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Phenotypic heterogeneity in hereditary non-polyposis colorectal cancer: identical germline mutations associated with variable tumour morphology and immunohistochemical expression
  1. Britta Halvarsson1,
  2. Wolfram Müller2,
  3. Maria Planck1,
  4. Anna Clara Benoni1,
  5. Peter Mangell3,
  6. Johan Ottosson4,
  7. Magnus Hallén5,
  8. Anna Isinger1,
  9. Mef Nilbert1
  1. 1Department of Pathology, Lund University Hospital, Lund, Sweden
  2. 2Gemeinschaftspraxis Pathologie Starnberg, Germany
  3. 3Department of Surgery, Malmö University Hospital, Malmö, Sweden
  4. 4Department of Surgery, Kristianstad Hospital, Kristianstad, Sweden
  5. 5Department of Surgery, Lund University Hospital, Lund, Sweden
  1. Correspondence to:
 Dr Britta Halvarsson
 Department of Pathology, Helsingborg Hospital, 251 87 Helsingborg, Sweden; Britta.Halvarsson{at}


Background: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes.

Aims and Methods: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised.

Results: The tumour morphology as well as the immunohistochemical expression of β-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features.

Conclusions: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.

  • APC, adenomatous polyposis coli
  • HNPCC, hereditary non-polyposis colorectal cancer
  • MMR, mismatch repair
  • TIL, tumour-infiltrating lymphocytes
  • hereditary non-polyposis colorectal cancer
  • histopathology
  • heterogeneity
  • MMR
  • mismatch-repair

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  • Published Online First 10 August 2006

  • Funding: Financial support was from the Swedish Cancer Society, the Nilsson Cancer Fund, the Kamprad Cancer Fund, and the Region Skåne Research Funds.

  • Competing interests: None.

  • Ethical approval was obtained from the Ethics Committee at Lund University.