Abstract
There are a number of inherited disorders that can affect the exocrine and/or endocrine function of the pancreas. These include inborn errors of metabolism such as hyperlipidemia, glycogen storage disorders, or maple syrup urine disease, which can be associated with pancreatitis. The autosomal dominant disorder hereditary chronic pancreatitis is discussed in detail in this chapter, together with cystic fibrosis, which may only present in late adolescence or early adulthood, and hereditary hemochromatosis. There are also a number of inherited syndromes that are associated with an increased risk of pancreatic cancer, which are briefly mentioned. Familial pancreatic cancer is discussed in more detail, particularly with reference to the role of screening in high-risk individuals.
There are a number of inherited disorders that can affect the exocrine and/or endocrine function of the pancreas. These include inborn errors of metabolism such as hyperlipidemia, glycogen storage disorders, or maple syrup urine disease, which can be associated with pancreatitis (see review by Simon et al. [1]). The autosomal dominant disorder hereditary chronic pancreatitis will be discussed in this chapter, together with cystic fibrosis, which may only present in late adolescence or early adulthood, and hereditary hemochromatosis. There are also a number of inherited syndromes that are associated with an increased risk of pancreatic cancer, which will be briefly mentioned. Familial pancreatic cancer will be discussed in more detail, particularly with reference to the role of screening in high-risk individuals. Inherited endocrine disorders are discussed in Chap. 20.
1 Cystic Fibrosis
Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7q31.2. More than 1,500 mutations have been described in the CFTR gene, but not all result in cystic fibrosis. This variation in genotype may account for the different phenotypes of cystic fibrosis and variation in disease severity. The CFTR gene encodes a protein that functions as a cell membrane chloride channel. Disruption of CFTR function leads to defective electrolyte transport across the cell membrane, particularly affecting the lung and pancreas. In the normal pancreas, the acinar cells secrete a relatively low volume of fluid rich in enzymes, while the duct system secretes a relatively large volume of bicarbonate-rich fluid. In cystic fibrosis, the volume of pancreatic fluid secreted is markedly lower than normal with resultant abnormally thick mucus in the pancreatic ducts, which leads to obstruction.
The incidence of cystic fibrosis in the Caucasian population is estimated to be 1 in 2,000 to 1 in 3,000. Males and females are affected equally, and most present in childhood with chronic sinopulmonary disease. Involvement of the pancreas manifests as recurrent acute pancreatitis, chronic pancreatitis, and pancreatic abnormalities on imaging. The sweat chloride test remains the gold standard for cystic fibrosis diagnosis but does not always give a clear answer. Moreover, genetic testing does not always provide clarity [2].
1.1 Macroscopy
Pancreatic involvement in cystic fibrosis is characterized by varying degrees of fibrosis, fatty replacement, and cyst formation. There may be narrowing of the pancreatic ducts due to the fibrosis. The cysts, which represent dilated ducts, may vary from 1 to 3 mm in diameter up to 3–5 cm diameter. These cysts may contain cloudy fluid or inspissated protein-rich secretions, which can undergo mineralization and stone formation. In some cases, the pancreas may be almost entirely replaced by adipose tissue (lipomatosis) (see Chap. 5).
1.2 Microscopy
The earliest change in cystic fibrosis is the dilatation of acini and ductules with accumulation of eosinophilic secretions within them. Larger ducts may also contain inspissated secretions and show varying degrees of dilatation and periductal fibrosis. The secretions may show concentric lamellations resembling corpora amylacea. The cells lining the dilated ductules and acini may be flattened, and there may also be squamous metaplasia.
With progression of the disease, there is acinar and lobular atrophy, with increasing intralobular and interlobular fibrosis, typical of chronic pancreatitis (see Chap. 7). There may be abundant islets, including enlarged islets, within the fibrous tissue, and fatty infiltration of the pancreas. There may be marked cystic dilatation of ducts filled with eosinophilic secretions (Fig. 6.1) and, when ducts rupture, an associated periductal acute and chronic inflammatory cell infiltrate. In advanced disease, there may be extensive fatty replacement with only scattered residual ducts and islets within this adipose tissue.
2 Hereditary Hemochromatosis
Hereditary hemochromatosis is an autosomal recessive disorder affecting the Caucasian population with a prevalence of between 1 in 200 and 1 in 300. The gene responsible for classic hereditary hemochromatosis is the HFE gene. Mutations in other iron genes, however, may be associated with hereditary iron overload syndromes and can cause all of the phenotypic features of classical hereditary hemochromatosis. The present definition of hereditary hemochromatosis, therefore, embraces the classic disorder related to HFE C282Y homozygosity and the rare disorders more recently attributed to loss of transferrin receptor 2, hepcidin, hemojuvelin, or, in very rare cases, ferroportin [3].
Hereditary hemochromatosis is characterized by inappropriately increased iron absorption from the duodenum and small intestine, with consequent deposition in various organs, notably the liver, endocrine glands, joints, heart, and skin, with resultant organ damage. Clinical features may be nonspecific and include lethargy and malaise or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation, and hypogonadism. The classical description is that of cutaneous hyperpigmentation, diabetes mellitus, and hepatomegaly. Clinical manifestations often occur at 40–60 years of age, and men tend to present earlier due to the protective mechanism of menstrual blood loss in women.
2.1 Macroscopy
The descriptions of pancreatic pathology in hereditary hemochromatosis are almost invariably restricted to autopsy studies [4]. Macroscopically, the pancreas can be enlarged and may be a light brown or chocolate color with distinct lobulation due to hemosiderin-laden lobules standing out from fibrous or fatty tissue.
2.2 Microscopy
On microscopy, hemosiderin deposition occurs throughout the pancreas and may be intracellular or extracellular. There is hemosiderin deposition within the acinar cells (Fig. 6.2), islets of Langerhans, and the interstitium. There may be marked fibrosis, but the amount of fibrous tissue varies considerably and may be unevenly distributed throughout the pancreas. There may also be increased adipose tissue within the pancreas.
3 Hereditary Chronic Pancreatitis
Hereditary chronic pancreatitis (HCP), a rare form of early onset chronic pancreatitis (accounting for 1–2 % of cases of chronic pancreatitis), was first described in 1952 [5] as hereditary chronic relapsing pancreatitis. It is an autosomal dominant disorder with incomplete (80 %) penetrance and variable disease expression. In affected individuals, the disease may vary from very mild to severe, and there is an increased risk of pancreatic cancer (see below).
In 1996, the gene for HCP was mapped to the long arm of chromosome 7 (7q35), and the p.R122H mutation was identified in the protease serine 1 (PRSS1) gene, which encodes cationic trypsinogen [6, 7]. Cationic trypsinogen (PRSS1) gene mutations account for approximately 60–80 % of all cases of HCP, with no mutation having been identified in the other 20–40 % of families. More than 30 mutations in the PRSS1 gene have now been described. With the exception of the p.R122x and p.N29x gain-of-function mutations, most of the mutations are not thought to be associated with chronic pancreatitis in an autosomal dominant manner. The p.R122H and p.N29I mutations in the PRSS1 gene account for the majority of patients with HCP. These mutations are thought to prevent the deactivation of inappropriately activated intrapancreatic trypsinogen or to increase trypsinogen activation, resulting in acinar cell autodigestion and subsequent pancreatitis. Mutation in the PRSS1 gene can also induce misfolding of cationic trypsinogen, resulting in intracellular retention and decreased secretion [8]. The central role of trypsin in pancreatitis, however, has recently been challenged [9].
Other genetic factors linked to chronic pancreatitis include mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene on chromosome 5q32, which encodes the pancreatic secretory trypsin inhibitor (PSTI), and the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see above). Although various loss-of-function mutations in the SPINK1 gene have been found in chronic pancreatitis, only the p.N34S mutation is believed to be associated with the disease. p.N34S is rare in HCP but may act as a disease modifier. The role (if any) of the CFTR gene in HCP is not clear.
3.1 Clinical Features
The typical presentation is with recurrent attacks of acute pancreatitis (without antecedent factors) before the age of 20 years (median age of onset about 10 years). There is subsequent progression to chronic pancreatitis (over a decade) in about half of the patients. The clinical features resemble those of idiopathic pancreatitis, but the clinical course may be more severe.
3.2 Diagnostic Criteria
The diagnosis of HCP can only be considered after exclusion of other causes of chronic pancreatitis in childhood, for example, anatomical anomalies (see Chap. 13), metabolic disorders, cystic fibrosis, trauma, and viruses. The diagnostic criteria for HCP include two first-degree relatives, or at least three second-degree relatives, in two or more generations, with recurrent acute pancreatitis and/or chronic pancreatitis for which there are no precipitating factors. Detection of p.R122H or p.N29I mutations in the cationic trypsinogen (PRSS1) gene is diagnostic.
3.3 Pathology
There are limited publications on the histopathological features of HCP [10, 11]. There may be dilated ducts containing protein plugs and calculi, periductal fibrosis, and pseudocysts, which may be detected on radiological imaging. The finding of a mutation does not predict the onset or severity of the disease. Patients may have entirely normal pancreas (Fig. 6.3), the classic features of chronic pancreatitis described above (Fig. 6.4), or may show extensive fatty infiltration (Fig. 6.5).
Pancreatic intraepithelial neoplasia (PanIN – see Chap. 8) is frequently found in patients with hereditary chronic pancreatitis [12] and includes all grades of PanIN. These PanINs occur at a younger age than in the general population (median age of 24 years), and the frequency is much higher than in the pancreata of normal subjects at the same age or in patients with alcoholic chronic pancreatitis.
3.4 Cancer Risk
Patients with HCP have an estimated 50-fold increased relative risk for developing pancreatic cancer and develop pancreatic cancer at a younger age than sporadic patients. This compares with a two- to fourfold increased risk of pancreatic cancer with cigarette smoking and a two- to 20-fold increased risk in chronic alcoholic pancreatitis (see below). Smoking also increases the risk of pancreatic cancer in HCP and seems to lower the age of onset of the cancer by nearly two decades. There is no difference in the risk of pancreatic cancer based on the type of PRSS1 gene mutation. The high risk of cancer is probably related to the repeated and progressive tissue destruction over a long period of time (30–40 years). Up to 40 % of patients with hereditary chronic pancreatitis may develop pancreatic cancer (conventional ductal type – see Chap. 9).
3.5 Management
HCP should always be considered in the differential diagnosis when chronic pancreatitis occurs in a child or young adult. If HCP is confirmed, then patients should be advised not to smoke, because of the increased risk of pancreatic cancer, and should avoid alcohol since it is a risk factor for acute and chronic pancreatitis. A screening program for the identification of HCP patients and screening for early cancer, using multimodality imaging and molecular analysis of pancreatic juice obtained at endoscopic retrograde cholangiopancreatography (ERCP), combined with clinical genetic counseling and consultation with a pancreatologist, has been implemented by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer.
4 Inherited Pancreatic Cancer
Familial forms of pancreatic cancer account for approximately 5 % of pancreatic carcinomas, and this inherited predisposition to pancreatic cancer occurs in three distinct clinical settings:
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1.
Hereditary tumor predisposition syndromes, such as familial atypical multiple mole melanoma (FAMMM), familial adenomatous polyposis (FAP), hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome, and Peutz-Jeghers syndrome (PJS)
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2.
Associated with chronic inflammation of the pancreas (cystic fibrosis and hereditary chronic pancreatitis)
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3.
Familial pancreatic cancer (FPC – see below), which accounts for the largest proportion of hereditary pancreatic carcinomas [13]
The penetrance of pancreatic cancer is highly variable in these inherited disorders with relative risks ranging from 2.3 to 132 compared to the general population (Table 6.1) [14]. These inherited risks of pancreatic cancer are generally much higher than the risks associated with cigarette smoking (2.5–3.8-fold increase), diabetes mellitus (2.1–2.6-fold increase), and nonhereditary pancreatitis (2–20-fold increase).
4.1 Pathology
The pancreatic cancers in patients with these inherited syndromes are usually conventional, pancreatic ductal adenocarcinomas, but they may arise in a background of intraductal papillary mucinous neoplasm (IPMN), which can give rise to colloid carcinomas as well as conventional type ductal carcinoma (see Chap. 17). Whenever a medullary variant of pancreatic ductal adenocarcinoma (see Chap. 9) is diagnosed, the possibility of Lynch syndrome (hereditary nonpolyposis colorectal cancer or HNPCC) should be highlighted in the pathology report (Table 6.1).
5 Familial Pancreatic Cancer
Familial pancreatic cancer (FPC) applies to families with two or more first-degree relatives with pancreatic cancer that do not fulfill the criteria of any other inherited tumor syndrome (Table 6.1). A pattern indicative of an autosomal dominant trait of inheritance has been identified in 58–80 % of FPC families. Germline mutations in BRCA2, PALB2 (partner and localizer of BRCA2), and ATM are thought to be causative in 20 % of FPC families [13], but the genetic basis of the majority of FPC cases has yet to be determined.
5.1 Cancer Risk
In familial pancreatic cancer (FPC), the risk for pancreatic cancer increases with the number of affected individuals. Thus, the risk for pancreatic cancer in individuals with one first-degree relative with pancreatic cancer is twofold higher than that for an individual without an affected first-degree relative, individuals with two affected first-degree relatives have a sixfold increased risk, and individuals with three or more affected first-degree relatives have a 14- to 32-fold increased risk for pancreatic cancer [15].
5.2 Clinical Features, Pathology, and Prognosis
Patients with FPC develop their cancers at the same age as those with sporadic forms of disease [16]. The sex distribution, pathology of the pancreatic carcinoma, and prognosis are similar to the sporadic form. The majority of patients develop conventional pancreatic ductal adenocarcinoma, but they may develop invasive carcinoma arising from intraductal papillary mucinous neoplasia (IPMN with associated invasive carcinoma – see Chap. 17) or variants of pancreatic ductal adenocarcinoma, including adenosquamous carcinoma, undifferentiated carcinoma, and signet ring cell carcinoma (see Chap. 9).
6 Screening High-Risk Individuals
Patients with a family history of pancreatic cancer are significantly more likely to harbor widespread pancreatic cancer precursor lesions, namely, pancreatic intraepithelial neoplasia (PanIN – see Chap. 8) and intraductal papillary mucinous neoplasia (IPMN – see Chap. 17), than those patients with sporadic pancreatic cancer. Furthermore, these pancreatic cancer precursors are more likely to contain higher grades of dysplasia [17] than are present in pancreata from patients without a family history. This has led to the use of radiological imaging to detect these preinvasive lesions (or asymptomatic small cancers) in high-risk individuals with an inherited predisposition to pancreatic cancer (Table 6.1), ultimately aiming to improve patient outcome [16].
PanIN can be associated with lobulocentric atrophy (see Chap. 5), which may be detected on endoscopic ultrasound (EUS) [18]. However, lobulocentric atrophy occurs with all grades of dysplasia and, therefore, there is a risk of overtreatment if pancreata are resected for lobulocentric atrophy which is only associated with low-grade dysplasia.
EUS and magnetic resonance imaging (MRI) can detect small cystic pancreatic lesions, which are often multiple and multifocal and the majority of which are branch-duct-type IPMNs. CT is not as good as MRI or EUS for detecting these small cysts. Magnetic resonance cholangiopancreatography (MRCP) provides the best visualization of cystic communication (for IPMNs) with the main pancreatic duct [19]. Most sporadic branch-duct IPMNs have low risk for malignancy and can be observed safely if they do not meet standard internationally accepted consensus criteria for resection (see Chap. 17). However, because these criteria have been validated only in patients with sporadic pancreatic cysts, it is unclear if they are appropriate for high-risk individuals [16].
The prevalence of PanINs and IPMNs increases with age; the likelihood of a prevalent lesion is much higher in patients over 50 years of age. Therefore, the recently published international guidelines on the management of patients with an inherited predisposition to pancreatic cancer [19] recommend that screening should start at 50 years of age. For patients with hereditary chronic pancreatitis (see above), screening typically should begin at 40 years of age because of the younger age of onset of pancreatic cancer in these patients. These guidelines also propose that initial screening should include EUS and/or MRI/MRCP but not CT or endoscopic retrograde cholangiopancreatography (ERCP).
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Further Reading
Ooi CY, Dupuis A, Ellis L, Jarvi K, Martin S, Gonska T, et al. Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? Thorax. 2012;67:618–24.
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Solomon S, Whitcomb DC. Genetics of pancreatitis: an update for clinicians and genetic counselors. Curr Gastroenterol Rep. 2012;14:112–7.
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Campbell, F., Verbeke, C.S. (2013). Hereditary Exocrine Disorders. In: Pathology of the Pancreas. Springer, London. https://doi.org/10.1007/978-1-4471-2449-8_6
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