Colonic adenomas are considered adenocarcinoma precursors[29
]. Even though this might not be entirely endorsed[30
], the predictive value of high grade dysplasia for the subsequent development of advanced adenomas and cancer is well documented and indisputable[31-34
]. In this setting, it is widely accepted that severe dysplasia and carcinoma in situ
bear a similar clinical significance and are therefore merged into a single category in most classification/reporting protocols. Molecular studies have shown an increased frequency of genetic alterations and DNA aneuploidy with increasing grade of dysplasia as assigned by the Vienna classification[35
]. Following a detailed evaluation of the examined dysplastic lesions and taking into account intra-lesion heterogeneity, our study is the first one to report a positive association between AMACR and increasing grade of dysplasia in sporadic colorectal adenomas at the immunohistochemical level.
The observed overall prevalence of AMACR expression in colorectal adenomas in our study (52.7%) appears to be somewhat lower than in previous publications (64%-91%)[5,6,10,11,17
]. It was difficult to compare our findings with the ones presented in these studies, in which the applied criteria for the classification of dysplasia were not provided. In the two studies that, to our knowledge, evaluated AMACR expression in relation to dysplasia, results did not significantly differ between low and high grade adenomas[17
] or among adenomas with mild, moderate or severe dysplasia[5
]. The above discrepancies can be attributed to the different antibodies used in each case and also to the different evaluation criteria set for immunopositivity, such as lower thresholds. These differences are further reflected in the reported positivity of normal colonic epithelia[5,11,14,17
], which was not observed in our series.
It was previously suggested that AMACR expression might be closely related to the early stages of neoplastic progression in the colon[10
]. The estimated prevalence of AMACR in adenomas bearing in situ
carcinoma cytoarchitectural features in our study (88.2%) is similar to that reported for colorectal carcinoma in the majority of publications (62%-83%)[5,9-12
]. In comparison, we observed AMACR positivity in only 40% of severely dysplastic and 18.8% of low grade lesions. These findings might suggest a more advanced state towards malignancy of in situ
carcinoma as compared to severe dysplasia, although both lesions are currently incorporated into the high grade category for management reasons.
The differences observed between lesions exhibiting morphological changes corresponding to the previously used terms of severe dysplasia and in situ
carcinoma at the molecular level prompt for morphologically identifying these lesions at least for research purposes[20,21
]. Of note, however, co-existing severely dysplastic and in situ
carcinoma areas in the same lesion did not significantly differ in terms of AMACR expression. AMACR expression seemed to be related to the co-existence of in situ
carcinoma rather than to in situ
carcinoma itself, since it was present in severely dysplastic areas in the vicinity of negative in situ
carcinomas. Severe dysplasia-like morphology does not differ in the simultaneous presence or absence of adjacent in situ
carcinoma. However, the same morphologic features might bear significant differences at the molecular level that seem to be more prominent in later stages of the dysplasia-carcinoma sequence.
Another implication of the above described intra-lesion AMACR heterogeneity is that, when examining the expression of AMACR and possibly other markers in adenomas on tissue microarrays, multiple areas should be sampled for adequate evaluation of the lesion.
Taken together, our data indicate that AMACR may play some role in the process of malignant transformation in the colon. What this role might be cannot be established by this study. As has also been suggested for AMACR in the prostate, it is uncertain whether its expression is directly involved in the process of malignant transformation or whether it is just an epiphenomenon triggered by the increased metabolic requirements of malignant cells[36
Studies like the present one are performed to approach a basic question: How can molecular or genetic information help to stratify risk in patients with adenomatous polyps[33
]. Currently, size ≥ 1 cm, villous configuration and high grade dysplasia constitute the consensus criteria based on which an adenoma is characterized as “advanced” and patient surveillance is adjusted accordingly[18,31,33,34
]. Based on these parameters, patients can be stratified at the time of colonoscopy into lower or higher risk groups for subsequent advanced neoplasia (adenomas with high grade dysplasia or cancer). However, debate on the clinical relevance of these factors continues to exist and many authors still address the need for more objective and standardized pathologic criteria[37-40
]. As we show here, except for its association with the grade of dysplasia, AMACR expression in colonic adenomas is also related to two additional pathologic risk factors, i.e. size and villous configuration, a finding not previously reported. Hence, AMACR could be a candidate parameter for further evaluation as an additional risk factor for the development of subsequent advanced neoplasia. Large scale studies with long term patient follow-up would be required for the evaluation of any marker in this setting, since patients with adenoma seldom develop carcinoma within a period of 3 years[32
Another observation that needs to be further evaluated is the significant difference in AMACR expression between severe dysplasia-like changes and carcinoma in situ-like changes, when these appear as independent lesions. Taking into account the drawbacks of our study (small sample size and lack of patient follow up), none of our findings directly raises any issues concerning the current guidelines for the reporting of dysplasia in colorectal adenomas that have been imposed by the need for simplicity and standardization. However as shown here a more detailed approach to the cytoarchitectural features of dysplasia in the context of observational studies might unravel meaningful and potentially useful associations.