The histopathology of PRSS1 hereditary pancreatitis

Abstract

Hereditary pancreatitis is an autosomal dominant disorder with 80% penetrance and variable expressivity. The vast majority of cases have been linked to mutations within the cationic trypsinogen gene, also referred to as serine protease 1 (PRSS1). Other than inheritance, PRSS1 pancreatitis has been considered clinically and pathologically indistinguishable from other etiologies of chronic pancreatitis. However, to date, the histologic findings of PRSS1 pancreatitis have not been well described. We, therefore, collected pancreatic specimens from 10 PRSS1 patients of various ages and examined their clinicopathologic features. Patients at the time of resection ranged in age from 9 to 66 years (median, 29 y), with a slight female predominance (60%). All patients reported a history of intermittent abdominal pain, with an age of onset ranging from infancy to 21 years of age. Examination of the gross and microscopic findings suggested a sequential pattern of changes with increasing patient age. In pediatric patients (n=4), although in most cases the pancreas was grossly normal, there was microscopic variation in lobular size and shape. Although the central portions of the pancreas displayed parenchymal loss accompanied by loose perilobular and interlobular fibrosis, the periphery was remarkable for replacement by mature adipose tissue. These changes were more developed in younger adults (n=2), in whom fatty replacement seemed to extend from the periphery to the central portions of the pancreas. With older patients (n=4), the pancreas showed marked atrophy and extensive replacement by mature adipose tissue with scattered islets of Langerhans and rare acinar epithelium concentrated near the main pancreatic duct. In summary, PRSS1 hereditary pancreatitis is characterized by progressive lipomatous atrophy of the pancreas.

FIGURE 1

A sequential pattern of histologic changes were identified in patients with germline mutations in PRSS1. A, Pancreata from pediatric patients were characterized by patchy parenchymal loss with replacement by loosely packed, perilobular and interlobular fibrosis. In addition, a mild increase in chronic inflammation was identified and primarily localized around dilated pancreatic ducts. B, At the periphery of the pancreas, a greater loss of acinar and ductal tissue was seen with residual islet of Langerhans organized in aggregates and surrounded by mature adipocytes and thin wisps of collagen. C, In young adults, progressive parenchymal collapse was observed with replacement by perilobular and interlobular fibrosis and scattered adipocytes. D, Ductal alterations including ectasia and metaplasia were common findings.

FIGURE 2

A, In older adults with germline PRSS1 mutations, the pancreas was grossly soft and shrunken. Marked atrophy with fatty replacement, ductal dilatation, and multiple intraductal calculi were seen in all cases. B, Microscopically, there was extensive parenchymal replacement by adipose tissue. Residual fibrosis was found cuffing the main pancreatic duct (filled arrowhead) and larger interlobular ducts, whereas intralobular and smaller interlobular ducts were reduced and/or scarred (open arrowhead). C and D, Among mature adipose tissue were scattered nerves and islets of Langerhans. C, In 2 cases, amyloid deposition was seen within the islets of Langerhans.

FIGURE 3

A, PanIN was identified in 3 patients with germline PRSS1 mutations. B, In these patients, PanINs were often situated in the background of mature adipose tissue.