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Progression and Tumor Heterogeneity Analysis in Early Rectal Cancer

Authors' Affiliations: Departments of ¹ Pathology, ² Medical Statistics, and ³ Surgery, Leiden University Medical Center, Leiden, the Netherlands; ⁴ Department of Surgery, IJsselland Hospital, Capelle a/d IJssel, the Netherlands; ⁵ Department of Surgery, Erasmus Medical Center, Rotterdam, the Netherlands; and ⁶ Department of Surgery, Reinier de Graaf Gasthuis, Delft, the Netherlands

Requests for reprints: Hans Morreau, Department of Pathology L1-Q, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, the Netherlands. Phone: 31-71-526-6630; Fax: 31-71-524-8158; E-mail: J.Morreau{at}lumc.nl.

Purpose: Adequate preoperative staging of large sessile rectal tumors requires identifying adenomas that already contain an invasive focus, specifically those that are growing in or beyond the submucosa. We systematically compared chromosomal instability patterns in adenoma and carcinoma fractions of the same lesion to assess specific steps in rectal tumor progression.

Experimental Design: We analyzed 36 formalin-fixed, paraffin-embedded tumors. Both the adenoma and carcinoma fractions were typed with single nucleotide polymorphism arrays and compared with 21 previously described pure adenomas. Eighteen cases were included in an intratumor heterogeneity analysis.

Results: Five specific "malignant" events (gain of 8q, 13q, and 20q and loss of 17p and 18q) and aberrant staining for p53 and SMAD4 were all increased in the adenoma fractions of carcinoma cases compared with pure adenomas. Paired analysis revealed that 31% of the samples had an equal amount of malignant aberrations in their adenoma and carcinoma fractions, whereas 25% had one and 33% had two or more extra malignant events in the carcinoma fraction. Analysis of three core biopsies per patient showed a large degree of intratumor heterogeneity. However, the number of malignant aberrations in the biopsy with the most aberrations per tumor correlated with the corresponding adenoma or carcinoma fraction (r = 0.807; P < 0.001).

Conclusion: Five specific chromosomal aberrations, combined with immunohistochemistry for p53 and SMAD4, can predict possible progression of sessile rectal adenomas to early rectal cancer and can, after validation studies, be added to preoperative staging. Preferably, three biopsies should be taken from each tumor to address intratumor heterogeneity.