Filamentous Inclusions in Nonneoplastic and Neoplastic Pancreas: An Ultrastructural and Immunogold Labeling Study

Abstract

Filamentous inclusions (FI) are unusual, irregularly shaped cytoplasmic inclusions, which are mostly found in acinar cell carcinomas of the pancreas and are consequently thought to be an abnormal zymogen granule type. This study describes identical inclusions in acinar, centroacinar, and small duct epithelial cells from nonneoplastic pancreas, as well as those found in tumor cells from a mixed acinar-endocrine pancreatic carcinoma. An ultrastructural and immunogold labeling demonstration indicates that these inclusions are aggregates of intermediate filaments immunoreacting with the anti-cytokeratin AE1/AE3 mixture and with V9 clone anti-vimentin monoclonal antibodies. Their pleomorphic appearance, variable immunoreactivity, and frequent association with lipid droplets and secondary lysosomes, mostly of the angulate type, led to the hypothesis that the FI undergo a degenerative remodeling pathway similar to that proposed for hepatic Mallory bodies. A survey of the literature on FI and human tumors suggests that they are a variably expressed ultrastructural feature of tumor cells originating from exocrine cell-containing tissues, namely the pancreas and gastrointestinal tract.

The Role of the Ubiquitin Proteasome Pathway in Keratin Intermediate Filament Protein Degradation

“…These different locations were correlated to stages of MDB formation in the griseofulvin-fed mouse model; in this model, smaller, globular aggresomes reflect early formation of MDBs, whereas in later stages of formation, the MDBs become larger, perinuclear structures (22). Aggresomes are also observed in renal cell carcinoma (23), nonneoplastic pancreatic cells (24), and patients with interstitial pneumonitis (25), as well as in the cytoplasm of especially swollen alveolar epithelial cells. These cytoplasmic aggresomes are composed of intermediate-type fine fibrils, which are positive for anti-keratin antibody-predominantly K8 and variable amounts of K18 assembled in a nonfilamentous manner (26).…”

“…The rate and extent of keratin IF disassembly and degradation exhibits a dependence on the degree of shear stress (30); increased levels of shear stress accelerate the rate of disassembly and reorganization of the keratin IF network. The disassembly and degradation of keratin proteins is regulated by posttranslational modifications, mainly phosphorylation and ubiquitination (24,26). The initial step in this process appears to be ''tagging'' the keratin protein for degradation via phosphorylation.…”

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer

“…The 3-mm thick paraffin sections of primary tumours were deparaffinised, treated with the heat-induced antigen retrieval technique, and epithelial pancreatic carcinoma cells were immunostained for 60 min using cytokeratin (CK) AE1/AE3 (20 : 1 ratio of AE1 to AE3, DAKO Corporation; diluted 1 : 200 in PBS), a mouse monoclonal antibody cocktail that reacts with all epithelial cells of normal pancreatic duct and tumour cells (Pasquinelli et al, 1995;Kurahara et al, 2007), and Ki-67 mouse monoclonal antibody (DAKO Corporation; diluted 1 : 50 in PBS) that reacts with proliferating cells at any phase of the cell cycle (except for G0 phase) (Igarashi et al, 1999). Reactions were developed using the avidin -biotin immunoperoxidase technique (ABC method; Hsu et al, 1981).…”

Nonductal neoplasms of the pancreas

“…A second granule type, the irregular fibrillary granule, is also highly characteristic of pancreatic acinar differentiation. 78,118,119,121 These granules are generally larger than the round zymogen granules, ranging up to 3500 nm, and are irregularly shaped, often elongated, angulated or bilobed, with fibrillary internal contents.…”