Predictive value of nuclear DNA content in breast cancer in relation to clinical and morphologic factors. A retrospective study of 227 consecutive cases.

The predictive value of nuclear DNA content in breast cancer in relation to clinical and morphologic factors was studied in 227 consecutive cases of invasive breast adenocarcinomas with follow-up periods of 8 to 13 years. The results show that, with the use of Cox multivariate analysis nuclear DNA content provided significant prognostic information additional to that given by all other clinical and histomorphologic variables taken together. This fact indicates that the DNA content of breast cancer cells reflects biological properties, associated with the malignant behavior of the tumor, other than those determining the stage of the disease. Nuclear DNA content was strongly correlated to histopathologic grading of the ductal carcinomas, with poorly differentiated tumors more likely to be aneuploid. On the other hand, no clear correlation was found to exist between nuclear DNA content and axillary node status, indicating that these two factors are independent prognostic parameters. It is noteworthy that DNA content provided additional prognostic information within both the node-negative and node-positive patient groups. In summary, the results shown here indicate that nuclear DNA content, as an objective biological marker of tumor aggressiveness, can significantly improve our prognostic capabilities within the currently designated stages.

Prognostic significance of DNA measurements in 409 consecutive breast cancer patients.

Four hundred nine consecutive breast cancer patients were studied retrospectively. Microspectrophotometric DNA measurements were performed using archival, fine-needle slide preparations upon which the primary diagnoses had been based 8 to 13 years earlier. The DNA distribution patterns of the tumor cell populations were analyzed according to various criteria and the cytochemical data were correlated to the clinical course, defined as distant recurrence-free survival. The results demonstrated a strong relationship between nuclear DNA content of the breast cancer cells and prognosis. Tumors exhibiting DNA values within the limits of normal tissues (DNA euploidy) were found to be correlated with a favorable prognosis. In contrast, tumors with increased and scattered DNA values (DNA aneuploidy) were found indicative of poor prognosis. This was found to be the case regardless whether the percentage of cells above 2.5c or 5c, DNA index/modal value, or the histogram typing according to Auer et al were utilized to discriminate low-grade from high-grade malignant cases. All of these DNA variables were also shown to be significantly correlated. With the aid of the Cox regression method, the additional prognostic value of any given variable was tested against the others. The statistical analyses showed that the histogram typing gives significant prognostic information in addition to that provided by any other variable. In conclusion, the current study demonstrates that tumor nuclear DNA content is a strong indicator of prognosis in patients suffering from invasive breast adenocarcinoma. However, the results also show that simple determination of the stemline position is not the optimal DNA measure of intrinsic tumor malignancy potential. The fraction of cells scattered outside the modal peaks of the histograms are of utmost importance for adequate cytochemical malignancy grading in breast carcinomas.

The reliability of microspectrophotometric and flow cytometric nuclear DNA measurements in adenocarcinomas of the breast.

The reliability of microspectrophotometric (MSP) and flow cytometric (FCM) nuclear DNA measurements has been studied in 50 human breast adenocarcinomas. The tumor material was obtained by means of fine-needle aspiration biopsy, and all samples except one were found to be highly representative. The results confirm earlier observations that a good correlation exists between modal value (MV) determined by MSP and DNA index (DI) determined by FCM. However, when tumors were classified into low and high malignant variants according to FCM/DI, FCM/S-phase percentages, and MSP histogram types, the concordance was less pronounced. This was found to be due mainly to the fact that in near-diploid tumors a discrepancy exists between MSP and FCM ploidy, as well as between MSP distribution pattern and the estimated percentages of cells in the S-phase region. Another source of discrepancy was observed in tumors with stemlines in the normal tetraploid region, including cells with highly scattered aneuploid DNA values. These tumors were judged by MSP as aneuploid/high malignant and by FCM as euploid/low malignant. In view of this discrepancy, we conclude that the simple determination of the stemline position by MSP/MV or FCM/DI is not sufficient for adequate cytochemical malignancy grading of breast carcinomas. We suggest that a combination of ploidy and percentage of cells scattered outside the modal peaks is a more sensitive method for optimal cytochemical malignancy grading in breast carcinomas.

Progression of mammary adenocarcinomas as reflected by nuclear DNA content.

In 18 breast cancer patients the DNA histograms observed in the primary tumor at the date of diagnosis were compared with those found in the corresponding local and distant metastases at autopsy up to more than 12 yr later. All patients, except one, exhibited the same type of DNA histogram in both the primary tumor and its metastases. In one patient the DNA histogram changed from an euploid type in the primary breast carcinoma to an aneuploid type in the metastases. The results are interpreted as indicating that mammary adenocarcinoma in general exhibit a high degree of stability of the nuclear DNA content during the history of the disease. It is suggested that in breast cancer progression of the tumor disease is more likely due to a net increase and/or dissemination of tumor cells exhibiting similar genetic properties and malignancy potential than to a progressive dedifferentiation and increase of malignancy of the tumor cells.

Cytophotometrical and biochemical characterization of nonpalpable, mammographically detected mammary adenocarcinomas.

Fifty nonpalpable, mammographically detected, invasive breast carcinomas were analysed with respect to DNA distribution pattern, steroid receptor content, and histopathological criteria. No significant histomorphological differences were found as compared to palpable breast carcinomas. In contrast, DNA distributions of palpable and nonpalpable tumors differed. Ninety percent of these relatively small breast carcinomas were found to exhibit nuclear DNA amounts within the diploid and tetraploid regions of normal breast epithelium. In earlier findings in palpable breast carcinomas, 55% are of the diploid-tetraploid type. The mean cellular content of the estrogen receptor was 1.0 fmole/microgram DNA in this group of mammographically detected carcinomas, which is significantly higher than in routinely detected, ie, larger, breast carcinomas. It is suggested that, despite the histomorphological findings, nonpalpable, mammographically detected breast carcinomas are dominated by biologically highly differentiated, slowly proliferating carcinomas with a favourable prognosis.