LAUSR

Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic cancer. They consist of cystically dilated ducts that are clinically detectable by imaging and are lined by neoplastic epithelium. Their detectability, relative frequent occurrence in the population, and risk for progression into pancreatic cancer, a disease with a dismal prognosis, have resulted in a clinical need for a better understanding of these lesions. In order not to overtreat patients, risk stratification of IPMN and either conservative management or prophylactic treatment is considered the preferable strategy. IPMNs can be classified into different subtypes, based on the expression of specific mucins and the morphological resemblance to the epithelium of other gastrointestinal organs: gastric-type, intestinal-type, and pancreatobiliary-type. Some studies suggest that these subtypes are associated with specific molecular pathways and with different risks of malignant progression and different prognosis, making them an interesting feature for risk stratification. Generally, gastric-type IPMNs are low-grade and associated with the smallest likelihood of invasion, pancreatobiliary-type IPMNs are high-grade and associated with the highest likelihood of invasion, and intestinal-type IPMNs are high-grade and associated with mucinous “colloid” adenocarcinomas (see Fig. 1) [1, 2]. However, subtyping of IPMNs is often not so clear cut as different subtypes can be mixed in one IPMN and high interobserver variability is known [3]. Moreover, it has been suggested that gastricand pancreatobiliary-type IPMNs are the same entity but with different grades of dysplasia (see Fig. 1) [4]. Omori et al. studied 60 cases of intestinal-type IPMN in an effort to elucidate the molecular mechanisms of the development and the progression of these IPMNs from lowgrade to high-grade dysplasia. The study by Omori et al. shows interesting dynamics in the development of IPMNs and pancreatic cancers. Based on their observations in tissue slides, they hypothesize the transition from gastric-type IPMN to intestinal-type IPMN. Although the claim to see evolutionary dynamics in tissue slides, fixed in time, is subjective, the authors have tried to substantiate their claims with auxiliary techniques. Historically, pathologists have used (immuno)histochemistry to investigate the common expression of certain molecules to infer a (clonal) relationship between cells, based on the heritability of epigenetic programs. Omori et al. describe shared expression of CDX2 in both gastric-type IPMN and intestinal-type IPMN. This observation provides evidence for a clonal relationship between these lesions. Omori et al. did an attempt to further substantiate the morphologically assumed clonal relationships between gastrictype and intestinal-type IPMN by mutation analysis of commonly mutated driver genes (GNAS and KRAS). Importantly, shared mutations in genes like GNAS and KRAS provide only limited evidence of clonal relatedness, as the same hotspot mutation in these genes can easily be seen in unrelated lesions through two different molecular events. In contrast, multiple shared passenger mutations (e.g., synonymous mutations) that do not influence the fitness of a clone, or mutations in driver