The histopathology of SPINK1-associated chronic pancreatitis

Abstract

Background: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis.

Methods: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated.

Results: Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases.

Conclusions: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.

Keywords: Alcohol; Fibrosis; Genetics; Pancreatitis; Pathology.

Figure 1.

The pancreata of SPINK1 carriers with a history of abdominal pain of < 4 years. An examination of pancreatic specimens identified mild atrophy that was characterized by decreasing size and variable shape of the pancreatic lobules (A and B). For a subset of cases, multifocal, cytoplasmic vacuolization of the acinar parenchyma (C) and focal intralobular fibrosis at the periphery of the pancreas (D) were seen.

Figure 2.

SPINK1 patients with a history of abdominal pain ranging from 4 to < 7 years. The pancreata exhibited a progressive loss of acinar parenchyma with coinciding mild interlobular and mild perilobular fibrosis. Fibrosis was typically composed of thick bundles of collagen, fibroblasts and scattered islands of neutrophilic inflammation (A and B). A brisk acute inflammatory infiltrate was also seen present within the pancreatic lobules (C and D).

Figure 3.

Pancreatic specimens from SPINK1 patients with a 7-to-15-year history of abdominal pain. The pancreata demonstrated increasing loss of acinar cell epithelium and intralobular ducts, which coincided with intralobular, interlobular and perilobular fibrosis (A and B). Ductal ectasia, squamous metaplasia and intraductal concretions were also present (C). The periphery of the pancreas was remarkable for complete loss of acinar and ductal epithelium, but preservation of islets of Langerhans and surrounding nerves (D). In addition, while the majority of patients were heterozygous for SPINK1, 3 patients were SPINK1 homozygotes with reported abdominal pain between 8.1 to 10 years and their pancreata exhibited similar histopathologic features as their SPINK1 heterozygous counterparts with ductal ectasia and intraductal concretions (E) and both intralobular and interlobular fibrosis (F).

Figure 4.

SPINK1 carriers with a history of abdominal pain that ranged between 21 and 25 years. Pancreatic specimens exhibited near complete to complete loss of acinar and ductal epithelium, and extensive parenchymal fibrosis (A and B). The remnant exocrine pancreas consisted primarily of a dilated main pancreatic duct and associated interlobular ducts (C). Scattered foci of reactive and hyperplastic intralobular ducts were also identified (D). At higher magnification, residual islets of Langerhans were found scattered throughout the pancreas but embedded in dense fibrosis (E and F).