Coexistent intraurothelial carcinoma and muscle-invasive urothelial carcinoma of the bladder: clonality and somatic down-regulation of DNA mismatch repair.

Department of Pathology, University Hospital of Malaga, 29071 Malaga, Spain.
Human pathology (Impact Factor: 3.03). 05/2009; 40(7):988-97. DOI:10.1016/j.humpath.2008.12.009
Source: PubMed

ABSTRACT Muscle-invasive urothelial carcinomas are heterogeneous neoplasms for which the clonal relationship with low-grade urothelial dysplasia and carcinomas in situ remains unknown, and both monoclonal and field change models have been proposed. Low-grade dysplasia (18) and carcinoma in situ (12) associated with muscle-invasive urothelial carcinoma were microdissected and topographically analyzed (intraepithelial and invasive superficial and deep to muscularis mucosa) for methylation pattern of androgen receptor alleles, TP53, RB1, WT1, and NF1 microsatellite analysis to assess clonal identity; MLH1 and MSH2 sequencing/immunostaining. Appropriate controls were run. Carcinoma in situ (100%) and invasive urothelial carcinoma (100%) revealed monoclonal patterns, whereas low-grade dysplasia was preferentially polyclonal (80%). Carcinoma in situ showed aneuploid DNA content and more abnormal microsatellites than the corresponding invasive compartments, opposite to low-grade dysplasia. Absent MLH1 protein expression with no gene mutations were identified in carcinoma in situ and nodular-trabecular urothelial carcinoma with high microsatellite abnormalities. Somatic mismatch repair protein down-regulation and the accumulation of tumor suppressor gene microsatellite abnormalities contribute to a molecular evolution for monoclonal carcinoma in situ divergent from coexistent muscle-invasive urothelial carcinoma. Low-grade dysplasia is however unlikely connected with this molecular progression.

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    ABSTRACT: Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning.
    International Journal of Molecular Sciences 01/2012; 13(2):1951-2011. · 2.46 Impact Factor


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May 14, 2012