Related terms

Medullary carcinoma, NOS

Definitions

Breast
ICD-O-3 topography code:	C50
ICD10:	C50

Medullary carcinoma belongs to the group of 'Carcinomas with medullary features'.

Classically, the following criteria were used to define MC ¹

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Pedersen L, Holck S, Mouridsen HT, Schødt T, Zedeler K (1999)
Prognostic comparison of three classifications for medullary carcinoma of the breast.
Histopathology 34: 175-8

²

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Ridolfi RL, Rosen PP, Port A, Kinne D, Miké V (1977)
Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up.
Cancer 40: 1365-85

: syncytial architecture in > 75% of the tumour mass, histological circumscription or pushing margins, lack of tubular differentiation, a prominent and diffuse lymphoplasmacytic stroma infiltrate, and round tumour cells with abundant cytoplasm and pleomorphic high-grade vesicular nuclei containing one or several nucleoli.

See Carcinomas with medullary features for images and detailed discussion.

Colon and rectum
ICD-O-3 topography code:	C18-C20
ICD10:	C18-C20

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 colon and rectum
This rare variant is characterized by sheets of malignant cells with vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm exhibiting prominent infiltration by intraepithelial lymphocytes. It almost invariably has MSI-H and usually a favourable prognosis ⁶

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Kirchner T, Reu S (2008)
[Development of molecular-pathologic entities of colorectal cancer].
Pathologe 29 Suppl 2: 264-9

⁷

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Selves J (2009)
[Histological types and prognostic factors in colorectal cancer].
Med Sci (Paris) 25 Spec No 1: 9-12

⁸

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

.

Small intestine
ICD-O-3 topography code:	C17
ICD10:	C17

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 of the thyroid gland, breast, colon, rectum, and small intestine.

Pancreas
ICD-O-3 topography code:	C25
ICD10:	C25

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 ⁹

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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

¹⁰

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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 ¹¹

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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 ¹²

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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

¹³

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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

¹⁴

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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

¹⁵

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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^{OMIM 16}

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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

¹⁷

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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 ¹⁸

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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 ¹⁹

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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

²⁰

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 ²¹

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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

). Most medullary carcinomas are microsatelliteunstable (MSI+) ²²

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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

and, as one would expect in an MSI+ neoplasm, most are wild-type for the KRAS2 gene, and diploid (no loss of heterozygosity) ²³

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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

²⁴

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 ²⁵

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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

²⁶

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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

²⁷

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

²⁸

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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

²⁹

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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

³⁰

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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 ³¹

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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

.
Despite poor differentiation, the prognosis for patients with medullary carcinomas is better than for those with ductal adenocarcinomas ³²

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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

³³

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

³⁴

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

³⁵

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 ³⁶

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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

³⁷

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

.