Natural history of intraductal papillary mucinous neoplasia: How much do we really know?

Core Tip

Natural history is defined as the “study of the natural development of a disease over a period of time”[1]. While this task for intraductal papillary mucinous neoplasm (IPMN) of the pancreas may seem straightforward, the recent recognition of IPMN as a distinct pathological entity coupled with its histopathological complexity makes this assignment exceedingly difficult. The initial description of IPMN was published in 1982[2]. However, it was not until 1996 (further clarified in 2000) that the World Health Organization formally differentiated it from other mucin-producing cystic lesions of the pancreas through a uniform classification scheme[3,4]. With this consensus nomenclature came the realization that IPMN consists of a spectrum of neoplasms (subtypes include: gastric, intestinal, pancreatobiliary and oncocytic) which show both morphological and immunohistochemical variation[5]. It is currently unknown whether these four subtypes represent distinct pathological entities (with different biological potentials) or simply histological variations along a single progressive neoplastic lineage[6]. Confounding these distinctions is the ambiguity over the exact sequence of events and the precise time frame of histopathological lesion progression from noninvasive (adenoma, borderline tumor, carcinoma-in-situ) to invasive adenocarcinoma. Even with recent data supporting the concept of clonal progression in IPMN[7], evidence substantiating a stepwise and orderly evolution by way of the adenoma to dysplasia to carcinoma sequence remains circumstantial at best[8-16]. In fact, while genetic evidence for the progression of pancreatic ductal adenocarcinoma is believed to be orderly and sequential (adenoma-carcinoma sequence), alternative theories of tumor development and progression do exist[17,18]. These differences may be explained by the recognition that not all IPMNs possess an equal potential for malignancy[19,20]. While there is broad consensus that the overall prognosis of patients with IPMN depends on the presence of invasive carcinoma, two distinct types of cancer (invasive ductal adenocarcinoma or invasive colloid carcinoma) associated with IPMN, each exhibit vastly different biological behaviors[6]. The five year survival rate in resected patients with IPMN was found to be significantly shorter (P < 0.01) in patients with invasive ductal adenocarcinoma (19%) than in patients with invasive colloid carcinoma (62%)[8]. These observations had been previously established by an independent group showing remarkably consistent findings of a five year survival rate of 12% for resected IPMN with invasive ductal adenocarcinoma vs a 57% five year survival for patients with colloid carcinoma[6,10]. These authors also found that colloid carcinoma was a favorable prognostic factor independent of patient age, tumor diameter or disease stage. Lastly, debate around the concepts of a local field defect versus disease multicentricity further clouds our understanding of the exact biology of these lesions[13,14,21-26].