Serrated adenoma has been proposed to be a distinct entity among colorectal neoplasms. Progression to frank carcinoma has been suggested in individual cases, but the prevalence of carcinomas originating from serrated adenomas and their clinico-pathological characteristics are not known. In the present study, a large series of colorectal cancers was analysed for the occurrence of serrated adenoma in association with carcinoma and clinico-pathological features were compared in cases with and without serrated adenoma. Specimens from 466 colorectal carcinoma patients undergoing operations between 1986 and 1996 were re-evaluated for the presence of juxtaposed serrated adenoma and carcinoma. Clinico-pathological features such as location, Dukes' stage, histological grade, mucinous differentiation, and prognosis were evaluated. Twenty-seven carcinomas (5.8%) were found in association with an adjacent serrated adenoma. Eight of the patients were male and 19 were female. All of these adenocarcinomas showed a serrated appearance resembling that of serrated adenomas. Nine (33%) cases were mucinous and a mucinous component was present in 11 (41%) additional cases. The majority of the tumours were located either in the caecum (14 cases; 51%) or in the rectum (9 cases; 33%). DNA microsatellite instability was more common in carcinomas associated with serrated adenoma (37.5%) than in other carcinomas (11.0%). It is concluded that carcinoma associated with serrated adenoma is a distinct type of colorectal neoplasm, accounting for 5.8% of all colorectal carcinoma cases in this study. Predilection for the caecum and the rectum may reflect their aetiological factors. Female preponderance is contrary to that reported for hyperplastic polyps and serrated adenomas.

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Summary Adjuvant therapies are increasingly used in colorectal cancers for the prevention of recurrence. These therapies have side-effects and should, thus, be used only if really beneficial. However, the development of recurrence cannot be predicted reliably at the moment of diagnosis, and targeting of adjuvant therapies is thus based only on the primary stage of the cancer. Loss of heterozygosity (LOH) in the long arm of chromosome 18 is suggested to be related to poor survival and possibly to the development of metastases. We studied the value of LOH at 18q21 as a marker of colorectal cancer prognosis, association with clinicopathological variables, tumour recurrence and survival of the patients. Of the 255 patients studied, 195 were informative as regards LOH status when analysed in primary colorectal cancer specimens using the polymerase chain reaction (PCR) and fragment analysis. LOH at 18q21 was significantly associated with the development of recurrence (P = 0.01) and indicated poor survival in patients of Dukes' classes B and C, in which most recurrences (82%) occurred. An increased rate of tumour recurrence is the reason for poor survival among patients with LOH at 18q21 in primary cancer. These patients are a possible target group for recurrence-preventing adjuvant therapies.

The precursors for colorectal cancer include polypoid (conventional), flat and serrated adenomas. Polypoid growth in polypoid adenomas and serrated adenomas is associated with K-ras mutations. The regulation of polypoid or nonpolypoid growth is not well known, but could be related to trophic stimuli, such as thyroid hormones. Hence, we investigated the expression pattern of thyroid hormone receptor TRb1 in colorectal mucosa and in colorectal tumours and its relationship to tumour growth type. One hundred fourteen colorectal carcinoma specimens were evaluated for TRb1. Normal mucosa, adjacent adenomatous component (N 5 46) and lymph node metastases (N 5 28) were analysed when present, and the results were confirmed by Western blot analysis in selected cases. Nuclear TRb1 was almost always present in normal epithelium (96%), but less frequent in adenomas (83%) and in cancer (68%; p < 0.001 and p < 0.001, respectively). TRb1 was associated with polypoid growth, presence of K-ras mutations and also with a higher WHO histological grade and advanced Dukes' stage. Cytoplasmic expression of TRb1 was observed in nonneoplastic and neoplastic epithelium. In Western blot analysis, a 58 kDa band corresponding to TRb1 was expressed in normal mucosa and in colorectal cancer specimens with positive immunohistochemistry. Association of TRb1 expression with growth pattern and the presence of K-ras mutations suggest that abnormalities in thyroid hormone signalling involving TRb1 play a role in the development of some types of colorectal adenocarcinomas. ' 2005 Wiley-Liss, Inc.Key words: colorectal cancer classification; thyroid hormone receptors beta; K-ras oncogene Colorectal cancer evolves via a sequence of alterations. In addition to the well-known adenoma-carcinoma sequence, some colorectal cancers are thought to arise either de novo or from flat adenomas. These 2 pathways are biologically different, as K-ras mutations occur with high frequency in polypoid adenomas, but are rare in flat adenomas and carcinomas.1,2 It has been thought that the oncogenic action of mutated K-ras protein results in increased proliferation common in polypoid adenomas. 3Thyroid hormones regulate growth, development, differentiation and metabolic processes. 4 The actions of 3,3 0 ,5-triiodo-L-thyronine (T3) are mediated by thyroid hormone nuclear receptors (TR), which regulate the expression of T3-targeted genes. T3, thyroxin (T4), as well as its lower iodinated metabolites exert direct biological effects by mechanisms not involving nuclear T3-receptors.5 T3 and its receptors regulate processes such as cell proliferation, differentiation and apoptosis in normal tissues and in some malignancies. [6][7][8][9][10][11] Knockout mice models have shown that T3 receptor TRa, but not TRb, is involved in the maturation of the intestine. 12,13 TRs are members of the steroid hormone and retinoic acid superfamily of ligand-dependent transcription factors, and are derived from two genes, TRa and TRb, located on human chromosomes 17 and 3, respectively. Both gene...

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