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WHO Classification of Tumours
Medullary carcinoma, NOS
Pancreas


Definition

A malignant epithelial tumour in which the cells form solid sheets and have abundant eosinophilic cytoplasm and large, vesicular nuclei with prominent nucleoli. An intraepithelial infiltrate of lymphocytes is characteristic. Typical sites of involvemet include carcinomas thyroid gland, breast, colon, rectum, and small intestine.

Medullary carcinoma of the pancreas
This is a malignant epithelial neoplasm characterized by poor differentiation, limited gland formation, pushing borders at the interface between the neoplasm and non-neoplastic tissues and a prominent syncytial growth pattern

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Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH (1998)
Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.
Am J Pathol 152: 1501-7




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Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



. Increased numbers of tumour- infiltrating leukocytes (CD3+) are present in some cases
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Nakata B, Yashiro M, Nishioka N, Aya M, Yamada S, Takenaka C, Ohira M, Ishikawa T, Nishino H, Wakasa K, Seki S, Hirakawa K (2002)
Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas.
Int J Cancer 102: 655-9



. Because of the histological overlap with acinar cell carcinoma, acinar differentiation should be excluded by immunolabelling for trypsin or chymotrypsin. Medullary carcinomas express keratin, and immunohistochemistry will often demonstrate the loss of expression of one of the DNA mismatch repair genes
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Banville N, Geraghty R, Fox E, Leahy DT, Green A, Keegan D, Geoghegan J, O'Donoghue D, Hyland J, Sheahan K (2006)
Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene.
Hum Pathol 37: 1498-502




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Kondo E, Furukawa T, Yoshinaga K, Kijima H, Semba S, Yatsuoka T, Yokoyama T, Fukushige S, Horii A (2000)
Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability.
Int J Oncol 17: 535-41




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Nakata B, Wang YQ, Yashiro M, Ohira M, Ishikawa T, Nishino H, Seki S, Hirakawa K (2003)
Negative hMSH2 protein expression in pancreatic carcinoma may predict a better prognosis of patients.
Oncol Rep 10: 997-1000




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Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



.
Medullary carcinomas may arise sporadically or in patients with Lynch syndrome

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Banville N, Geraghty R, Fox E, Leahy DT, Green A, Keegan D, Geoghegan J, O'Donoghue D, Hyland J, Sheahan K (2006)
Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene.
Hum Pathol 37: 1498-502




Click to access Pubmed
Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K (2001)
Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability.
Cancer Res 61: 3139-44



. It has been reported that patients with medullary carcinoma of the pancreas are more likely to have a family history of cancer than are patients with ductal adenocarcinoma of the pancreas
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Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



. The age and sex distributions are similar to those for ductal adenocarcinoma
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Nakata B, Yashiro M, Nishioka N, Aya M, Yamada S, Takenaka C, Ohira M, Ishikawa T, Nishino H, Wakasa K, Seki S, Hirakawa K (2002)
Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas.
Int J Cancer 102: 655-9




Click to access Pubmed
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



.
Medullary carcinomas in patients with Lynch syndrome harbour biallelic mutations (one germline, the second somatic) in one of the DNA mismatch repair genes (i.e. MLH1 and MSH2

Click to access Pubmed
Banville N, Geraghty R, Fox E, Leahy DT, Green A, Keegan D, Geoghegan J, O'Donoghue D, Hyland J, Sheahan K (2006)
Medullary carcinoma of the pancreas in a man with hereditary nonpolyposis colorectal cancer due to a mutation of the MSH2 mismatch repair gene.
Hum Pathol 37: 1498-502



). Most medullary carcinomas are microsatelliteunstable (MSI+)
Click to access Pubmed
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



and, as one would expect in an MSI+ neoplasm, most are wild-type for the KRAS2 gene, and diploid (no loss of heterozygosity)
Click to access Pubmed
Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH (1998)
Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.
Am J Pathol 152: 1501-7




Click to access Pubmed
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



. Medullary carcinomas also can harbour BRAF mutations, FHIT homozygous deletions, and biallelic inactivating mutations of the ACVR2 and TGFBR2 genes
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Calhoun ES, Jones JB, Ashfaq R, Adsay V, Baker SJ, Valentine V, Hempen PM, Hilgers W, Yeo CJ, Hruban RH, Kern SE (2003)
BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets.
Am J Pathol 163: 1255-60




Click to access Pubmed
Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH (1998)
Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.
Am J Pathol 152: 1501-7




Click to access Pubmed
Hempen PM, Zhang L, Bansal RK, Iacobuzio-Donahue CA, Murphy KM, Maitra A, Vogelstein B, Whitehead RH, Markowitz SD, Willson JK, Yeo CJ, Hruban RH, Kern SE (2003)
Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers.
Cancer Res 63: 994-9




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Hilgers W, Groot Koerkamp B, Geradts J, Tang DJ, Yeo CJ, Hruban RH, Kern SE (2000)
Genomic FHIT analysis in RER+ and RER- adenocarcinomas of the pancreas.
Genes Chromosomes Cancer 27: 239-43




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Su GH, Bansal R, Murphy KM, Montgomery E, Yeo CJ, Hruban RH, Kern SE (2001)
ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma.
Proc Natl Acad Sci U S A 98: 3254-7




Click to access Pubmed
Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K (2001)
Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability.
Cancer Res 61: 3139-44



. A medullary carcinoma with Epstein-Barr virus (EBV) infection of the neoplastic cells has been reported
Click to access Pubmed
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51



.
Despite poor differentiation, the prognosis for patients with medullary carcinomas is better than for those with ductal adenocarcinomas

Click to access Pubmed
Nakata B, Wang YQ, Yashiro M, Ohira M, Ishikawa T, Nishino H, Seki S, Hirakawa K (2003)
Negative hMSH2 protein expression in pancreatic carcinoma may predict a better prognosis of patients.
Oncol Rep 10: 997-1000




Click to access Pubmed
Nakata B, Yashiro M, Nishioka N, Aya M, Yamada S, Takenaka C, Ohira M, Ishikawa T, Nishino H, Wakasa K, Seki S, Hirakawa K (2002)
Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas.
Int J Cancer 102: 655-9




Click to access Pubmed
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000)
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Am J Pathol 156: 1641-51




Click to access Pubmed
Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K (2001)
Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability.
Cancer Res 61: 3139-44



. On the basis of extensive experience with MSI+ colorectal carcinomas, it is likely that medullary carcinomas of the pancreas will not respond to 5-fluorouracil therapy
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Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B (2009)
Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis.
Eur J Cancer 45: 1890-6




Click for details
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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