Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression
Britta Halvarsson 1*, Wolfram Müller 2, Maria Planck 3, Anna Clara Benoni 4, Peter Mangell 5, Johan Ottosson 6, Magnus Hallen 7, Anna Isinger 4 and Mef Nilbert 8
1 Pathology, Lund University Hospital, Sweden
2 2Gemeinschaftspraxis Pathologie Starnberg, Germany
3 Department Oncology, Lund University Hospital, Sweden
4 Dept Oncology, Lund University Hospital, Sweden
5 Dept Surgery, Malmö University Hospital, Sweden
6 Dept. Surgery, Kristianstad Hospital, Sweden
7 Dept Surgery, Lund University Hospital, Sweden
8 Dept. Oncology, Lund University Hospital, Sweden
* To whom correspondence should be addressed. E-mail: britta.halvarsson{at}med.lu.se.
Accepted 20 July 2006
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Abstract |
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Background: Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumors. Colorectal cancer in HNPCC is characterized by poor tumor differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumor-infiltrating lymphocytes.
Objectives & Methods: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumor phenotype is influenced by the underlying genetic alteration, we morphologically and immunohistochemically characterized 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families.
Results: The tumor morphology as well as the immunohistochemical expression of B-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumor differentiation, an expanding growth pattern, and tumor-infiltrating lymphocytes occurred at higher frequencies in proximal tumors, 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, family history and age of onset may be particularly relevant to obtain in these tumors in order to identify individuals with HNPCC.
Key Words:
Hereditary Nonpolyposis Colorectal Cancer, Heterogeneity, Histopathology, Immunostaining, Mismatch repair
