Pancreatic cancer risk in Peutz-Jeghers patients; results of a large Dutch cohort study
and implications for surveillance
F. Harinck1, S.E. Korsse1, M.G.F. van Lier1, K. Biermann2, G.J.A. Offerhaus3,4, N. Krak9,
C.W.N. Looman5, W. van Veelen1, E.J. Kuipers1,6, A. Wagner8, E. Dekker7, E.M.H. MathusVliegen7, P. Fockens7, M.E. van Leerdam1, M.J. Bruno1
1
Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam,
The Netherlands;
2
Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands;
3
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands;
4
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherland;
5
Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands;
6
Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The
Netherlands;
7
Department of Gastroenterology & Hepatology, Academic Medical Center, University of
Amsterdam, The Netherlands;
8
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The
Netherlands;
9
Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Although Peutz-Jeghers syndrome (PJS) is thought to be associated with an increased
pancreatic cancer (PC) risk, estimates of this risk differ widely. This hampers counseling of
PJS patients and the development of optimal screening strategies. We therefore aimed to
determine the risk of developing PC in a large cohort of Dutch PJS patients.
All patients included in this cohort study had a definite diagnosis of PJS as defined by
diagnostic criteria recommended by the WHO, a proven LKB1 germline mutation, or both.
Patients were followed prospectively between January 1995 and July 2011; clinical data from
the period before 1995 were collected retrospectively. All patients with a diagnosis of PC
were identified. As screening of the pancreas can also lead to the detection of other
malignancies in the pancreatic region, we also selected patients diagnosed with distal
cholangiocarcinoma or ampullary carcinoma. To ascertain the diagnosis, clinical, radiological
and histological data was reviewed by experts of all relevant disciplines. In inconclusive
cases, immunohistochemical staining was performed. Cumulative risks were calculated using
Kaplan-Meier analysis and relative risks using Poisson regression analysis.
We included 144 PJS patients (49% males) from 61 families, accounting for 5640 person
years of follow-up. Seven PJS patients (6 males) from 7 families developed PC at a median
age of 54 years (IQR 36-62 years), 6 of whom had ductal adenocarcinoma and one acinar cell
carcinoma. All 7 patients were symptomatic at the time of presentation with advanced stage
disease. The median survival after diagnosis was 5 months (IQR 3-17 months). Additionally,
2 cases of distal cholangiocarcinoma and 2 cases of ampullary carcinoma were diagnosed (3
males) at a median age of 55 years (IQR 44-69). The cumulative PC risk was 23% (95% CI
4.1;41.3) by the age of 70 years (Figure). Compared to the general population the PC risk was
significantly increased (HR 76.2, p<0.001). The cumulative risk for developing PC, distal
cholangiocarcinoma or ampullary carcinoma was 29% (95% CI 10.4;47.6) by the age of 70
years (Figure).
Conclusion: Patients with Peutz-Jeghers syndrome are at very high risk for developing
cancer in the pancreatic region, including pancreatic cancer, with a cumulative risk of 29% by
the age of 70 years. This very high risk and the notion that early detection of these
malignancies or its precursors will hopefully lead to an improved survival, make PJS patients
1
good candidates for screening. This screening should be performed with annual endoscopic
ultrasonography (EUS) and/or MRI within well-defined research protocols. The impact of
such an approach on survival of these patients remains to be demonstrated.
Cumulative
cancer risk (%)
Cumulative cancer risk for (A) pancreatic cancer
and (B) cancer in pancreatic region
among 144 Peutz-Jeghers syndrome patients.
50
A: pancreatic cancer (n=7)
40
B: cancer in the pancreatic
region (n=11)
30
20
10
0
0
20
40
60
80
Age in years
2