Pancreas

• Autosomal dominant disorder caused by mutations of serine protease 1 (PRSS1), also known as the cationic trypsinogen gene, characterized by progressive irreversible lipomatous atrophy of the pancreatic parenchyma leading to pancreatic insufficiency (Am J Surg Pathol 2014;38:346)
• Most common subtype of familial hereditary pancreatitis (80%); other gene mutations associated with chronic pancreatitis include SPINK1, CFTR and CTRC
• Incomplete penetrance; 40 - 93% of mutation carriers develop chronic pancreatitis
• Patients may develop pancreatic intraepithelial neoplasia (PanIN) and have an increased lifetime risk of pancreatic cancer

• Recurrent episodes of acute pancreatitis, typically starting in childhood, with progression to chronic pancreatitis over time
• Presentation of acute and chronic pancreatitis is clinically indistinguishable from other etiologies for pancreatitis

• Patients should be suspected of PRSS1 associated hereditary pancreatitis with the following: acute pancreatitis occurring in childhood; recurrent acute pancreatitis of unknown etiology; chronic pancreatitis of unknown cause (especially among individuals before age 25); a family history of recurrent acute pancreatitis and chronic pancreatitis following an autosomal dominant pattern of inheritance; and a family history of pancreatitis and pancreatic cancer
• Considering the aforementioned suspected clinical findings, a diagnosis is established by the identification of a heterozygous pathologic mutation in PRSS1
• Rare cases of PRSS1 R122H and A16V mutations have been reported in nonhereditary pancreatitis; therefore, family history prior to genetic testing is important to avoid misclassification and unnecessary testing (Clin Genet 2001;59:189, Pancreas 2001;22:18)

Contributed by Aatur D. Singhi, M.D., Ph.D.

Contributed by Aatur D. Singhi, M.D., Ph.D.

• 2 most common PRSS1 mutations are the R122H and N29I missense mutations
• > 30 mutations within PRSS1 have been identified; other less common mutations include A16V, R122C, N29T, D22G and K23R (Clin Gastroenterol Hepatol 2004;2:252)

A 20 year old man with a family history of recurrent pancreatitis and diabetes was found to have a PRSS1 mutation after being tested at age 5 during his first documented episode of pancreatitis. Regarding this entity, which of the following statements is true?


1. Diagnosis is made based primarily on radiology
2. Most common PRSS1 mutations are N29I and A16V
3. Patients are at an increased risk of pancreatic cancer
4. Pattern of inheritance for this entity is autosomal recessive

C. Patients are at an increased risk of pancreatic cancer. This picture shows a pancreas with partial replacement of normal parenchyma with loose perilobular and interlobular fibrosis with scattered adipocytes. In a patient with a family history of recurrent pancreatitis, identification of a pathologic mutation in PRSS1 in this patient establishes a diagnosis of PRSS1 hereditary pancreatitis. As the patient's disease progresses, the pancreas will continue to undergo replacement largely by adipocytes with primarily perilobuductal fibrosis. PanIN has been seen in several cases of hereditary pancreatitis and these patients are at an increased risk of pancreatic cancer.

Inheritance is in an autosomal dominant pattern with variable penetrance. The most common PRSS1 mutations are R122H and N29I. Patients' clinical, laboratory and radiological presentations of acute and chronic pancreatitis are the same as for other etiologies. Careful family history taking and testing for a PRSS1 mutation in a suspected individual is what establishes the diagnosis.

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Reference: PRSS1 hereditary pancreatitis

Which of the following statements is true regarding the histologic findings in PRSS1 hereditary pancreatitis?


1. Definitive diagnosis can be made if lipomatous atrophy is present
2. Islets of Langerhans are preferentially lost in early stages of the disease while acinar tissue is preserved
3. Pancreatic intraepithelial neoplasia can be present at any age
4. Presence of intraductal calcifications is associated with an increased risk of pancreatic cancer

C. Pancreatic intraepithelial neoplasia can be present at any age. PRSS1 hereditary pancreatitis is a progressive disease. In early stages, fibrosis and loss of acinar and ductal tissue is mild and patchy while islets of Langerhans are relatively preserved, which can result in a hyperplastic appearance. As the disease progresses, the pancreatic parenchyma undergoes near complete replacement by mature adipose tissue and fibrosis. Lipomatous atrophy is a nonspecific finding, which can be seen as a degenerative change in the obese and elderly or in patients with cystic fibrosis or other genetic syndromes. Intraductal calcifications are not associated with an increased risk of cancer and are one of several nonspecific microscopic changes seen in hereditary pancreatitis, along with ductal dilatation, squamous metaplasia and amyloid deposition. Patients with PanIN are at an increased risk of pancreatic cancer and PanIN can be seen at any age.

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Reference: PRSS1 hereditary pancreatitis