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WHO Classification of Tumours
Mixed ductal-neuroendocrine carcinoma
Pancreas


Definition

Carcinomas with mixed differentiation are malignant epithelial neoplasms of the pancreas with significant components of more than one distinct direction of differentiation
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Hoorens A, Lemoine NR, McLellan E, Morohoshi T, Kamisawa T, Heitz PU, Stamm B, Rüschoff J, Wiedenmann B, Klöppel G (1993)
Pancreatic acinar cell carcinoma. An analysis of cell lineage markers, p53 expression, and Ki-ras mutation.
Am J Pathol 143: 685-98
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Horie A, Haratake J, Jimi A, Matsumoto M, Ishii N, Tsutsumi Y (1987)
Pancreatoblastoma in Japan, with differential diagnosis from papillary cystic tumor (ductuloacinar adenoma) of the pancreas.
Acta Pathol Jpn 37: 47-63
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Schron DS, Mendelsohn G (1984)
Pancreatic carcinoma with duct, endocrine, and acinar differentiation. A histologic, immunocytochemical, and ultrastructural study.
Cancer 54: 1766-70
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Ulich T, Cheng L, Lewin KJ (1982)
Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules.
Cancer 50: 2099-105


 . “Collision tumours” composed of two topographically separate neoplasms are not included in the mixed differentiation. Rare acinar neoplasms have a substantial proportion (> 30%) of more than one cell type
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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007
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Labate AM, Klimstra DL, Zakowski MF (1997)
Comparative cytologic features of pancreatic acinar cell carcinoma and islet cell tumor.
Diagn Cytopathol 16: 112-6
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Nojima T, Kojima T, Kato H, Sato T, Koito K, Nagashima K (1992)
Alpha-fetoprotein-producing acinar cell carcinoma of the pancreas.
Hum Pathol 23: 828-30
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Ohike N, Kosmahl M, Klöppel G (2004)
Mixed acinar-endocrine carcinoma of the pancreas. A clinicopathological study and comparison with acinar-cell carcinoma.
Virchows Arch 445: 231-5
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Villanueva RR, Nguyen-Ho P, Nguyen GK (1994)
Needle aspiration cytology of acinar-cell carcinoma of the pancreas: report of a case with diagnostic pitfalls and unusual ultrastructural findings.
Diagn Cytopathol 10: 362-4


 . Of these, the best characterized is mixed acinar-neuroendocrine carcinoma
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Labate AM, Klimstra DL, Zakowski MF (1997)
Comparative cytologic features of pancreatic acinar cell carcinoma and islet cell tumor.
Diagn Cytopathol 16: 112-6


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Mixed ductal-neuroendocrine carcinoma
Patients with mixed ductal-neuroendocrine carcinoma are usually older adults and present with nonspecific symptoms. This neoplasm is characterized by an intimate admixture of neoplastic ductal and neoplastic neuroendocrine cells in the primary neoplasm as well as in its metastases. Two patterns can be distinguished, one consisting of intermingled neoplastic ductal and neuroendocrine cells forming glandular (occasionally also squamoid) and solid structures, and another consisting of moderately differentiated neoplastic ductal structures embedded in a solid neuroendocrine cell compartment
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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007
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Ohike N, Jürgensen A, Pipeleers-Marichal M, Klöppel G (2003)
Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells.
Virchows Arch 442: 258-65


 . By definition, each component should comprise at least one third of the neoplastic tissue. Ductal differentiation is defined by mucin production and the expression of ductal markers such as carcinoembryonic antigen (CEA) or MUC1. The neoplastic neuroendocrine cells are typically of high grade on the basis of mitotic rate and express neuroendocrine markers such as synaptophysin, chromogranin A, and pancreatic hormones.
These neoplasms are exceptionally rare in the pancreas
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Ohike N, Jürgensen A, Pipeleers-Marichal M, Klöppel G (2003)
Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells.
Virchows Arch 442: 258-65
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Sessa F, Bonato M, Frigerio B, Capella C, Solcia E, Prat M, Bara J, Samloff IM (1990)
Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells.
Gastroenterology 98: 1655-65
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Solcia E, Capella C, and Kloppel G
Tumours of the Pancreas.
Armed Forces Institute of Pathology: Washington, DC 1997


 . It is much more common to find a neuroendocrine neoplasm that has entrapped non-neoplastic ductal cells
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Nonomura A, Kono N, Mizukami Y, Nakanuma Y, Matsubara F (1992)
Duct-acinar-islet cell tumor of the pancreas.
Ultrastruct Pathol 16: 317-29
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Tomita T, Bhatia P, Gourley W (1981)
Mucin producing islet cell adenoma.
Hum Pathol 12: 850-3
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van Eeden S, de Leng WW, Offerhaus GJ, Morsink FH, Weterman MA, de Krijger RR, Klöppel G, Klimstra DS (2004)
Ductuloinsular tumors of the pancreas: endocrine tumors with entrapped nonneoplastic ductules.
Am J Surg Pathol 28: 813-20


 . The trapped ductal cells are cytologically benign and limited by the well-demarcated edges of the underlying neuroendocrine neoplasm.
The latter behave like pure neuroendocrine neoplasms, while true mixed ductal-neuroendocrine carcinomas behave like the usual ductal adenocarcinoma.
Mixed ductal-neuroendocrine carcinomas should also be distinguished from ductal adenocarcinomas with reactive non-neoplastic neuroendocrine cells
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Ohike N, Jürgensen A, Pipeleers-Marichal M, Klöppel G (2003)
Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells.
Virchows Arch 442: 258-65


 . Scattered non-neoplastic neuro - endocrine cells are found in 40–80% of ductal adenocarcinomas and seem to be particularly frequent in well-differentiated adenocarcinomas, where they tend to either line up along the base of the neoplastic ductal structures or lie between the neoplastic columnar cells
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Chen J, Baithun SI, Pollock DJ, Berry CL (1988)
Argyrophilic and hormone immunoreactive cells in normal and hyperplastic pancreatic ducts and exocrine pancreatic carcinoma.
Virchows Arch A Pathol Anat Histopathol 413: 399-405
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Ohike N, Jürgensen A, Pipeleers-Marichal M, Klöppel G (2003)
Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells.
Virchows Arch 442: 258-65
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Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010


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