Familial pancreatic cancer: Concept, management and issues

Table 1 Relative risk of pancreatic cancer in hereditary cancer syndromes

Inherited syndrome	Relative risk	Cumulative risk of PC	Responsible gene
Peutz-Jeghers syndrome[27]	132	11%-36%	STK11
Hereditary pancreatitis[28-31]	53-87	40%-55%	PRSS1
Familial atypical multiple mole melanoma[32,33]	13-22	17%	CDKN2A
Hereditary breast-ovarian cancer syndrome[34-37,73]	4-13	2%-7%	BRCA1, BRCA2
Lynch syndrome[38,39]	5-9	4%	MLH1, MSH2, MSH6, PMS2
Familial adenomatous polyposis[40]	5	-	APC, MUTYH

PC: Pancreatic cancer.

Table 2 Screening candidates with high risks¹

Individuals with ≥ 3 affected relatives, with ≥ 1 affected FDR

Individuals with ≥ 2 affected FDRs with PC, with ≥ 1 affected FDR, reaching a certain age

Individuals with ≥ 2 affected relatives with PC, with ≥ 1 affected FDR

Peutz-Jeghers syndrome patients, regardless of family history of PC

CDKN2A mutation carriers with one affected FDR

BRCA2 mutation carriers with one affected FDR

BRCA2 mutation carriers with two affected family member pf PC

PALB2 mutation carriers with one affected FDR

Mismatch repair gene mutation carrier (lynch syndrome) with one affected FDR

¹Quoted from the reference[69]. FDR: First-degree relative; PC: Pancreatic cancer.

Table 3 Non-genetic risk factors of pancreatic cancer

Factors	Risk level
Smoking[8-10]	OR = 1.5-2.2
Diabetes[11,12]	RR = 1.8-1.9
Obesity[13,14]	RR = 1.1-1.4
Chronic pancreatitis[6,7]	SIR = 13-14
Intraductal papillary mucinous neoplasm[5]	SIR = 16
Dilated main pancreatic duct [3]	HR = 6.4
Pancreatic cyst[3,4]	HR = 6.2; OR = 10.3

SIR: Standardized incidence ratio.

Table 4 Outcomes of pancreatic cancer surveillance of high risk individual

Ref.	Year	Country/registry	Entry period	Subjects conditions	Age (range), yr	n	Duration (mo)	Modality	Ratio of surgical cases (n)	Pathology of the pancreatic lesion: n			Ratio of unresectable advanced PC (n)
								(surveillance→examination)		Benign1	Border/CIS2	PC
Brentnall et al[42]	1999	United States	NA	FPC kindred	41 (28-65)	14	15	EUS, CT → ERCP	50.0% (7)	0	75	0	0% (0)
Canto et al[101]	2004	United States	1998-2001	FPC kindred, PJS	58 (NA)	38	22	EUS → CT, EUS-FNA, ERCP	18.4% (7)	4	2	1	0% (0)
Canto et al[97]	2006	United States	2001-2004	FPC kindred, PJS	52 (32-77)	78	12	EUS, CT → EUS-FNA, ERCP	9.0% (7)	4	3	0	1.3% (1)
Langer et al[50]	2009	FaPaCa	1999-2007	FPC kindred, BRCA2 (+)4, CDKN2A (+) FAMMM family	60 (35-85)	76	NA	EUS, MRI → EUS-FNA	9.2% (7)3	6	0	0	0% (0)
Poley et al[95]	2009	Netherlands	2005-2007	FPC kindred, HP, PJS, FAMMM, BRCA1/2 (+), TP53 (+)	50 (32-75)	44	Initial6	EUS → CT, MRI	6.8% (3)	0	0	3	0% (0)
Verna et al[124]	2010	United States	2005-2008	FPC kindred, BRCA1/2 (+), LS, FAMMM	52 (29-77)	51	Initial	EUS, MRI → EUS-FNA, ERCP	9.8% (5)	4	0	1	2.0% (1)
Ludwig et al[114]	2011	United States	2002-2009	FPC kindred, BRCA1/2(+)	54 (33-86)	109	Initial	MRI → EUS, EUS-FNA	5.5% (6)	3	2	1	0% (0)
Vasen et al[125]	2011	Netherlands	2000-2010	CDKN2A-Leiden (+)	56 (39-72)	79	48	MRI	6.3% (5)	0	0	5	2.5% (2)
Zubarik et al[126]	2011	United States	2006-2009	FDR of PC with sCA19-9↑	59 (NA)	26	NA	EUS → EUS-FNA	11.5% (3)	2	0	1	0% (0)
Al-Sukhni et al[127]	2012	Canada	2003-2011	FPC kindred, PJS, HP, CDKN2A (+), BRCA1/2 (+), STK11 (+)	54 (22-89)	262	50	MRI → MRI, EUS, EUS-FNA, ERCP	1.5% (4)	3	0	1	0.8% (2)
Sud et al[91]	2014	United States	2008-2011	FPC kindred, HP, CDKN2A (+), BRCA1/2 (+), PJS, LS	51 (20-75)	16	NA	EUS → EUS-FNA	18.8% (3)	1	0	2	0% (0)
Del Chiaro et al[92]	2015	Sweden	2010-2013	FPC kindred, individuals with increased genetic risk	50 (23-76)	40	13	MRI → EUS, EUS-FNA	12.5% (5)	2	0	3	0% (0)
Vasen et al[94]	2016	FaPaCa	2000-2015	FPC kindred, CDKN2A (+), BRCA1/2 (+), PALB2 (+)	46-56 (25-81)	411	16-53	MRI ± EUS → EUS, CT → EUS-FNA	7.3% (30)	15	4	11	1.0% (4)

¹Benign lesions included low-moderate grade of intraductal papillary mucinous neoplasm (IPMN), grade 1-2 of pancreatic intraepithelial neoplasm (PanIN), serous cystadenoma, and neuroendocrine tumor;

²High-grade precursors and PanIN3;

³No lesion detected in one case of resected pancreas;

⁴(+): mutation carrier;

⁵Wide spread dysplasia;

⁶Evaluated only by the initial surveillance, one resectable pancreatic cancer case (T1N0M0) not resected because of metastatic melanoma. PC: Pancreatic cancer; FPC: Familial pancreatic cancer; PJS: Peutz-Jeghers syndrome; HP: Hereditary pancreatitis; FAMMM: Familial atypical multiple mole melanoma; LS: Lynch syndrome; FDR: First degree relative; FaPaCa: German national case collection for familial pancreatic cancer; NA: Not available, EUS: Endoscopic ultrasonography; EUS-FNA: EUS-guided fine needle aspiration; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography; MRI: Magnetic resonance imaging.