Familial and hereditary pancreatic cancer families included in PANGENFAM registry

Since 2009, 290 individuals from 144 families have been enrolled in PANGENFAM, including 52 PDAC cases and 238 high-risk individuals. The family phenotypes are shown in Table 1. The majority of families (58%) are classified as FPC with at least 2 first degree affected relatives.

Table 1 Distribution of family phenotypes included in the PANGENFAM registryPancreatic anomalies identified during screening

Of the 238 high-risk individuals, 189 (79%) were eligible and consented to enroll in the screening program. The median age at the start of screening was 50 years (29–83) and 62% were females. Most high-risk individuals in screening were from FPC families (58%) and HBOC families (21%). On baseline imaging when entering the screening program, of the 189 individuals, 141 (78%) had a normal pancreas and 39 (22%) had pancreatic findings. These pancreatic findings included: 14 cysts (4 suspected intraductal papillary mucinous neoplasms-IPMN), 8 inhomogeneous pancreatic parenchyma, 1 solid lesion, 1 dilation of the main pancreatic duct, 1 chronic pancreatitis, 1 pancreatic steatosis, 1 pancreas divisum. There were no significant differences regarding age and gender distribution between individuals with normal and abnormal baseline imaging (51 years (29–83, 60% females) normal imaging vs. 53 years (29–77, 72% female) abnormal pancreas imaging).

Of the 189 individuals that initiated screening, 68% underwent at least a second imaging round. In total, 627 rounds of screening were performed in these individuals, ranging from 1 round only to 12 rounds of screening. Excluding individuals that had only undergone one round of follow-up, the median time in follow-up was 3.81 years (0.99–11.33). Currently, there are 143 high-risk individuals in active follow-up.

During follow-up imaging, a normal looking pancreas was consistently identified in 86 (48%) individuals and some type of pancreatic finding was detected in 94 (52%) individuals. Pancreatic cysts were identified in 57 high-risk individuals (32%). Of these, the lesion was consistently identified as a cyst during follow-up in 20 individuals (11%). IPMN were identified on entry into screening and consistently throughout screening in 9 individuals (5%). Inhomogeneous pancreatic parenchyma was detected in 28 individuals and chronic pancreatitis imaging stigmas were detected 4 individuals. Pancreatic anomalies found by imaging are summarized in Fig. 1.

Fig. 1

Consensus diagnosis of pancreas imaging of the 180 individuals in follow-up

Imaging findings according to family phenotype are summarized in Fig. 2, 63% of high-risk individuals from FPC families and 49% from HBOC families had abnormal pancreas imaging during screening. The 9 lesions consistently identified as IPMN were only found in FPC families, whereas, the 19 lesions consistently identified as cysts were mainly found in FPC families (58%) and HBOC families (32%), as well as PJS (5%) and Lynch syndrome (5%). Of the 15 high-risk individuals from PDAC < 50 years families, 66% had abnormal pancreas imaging, the pancreatic abnormalities included 1 individual with a cyst, another with a cyst/IPMN, and 2 other individuals with an inhomogeneous pancreas. The fifth individual had a highly suspicious image on screening entry and finally underwent a surgical resection (Table 2). One individual with Lynch syndrome had a cyst and another individual with HNPCC had an inhomogeneous pancreas. The 2 high-risk individuals from FAMMM, 2 from ATM and one from a HP family had normal pancreas imaging. Of the 3 high-risk from PJS families, one had a cyst and the other 2 had a normal pancreas.

Fig. 2

Frequency of normal and abnormal pancreas imaging during screening according to family phenotype

Table 2 Summary of suspicious lesions detected during the screening program that underwent a surgical resection. *previously reported [14, 15]

Eight high-risk individuals had more than one pancreatic finding, and each finding was counted separately. In 6 cases, the high-risk individual was first diagnosed with an inhomogeneous pancreas and was subsequently diagnosed with a cyst. One individual was diagnosed with chronic pancreatitis in round 3 of imaging at age 50 and then with a cyst 6 years later. Another individual was first diagnosed with pancreatic duct dilation aged 64 and was finally diagnosed with an IPMN aged 66. There were no significant differences regarding age and gender distribution between those individuals with normal and abnormal imaging on follow-up. The mean age at diagnosis of inhomogeneous pancreas parenchyma was significantly lower than for cysts and IPMN; (48 years (29–67) vs. 55 years (38–83) and 55.5 years (30–83), respectively.

The overall concordance rate between imaging tests was 66% and the best concordance rate was seen with normal pancreas imaging. Within the non-concordant imaging rounds, the majority (85 rounds, 14%) were diagnosed as a non-normal looking pancreas vs. a normal looking pancreas, these abnormalities were mainly inhomogeneous pancreas parenchyma versus a normal looking pancreas. There was a discrepancy between the pancreatic lesion being a cyst or an IPMN in 28 rounds (4%), a normal looking pancreas and a cyst in 6 rounds (1%) and a normal looking pancreas and IPMN and 10 rounds (1.6%).

Surgical intervention due to a suspicious lesion

After discussion by the multidisciplinary team, 4 high-risk individuals have undergone a surgical resection due to the detection of highly suspicious pancreatic lesions. These lesions were detected on baseline imaging in 2 individuals, which were eventually resected with the identification of Pan-IN-1 lesions in the resected specimen. Another individual underwent a surgical resection of a pancreatic neuroendocrine tumour detected during follow-up. These 3 cases have previously been reported and they are still under follow-up and are currently disease free [14, 15]. A solid adenocarcinoma was detected in another individual, which was surgically resected, and the patient underwent adjuvant treatment with modified FOLFIRINOX, and currently has no evidence of disease. The imaging findings that led to the surgical intervention are summarized in Table 2. All individuals were negative for targeted panel sequencing using a custom designed panel of 66 familial cancer related genes [10]

Extrapancreatic findings

No extra-pancreatic lesions were identified in 33% of high-risk individuals and a total of 236 extra-pancreatic lesions were detected in the remaining 67% of individuals. The most frequent extra-pancreatic lesions were hepatic cysts (23) and renal cysts (21), followed by biliary cysts (8), cholelithiasis (6), hepatic steatosis (4), vesicular polyp (5), focal hepatic lesions (3), accessory spleen (3) and hiatal hernia (2%). A full list of extrapancreatc lesions identified is available in Supplementary Table 1. One duodenal ampuloma was identified by EUS in an 83-year-old female. It was successfully resected endoscopically and definitively histology revealed a low-grade tubular adenoma. The same patient was subsequently diagnosed with a papillary urothelial carcinoma (pTaG3) a few months later.

Updated PANGENFAM inclusion and screening criteria

Based on our 10-year experience of the follow-up of high-risk individuals and according to the recent international guidelines [16, 17], the inclusion criteria for high-risk screening have been updated as follows: (1).  ≥ 2 relatives with pancreatic cancer on the same side of the family where 2 affected individuals are first degree relatives and at least 1 affected individual is a first degree relative of the high-risk individual considered for screening. (2). Peutz-Jeghers syndrome (carriers of germline pathogenic mutation in STK11/LKB1), FAMMM (carriers of pathogenic germline CDKN2A mutation), Hereditary Pancreatitis (carriers of a pathogenic mutation in PRSS1), and carriers of a germline pathogenic mutation in BRCA1, BRCA2, with at least one first degree relative with pancreatic cancer. (3). Carriers of germline pathogenic mutation in PALB2, ATM, MLH1, MSH2, MSH6, PMS2 or EPCAM with a first degree relative with pancreatic cancer.

Regarding the screening protocol, this is will be in accordance with the recommendations of the CAPS consortium, starting at age 50 or 10 years before the diagnosis of the youngest relative with PDAC in the family. With the following specific exceptions: individuals with Peutz-Jeghers syndrome (STK11 mutation) from 35 years of age, FAMMM (CDKN2A mutation) from 40 years of age and Hereditary pancreatitis (PRSS1 mutation) from 40 years of age [18]. Basal imaging using EUS and MRI will be performed in all high-risk individuals that enter screening, due to their complementary nature in high-risk screening. From then on, imaging will alternate between EUS or MRI according to the CAPS recommendation or participant's preferences [16,17,18]. Regarding interpretation of the imaging tests, the standard reports developed by the PRECEDE consortium for EUS [19] and MRI [20] will be used.

Description of the costs of screening

189 high-risk individuals had some imaging performed within the screening program. 1160 imaging tests were performed since the study beginning in in 2010, including 522 MRI, 528 EUS, 70 CT and 40 other types of imaging, mainly thoracic CT and abdominal echography. Of all imaging tests, 66% were considered as a normal looking pancreas and 44% an abnormal pancreas. The total cost of screening these individuals via imaging was 546,000€, based on approximate costs of EUS, MRI and CT imaging in the public health system in Spain. In accordance with the current screening guidelines and based on our own experience, the approximate cost of only screening individuals more than 50 years of age is 328,000€, which equates to a saving of 40%. Whereas, the cost of only screening individuals greater than 50 years of age and alternating between EUS and MRI annually, is 177,900€, a saving of 67% based on our current screening criteria and protocol. The approximate annual cost of screening the 143 individuals in active screening in our hospital when applying the new criteria is 71,500€.