Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway

Abstract

Acinar cell carcinomas (ACCs) are rare malignant tumors of the exocrine pancreas. The specific molecular alterations that characterize ACCs have not yet been elucidated. ACCs are morphologically and genetically distinct from the more common pancreatic ductal adenocarcinomas. Instead, the morphological, immunohistochemical, and clinical features of ACCs overlap with those of another rare pancreatic neoplasm, pancreatoblastoma. We have recently demonstrated a high frequency of allelic loss on chromosome arm 11p and mutations in the APC/beta-catenin pathway in pancreatoblastomas, suggesting that similar alterations might also play a role in the pathogenesis of some ACCs. We analyzed a series of 21 ACCs for somatic alterations in the APC/beta-catenin pathway and for allelic loss on chromosome 11p. In addition, we evaluated the ACCs for alterations in p53 and Dpc4 expression using immunohistochemistry, and for microsatellite instability (MSI) using polymerase chain amplification of a panel of microsatellite markers. Allelic loss on chromosome 11p was the most common genetic alteration in ACCs, present in 50% (6 of 12 informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 23.5% (4 of 17) of the carcinomas, including one ACC with an activating mutation of the beta-catenin oncogene and three ACCs with truncating APC mutations. One ACC (1 of 13, 7.6%) showed allelic shifts in four of the five markers tested (MSI-high), two (15.4%) showed an allelic shift in only one of the five markers tested (MSI-low), and no shifts were detected in the remaining 10 cases. The MSI-high ACC showed medullary histological features. In contrast, no loss of Dpc4 protein expression or p53 accumulation was detected. These results indicate that ACCs are genetically distinct from pancreatic ductal adenocarcinomas, but some cases contain genetic alterations common to histologically similar pancreatoblastomas.

Figure 1.

Histopathological appearance of pancreatic ACC. The neoplastic epithelial cells show variable growth patterns including areas of sheet-like growth divided by bands of fibrous tissue (A) and areas of acinar differentiation (B). Identical growth patterns can be present in ACCs and pancreatoblastomas, but characteristic squamoid corpuscles are not seen in the former.

Figure 2.

Alterations in the APC/β-catenin pathway in ACCs. A: DNA sequencing from case A13, showing an ACC (threonine) → ATC (isoleucine) mutation at codon 41 of the β-catenin gene. Sequencing of nonneoplastic tissue from this patient shows only wild-type β-catenin, confirming the somatic nature of the β-catenin mutation. B: Frameshift APC mutations in cases A16 and A18. DNA sequencing shows a 1-bp insertion A into a 6 base poly(A) tract spanning codons 1554 to 1556 in each case. The corresponding wild-type APC sequence from a different ACC is shown above. C: Nonsense APC mutation in case A2. DNA sequencing shows a CAA (glycine) → TAA (stop) mutation at codon 1444 that is present in the ACC but not in the nonneoplastic tissue from this patient.

Figure 3.

Immunohistochemical labeling for β-catenin in an ACC. Nuclear and cytoplasmic accumulation of β-catenin in neoplastic epithelial cells is present in this example (case A16), which also showed a truncating APC gene mutation. Stromal cells in the intervening fibrous bands show membranous β-catenin labeling, but are negative for nuclear and cytoplasmic accumulation.

Figure 4.

Allelic loss on 11p15.5 in ACC. LOH is present with both the D11S1984 and TH1 microsatellite markers for case A12, which was informative for both markers. N, normal; T, ACC.

Figure 5.

MSI in an ACC. A: Case A19 demonstrates MSI-high, with allelic shifts in the microsatellite markers D5S346, D17S250, Bat-25, and Bat-26. Only D2S123 is stable. In contrast, no allelic shifts are present in case A12, which is microsatellite stable. B: The histopathological features of case A19 overlapped with those of medullary carcinoma of the pancreas, with areas of poor differentiation and syncytial growth. C: Unlike cases of previously described medullary carcinoma, foci of clear-cut acinar differentiation were also present.