review of literature on clinical pancreatology - The Pancreapedia

emain to be solved in screening for early pancreatic cancer. Risk stratification needs to beimproved and high-risk patients included in research-based screening programmes. It will beimpossible to confirm that screening can detect cancers early enough for curative treatmentuntil the results <strong>of</strong> these prospective studies become available. Registries <strong>of</strong> high-riskpatients may include hereditary pancreatitis kindreds, families from various general cancersyndromes and those with a specific predisposition for pancreatic cancer. Unfortunately,such registries may well also include families that have multiple cases <strong>of</strong> pancreatic cancerdue to chance, unaffected members <strong>of</strong> the latter group having no elevated risk. TheEuropean Registry <strong>of</strong> Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC)recruits patients with at least two cases <strong>of</strong> pancreatic cancer or pancreatitis in first- orsecond-degree relatives. A family tree <strong>of</strong> at least three generations is produced. To avoid asmany random clusters as possible, only families which are consistent with autosomaldominant inheritance <strong>of</strong> either pancreatic cancer or pancreatitis are included as havingfamilial pancreatic cancer (FPC) or hereditary pancreatitis (HP). When the participantsconsent, EUROPAC also tests for mutations in PRSS1 for HP families and BRCA2 for FPCfamilies. If cases <strong>of</strong> melanoma are reported, the CDKN2A gene (coding for p16) is alsotested. Relatives <strong>of</strong> pancreatic cancer patients have an elevated risk <strong>of</strong> pancreatic cancerthemselves. In a study <strong>of</strong> 570 families where the proband had pancreatic cancer, 7 hadmultiple first- or second-degree relatives who had had the disease. This suggests that over 1percent <strong>of</strong> pancreatic cancer cases occur in high-risk families. Consensus recommendationsfor secondary screening <strong>of</strong> high-risk groups were proposed at the Fourth InternationalSymposium on Inherited Diseases <strong>of</strong> the Pancreas. It was concluded that secondaryscreening should only be carried out on a research basis and only in patients with HP,individuals from Peutz-Jeghers (PJS) kindreds or families with a history <strong>of</strong> pancreatic cancer.In the latter case the family history should include at least two first-degree relatives (or 3more distant relatives), unless the participant requesting screening has a mutation in either <strong>of</strong>the BRCA genes or CDKN2A (p16). The causative genetic mutation remains unknown in themajority <strong>of</strong> families, although BRCA2 has been detected in 19 percent <strong>of</strong> EUROPAC/FaPaCafamilial pancreatic cancer kindreds. Hereditary pancreatitis is consistent with autosomaldominance and in contrast to FPC, most but not all <strong>of</strong> the responsible mutations have beenidentified in PRSS1 . Cancer risk to 75 years has been variously calculated as 35 to 54percent. The risk <strong>of</strong> a pancreatic cancer in those affected by HP in the EUROPAC populationis 4-5 times less than in FPC families. The risks <strong>of</strong> surgery are ameliorated as any resectionwould be <strong>of</strong> diseased pancreatic tissue, with affected individuals likely to already haveendocrine and exocrine pancreatic failure. PJS is characterised by autosomal dominantinheritance <strong>of</strong> hamartomatous polyposis. It is described as conferring a 132-fold increasedrisk <strong>of</strong> pancreatic cancer. In many cases those affected by this syndrome have mutations inthe STK11 gene, but it is worth noting that mutations in this gene do not appear in FPCkindreds. Familial atypical multiple mole melanoma (FAMMM) is characterised by multipleatypical (dysplastic) naevi and malignant melanoma. An association between FAMMM andpancreatic cancer is well established, but seems to be limited to a subset <strong>of</strong> families whichhave been defined on this basis as suffering from FAMMMpancreatic carcinoma syndrome.Mutations in the tumour suppressor CDKN2A are associated with FAMMM and have beendescribed in families with multiple cases <strong>of</strong> pancreatic cancer but only in families which alsohave a high incidence <strong>of</strong> melanoma. Breast ovarian cancer syndrome is <strong>of</strong>ten associatedwith mutations in BRCA2 or BRCA1 genes and BRCA2 is associated with some FPCfamilies. BRCA1 has not been linked to FPC and only confers a slight increase in pancreaticcancer risk (between 1.3- and 4.1-fold increase). However, it cannot be excluded that, in amanner similar to BRCA2, it may confer a much greater risk in the rare families that alreadyinclude a case <strong>of</strong> pancreatic cancer. If 100,000 individuals were screened with a modalitythat had 98 percent specificity there would be 2,000 false positives and only 10 possible livessaved by early detection (even assuming 100 % sensitivity). The pre-test incidence <strong>of</strong> cancerwould have to be at least 2 percent in order for a screening programme with this level <strong>of</strong>specificity to potentially benefit more people than it harmed. Only the high-risk groupsdescribed above <strong>of</strong>fer the possibility <strong>of</strong> this level <strong>of</strong> incidence in a reasonable screening