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Medullary Carcinoma of the Colon and Rectum

Definition

  • Poorly differentiated adenocarcinoma with regular nuclei and pushing border arising in the colon or rectum

Alternate/Historical names

  • Large cell carcinoma with minimal differentiation
  • Solid type poorly differentiated carcinoma
  • Poorly differentiated carcinoma of medullary type
  • Undifferentiated carcinoma solid pattern type

Diagnostic Criteria

  • Solid sheets, nests and trabeculae
    • No to rare gland formation
  • Uniform small to medium sized cells
    • Vesicular nuclei with prominent nucleoli
    • High nuclear/cytoplasmic ratio
      • Scant to moderate cytoplasm
        • Eosinophilic to amphophilic
  • Pushing, expansive border
  • Prominent lymphocytic infiltrate
    • Intraepithelial lymphocytes, ≥3 per HPF
    • Crohn-like response at edge of carcinoma
      • Lymphoid aggregates / follicles with or without germinal centers not associated with a lymph node
  • Neuroendocrine markers must be negative
    • At most, focal or scattered staining
  • May have intracytoplasmic mucin
  • Mitotic figures may be frequent
  • May have geographic or comedo necrosis
    • Lacks dirty necrosis pattern
  • 80% of neoplasm has distinctive features
    • Up to 20% may range from well differentiated adenocarcinoma to mucinous carcinoma
  • Almost always microsatellite unstable

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 1/31/10, 11/12/11

Supplemental studies

Immunohistology

  • By definition, chromogranin and synaptophysin show at most focal or scattered staining
  • One report suggests that calretinin distinguishes medullary carcinoma from poorly differentiated carcinoma NOS
    • Medullary 73%
    • NOS 12%
  • Other markers tested do not provide clear distinction:

    CK7

    13%

    CK20

    14%

    CDX2

    15-20%

    MUC1

    67%

    MUC2

    60%

Genetic Analysis

  • Frequently MSI unstable
    • Usually MLH1 negative
      • 80-100% of cases

Differential Diagnosis

Colorectal Medullary Carcinoma Colorectal Poorly Differentiated Carcinoma NOS
Lacks any gland formation At least 5% gland formation
Uniform small to medium sized nuclei Pleomorphic large nuclei
Uniformly prominent nucleoli Variable nucleoli
Pushing border Infiltrative border
Prominent lymphoid infiltrate in virtually all cases Lymphoid infiltrate variable

Colorectal Medullary Carcinoma Colorectal Undifferentiated Carcinoma NOS
Lacks any gland formation May have <5% gland formation
Uniform small to medium sized nuclei Pleomorphic large nuclei
Uniformly prominent nucleoli Variable nucleoli
Pushing border Infiltrative border
Prominent lymphoid infiltrate in virtually all cases Lymphoid infiltrate variable

Colorectal Medullary Carcinoma Poorly Differentiated Neuroendocrine Carcinoma, Large Cell Type
Chromogranin and synaptophysin at most focal or scattered Chromogranin or synaptophysin must be positive in at least 20-50% of cells
Vesicular nuclei Chromatin finely granular, stippled
Prominent nucleoli Inconspicuous nucleoli
Does not form rosettes May form rosettes

Clinical

Grading / Staging

Grading

  • There is no defined grading scheme for medullary carcinoma
    • Cytologically, it appears high grade
    • As with other MSI-H colorectal carcinomas, behavior is more typical of low grade

Staging

Bibliography

  • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010
  • Jessurun J, Romero-Guadarrama M, Manivel JC. Medullary adenocarcinoma of the colon: clinicopathologic study of 11 cases. Hum Pathol. 1999 Jul;30(7):843-8.
  • Wick MR, Vitsky JL, Ritter JH, Swanson PE, Mills SE. Sporadic medullary carcinoma of the colon: a clinicopathologic comparison with nonhereditary poorly differentiated enteric-type adenocarcinoma and neuroendocrine colorectal carcinoma. Am J Clin Pathol. 2005 Jan;123(1):56-65.
  • Winn B, Tavares R, Fanion J, Noble L, Gao J, Sabo E, Resnick MB. Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation. Hum Pathol. 2009 Mar;40(3):398-404.
  • Rüschoff J, Dietmaier W, Lüttges J, Seitz G, Bocker T, Zirngibl H, Schlegel J, Schackert HK, Jauch KW, Hofstaedter F. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol. 1997 May;150(5):1815-25.
  • Sugao Y, Yao T, Kubo C, Tsuneyoshi M. Improved prognosis of solid-type poorly differentiated colorectal adenocarcinoma: a clinicopathological and immunohistochemical study. Histopathology. 1997 Aug;31(2):123-33.
  • Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, Loda M, Appelman HD, Cho KR, Fearon ER. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol. 2001 Dec;159(6):2239-48.
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