Biomedical subjects

P Kronqvist

Publications and source records attributed to P Kronqvist.

16 recordsLinked to original sources

PubMed2006

Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index.

AIMS: Counting mitotic figures is considered to be a reliable prognosticator, but evaluation of Ki67 immunohistochemistry has become more popular in evaluating proliferation. Our previous studies suggested an occasional discrepancy between mitotic figures and Ki67 fraction. The aim of this study was to investigate this more closely and also to study the associations between bcl-2 and p53 expression and proliferation. METHODS AND RESULTS: Two hundred and sixty-five infiltrating breast carcinomas were immunostained for Ki67, p53 and bcl-2. The standardized mitotic index (SMI) was determined. Four proliferation groups were based on Ki67 positivity fraction and SMI at optimal cut-off points. Cox's multivariate model was used to test the power of the prognosticators. SMI and nodal status were the most powerful individual prognosticators. Ki67 was an independent prognosticator if nodal status, tumour size, age and histological grade were included in the analysis but not if analysed with SMI. The group with low SMI and low Ki67 fraction had the best prognosis. Groups with high SMI had the poorest prognosis. The group with low SMI and high Ki67 fraction had a favourable prognosis. Bcl-2 negativity and p53 positivity correlated with proliferation. CONCLUSIONS: We have found a 'wrong positive' Ki67 group with favourable prognosis. SMI cannot be replaced by Ki67 because of the danger of misclassification of some patients.

Adult↗

PubMed2004

Predicting aggressive outcome in T1N0M0 breast cancer.

Despite the excellent overall prognosis, unpredictable breast cancer recurrences and deaths also occur among T1N0M0 patients. We have evaluated clinically applicable methods for identifying aggressive outcome in T1N0M0 breast cancer. The material is based on aggressive T1N0M0 invasive ductal and lobular carcinomas diagnosed in Turku University Hospital and Jyväskylä Central Hospital, Finland, during 1987-1997. We studied all the T1N0M0 breast cancers that had led to recurrency or death (n=21, 95% T1cN0M0) during the follow-up period (4-14 years). The study is based on statistical analyses of matched case-control data in which the prognostic factors of each individual patient with aggressive disease were compared with control patients (n=45) individually matched by tumour size, age at diagnosis, histological type of tumour and length of follow-up. The cancer cases were examined for clinically applicable conventional and immunohistochemical pathologic prognostic factors. High Ki-67 immunopositivity was the strongest prognosticator of breast cancer death or recurrence in T1N0M0 breast cancer. Also, high p53 immunopositivity, low oestrogen receptor immunopositivity and Her-2/neu oncogene amplification by chromogen in situ hybridisation were reliable indicators of unfavourable outcome. Our statistical methods also allowed us to determine for the present material a range of clinical significance for each immunohistochemical prognostic feature with the associated relative risk for breast cancer death and recurrence. The paper suggests guidelines for predicting aggressive outcome in T1N0M0 breast cancer.

Adult↗

PubMed2002

Morphometrical malignancy grading is a valuable prognostic factor in invasive ductal breast cancer.

The aim of the present study is to augment the prognostic power of breast cancer grading by elaboration of quantitative histopathological methods. We focus on the recently introduced morphometrical grading system in which the three grading sub-features of the WHO grading system are evaluated with the help of computerised nuclear morphometry, and quantitative methods for assessing mitotic activity and tubular differentiation. The prognostic value of the morphometrical grading system is now confirmed in a material of 159 cases of invasive ductal breast cancer. In the current material the morphometrical grading system very efficiently predicted the prognosis of breast cancer by dividing the patients into favourable (grade I), intermediate (grade II), and unfavourable (grade III) outcome (P<0.0001). The morphometrical grading system was especially efficient in identifying patients with the most unfavourable outcome. In our material the morphometrical grade III was associated with a 5.4-fold risk of breast cancer death. In light of the present results, the morphometrical grading can be applied to clinical use as an aid in treatment decisions of patients with invasive ductal breast cancer.

Adult↗

PubMed2000

Quantitative thresholds for mitotic counts in histologic grading: confirmation in nonfrozen samples of invasive ductal breast cancer.

Increasing evidence in the medical literature suggests that freezing a sample before fixation causes changes in the histologically observed mitotic activity. In a recent study we determined quantitative thresholds for mitotic counts in invasive ductal breast cancer in both nonfrozen and frozen formalin-fixed specimens. Survival- and recurrence-based analyses of this study material indicated grading thresholds of 17 and 32 mitoses/mm(2) for standardized mitotic index (SMI) and 13 and 35 mitoses/10 high-power fields for mitotic activity index (MAI). The purpose of the present study is to confirm and adjust the introduced thresholds in only nonfrozen formalin-fixed samples. The SMI and MAI in 202 cases of nonfrozen formalin-fixed samples were analyzed to determine optimal cutpoints for prognostication of invasive breast cancer on the basis of mitotic activity. The SMI thresholds were identical in both the present nonfrozen specimens and the previous combined specimens. The optimal MAI thresholds in the nonfrozen material changed to 11 and 37 mitoses/10 high-power field. The confirmation and adjustment of the mitotic thresholds improved the prognostic significance of the method in the nonfrozen material, which will contribute to the clinical applicability of a morphometric grading system.

Adult↗

PubMed2000

Morphometric grading of breast cancer: thresholds for tubular differentiation.

We evaluated the degree of tubular differentiation in 172 samples of invasive ductal breast cancer in order to determine numerical thresholds for histological breast cancer grading. The tubular differentiation in each sample was defined as the fraction of fields showing tubular differentiation (FTD). The analysis was based on Kaplan-Meier curves reflecting survival and recurrence of disease, univariate and multivariate analyses of Cox's regression, and maximum efficiencies of ROC analysis. The minimum P-value cut-off for FTD was determined at 59%. The practical interpretation is that tubular differentiation in the neoplasm observed in at least 60% of microscopical fields in the tumour area indicates favourable prognosis of disease. The relative risks for breast cancer death for patients with FTD below 59% as compared with those with FTD above 59% were 6.7--and 6.3-fold (univariate and multivariate analyses respectively). Another threshold could be determined at FTD 23%, although this threshold was associated with clearly lower statistical significancies. The paper introduces two possible solutions for application of the thresholds to the morphometric breast cancer grading system. The study also emphasizes the clinical relevance of the evaluation of tubular differentiation in breast cancer. The consistent morphometric evaluation method was vital in allowing the full weight of the biological significance of tubular differentiation to emerge.

Adenocarcinoma↗

PubMed1999

Immunohistochemical labelling for prostate-specific antigen in breast carcinomas.

Immunohistochemical detection of prostate-specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non-prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma. Sections of formalin-fixed, paraffin-embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow-up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32%) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA-negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.

Adult↗

PubMed1999

The fraction of fields showing neoplastic tubules: a practical estimate of tubular differentiation in breast cancer.

AIMS: The purpose of the study is to evaluate histological measurement methods for quantitative assessment of the degree of tubular differentiation in breast cancer. METHODS AND RESULTS: We evaluated tubular differentiation in 20 cases of invasive breast cancer by four different assessment methods. Method 1 was the traditional subjective evaluation of the amount of malignant tubules in each sample. Method 2 evaluated the fraction of fields presenting tubular differentiation by registering the presence or absence of neoplastic tubular structures in each microscopic field. In method 3 the area fraction of malignant epithelial cells presenting tubular differentiation was assessed field-by-field and expressed as an average of the whole tumour area. Method 4 applied point counting for evaluating the fraction of malignant epithelial cells in tubular structures. By correlation and reproducibility analyses, method 1 was inferior to the other methods. Method 4 was accurate but too laborious and time-consuming for clinical use. Methods 2 and 3 were both efficient and reproducible and could be used interchangeably. With the time and effort used in the measurements taken into consideration method 2 was best applicable to clinical practice. CONCLUSION: Accurate evaluation of tubular differentiation in breast cancer is possible by defining the presence or absence of tubular differentiation in microscopic fields of a histological section. Assessment of the fraction of fields with tubular differentiation (FTD) is simple, unambiguous, objective and fast--even a large sample can be screened in less than 10 min. In our results, FTD has clear advantages over subjective or point counting-based evaluation methods of tubular differentiation.

Breast Neoplasms↗

PubMed1998

Cysteine proteinase inhibitor cystatin A in breast cancer.

Cystatin A (acid cysteine proteinase inhibitor; ACPI) is a natural inhibitor of cysteine proteinases. It has been suggested that an inverse correlation exists between cystatin A and malignant progression. We wanted to assess the biological and clinical significance of cystatin A in infiltrative breast carcinoma by immunohistochemical staining. Formalin-fixed paraffin-embedded material from 440 cases treated during the years 1988-1991 was used in the study. After exclusion of patients with disseminated disease at diagnosis, previous contralateral breast carcinoma, and absence of follow-up data, 384 patients could be included in the survival analysis. For immunohistochemical analysis of cystatin A, we used monoclonal cystatin A antibody WR-23/2/3/3, the binding of which was detected by the avidin-biotin-peroxidase method. Immunohistochemical analysis of Bcl-2 and p53 was also done, and mitotic activity was evaluated. Positive staining for cystatin A was found in 52 of 440 cases. The staining was irregular but showed irrefutably positive areas within neoplastic tissue. Most of the positive tumors were of the ductal infiltrative type, but two were mucinous carcinomas, one medullary and one squamous cell carcinoma. No lobular carcinomas showed positive staining. Focal cystatin A positivity was seen in myoepithelial cells of benign ducts. Occasional apoptotic bodies within the neoplasm showed strong positivity for cystatin A. Tumors positive for cystatin A were of larger size and had higher mitotic activity than cystatin A-negative tumors. Cystatin A was associated with negative Bcl-2 staining, but there was no statistically significant association between axillary lymph node status or p53 immunostaining. The risk for breast cancer-related death was significantly higher in patients with cystatin A-positive tumors than in those with cystatin A-negative ones. The risk increase was significant also in lymph node-negative patients. After adjusting for the effect of tumor size, histological grade, and lymph node status, cystatin A-positive patients still had a higher risk of death. Patients with cystatin A and p53 coexpression had a higher risk of death than the other patients. The findings reveal a new variant of aggressive breast cancer. This type of carcinoma may develop during tumor progression through genetic instability that allows cystatin A expression and gives growth advantage to a clone of tumor cells.

Adenocarcinoma, Mucinous↗

PubMed1998

Morphometric grading in breast cancer: thresholds for mitotic counts.

Three hundred sixty-four cases of invasive ductal breast cancer diagnosed during the years 1988 to 1991 were analyzed to determine quantitative thresholds for mitotic activity. Mitotic counts were calculated in each sample and expressed as standardized mitotic index (SMI) and mitotic activity index (MAI). Based on Kaplan-Meier curves, univariate and multivariate analysis of Cox's regression, and maximum efficiencies of ROC analysis, optimal thresholds were determined on the basis of survival and recurrence of disease. In our material, with a follow-up time of 5 years 9 months, we found two thresholds--a lower and a higher--for both SMI (17 mitoses/mm2 and 32 mitoses/mm2) and MAI (13 mitoses/10 HPF and 35 mitoses/10 HPF). The thresholds were the same in the whole material and in subgroups divided according to the patients' age and axillary lymph node status at the time of diagnosis, and tumor size. The thresholds clearly separated patients with favorable, intermediate, and unfavourable outcome of disease. In our material, the risk of breast cancer death associated with the determined thresholds (ranging from 4.7 to 3.8) clearly exceeded those of menopausal status, axillary lymph node status and tumor size. The risk of breast cancer death associated with the determined thresholds was still emphasized in the groups of premenopausal and axillary lymph node-negative patients, and with tumor size less than 2 cm in diameter (risk ratios, 11.8, 6.0, and 6.7, respectively). The results suggest that the presented quantitative thresholds could be applied in grading of invasive ductal breast cancer.

Adult↗

PubMed1998

Morphometric grading of invasive ductal breast cancer. I. Thresholds for nuclear grade.

We analysed 170 histological samples of invasive ductal breast cancer from years 1988-91 by computerized nuclear morphometry, to find objective and quantitative thresholds for nuclear grade. Based on Kaplan-Meier curves reflecting survival and recurrence of disease and univariate analysis by Cox's regression, optimal thresholds were determined for features related to nuclear size and size variation. In our material, with mean follow-up time of 5 years 9 months, the determined thresholds for nuclear profile area (32 microm2 and 47 microm2), nuclear diameter (6.4 microm and 7.4 microm) and mean shortest nuclear axis (4.8 microm and 6.4 microm) best separated the cases with favourable, intermediate and unfavourable course of disease. In this material from the era of mammography and adjuvant therapy, the mean shortest nuclear axis was found to be a significant prognostic factor, with a risk ratio (RR) exceeded only by that of tumour size (RRs 2.9- and 3.5-fold respectively). The results suggest that morphometric grading criteria can be developed for application in Bloom-Richardson grading and in the Nottingham Prognostic Index.

Adult↗

PubMed1997

The reproducibility of nuclear morphometric measurements in invasive breast carcinoma.

The intraobserver and interobserver reproducibility of computerized nuclear morphometry was determined in repeated measurements of 212 samples of invasive breast cancer. The influence of biological variation and the selection of the measurement area was also tested. Morphometrically determined mean nuclear profile area (Pearson's r 0.89, grading efficiency (GE) 0.95) and standard deviation (SD) of nuclear profile area (Pearson's r 0.84, GE 0.89) showed high reproducibility. In this respect, nuclear morphometry equals with other established methods of quantitative pathology and exceeds the results of subjective grading of nuclear atypia in invasive breast cancer. A training period of eight days was sufficient to produce clear improvement in consistency of nuclear morphometry results. By estimating the sources of variation it could be shown that the variation associated with the measurement procedure itself is small. Instead, sample associated variation is responsible for the majority of variation in the measurements (82.9% in mean nuclear profile area and 65.9% in SD of nuclear profile area). This study points out that when standardized methods are applied computerized morphometry is a reproducible and reliable method of assessing nuclear atypia in invasive breast cancer. For further improvement special emphasize should be put on sampling rules of selecting the microscope fields and measurement areas.

Breast Neoplasms↗

PubMed1997

Subjective breast cancer grading. Analyses of reproducibility after application of Bayesian belief networks.

OBJECTIVE: To examine the influence of Bayesian belief networks (BBNs) on the reproducibility of subjective breast cancer grading. STUDY DESIGN: Twenty samples were analyzed for intraobserver and 128 samples for interobserver reproducibility using the Bloom-Richardson and Helpap grading systems. The expression of diagnostic features was evaluated subjectively, and for each a decision it was determined to what extent it represented one of the different outcomes. Evidence was then entered, for each diagnostic feature, into four different BBNs, recently described for breast cancer grading, in the form of a relative likelihood ratio vector. RESULTS: With all cases considered, the use of decision support based on the Bloom-Richardson and Helpap grading systems did not improve intraobserver reproducibility. This was found to be 68% and 80% in subjective gradings, respectively, and 60% and 70% in the BBN-supported method. Interobserver reproducibility was not improved (58% and 70% in subjective gradings and 51-59% based on assessment with decision support). However, when only cases associated with high beliefs were considered, both intraobserver reproducibility (agreement rose from 68% to 93%) and interobserver reproducibility (agreement rose from 60% to 87%) of BBN-supported gradings exceeded the results of subjective assessments. CONCLUSION: The results showed that the observers did not reach the same diagnosis (or grade) and that their observational assessment of histologic features lacked agreement. Since BBNs reflected only the data entered, poor agreement existed in the contribution to the final diagnostic belief by the different features and, ultimately, in belief in the final decision.

Bayes Theorem↗

PubMed1995

Nuclear morphometry in breast cancer: the influence of sampling rules and freezing of samples.

We studied nuclear morphometry of human breast cancer with special emphasis on two sources of variation: freezing prior to fixation and selection of measured objects on the basis of different sampling rules. Samples of 147 histologically verified invasive breast cancer cases were examined with a computer-based image overlay drawing system. Thirty-eight of the 147 samples of tissue frozen before embedding in paraffin were analyzed separately. Among the latter we found shrinkage of 35% and 46% (depending on the sampling rule) of the nuclear profile area as compared with samples not frozen before the standard tissue processing. These findings confirm that nuclear morphometry results from frozen and unfrozen tissue are not comparable. Frozen tissue later embedded in paraffin should not be used with prognostication models based on traditionally fixed tissue. In morphometry we applied two sampling rules that differed in the criteria used for selecting nuclei for measurement. We registered a significant difference in nuclear size and in the variation of nuclear size between the two sampling methods. Of the morphometric features studied, nuclear area was affected most. Finally, we examined the two sampling rules in light of the established prognosticators in breast cancer: tumor size, axillary lymph node status, and the Multivariate Prognostic Index (MPI). The two sampling rules resulted in different distributions of morphometric results in the prognostic groups. Our findings emphasize the significance of the sources of variation in nuclear morphometry. They also stress the need for well-standardized morphometric methods in predicting the outcome of breast cancer.

Breast Neoplasms↗

PubMed1995

Management of uncertainty in breast cancer grading with Bayesian belief networks.

OBJECTIVE: To examine the potential of different constructs of Bayesian belief networks (BBN) to manage uncertainty in breast cancer grading. STUDY DESIGN: We developed four networks, two based on Bloom-Richardson's and two on Helpap's grading systems. The function of the networks was based either on an expert's experience or frequency counts derived from subjective grading of a large number of samples. The four BBNs were tested on 20 specimens, and the resulting final beliefs were compared with the subjective gradings. RESULTS: The BBNs showed agreement with the subjective gradings in 60-85% of cases. Different constructs of BBNs, however, differed in their performance. The mean beliefs in frequency-based networks were slightly higher than in experience-based networks. In addition, as compared with the Bloom-Richardson-based networks, the Helpap-based BBNs resulted in higher maximum beliefs but produced a larger fraction of discrepancies with the subjectively graded cases. Depending on the type of network, 65-90% of the BBN grades were associated with high beliefs. CONCLUSION: The results suggest that for reliable results, grading systems with more than three or four variables may be necessary. When based on relevant information, BBNs seem to have the potential to become a valuable method of assisting the pathologist in breast cancer grading.

Breast Neoplasms↗

PubMedDate not supplied

Bcl-2 immunostaining: a way to finding unresponsive postmenopausal N+ breast cancer patients.

BACKGROUND: Bcl-2 staining positivity has shown limited prognostic value. However, we have decided to study this issue in the era of mammography screening, and adjuvant treatment protocols. METHODS: Paraffin sections of 414 breast cancers were stained for bcl-2 and staining intensity graded. Association of bcl-2 with established prognosticators was analysed with chi 2 test and odds ratios in 2 x 2 tables. Kaplan-Mayer analysis and Cox's regression were used to evaluate the prognostic value of bcl-2 and other prognosticators. RESULTS: Bcl-2 immunostaining was associated with tumor size, lymph node status, histological type, multivariate prognostic index, standardized mitotic index, Ki-67 fraction, DNA-index, proportion of cells with DNA above 5c, estrogen receptor status, and histological grade. ER status showed the best association with bcl-2 positivity (odds ratio 11.3, 95% CI 5.6-22.7). In the whole group of patients bcl-2 positivity was not an independent prognosticator. However, among N+ patients bcl-2 staining was significant, and among postmenopausal N+ patients bcl-2 immunostaining was a stronger independent prognosticator than tumor size. CONCLUSIONS: The prognosis of N+ breast cancers can potentially be evaluated with bcl-2 positivity, in association with tumor size, and mitotic activity. Among postmenopausal N+ patients, most of whom have received anti-estrogen therapy, bcl-2 positivity is an independent prognosticator. Also, the close association of bcl-2 positivity with ER status supports the view that bcl-2 negativity reveals a patient group which might benefit from additional treatment in association with anti-estrogen therapy.

Breast Neoplasms↗

PubMedDate not supplied

Nuclear volume and breast cancer prognosis.

BACKGROUND: In breast cancer, nuclear volume estimates can be expected to be better prognosticators than nuclear profile areas because biological variation is wider in volume estimates than in area measurements. MATERIALS AND METHODS: 191 invasive breast cancer samples were available for nuclear volume measurements. To estimate the volume weighted mean nuclear volume, point-sampled linear intercepts were used on micrographs. The nuclear profile area was measured from 148 cases matching volume measurements and run by the Prodit morphometry program. Measurements were compared as prognosticators after a follow-up of 5 years. A computerized method on a randomly selected large number of nuclei was also applied in 17 cases. Bcl-2 immunostaining was compared with nuclear measurements. RESULTS: The correlation of volume and area measurements was statistically significant, but the correlation coefficients were low. The nuclear area showed a significant difference in survival at the 75 percentile cut-point but the volume-weighted mean nuclear volume did not allow distinction of different prognostic groups. Computerized volume measurements based on a large number of nuclei and measurements based on the simpler method did not show statistically significant correlation. Bcl-2 staining did not show any correlation with volume or area measurements. CONCLUSIONS: Although the prognostic value of nuclear area was shown in our study, the volume-weighted mean nuclear volume did not show prognostic significance. Improvement of the methodology which could decrease method variation and increase reproducibility of measurements is urgent for verification of the prognostic value of nuclear volume measurements. Bcl-2 immunostaining and nuclear area measurements were independent prognostic variables.

Breast Neoplasms↗