute pancreatitis occurred in 23% of 140 patients with main duct variant IPMN.77
Both genders are affected by IPMNs, with a moderate male predominance in some series. Patients with IPMN tend to be older, with a mean age of 65 years, as compared with those having MCN who are predominantly perimenopausal. Similar to the situation with MCN, IPMN patients demonstrated to have a malignancy, a trend toward being older, again suggestive of an adenoma-to-carcinoma sequence of progression and the time necessary to undergo this transformation. Main duct type IPMNs are more likely to demonstrate the development of malignancy. Of note, malignant IPMNs are more likely to present with symptoms typically attributed to ductal adenocarcinoma, such as obstructive jaundice and weight loss.5,77
The development of symptoms more commonly attributed to ductal adenocarcinoma in patients with IPMN may herald the occurrence of carcinoma either synchronously or metachronously in the gland. Several studies have demonstrated the presence of an invasive ductal adenocarcinoma elsewhere in the pancreas, distinct from the location of the cystic neoplasm in up to 10% of IPMN patients.40,78,79 Ingkakul and colleagues recently showed that, in a multivariate analysis, worsening diabetes (odds ratio 15.73 [95% CI: 4.40–56.25]; p < .001), and an abnormal CA 19-9 (odds ratio 3.70 [95% CI: 1.19–11.48]; p = .024) are independent factors predictive of synchronous or metachronous separate ductal adenocarcinoma in patients with IPMN.79 In a report from Memorial Sloan-Kettering, Allen et al sought to characterize those cystic lesions which should be initially resected.40 Asymptomatic cystic neoplasms, less than 2.5 cm in size, without septations or a solid component were followed over time. Eventually, 28 of 369 patients, initially managed conservatively, were operated upon primarily for cyst growth. Malignancy was found in 11 of these 28 patients (38%): three were cystic neuroendocrine tumors, while 8 of 11 were ductal adenocarcinomas. Further review of these eight ductal adenocarcinomas demonstrated that the cancer arose adjacent to the initially discovered cyst. This study demonstrates the need to thoroughly investigate the entire pancreas when electing to observe a cystic neoplasm. In addition, the incidence of extrapancreatic malignancies appears to be higher in patients with IPMN.80,81 The development of colorectal adenomas and carcinomas, Barrett's mucosa and gastric carcinomas appear to be important entities seen in IPMN patients.
CT scanning (with all of its advances up to multidetector imaging) has been the primary method for imaging the pancreas in the past. However, the use of MRI, particularly in combination with MRCP imaging has allowed for more thorough identification of IPMN. IPMNs characteristically appear as cystic masses resulting from dilatation of the main pancreatic duct or side branch ducts. Polypoid projections (mural nodules) into the cystic spaces may be present. Approximately half of IPMNs occur in the pancreatic head, though they may be present anywhere within the pancreas and can diffusely involve the entire gland. Currently MRCP is the modality of choice for defining mural nodules, demonstration of the communication of the cystic neoplasm with the pancreatic ductal system, and evaluating the extent of the pancreatic ductal dilatation.82 Use of MRCP has largely supplanted endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of IPMN, since MRCP is noninvasive, does not require sedation, and does not carry the risks of pancreatitis and perforation which accompany ERCP.
With the increasing emphasis on managing asymptomatic branch duct type IPMN by observation, imaging studies have sought to define features associated with invasive carcinoma by correlating preoperative imaging with pathology obtained by resection. Several imaging features suggestive of the presence of malignancy have been demonstrated, including tumor size (cyst diameter ≥30, 40, or 50 mm), main duct type IPMN, main duct dilatation greater than or equal to 10 or 15 mm, patulous papilla, mural nodules (≥3, 5, or 10 mm in size), presence of biliary ductal dilatation greater than or equal to 15 mm, a solid mass, or occurrence of an area of abnormal attenuation in the surrounding pancreas.82–90 Importantly, a recent report from Verona, Italy by Salvia and colleagues notes that they followed 121 patients with multifocal branch duct IPMN (median diameter of the largest lesion being 1.7 cm) over a 40-month observation period.91 All of the 121 patients remained alive, without surgery, and all remained asymptomatic. Thus, there is clearly a role for conservatism in the management of patients with branch duct IPMNs and no additional worrisome features.
Endoscopic ultrasound (EUS) may provide additional information which may prompt resection or promote a more conservative approach. Ohno et al demonstrated that the finding of a papillary mural nodule or a nodule exhibiting an invasive component on EUS was predictive of malignancy with a sensitivity of 60%, specificity of 93%, and an accuracy of 76%.92 EUS-FNA may also be useful in reinforcing a decision not to resect a branch duct type IPMN, if it is otherwise without features predictive of malignancy. Marie and colleagues found that the combination of a CEA level less than 200 ng/mL and a CA 72.4 level greater than 40 U/mL retrieved from the cystic material of an IPMN together had a 96% negative predictive value for the diagnosis of malignancy.93
The Japan Pancreas Society performed a multi-institutional, retrospective study of 1379 cases of IPMN drawn from 98 of their member programs. The clinicopathologic features of benign IPMN (see Table 58-2) (adenoma [low-grade dysplasia] and borderline lesions [moderate dysplasia]; n = 564) were strikingly different when compared with tumors containing frank adenocarcinoma (n = 445).85 Patients with adenocarcinoma were significantly older (67 vs 65 years, p = .0002) and more frequently symptomatic (49 vs 35%, p < .0001), as compared to the noncarcinoma group. Cancer occurred more commonly in either main duct type or combined-type tumors, as compared to branch duct type neoplasms (60, 65, and 30%, p < .001), respectively. The preoperative imaging of patients who were subsequently found to have adenocarcinoma on pathology, demonstrated a higher incidence (63 vs 28%) and size of mural nodules (12 vs 5 mm) when compared with those who had benign lesions (both p < .0001). Branch duct type tumors with cancer were larger (35 vs 28 mm, p < .0001) than those without cancer.
Based on the data generated in the earlier report, the International Association of Pancreatology convened a consensus conference in Sendai, Japan in 2004. The subsequent guidelines published in 2006, have become a new benchmark for the management of IPMN.14 These guidelines recommend the resection of all IPMN of a main duct type and mixed variants, those showing main pancreatic duct dilatation greater than or equal to 10 mm, as well as those with the presence of mural nodules, or a positive cytology, provided the patients are reasonable candidates for surgery with an acceptable life expectancy. All symptomatic IPMNs were deemed to warrant resection. These recommendations were predicated upon the risk of carcinoma in symptomatic or main duct type lesions. Branch duct IPMNs less than 30 mm in diameter, without evidence of mural nodules or main duct dilatation, were felt to be of low malignant potential and were candidates for careful observation. At follow-up examinations, appearance of symptoms, cyst expansion to greater than 30 mm, detection of positive cytology on FNA, development or identification of mural nodules or main pancreatic duct dilatation (≥6 mm) were deemed indications for resection.
Since the development of the Sendai guidelines, much of the subsequent literature has sought to examine the accuracy of the recommendations, particularly with regard to the observation of asymptomatic branch duct type IPMN. Pelaez-Luna and colleagues identified 147 patients with branch duct type IPMN, of whom 66 underwent resection at diagnosis and 81 were followed over time (of which 11 were resected during the follow-up period).94 Of the patients undergoing resection who demonstrated Sendai consensus guideline indications for surgical therapy, 9/61 (15%) had carcinoma on pathology, whereas none of the 16 patients without consensus indications for resection had malignancy (p = .1). A single guideline indication for resection taken as an indicator of carcinoma had a sensitivity, specificity, positive predictive value, and negative predictive value of 100, 23, 14, and 100%, respectively.
Several studies have suggested that the development of mural nodules is predictive of the risk of developing malignancy, while a progressive dilatation of duct size remains controversial. Schmidt and colleagues identified 103 patients with branch duct type IPMN.95 The mean size of the 20 malignant lesions was 2.0 ± 0.1 cm, while the mean size of the nonmalignant neoplasms was 2.2 ± 0.1 cm, suggesting that size alone is an insufficient indicator of malignancy. In multivariate analysis, only the presence of mural nodules and atypical cytopathology were predictive of the presence of carcinoma. Tanno et al prospectively followed 82 patients with flat lesions within branch duct type IPMN diagnosed by CT or MR and EUS.96 During a median follow-up of 59 months, 9/82 patients (11%) exhibited progressive dilatation of the cystic lesion. Six elected to continue regular screening, while three underwent resection; the IPMNs resected were staged as IPMN-adenoma in two and IPMN-borderline in one. Four patients (5%) developed mural nodules during a median follow-up of 105 months. All four of these individuals were resected, demonstrating IPMN-adenoma in three and carcinoma in situ in the fourth. Sixty-nine of the 82 patients (84%) showed no changes in their dilated branch duct lesions over a median follow-up of 57 months.
A recent study from Kyushu University attempted to determine whether cyst size is predictive of the malignant potential in flat branch duct type IPMN.97 One hundred seventy patients with branch duct type IPMNs without mural nodules were retrospectively identified from their previous 10-year experience. Seventy-three patients underwent resection of their IPMN: 26 patients had lesions less than 30 mm in size, while 47 patients had neoplasms greater than 30 mm in diameter. All of the noninvasive (n = 5) and invasive (n = 1) malignancies were seen in the IPMN of greater than or equal to 30 mm. In a similar report, Salvia and coworkers followed 89 patients with flat branch duct type IPMN less than or equal to 3.5 cm in size for a median time period of 32 months.98 Five patients (5.6%) exhibited an increase in diameter of the cystic lesion, none of which demonstrated carcinoma in the resection specimen pathologically. Clearly, longer follow-up will be needed to determine whether or not clear evidence of carcinoma develops in patients without Sendai consensus guidelines for surgical therapy. As might be anticipated, increasing knowledge and follow-up has raised questions about the universal accuracy of the consensus guidelines.
The majority of studies, particularly those following IPMNs conservatively in a prospective fashion, would suggest that the development of invasive carcinoma in flat branch duct IPMN less than 30 mm in size is unusual. The occurrence of high-risk stigmata (mural nodules, dilated main duct, or positive cytology) clearly have great predictive value for the ultimate finding of malignancy. EUS appears to be an important adjuvant to fully evaluate IPMN patients for the presence of mural nodules, as well as for aspiration of cytologic specimens. Some authorities insist that any lesion which is to be followed conservatively should be examined by EUS at regular intervals. We have tended to use MRI or MRCP for serial surveillance of small (<3 cm) branch duct IPMNs, as this is a noninvasive procedure (as compared to EUS) which avoids radiation exposure (as compared to CT).
Given the excellent survival following resection of IPMN free of an invasive component, every effort must be made to define lesions at risk for the development of carcinoma at the earliest point possible (Fig. 58-12). Schnelldorfer and coworkers have demonstrated that the survival after pancreatectomy of patients with IPMN with invasive adenocarcinoma is equivalent to that of a matched cohort of patients following resection of ductal adenocarcinoma (median survival, 32 vs 21 months; 5-year survival rate, 31 vs 24%; p = .26).99 Other studies have revealed that survival of patients without lymph node involvement and invasive IPMN is quite good, while patients with lymph node involvement and invasive IPMN have equivalent outcomes to patients with lymph node–positive pancreatic ductal adenocarcinoma.5 Despite the poor survival in patients with invasive disease, surgery remains the best opportunity for cure. Swartz et al have recently shown that adjuvant chemoradiotherapy confers a 57% decrease in the relative risk of mortality after pancreaticoduodenectomy for invasive IPMN after adjusting for major confounders.100 This effect was most significant in patients with lymph node metastases or positive surgical margins.
Kaplan-Meier actuarial survival curves comparing 84 patients with noninvasive IPMN to 52 patients with invasive IPMN following pancreatic resection at the Johns Hopkins Hospital (1987–2003). Patients with noninvasive IPMN have a significantly greater survival than those with invasive carcinoma (p < .0001). (Reproduced, with permission, from Sohn TA, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg. 2004;239:788–797.)
Use of the Sendai consensus guidelines means that the preponderance of resections for IPMN will be performed with at least a suspicion of the presence of carcinoma. Targeted pancreatectomies, either pancreaticoduodenectomy or distal pancreatectomy with en bloc splenectomy, have been advocated so as to adhere to oncologic principles of resection. Most centers have advocated the use of frozen-section examination of the pancreatic margin, with attempted clearance of microscopically malignant margins by re-resection and occasional conversion to total pancreatectomy when needed to achieve negative margins. Skip lesions clearly occur, such that a normal resection margin may not be indicative of a lack of neoplasia in the pancreatic remnant. A recent report by Nara et al from Tokyo analyzed 130 consecutive patients undergoing resection for IPMN with frozen-section analysis of the pancreatic margin101. While most initial frozen-section results showed no neoplasia at the margin, 29 patients had additional pancreas resected for “positive” frozen-section results (12 for low or moderate dysplasia, 10 for high-grade dysplasia, 1 for floating cancer cells, and 6 for invasive cancer). Most patients who recurred following re-resection had their recurrence at a distance from the pancreatic margin (peritoneum, liver, and lymph nodes), raising doubt about the true value of re-resection for margins determined to be positive at frozen section. The role of total pancreatectomy to achieve clearance of all dysplastic epithelium, even prophylactic total pancreatectomy, is controversial. Notably, of the 84 patients with noninvasive IPMN described by Sohn and colleagues,5 7 patients developed recurrent disease in the pancreatic remnant. Negative margins at resection do not eliminate the need for chronic surveillance of the pancreatic remnant, perhaps best done by annual MRI/MRCP.