title: Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features.
abstract: Undifferentiated (anaplastic) carcinoma with rhabdoid features is a rare and aggressive subtype of pancreatic carcinoma. Here, we report the clinical, histological, and immunohistochemical phenotypes in six autopsy cases of anaplastic carcinoma with rhabdoid features. The patients ranged between 44 and 76 years of age (median, 61 years) and consisted of four males and two females. All patients except one case died within 3 months of diagnosis, as these tumors were found at an advanced stage and were chemoresistant. At autopsy, tumor masses measuring 4-22 cm in maximum diameter were mainly located in the pancreatic body and tail. Microscopically, all cases showed anaplastic carcinoma with rhabdoid features that were discohesive with round to polygonal eosinophilic cytoplasm with occasional inclusions, and that had vesicular nuclei, and prominent nucleoli. Immunohistochemistry showed that the rhabdoid cells, particularly the inclusions, were strongly positive for pan-cytokeratin (AE1/AE3) and vimentin. Meanwhile, downregulation or aberrant cytoplasmic localization with focal aggregation of E-cadherin, β-catenin, and EMA were frequently observed in the rhabdoid cells. Moreover, the intracytoplasmic inclusions were labeled with selective autophagy-related molecules including p62/SQSTM1, ubiquitin, and kelch-like ECH-associated protein 1 (KEAP1). In addition, nuclear factor erythroid 2-related factor 2 (NRF2) and overexpression of its target molecule multidrug resistance-associated protein 1 (MRP1) were commonly observed in the rhabdoid cells. Therefore, these results suggest that p62-mediated aggregation of ubiquitinated intermediate filaments and membranous proteins is an important phenomenon in the rhabdoid phenotype. Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features.
authors.affiliation: Division of Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan, sano.makoto@nihon-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sano
authors.forename: Taku
authors.initials: T
authors.lastname: Homma
authors.forename: Emiko
authors.initials: E
authors.lastname: Hayashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Noda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Amano
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Tsujimura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yamada
authors.forename: Brian
authors.initials: B
authors.lastname: Quattrochi
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nemoto
mesh_terms: D000328:Adult; D000368:Aged; D001344:Autopsy; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002277:Carcinoma / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; D007633:Keratins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014746:Vimentin; C421109:multidrug resistance-associated protein 1