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Quantitative nuclear feature analysis in the prognosis of benign breast disease and ductal carcinoma in situ

University of British Columbia

Except of the diagnostic categories based on the morphology of cells and tissue there are currently no significant prognostic markers for patients with benign breast disease or ductal carcinoma in situ (DCIS). This thesis proposed that such prognostic information could be obtained based on quantitative nuclear feature analysis of diagnostic cells and/or normal appearing cells in breast tissue. Image cytometry (IC) measurements provide numerous quantitative nuclear features which reflect the DNA content, nuclear morphology and chromatin condensation patterns in stained nuclei. With the use of this technique it is possible to detect slight morphological nuclear changes which can not be observed by the human eye. Measurements on tissue sections were chosen for this study because in these specimens visualization of tissue histology and precise identification of affected glands is possible. The thesis involved testing of the following postulates: 1) DNA ploidy can be evaluated by IC measurements of tissue sections DNA content measurements of archival breast specimens showed that the performance of manual IC measurements of nuclei on tissue sections was comparable to the results of flow cytometry and automated IC techniques. 2) Quantitative nuclear features change in different histological patterns of breast diseases The analysis of normal tissue, non-proliferative breast disease, proliferative breast disease, carcinoma in situ and invasive cancer specimens demonstrated differences in nuclear features between different h istopatholog ical patterns. Compared to normal tissue characteristics, the deviations of features related to the nuclear area, shape, DNA content and chromatin texture all increased with advancing morphological changes. 3) Various histological types of DCIS can be characterized on the basis of the nuclear features The differences in quantitative nuclear features were defined for various histological types of DCIS. The nuclear DNA content, size, irregularity of shape and chromatin texture, all increased from the lowest values in cribriform type to the highest values in comedo type DCIS. Aneuploidy was demonstrated in about 60% of non-comedo DCIS and in about 95% of comedo DCIS. 4) Differences in nuclear morphology, which may be related to the invasive potential of ductal carcinomas in situ (DCIS), exist between I) pure DCIS, and ii) DCIS with synchronous invasive carcinoma An important task of this thesis was to obtain a prognostic indicator for ductal carcinoma in situ (DCIS). Nuclear features of DCIS which were associated with the presence of invasive carcinoma in the surrounding breast tissue were identified. A classification system based on these nuclear features was then used to discriminate between cases with pure DCIS and cases of DCIS with invasive cancer in the surrounding tissue. This classification predicted accurately the presence of invasive carcinoma in about 80% of non-comedo DCIS and in about 100% of comedo DCIS cases. 5) Subtle changes of nuclear morphology exist in epithelial cells of normal appearing breast tissue adjacent to invasive carcinoma (malignancy associated changes) The final goal was to test the hypothesis that small deviations in nuclear morphology, indicative of the malignancy in the surrounding tissue, can be detected through nuclear measurements of non-diagnostic, normal appearing cells in the vicinity of DCIS or invasive carcinoma. This phenomenon has been previously studied in other tissues and has been described as a part of malignancy associated changes (MAC). The present study illustrated the existence of MAC in the normal appearing breast tissue adjacent to in situ, or invasive carcinoma. Patients with benign or malignant diseases could be distinguished solely on the basis of the measurements of epithelial nuclei from the normal appearing glands. With the analysis of MAC about 85% of cases were correctly classified as benign or malignant. In conclusion: A) Differences in nuclear features which were demonstrated for various groups of breast diseases suggest that these features could be applied as an objective aid in the classification and diagnosis of breast diseases. B) The analysis of DCIS nuclei can provide useful prognostic information making it possible to suspect the presence of invasive carcinoma in the breast when only DCIS is present in the biopsy. Moreover, specific changes in nuclear morphology, which are characteristic of DCIS associated with invasive carcinoma in the surrounding breast might be associated with the progressive capacity of DCIS and may be helpful as a marker predictive of the subsequent behavior of DIS tumors. C) Nuclear features, characteristic of MAC, are important as markers for occult malignancy in cases where only benign breast disease is found in a biopsy. In addition, a high frequency of “MAC” nuclei in a benign breast tissue may be suggestive of a higher progressive potential and of an increased risk for the development of invasive carcinoma from benign breast tissue which has a high frequency of “MAC” nuclei. In view of the clinical relevance of these findings it is very important to confirm and expand the results with further studies on larger number of patients.

Thesis/Dissertation

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2009-04-08

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http://hdl.handle.net/2429/6943

Pathology

University of British Columbia

UBCV

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