Pancreatic intraductal papillary-mucinous neoplasms: a new and evolving entity
- First Online:
- Cite this article as:
- Andrejevic-Blant, S., Kosmahl, M., Sipos, B. et al. Virchows Arch (2007) 451: 863. doi:10.1007/s00428-007-0512-6
- 399 Views
For a long time, intraductal tumors of the pancreas were neglected because they were misdiagnosed as mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, or chronic pancreatitis. Only in recent years have they been recognized as clinical and pathological entities. Most common are the intraductal papillary-mucinous neoplasms. Although they show an adenoma-carcinoma sequence, they have proved to have a more favorable prognosis than ductal adenocarcinoma, when resected in a preinvasive state. Recently, it has become clear that they constitute a heterogeneous group with at least four subtypes. Their stratification reveals that the various intraductal papillary-mucinous neoplasm subtypes have different biological properties with different prognostic implications.
KeywordsIntraductal papillary mucinous neoplasmPancreasOutcome
Historical notes and a rising incidence
The new incidence data on IPMNs raise the question whether their increase in number is real or not. Of course, it is difficult to accept that IPMNs might have been overlooked in the past, not only clinically but also morphologically. There are good reasons, however, to believe that IPMNs did always exist and did not really increase in frequency. One reason is related to the rapid improvements in modern imaging techniques, which enable more precise recognition of cystic lesions, even if they are small and asymptomatic. Another is connected with the decreasing risk of pancreatic surgery. The most important fact, however, may be that until 1999, the distinction between IPMNs and mucinous cystic neoplasms (MCNs) was unclear, so that many IPMNs were classified as MCNs  or regarded as ductal adenocarcinomas or chronic pancreatitis.
In IPMNs, the normal ductal epithelium is replaced by mucin-producing columnar cells showing papillary proliferations and variable degrees of cellular atypia, even within an individual neoplasm. They are graded according to the most atypical area as IPMN with low grade dysplasia (adenoma), IPMN with moderate dysplasia (borderline), and IPMN with high grade dysplasia (carcinoma in situ). An invasive component may be found in 38–50% of the cases [7, 26, 40, 43]. Progression from adenoma to carcinoma is estimated to occur at about 5 years . IPMNs therefore provide a model of neoplastic progression from a benign intraductal neoplasm through increasing grades of dysplasia to invasive carcinoma.
Prognosis after resection
Five year survival rate and recurrence in 349a intraductal papillary-mucinous neoplasms
up to 6%
Several studies have reported recurrences after resection of noninvasive IPMNs, some of which revealed only moderate dysplasia [12, 43, 47, 48]. The recurrences were either local or metastatic (Table 2). To explain the recurrences, particularly the local ones, it has to be assumed that either tumor tissue was overlooked at the pancreatic resection margin, or an invasive component remained undetected in the resected specimen, or there was multifocal disease. The last possibility has to be considered if the surgical margins were negative and the recurrence occurred in the pancreatic remnant. This has been observed only in a few cases . When metastatic recurrences occur, it is most likely that they resulted from inadequate sampling that failed to detect an invasive component. Regarding the impact of a positive resection margin on IPMN recurrence, it is interesting to note that it has been reported that even IPMNs with positive margins did not recur during a median follow-up period varying from 19–40 months [13, 48]. The reason for this phenomenon might be that the growth of the remaining intraductal tumor tissue is so slow that clinical symptoms only appear after a follow-up period of 2 to 3 years. However, even if intraductal recurrences may take a long time to become clinically apparent, a positive margin in any IPMN case should lead to further tissue resection.
Histological type and prognosis
In 1991, it was reported that the invasive component of IPMNs corresponded either to an ordinary ductal adenocarcinoma or, more frequently, to that of a mucinous (colloid) carcinoma . This observation suggested that IPMNs form a group of heterogeneous neoplasms. A further argument for the heterogeneity of IPMNs was the detection of IPMNs in branch ducts rather than in the main duct, where most of the IPMNs are found. Finally, it was recognized that IPMNs differ in their histological and cytological features and in their mucin profile [3, 4, 18, 28, 32, 33]. Currently, four subtypes of IPMN can be distinguished: an intestinal type, a pancreatobiliary type, an oncocytic type, and a gastric type .
Histopathological data on 105 intraductal papillary-mucinous neoplasms collected during a period of 26 years
Gastric (n = 27) (26%)
Intestinal (n = 57) (54%)
Pancreatobiliary (n = 7) (7%)
Oncocytic (n = 14) (13%)
n = 20 (74%)
n = 35 (62%)
n = 3 (43%)
n = 10 (72%)
Carcinoma in situ
n = 7 (26%)
n = 22 (38%)
n = 4 (57%)
n = 4 (28%)
The pancreatobiliary type of IPMN is much rarer than the intestinal type IPMN (Table 3). It shows complex arborizing papillae and expresses MUC1 only (Fig. 1c,d). Its invasive component usually corresponds to a conventional ductal adenocarcinoma. The prognosis of this type of IPMN, if invasive, seems to be similar to that of ductal adenocarcinoma and therefore poorer than that of the intestinal type of IPMN .
The oncocytic type of IPMN (also called intraductal oncocytic papillary neoplasm ) shows the same complex papillae as the pancreatobiliary type, but the lining cells reveal strongly eosinophilic cytoplasm. In addition, there are often numerous goblet cells. The tumor cells express MUC1 and MUC2 inconsistently (Fig. 1e,f). With fewer than 20 cases reported in the literature to date [2, 20, 34, 35, 37, 38, 42], the clinical and pathological behavior of this type is still unclear. Most of the cases (94%) were diagnosed as carcinoma, some of them with an invasive component or even distant metastases . As the follow-up in this patient group is very short, no relevant data are available yet on survival and outcome.
Although the malignant potential of IPMNs of the gastric type seems to be rather low, it has to be pointed out that the fibrocystic changes that have been described in pancreata removed from patients with a strong family history of pancreatic cancer [11, 30] are similar, if not identical, to IPMNs of the gastric type and their associated PanIN lesions. This implies that IPMNs of the gastric type/PanIN-1 lesions are not innocuous lesions but have a malignant potential.
Summary and perspectives
The significance of IPMNs among the pancreatic tumors has increased greatly in recent years because of their improved recognition, both clinically and histopathologically and their much better prognosis than ordinary ductal adenocarcinomas. Moreover, they appear to fall into four subtypes that have special biological properties with prognostic implications. Of particular interest in relation to the development of ductal adenocarcinomas is the fact that the so-called gastric type IPMNs seems to occur in pancreata from patients with a strong family history of pancreatic cancer. Furthermore, it is of interest that the pancreatic IPMNs have their counterparts in IPMNs of the biliary duct system, where the same subtypes may occur [1, 23, 51, 52]. The treatment of choice is resection, but future trials may reveal that the extent of resection could depend on the IPMN subtype.