Fig. 5.1
Intraductal papillary mucinous neoplasm (IPMN), intestinal type papillae, with moderate dysplasia (a) and MUC2-positivity (b)
Fig. 5.2
IPMN, pancreatobiliary type papillae, with severe dysplasia (a) and MUC1-positivity (b)
Fig. 5.3
IPMN-branch-duct, gastric type, of the uncinate process, with low-grade dysplasia (a) and MUC5AC-positivity (b)
Fig. 5.4
IPMN-oncocytic type. The papillary proliferations are lined by cells with a finely granular cytoplasm and containing nuclei with prominent nucleoli
Patients with the first type have a good prognosis while those with the second type have a poorer prognosis. In the third type there is frequent involvement of branch ducts; the fourth type is not yet clinically well characterized.
The invasive component, present in approximately one-third of patients, is either a tubular or a mucinous invasive component. The former resembles the conventional ductal carcinoma (Fig. 5.5), while the latter shows features of colloid (mucinous non-cystic) carcinoma (Fig. 5.6). Although MUC2+ intestinal IPMNs can be considered as precursors of MUC2+ mucinous non-cystic carcinoma, characterized by good prognosis, MUC2-/MUC1+ pancreatobiliary IPMNs appear to be closely associated with an aggressive tubular carcinoma [12, 13]. The progression from benign IPMN to malignancy can be radiologically detected, considering either the increase in the diameter of the main duct or the cyst, or the emergence of a mural nodule [14].
Fig. 5.5
IPMN with tubulartype carcinoma, characterized by infiltrating, irregular tubular structures, similar to those of ordinary ductal carcinoma
Fig. 5.6
IPMN with “muconodular” carcinomatous transformation. Wholemount macrosection from a duodenopancreatectomy shows multiple areas of nodular gelatinous carcinomatous tissue
Interestingly, IPMNs can be associated with familial syndromes. For example, they have been detected in asymptomatic family members of patients with familial pancreatic cancer [15], in patients with Peutz-Jeghers syndrome (PJS), with inactivation of the STK11/LKB1 gene [16], and in association with familial adenomatous polyposis (FAP) [17]. These findings highlight that in patients with IPMN screening for curable pancreatic neoplasia may be possible.
In our experience in collaboration with the Massachusetts General Hospital, among 140 patients with MD-IPMNs who were treated by resection, 12% had adenoma, 28% borderline disease, 12% carcinoma in situ, and 42% invasive carcinoma. Similar data have been reported by other authors [18, 19]. Tanaka et al. found that MD- and BD-IPMNs were associated with malignancy in 70% and 25% of the cases, respectively, while the rate of invasive carcinoma was 43% for MD-IPMN and 15% for the BD type. Thus, these two neoplasms seem to have a significantly different biological behavior, which may influence clinical decision-making with regard to the appropriate management of these two entities.
Moreover, it is not uncommon to recognize different degrees of dysplasia within the same surgical specimen. In our experience, the average age of patients with malignant MD-IPMN is 6.4 years older than that of patients with adenoma or borderline tumor; these observations support the theory of a clonal progression to malignancy in this variant [20].
5.4 Genetics
Regarding the molecular pathogenesis of IPMNs, KRAS activating mutations have been identified as an early event that increases in occurrence according to the histological severity of the neoplasm. Mutations in the KRAS, p16, and p53 genes are present but are less common in IPMN than in ductal carcinoma, and DPC4 loss is usually not detected. In a study of 23 cases of resected IPMNs, Wada et al. showed that 65% had a KRAS mutation. A loss of heterozygosity (LOH) in 9p21 (p16) increased from 12.5% in adenomas to 75% for carcinomas while LOH in 17p13 (p53) was present only in invasive carcinomas [20]. These results suggest LOH in 9p21 (p16) as an “early” event and LOH in 17p13 (p53) as a later event, providing additional support for a clonal progression process.
A recent report showed that DNA damage checkpoint activation due to CHK2 inactivation occurs in the early stage of IPMN and seems to prevent its progression whereas p53 accumulation was mostly detected in malignant IPMNs. It was suggested that the DNA damage checkpoint exerts selective pressure on the p53 mutation and that a disturbance of CHK2 inactivation or p53 mutation contributes to the carcinogenesis of IPMNs.
Several other genetic alterations have also been reported in IPMNs. AKT/PKB and HER2/EGFR activation has been demonstrated in a large portion of these neoplasms, while CDKN2A/P16 expression is frequently lost, suggesting a correlation with the hypermethylation of the promoter region of P16, more frequently detected in high-grade neoplasms. Some IPMNs show abrogation of TP53, especially those with high-grade atypia [21–26]. Despite frequent hemizygous or homozygous deletions of chromosome 18q, SMAD4 is completely retained in IPMNs [27, 28].
Mutation of STK11/LKB1, a PJS gene, and the abrogated expression of DUSP6/MKP-3, a gene identified in the deleted region 12q21-q22, suggest a role for these molecules in the development of a subset of IPMNs [29, 30]. Aberrant hypermethylation of at least one CpG island is detected in about 80% of IPMNs, with the overall number of methylated loci significantly higher in high-grade tumors. Genes encoding cyclin D2, TFPI-2 and SOCS-1 have been reported as aberrantly methylated in IPMNs [31].
Global gene expression analysis performed for IPMNs revealed that many of the overexpressed genes are also highly expressed in pancreatic ductal adenocarcinomas. In addition, gene expression profiles evidenced the up-regulation of the genes encoding members of the trefoil factor family (TFF1 and TFF3), CLD4, CXCR4, S100A4, and mesothelin. Some of the encoded proteins have been suggested to play a role in the progression to the invasive form of IPMNs [32–34]; among the underexpressed genes in IPMNs, CDKN1C/P57KIP2 has been shown to be epigenetically down-regulated.
Recent investigations suggest the involvement of the sonic hedgehog (SHH) pathway in the tumorigenesis of IPMN and that SHH measurement of pancreatic juice may provide some advantages in the treatment or follow-up of a subset of patients with these tumors. The study by Ohuchida et al. [35] provides an outstanding survey of the SHH pathway involvement of IPMN, with its possible clinical implications. The involvement of this pathway was further supported by the report of Jang et al. [36] in their study of the immunohistochemical expression of SHH in IPMNs.
Fascin expression was found to be significantly higher in borderline neoplasms and carcinomas than in adenomas, suggesting that overexpression is involved in the progression of IPMNs. Thus, fascin could become a new therapeutic target for the inhibition of IPMN progression or, at least in the short term, a prognostic marker of IPMN [37].
PIK3CA mutations have been reported in 11% of IPMNs, providing evidence that the oncogenic properties of this gene contribute to these neoplasms [38].
Recent results suggest that HTERT expression in epithelial cells is an indicator of malignant transformation in IPMN. Immunohistochemical detection of HTERT in cells derived from pancreatic juice may therefore provide a powerful diagnostic tool and, in this case, a marker of the malignant progression of IPMN [39].
MUC4 and MUC5AC were recently evaluated as potential markers in distinguishing more aggressive IPMNs from less malignant ones, in a study by Kanno et al. [40].
5.5 Clinical Presentation
There are no signs or symptoms suggestive of IPMNs. Patients with MDIPMN are more often symptomatic, complaining of abdominal pain, pancreatitis, steatorrhea, jaundice, diabetes, or weight loss [41]. Even though some patients with BD-IPMN may present with the above-described symptoms, most are asymptomatic and the neoplasms are incidentally detected during a radiological work-up performed for unrelated problems [42, 43].
It is remarkable that, unlike in pancreatic adenocarcinoma, jaundice is an uncommon presentation of IPMN and occurs only in 15–20% of patients. Jaundice and steatorrhea at presentation are a cause for concern as together they are associated with a much higher incidence of malignant IPMN (8- and 5- fold, respectively). A recent onset or worsening of diabetes is more common in patients with IPMNs with invasive carcinoma (3-fold). In our experience, patients with benign IPMNs had a higher frequency of abdominal pain and a longer duration of symptoms.
5.6 Diagnostic Work-up
Previously, Ohhashi’s triad, consisting of a bulging ampulla of Vater, mucin secretion, and dilated main pancreatic duct, was an indicator of IPMN. Today, the great majority of IPMNs are characterized on cross-sectional imaging study, such as computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP). The radiological and endoscopic features of IPMNs vary according to the morphologic type of the neoplasm. The typical feature of MD-IPMNs is dilatation of the main pancreatic duct > 1cm (Fig. 5.7), eventually extending into the secondary branches, which may appear as cysts (Fig. 5.8). The dilatation can involve the duct of the distal pancreas or, if it is located in the head or in the uncinate process, may be present throughout because of an obstructive effect. BD-IPMN appears as cysts or a cluster of cysts without dilatation of the main duct and is more commonly located in the head-uncinate process. Between 39% and 64% of BD-IPMNs are multifocal (Fig. 5.9a, b).
Fig. 5.7
Main pancreatic duct IPMN (MD-IPMN). Coronal magnetic resonance cholangio-pancreatography (MRCP) shows diffuse dilatation of the main pancreatic duct due to the involvement of the entire pancreatic ductal system
Fig. 5.8
Side-branch IPMN (SB-IPMN). Coronal MRCP shows a cystic dilatation of a side branch in the head of the pancreas, connected with the Wirsung duct
Fig. 5.9
Multifocal SB-IPMN. Coronal MRCP shows a cystic dilatation of multiple side branches located along the whole pancreas (a). Axial T2-weighted image shows the connection between the cystically dilated side branches and the main pancreatic duct (b)
Calcifications are detected in 11% of cases. Nodules and papillary projections, which are significantly associated with the presence of a malignant neoplasm, usually appear as filling defects within the cystic lesions (Fig. 5.10). The pancreatic gland may be enlarged, with signs of pancreatitis, or it may be atrophic. CT and MRCP can localize the tumor and assess its relationship with nearby vessels and other organs. MRCP is particularly useful in the characterization of single or multifocal BD-IPMNs, given the ability of this imaging technique to demonstrate a communication between the main duct and the cyst.
Fig. 5.10
MD-IPMN: mural nodule. Axial T2-weighted image shows dilatation of the main pancreatic duct, with a mural nodule on the non-dependent wall of the duct (arrow), indicative of malignant IPMN, which was surgically confirmed
At our institution, in the initial assessment of patients with suspected IPMN we additionally use contrast-enhanced ultrasound (US), which is able to identify and characterize the “cysts” in detail [44].
In those cases in which the diagnosis is uncertain, endoscopic ultrasound (EUS) may be helpful, as it can well identify the dilated main pancreatic duct. In addition, EUS demonstrates the morphological details of any solid component, nodules, or small projections, in the main duct and/or in the cyst communicating with it. EUS is also a safe method for fluid sampling and targeted biopsies by fine-needle aspiration or core biopsy. Examination of fluid sampled from an IPMN provides diagnostic information about the tumor, revealing its viscous aspect, the presence of mucin or mucinous cells, and carcinoembryonic antigen levels [45]. However, it is important to keep in mind that the puncture is done through the gastric or duodenal wall, potentially allowing the needle to carry tumor cells.
Cytologic examination of the pancreatic juice and the subsequent detection of a KRAS mutation can also be helpful and, to a limited extent, may predict the likelihood of malignancy, even though this procedure has a low sensitivity (< 20%). More recent work has shown that high-grade atypia on cytology has a sensitivity of 72% for malignancy for all mucinous cysts (mostly IPMN) [46]. We consider EUS as a second-level procedure that should be performed only in selected cases.
In recent years, intraductal endoscopy and/or peroral pancreatoscopy have been introduced but experience is limited and further studies are needed.
Blood tests that include tumor markers are mandatory, with measurements of CEA, Ca19-9, and Ca125.
Clinical history, radiology, and endoscopy should contribute to obtaining a correct diagnosis of IPMN and to differentiate it from other cystic neoplasms, such as serous cystadenoma or mucinous cystic neoplasms, and from other cystic lesions of the pancreas (pseudocyst, true pancreatic cyst). Once IPMN is identified, the following step is the differential diagnosis between MD- and BD-IPMN and the determination of those parameters associated with a high risk of malignancy. Jaundice, steatorrhea and new or worsening diabetes should raise suspicion for degeneration. A lesion > 30 mm in diameter, a dilated main pancreatic duct (> 10 mm), and the presence of nodules, thick walls, or papillary projections are morphological aspects that should always alert clinicians [47].
5.7 Management
During the consensus conference held in Sendai in 2005, a group of surgeons, gastroenterologists and pathologists edited the first guidelines pertaining to the management of IPMNs. Before 2005, all patients with a diagnosis of IPMN were considered to be at risk of developing malignancy, and therefore surgery was always proposed. Since the Sendai meeting, two different approaches have been defined when considering MD-IPMN (including the mixed form) and BD-IPMN.
5.7.1 Main Duct-IPMNs
Patients with MD-IPMN or the mixed form, when surgically fit, should always be candidates for resection because of the high prevalence of in situ and invasive carcinoma found in resected specimens (70%). Of note is the observation that in patients with MD-IPMNs there may be malignancy regardless of the presence or absence of symptoms. Accordingly, the radiological aspect of these lesions can determine the indication for surgery.
The surgical management of MD-IPMNs is challenging. While in other pancreatic tumors preoperative imaging can accurately locate the tumor and thereby allow the planning of a pancreatic resection, this is not always the case in MD-IPMNs. Segmental dilatation of the main duct, as seen on preoperative studies, may occur both proximal and distal to the tumor, because of mucus overproduction. In such case, localization of the neoplasm is more difficult.
A typical resection (pancreaticoduodenectomy, left pancreatectomy, total pancreatectomy, according to the site and extension of the disease) with lymph node dissection is mandatory. Limited resections, such as middle pancreatectomy, have been proposed for MD-IPMN, but in our experience with MDIPMN patients this results in a high rate of positive resection margins and recurrences, with similar results reported by other authors [48]. Consequently, in this setting we recommend standard resections. Since IPMN extends along the pancreatic duct and may do so without macroscopic tumor, it is important to exclude residual tumor on frozen section [49].
Three different aspects of the ductal mucosa can be detected by analyzing the surgical margin: (1) normal ductal epithelium in the main duct means that radical resection has been achieved; (2) de-epithelialized or a denuded epithelium should not be considered as a negative margin since local recurrence is also possible; (3) adenoma, borderline, or carcinoma requires an extension of the surgical resection up to total pancreatectomy.
In cases of de-epithelialization, adenoma, or borderline tumor at the surgical margin, the optimal surgical strategy is controversial: we usually extend the resection by a few centimeters to obtain a new margin, aiming to achieve a negative resection margin. In our experience involving 140 patients with MD-IPMN who underwent surgical resection, the rate of negative margins in the surgical specimen was 58.5%, and the results of the intraoperative frozen section analysis modified the surgical plan, leading to an extension of the resection or to total pancreatectomy in 29 patients (20.7%) [50].
Recurrence in the pancreatic remnant may develop even if the transection margin is negative and even in patients with noninvasive disease. The presence of a positive resection margin, multicentric IPMNs with synchronous skip lesions along the main duct that are still present (but not detectable) at the time of surgery, and metachronous lesions (given that IPMN may be a marker of a “field defect” associated with a propensity for tumor development) may explain recurrence in the pancreatic remnant after the resection of a MDIPMN.
For all these reasons, the role of total pancreatectomy in IPMN must be carefully evaluated and tailored to each single patient. Some authors have reported that for malignant IPMNs the frequency of recurrence (local recurrence or distant metastases) is similar whether or not total pancreatectomy is performed [51, 52]; Chari et al. reported a recurrence rate of 62% after total pancreatectomy and of 67% after partial pancreatectomy [19]. The risks and long-term complications of total pancreatectomy must be considered and discussed with patients. Finally, in patients with MD-IPMN undergoing pyloruspreserving pancreaticoduodenectomy, pancreaticogastrostomy may be preferred instead of pancreaticojejunostomy because it allows direct endoscopic access to the pancreatic stump during follow-up, leaving open the possibility of pancreatic juice sampling for cytological examination [53].
5.7.2 Branch-Duct IPMNs
The prevalence of malignancy is much lower (25%) in BD-IPMNs than in MD-IPMNs and it is predictable on the basis of symptoms, tumor size, and morphological criteria. Thus, a strict follow-up is advocated for patients with BD-IPMN < 3 cm, with no nodules or duct dilatation (which would imply a combined IPMN). Follow-up consists of MRCP repeated 6 months after the first diagnosis and then yearly, together with measurement of Ca19-9 levels, unless there is an increase in size, the development of nodules, or the onset of symptoms. It should be emphasized that this non-operative approach should be carried out in experienced centers and that data from large series are still needed for its validation (Fig. 5.11a, b).
