German national case collection for familial pancreatic cancer (FaPaCa): ten years experience

Abstract

Familial pancreatic cancer (FPC) is a rare hereditary tumor syndrome. The 10-years experience of the national case collection for familial pancreatic cancer of Germany (FaPaCa) is reported. Since 1999 FaPaCa has collected families with at least two first-degree relatives with confirmed pancreatic cancer (PC), who did not fulfill the criteria of other hereditary tumor syndromes. Histopathological verification of tumor diagnoses, and genetic counseling were prerequisites for enrollment of families in FaPaCa. 94 of 452 evaluated families fulfilled the criteria for partaking in FaPaCa. PC represented the sole tumor entity in 38 (40%) families. In 56 families additional tumor types occurred, including breast cancer (n = 28), colon cancer (n = 20) and lung cancer (n = 11). In 70 (74%) families the pattern of inheritance was consistent with an autosomal dominant trait. Compared to the preceding generation, a younger age of onset was observed in the offspring of PC patients (median: 57 vs. 69 years), indicating anticipation. Mutation analyses of BRCA2, PALB2, CDKN2a, RNASEL, STK11, NOD2, CHEK2 and PALLD, revealed deleterious causative germline mutations of BRCA2 and PALB2 in 2 of 70 (3%) and 2 of 41 (4.9%) German FPC families, respectively. Prospective PC screening with EUS, MRI and MRCP detected precancerous lesions (IPMN, multifocal PanIN2/3) or carcinoma in 5.5% (4 of 72) to 12.5% (9 of 72) of individuals at risk, depending on histological verification. Appropriate inclusion of families at high risk for PC in registries, such as FaPaCa, provides a unique and excellent tool to gain clinical and genetic knowledge of FPC. Focused research projects can be conducted most efficiently, when data of different FPC registries are combined.

Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer

“…During long term follow-up [36] (24 mo-extended surveillance), this study showed histologically proven precancerous or cancerous lesions in 4 individuals (5.5%) and additional branch duct IPMN in 5 ones, with a diagnostic yield of up to 12.5%, close to the previous rates reported by the Johns Hopkins and the Rotterdam groups.…”

“…This risk has been estimated to be 2.3 to 4.5-fold greater in individuals with one FDR with pancreatic cancer, 6.4-fold greater in individuals with two FDRs with the disease and 32 to 57-fold greater in individuals with three or more FDRs affected [29][30][31][32] . Similarly to other familial tumors, the median age of presentation in patients with FPC is up to 20 years earlier than in patients with sporadic cancer (49 years vs 61 years) [33][34][35] with an ''anticipation phenomenon'' in the affected kindred and a trend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next [35,36] . Currently, the genetic etiology of most cases of FPC remains undetermined but complex segregation analysis of these patients has led to the discovery of various candidate pancreatic cancer susceptibility genes such as BRCA2 (6%-17% of cases) [37,38] , partner and localizer of BRCA2 (PALB2) (1%-4% of cases) [39,40] and palladin, even if mutations of the latter have been identified in normal controls as well [41][42][43] .…”

“…There is no consensus also on the frequency, because evidence on the natural history and rate of progression of pancreatic cancer in high risk patients is still lacking. However, yearly screening seems to be the most suitable approach [21,22,36,103] even if some centers recommend 3 years intervals in case of negative screening exam and absence of other risk factors associated. A more aggressive protocol can be used for patients with abnormal findings at the last screening [52] .…”

“…A more aggressive protocol can be used for patients with abnormal findings at the last screening [52] . In these cases a subsequent screening could be done every 3-6 mo [22,103] or every 3-12 mo [21,36,100] . The majority of studies have generally used the same imaging test for surveillance as for baseline screening, while others suggest an alternating use of MRI/MRCP and EUS [36,98] ( Figure 1).…”

Pancreatic Cancer Screening: Attempts and Possibilities

“…EUS-FNA is the preferable approach in resectable disease because of better diagnostic yield and lower risk of peritoneal seeding compared to percutaneous approach [49,50].…”