Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features
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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.
KeywordsUndifferentiated carcinoma Pleomorphic carcinoma Rhabdoid feature Autophagy Chemoresistance
The authors thank Ms. Yukari Hirotani for excellent technical support.
Conflict of interest
The authors declare no conflicts of interest.
- 12.Jamali M, Serra S, Chetty R (2007) Adenosquamous carcinoma of the pancreas with clear cell and rhabdoid components. A case report. JOP J Pancreas 8:330–334Google Scholar
- 16.Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L, Kleinert R, Prinz M, Aguzzi A, Denk H (2002) p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160:255–263. doi: 10.1016/S0002-9440(10)64369-6 PubMedCrossRefPubMedCentralGoogle Scholar
- 19.Klöppel G, Adler G, Hruban RH, Kern SE, Longnecker DS, Partanen TJ (2000) World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Tumours of the exocrine pancreas. International Agency for Research on Cancer (IARC), Lyon, FranceGoogle Scholar
- 22.Bourdeaut F, Freneaux P, Thuille B, Lellouch-Tubiana A, Nicolas A, Couturier J, Pierron G, Sainte-Rose C, Bergeron C, Bouvier R, Rialland X, Laurence V, Michon J, Sastre-Garau X, Delattre O (2007) hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities. J Pathol 211:323–330. doi: 10.1002/path.2103 PubMedCrossRefGoogle Scholar
- 24.Izumi T, Oda Y, Hasegawa T, Nakanishi Y, Iwasaki H, Sonobe H, Goto H, Kusakabe H, Takahira T, Kobayashi C, Kawaguchi K, Saito T, Yamamoto H, Tamiya S, Iwamoto Y, Tsuneyoshi M (2006) Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Mod Pathol Off J U S Can Acad Pathol Inc 19:820–831. doi: 10.1038/modpathol.3800599 Google Scholar
- 28.Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, Copple IM, Williams S, Owen A, Neoptolemos JP, Goldring CE, Park BK (2011) Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer 10:37. doi: 10.1186/1476-4598-10-37 PubMedCrossRefPubMedCentralGoogle Scholar
- 29.Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, Schreiber S, Schafer H (2012) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. doi: 10.1038/onc.2012.493 PubMedGoogle Scholar