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

Ralph Schneider • Emily P. Slater •

Mercede Sina • Nils Habbe • Volker Fendrich •

Elvira Matthai • Peter Langer • Detlef K. Bartsch

Published online: 5 January 2011

� Springer Science+Business Media B.V. 2011

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. Histopa-

thological 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), indi-

cating 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 precancer-

ous 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 inclu-

sion 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.

Keywords Familial pancreatic cancer � Genetic

susceptibility � Screening � Hereditary tumor syndrome

Introduction

Pancreatic Cancer (PC) is a challenging tumor entity with

an increasing incidence and a dismal prognosis. The overall

five-year-survival rate is less than 5% attributed to late

clinical symptoms, low resection rates and poor response to

radio- and chemotherapy [1]. Long-time survivors are

observed, but only if the tumor is diagnosed in its early

stage [2].

An inherited predisposition to PC is currently believed

to occur in three distinct clinical settings. First, it occurs in

hereditary tumor predisposition syndromes such as Peutz-

Jeghers-Syndrome (PJS), pancreatic-melanoma cancer-

syndrome (PCMS) or familial-atypical multiple mole

melanoma (FAMMM), hereditary breast and ovarian can-

cer, Li-Fraumeni-syndrome and others. These syndromes

are characterized by a clinical phenotype other than PC, but

are known to be associated with an increased risk of PC.

Hereditary pancreatitis and cystic fibrosis are the second

setting; here genetically determined early changes of the

pancreas can predispose to the development of PC. The risk

for the development of PC in these diseases/syndromes,

whose underlying gene defects are largely known, varies

from \5% to up to 40% (Table 1). The third setting is

R. Schneider � E. P. Slater � N. Habbe � V. Fendrich �E. Matthai � P. Langer (&) � D. K. Bartsch

Department of Visceral, Thoracic and Vascular Surgery, Philipps

University Marburg, Baldingerstrasse, 35043 Marburg, Germany

e-mail: langerp@med.uni-marburg.de

M. Sina

Institute of Clinical Genetics, Philipps University Marburg,

Marburg, Germany

123

Familial Cancer (2011) 10:323–330

DOI 10.1007/s10689-010-9414-x

familial pancreatic cancer (FPC) which is applied to fam-

ilies with two or more first-degree relatives with PC that do

not fulfill the criteria for another inherited tumor syndrome

[3]. Some groups also use the term FPC for families with

PC in three or more relatives of any degree [4, 5].

Initially, several case reports of familial aggregation of

PC suggested the existence of hereditary pancreatic cancer

[6–8]. In 1989, Lynch was the first to publish a systematic

study of a larger cohort of 18 families with PC [9]. Sub-

sequently, national and international tumor registries such

as the North American National Familial Pancreatic Tumor

Registry (NFPTR), the German National Case Collection

of Familial Pancreatic Cancer (FaPaCa) and the European

Registry of Hereditary Pancreatitis and Familial Pancreatic

Cancer (EUROPAC) were established to collect data on

FPC families [5, 10–12]. Based on the strict inclusion

criteria of confirmation of the PC diagnosis by histopa-

thology and medical reports, a familial aggregation of PC

was reported to be only 2.7 and 1.9% in two prospective

studies from Sweden and Germany, respectively [13, 14].

In order to investigate the clinical and genetic charac-

teristics of FPC, the German national case collection for

familial pancreatic cancer (FaPaCa) was established in

1999. Here, we report the 10-years experience of this

collection and the concept of genetic and clinical screening

of family members at risk.

Patients and methods

The FaPaCa registry is a national case collection for

familial pancreatic cancer families funded by the Deutsche

Krebshilfe (Grant 106 925). Families with two or more

first-degree relatives with a confirmed diagnosis of PC and

without evidence of any other inherited tumor syndrome

were collected. Families with an occurrence of melanoma

or PC in two first-degree relatives representing the FAM-

MM or PCMS-syndrome, were also collected in FaPaCa,

but not analyzed in this report.

Multiple centers contributed to the establishment of

FaPaCa which is coordinated by the Philipps University of

Marburg in Germany and has been described in detail in

previous publications [10, 13]. Members from FPC fami-

lies were recruited between July 1999 and July 2009 by

direct referral via their physicians or by personal contact to

the FaPaCa study-office based on information about the

study, e.g. via the internet (http://www.fapaca.de). All

eligible persons and families were genetically counseled by

a genetic counselor (M.S.) and a three-generation family

pedigree was constructed. All participating persons

underwent a physical examination. All cancer diagnoses

were confirmed by review of medical and pathological

records, deaths certificates and by examination of the

pathology slides whenever available.

All diseased index patients of FPC families were sub-

jected to mutation analysis of the genes BRCA2, CDKN2a,

PALB2, PLLD, CHEK2, RNASEL, NOD2 and STK11 as

described previously [15–22]. If a germline mutation was

identified in the index patient, predictive genetic testing of

this mutation was offered to all family members after

genetic counseling. The result of the predictive testing was

revealed to the family members during another interdisci-

plinary counseling, involving a geneticist, a psychologist, a

surgeon and gastroenterologist.

Individuals at risk (IAR) older than 18 years were

encouraged to participate in a prospective screening pro-

gram that was conducted at our institution. The screening

started 10 years before the earliest age of onset of PC in the

family or at age 40 years, whichever was first. The fol-

lowing individuals from families registered in FaPaCa

were classified as IAR and encouraged to participate in the

study:

Table 1 Cumulative lifetime

risk of PC in the different

settings of inherited PC

FAMMM-syndrome familial

atypical multiple mole-

melanoma syndrome

Setting of inherited PC Gene PC-risk (%)

until 70 years

1. Hereditary tumor predisposition syndromes

Peutz-Jeghers syndrome LKB1 36

FAMMM syndrome CDKN2a 17

Hereditary breast and ovarian cancer BRCA1, BRCA2 3–8

Li-Fraumeni TP53 \5

Hereditary nonpolyposis colorectal carcinoma MLH1, MSH2 \5

Familial adenomatous polyposis APC \5

Ataxia telangiectasia ATM \5

2. Tumor syndromes with chronic inflammation/dysfunction of the gland

Hereditary Pancreatitis PRSS1, SPINK1 40

Cystic fibrosis CFTR \5

3. FPC-syndrome BRCA2, PALB2,…? *40

324 R. Schneider et al.

123

– first-degree relative of an affected patient of a FPC

family;

– members of a FPC-family carrying a predisposing

mutation such as BRCA2, PALB2 or CDKN2a, inde-

pendent of the degree of relationship.

The FaPaCa registry was approved by the Ethics Com-

mittee of the Philipps-University of Marburg (36/1997, last

amendment 2009) and all participants provided written

informed consent.

Results

In a 10-year period, 452 potential FPC families were

admitted to the study office of FaPaCa. After genetic

counseling of the index patient, it was possible to obtain

contact with 284 families. More than half (58%, n = 167)

of potential FPC families were not included in FaPaCa for

different reasons: a, family members denied participation in

the project, so that anamnestic data could not be confirmed

(n = 57, 34%); b, histological verification of the diagnosis

was not possible due to the lack of medical records of

family members deceased for more than 20 years (n = 48,

29%); c, pedigree evaluation showed that affected family

members were not first-degree relatives (n = 42, 25%), d,

examination of histological reports revealed a pathology

other than ductal pancreatic adenocarcinoma (n = 20,

12%). Five families are still under evaluation. Eighteen

pancreatic cancer/melanoma-prone (PCMS) families were

not analyzed in the current study, since these were recently

published as a separate disease entity [23].

So far, 94 FPC families fulfilled the inclusion criteria

and underwent genetic counseling, including the prepara-

tion of a three-generation pedigree. A representative family

is shown in Fig. 1. All families were Caucasian with none

reporting Ashkenazi Jewish heritage. A total of 442 family

members underwent genetic counseling and physical

examination with median 4 (range 1–29) family members

counseled. Blood was collected from 421 family members,

of whom 67 were affected with PC. Pancreatic tumor tissue

could be collected from 40 FPC patients.

Of the 94 verified FPC families, 38 (40%) revealed only

PC. Twenty-eight (30%) families showed both PC and

breast cancer. In two of these families 3 female patients

developed both tumors, synchronous and metachronous.

PC and colon cancer occurred in 20 (21%) families, PC and

lung cancer in 11 (12%) families, PC and prostate cancer in

6 (6%) families, and PC and other tumor types in 7 (7%)

families, respectively (Table 2). Four (4%) families

revealed an accumulation of family members with insulin-

dependent diabetes mellitus and five families (5%) had a

history of pancreatitis. Of the 94 FPC families, 1 family

had 5 affected members with PC, 11 families had 4, 9

families had 3 and 73 families had two affected members.

Three generations were affected in 3 families, two gener-

ations in 67 families and 1 generation was affected in 24

families. Among patients affected with PC were 116 males

and 106 females. The median age of diagnosis of PC was

63 years (range 31–91). Thirty-five (16%) of the affected

PC patients had a young age of onset of the disease

Fig. 1 Representative FPC

family with an isolated

accumulation of PC. Four

patients in two generations are

affected (y years of age; dg age

at diagnosis)

Table 2 Tumor combinations reported in our 94 FPC families

Tumor combinations Number of affected families

PC only 38/94 40.4%

PC ? breast cancer 28/94 29.8%

PC ? colorectal cancer 20/94 21.3%

PC ? lung cancer 11/94 11.7%

PC ? prostate cancer 6/94 6.4%

PC ? other tumor types 7/94 7.5%

PC pancreatic cancer; other tumor types include: endometrial, tes-

ticular and gastric cancer; lymphoma, melanoma and brain tumor

German national case collection for familial pancreatic cancer (FaPaCa) 325

123

(\50 years). In 70 families with 2 or more affected gen-

erations the age at onset revealed a shift towards an earlier

age in the younger generations (median 69 years, range

42–91 years vs. median 57 years, range 31–81 years). An

analysis of 80 parent/child pairs from EUROPAC and

FaPaCa registries had already demonstrated a significant

shift towards an earlier age of death of about 10 years

(70 years vs. 64 years vs. 49 years) in the younger gener-

ations, indicating anticipation in 85% of families [24].

We performed mutation analyses of potential causative

candidate genes, either in our cohort of families or by

pooling families with the EUROPAC registries or the

Polish case collection (Szczecin registry) [20]. In a first

step only affected patients were screened for germline

mutations. Initially, we identified BRCA2 mutations in 5 of

26 (15%) of European FPC families [15]. The current

status of 70 analyzed German families showed deleterious

BRCA2 mutations in only 3% (2 families) and unclassified

variants of unknown clinical importance in 8.6% (6 fami-

lies) [25]. PALB2 mutations have been detected in 2 of 41

(5%) analyzed German families [22]. CDKN2a mutations

were only identified in 2 of 18 PC/melanoma-prone fami-

lies, so called PCMS or FAMMM-PC families [23], but in

none of the FPC families without melanoma. None or non

deleterious germline alterations could be identified in

PALLD [21], RNASEL [16], STK11 [19], CHEK2 [17] and

NOD2 [20] genes. In total, 4 (2/70 BRCA2 and 2/41

PALB2) of the FPC families carried deleterious causative

germline mutations and another 6 families had unclassified

variants of BRCA2, that might have clinical importance.

Eighty-eight family members of these 10 families under-

went predictive genetic testing after genetic counseling and

35 mutation carriers were identified.

The participation in a clinical screening program for the

early detection of PC was recommended to 207 IAR of

FPC families. The screening program was restricted to

mutation carriers, if the underlying gene defect was known

in the family. The screening program as outlined in

Algorithm 1 started 10 years before the earliest age of

onset in the family, at the latest by the age of 40 years. The

results of the first 5 years of prospective screening in FPC

and PCMS families from July 2002 until December 2007

were previously published [26]. After a 24 month extended

screening period (until December 2009, median follow-up

44 months) 72 IAR of FPC families participated in the

screening program with a total of 210 examination visits

(median 2, range 1–11). Forty-six IAR (63.9%) had a

normal pancreas based on the evaluation by endoscopic

ultrasound (EUS) and magnetic resonance imaging (MRI)

with MRCP. Twenty-six (36.1%) IAR showed lesions and/

or abnormalities in the pancreas, of whom 10 were oper-

ated on and 16 IAR, including 5 with potential side branch

IPMN (Fig. 2), are under close observation. In one patient

surgical exploration could not confirm the small hypoech-

oic lesion seen in EUS, therefore no pancreatic resection

was carried out. Nine IAR underwent pancreatic resection

and had the following pathologies: PC (n = 1), serous

cystadenoma (n = 3), PanIN3 (n = 1), IPMN (n = 2),

PanIN1/2 lesions (n = 2). Interestingly, one patient with

IPMN also revealed multifocal PanIN2 lesions (Table 3).

These resulted in a diagnostic yield of malignant (PC) or

potentially malignant precursor lesions of PC (IPMN, Pa-

nIN3, multifocal PanIN2) between 5.5% (4 of 72) to 12.5%

(9 of 72), depending on inclusion of the 5 IAR with branch

duct IPMNs on imaging.

Algorithm 1 Screening-algorithm of the FaPaCa prospective

screening program for PC

Fig. 2 MRI image of an IAR showing suspicious lesions for IPMN

(arrows). The postoperative histopathological examination of the

resected pancreatic specimen revealed IPMN and multifocal PanIN2

lesions

326 R. Schneider et al.

123

Discussion

A registry for FPC allows for the testing and refining of

assumptions on the epidemiology of the disease. Moreover,

the registry may be used to test novel screening modalities

to identify early, resectable tumors providing tissue sam-

ples that can reveal vital features of the early stages of the

disease, or even better, its precursor lesions. Finally, reg-

istries allow for linkage and association studies to identify

novel mutations or polymorphisms that predispose to PC.

These motives for establishing a registry for FPC have

ensured that many have been created, most of which have

remained small. However, size is critical if the registry is

intended to supply solid epidemiological and genetic data.

The National Familial Pancreas Tumor Registry (NFPTR)

based at Johns Hopkins University is the largest and reg-

istered up until December 2008 2,505 FPC families with at

least 2 first-degree relatives (http://pathology.jhu.edu.

pancreas/PartNFPTR.php). The European Registry of

Familial Pancreatic Cancer and Hereditary Pancreatitis

(EUROPAC), coordinated in Liverpool, UK and Greifs-

wald, Germany) had collected 233 FPC families with two

or more PC cases by February 2008. FaPaCa is the third

largest FPC collection and collaborates closely with the

EUROPAC registry regarding epidemiological and genetic

data [15, 16, 19, 21, 24] to strengthen the results and

conclusions of the respective studies.

Over a 10 year period, FaPaCa evaluated 452 potential

FPC families, but only 94 could be enrolled in the registry.

It is a major effort in Germany to obtain contact with the

family and the permission to verify the tumor diagnosis of

family members by pathology and medical reports. More

than 30% of eligible families did not want to participate in

the registry. Furthermore, about 41% of families could not

be included, because the PC diagnosis either could not be

confirmed as pathological reports were no longer available

(29%) or the PC diagnosis was incorrect (12%). However,

we insisted on verification of the PC diagnosis to ensure

that the families were true FPC families, whereas other

groups do not require histological confirmation or first-

degree relationship [12, 27]. We strongly believe that

verification of the PC diagnosis is important for any epi-

demiologic or genetic analysis, as well as for the risk

adjustment and screening recommendations of family

members.

The phenotypic appearance of our FPC families fits well

into the concept that FPC generally can be divided into

groups, namely pure PC families and those associated with

other tumor types. The three most frequent other tumor

types were breast cancer (30%), colon cancer (21%) and

lung cancer (12%). This observation is similar to the

reports from other groups [9, 12]. Whether this is a hint for

a common predisposing gene defect (e.g. BRCA2,

CDKN2a) or just chance, given the high prevalence of

these tumors in the German population, remains specula-

tive. The pattern of inheritance was consistent with an

autosomal dominant trait in 70 families (74%), comple-

mentary to that reported by the EUROPAC registry (58%,

125/233) [28]. In contrast to previous studies from the

United States [3, 4] there seems to be an earlier age of

Table 3 Characteristics of IAR operated on for pancreatic lesions

ID, age at surgery Sex Surgery Pathology Morbidity Follow-up F-up

[mo]

25-4-25-204, 44 f Exploration, liver-

wedge

No pancreatic tumor, FNH in specimen of the liver None Incisional

hernia

118

25-2-28-204, 61 f DP ? SE Serous oligocystic adenoma Fistula No pathologies 76

25-7-85-2, 61 f DP ? SE Serous oligocystic adenoma,

lobular fibrosis with PanIN1

None Cystic lesion

pancreatic head

(prev. known)

85

25-7-41-109, 54 m SPDP Focal fibrosis with

PanIN1/2 lesions

Fistula No pathologies 69

25-4-5-2, 42 f SPDP Serous oligocystic adenoma None No pathologies 40

25-1-91-1, 54 m DP ? SE Lobular Fibrosis with PanIN1 ? sqamous

metaplasia

None No pathologies 37

25-5-67-24, 53 f SPDP Lobular fibrosis with PanIN1 ? gastric type IPMN None NIDDM 30

25-5-67-26, 52 f TP Pancreatic cancer Diabetes Lung metastasis 12

25-4-48-206, 58 f TP Multifocal PanIN2 ? IPMN Diabetes No pathologies 4

25-5-67-28, 51 f TP PanIN3 ? multifocal PanIN1/2 Diabetes No pathologies 3

F-up follow-up time, liver-wedge liver-wedge-resection, FNH focal nodular hyperplasia, DP ? SE distal pancreatectomy ? splenectomy, SPDPspleen preserving distal pancreatectomy, TP total pancreatectomy, IPMN intraductal pancreatic mucinous neoplasia, NIDDM non insulin

dependent diabetes mellitus, fistula postoperative pancreatic fistula (conservatively treated), prev. known previously known

German national case collection for familial pancreatic cancer (FaPaCa) 327

123

onset of the disease in the setting of FPC. The median age

of diagnosis was with 63 years about 5 years younger than

reported for patients with sporadic disease in Germany [29]

and 35 (16%) patients were younger than 50 years at

diagnosis. We also observed the phenomenon of anticipa-

tion in about 59% of our families, which was already

suggested in a large collaborative study between EUR-

OPAC and FaPaCa on 80 parent/child pairs [24].

The FaPaCa registry allowed for a variety of genetic

analyses. In collaboration with EUROPAC we initially

hypothesized that BRCA2 mutations are causative for the

disease in about 15% (4 of 26) of FPC families, even in the

absence of breast cancer [15]. This was also reported by

the Hopkins group, who identified BRCA2 mutations in

17% (5 of 29) FPC families [30]. However, the subsequent

analysis of index patients of 70 German FPC families

revealed deleterious BRCA2 mutations in only 3% (2 of 70

families) and unclassified variants of unknown clinical

importance in 8.6% [25]. This supports the observation of

the Hopkins group, who observed BRCA2 mutations in 10

of 180 FPC families according to a prevalence of 6% [31].

Nevertheless, BRCA2 germline mutations are still the most

frequently inherited genetic alteration identified in FPC. We

provide rising evidence, that CDKN2a mutations will only

be identified in PC families with an occurrence of mela-

noma, so called FAMMM-PC or PCMS families [18, 25].

Recently, PALB2 was reported to be a new pancreatic

cancer susceptibility gene as determined by exomic

sequencing, since truncating PALB2 mutations were iden-

tified in three of 96 (3.1%) American patients with FPC

[32]. We identified truncating PALB2 mutations (R414X

and 508-9delAG) in two of 41 (5%) FaPaCa families.

Interestingly, both families also had a history of breast

cancer. A collaborative analysis of PALB2 with the EUR-

OPAC-registry revealed potentially relevant mutations in 3

(3.7%) of 81 European FPC families [22]. Therefore,

mutations might be causative for FPC in a small subset of

families, especially in those with an additional occurrence

of breast cancer.

The oncogenic mutation P239S in the Palladin (PALLD)

gene, located at 4q32, has been proposed to be a major

pancreatic cancer susceptibility gene, since it was discov-

ered by linkage analysis of one large FPC family (family X)

[33]. However, the analysis of 74 families from EUROPAC

and FaPaCa families revealed neither linkage nor any PLLD

mutation [21, 34], so that PLLD mutations seem not to be

associated with European FPC families. We also could not

identify unequivocal causative germline mutations in

CHEK2, RNASEL, NOD2 or STK11 genes [16, 17, 19, 20].

Taken together germline alterations in BRCA2 and

PALB2 that might predispose to PC were so far detected in

4–10 families depending on the inclusion of unclassified

variants. Based on the aforementioned data, the clinical

management of FPC families of FaPaCa routinely

encompasses only mutation analyses of BRCA2; PALB2;

and CDKN2a, if a melanoma occurred in the family.

According to a recent consensus conference of experts,

it is considered appropriate to perform PC screening under

research protocol conditions for those individuals who are

deemed at risk for developing PC [35]. First-degree rela-

tives of PC patients of FPC kindreds as in our registry are

considered IAR, since they carry a 5 to [10-fold risk of

developing PC depending on the number of affected rela-

tives. No consensus opinion exists on a specific approach

for PC screening in IAR. Many centers, including our own,

use an EUS-based approach based on its ability to detect

pancreatic masses \ 1 cm in size in the absence of chronic

inflammation of the gland [26, 36–38]. We previously

reported our results of 5 years prospective screening

(2002–2007) in 76 IAR, including those of PCMS-families,

with a total of 182 examination visits [26]. We showed that

an EUS/MR-MRCP-based screening program leads to the

detection of potential precursor lesions of PC in FPC and

PCMS families, but the diagnostic yield of significant

precancerous lesions (IPMN, PanIN2/3) was low (1.3%, 1

of 76 IAR). The 24 months-extended screening period on

72 IAR, exclusively from FPC families, showed histolog-

ically proven precancerous/cancerous lesions in 4 IAR

(5.5%) and additional branch duct IPMN in 5 IAR who are

still under observation, resulting in a diagnostic yield of up

to 12.5%. Thus, the diagnostic yield increased during long-

term follow-up, and is now close to the 10% rate reported

by the Johns Hopkins group [36] and the 16% rate reported

by the Rotterdam group [38]. Nevertheless, it has to be

pointed out that neither the 5 potential IPMN in our study

nor the 7 IPMN in the Dutch study [38] have been con-

firmed histologically and are solely an EUS-diagnosis so

far. The 12.5% and 16% may therefore be overestimations.

The five IPMN still being under surveillance in our study

are side-branch-IPMN being all smaller than 10 mm. The

higher prevalence in the Dutch study may also be related to

the selection of IAR. In the Rotterdam study the proportion

of IAR with clearly defined tumor syndromes such as

FAMMM or HBOC with germline mutations (CDKN2a

and BRCA2) was much higher than in the Hopkins study or

in the presented study, who screened in the majority IAR of

FPC kindreds. On the other hand, other environmental risk

factors, e.g. smoking, have to be taken into account. Cur-

rently, the EUS-based PC screening of IAR seems to be the

most sensitive, although neither the best management of

IAR with precursor lesions is established, nor are different

high risk groups clearly characterized, nor has the long-

term cost-effectiveness of PC screening in IAR been

evaluated. Therefore, it seems mandatory that PC screening

of IAR only be performed within board-approved screening

protocols with scientific evaluation at expert centers.

328 R. Schneider et al.

123

The question as to which surgical procedure should be

used once a reproducible pancreatic lesion is diagnosed in

an asymptomatic IAR also remains unresolved. Some

centers advocate total pancreatectomy, if the imaginable

lesions were intraoperatively confirmed as preneoplastic or

cancerous lesion by frozen section [39]. The rationale for

this approach is that IAR often have multifocal precursor

lesions or neoplasia. This excludes any type of operation

that would leave behind pancreatic tissue [13]. Based on

the available screening data, we and others [37, 38] offer

IAR partial pancreatectomy to avoid both, overtreatment

and the significant drawbacks of total pancreatectomy such

as brittle diabetes. We first resect the part of the pancreas

that contains the suspicious lesion(s) and only proceed to

total pancreatectomy, if the frozen section diagnoses a PC

or multifocal high grade PanIN or IPMN.

In summary, the collection and careful clinical investi-

gation of FPC families, as in FaPaCa, provide the basis for

identifying the underlying gene defect(s) and the assess-

ment of the PC risk of family members. Screening and

potentially future chemoprevention strategies for IAR can

be evaluated in a board approved clinical research setting.

In addition, IAR from FPC families can be investigated for

a variety of environmental factors that may modulate the

deleterious cancer-prone phenotype. Most importantly,

focused research projects can be conducted most efficiently

and profoundly when data from the various FPC registries,

as demonstrated by EUROPAC and FaPaCa, are combined.

Acknowledgments We are grateful to all FPC families for partic-

ipating in the registry. This study was supported by grants 70-2362-

Ba2, 70-2828-Ba3 and 103709 of the Deutsche Krebshilfe.

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