Ingrid Idvall

Tumour biological features of BRCA1-induced breast and ovarian cancer

BRCA1 mutations, although implicated in disease predisposition in a major part of the hereditary breast cancer population, do not seem to be crucially involved in tumorigenesis of sporadic breast and ovarian cancers. This suggests that tumours arising in BRCA1 mutation carriers may differ from BRCA1 negative hereditary and sporadic cancer in genetic and biological features, as well as in clinical behaviour. Prior to BRCA1 analysis, 79 breast and 19 ovarian tumours from 57 breast and breast-ovarian cancer families, and 170 tumours from a comparison group of stage II breast cancers were studied with regard to histopathological features; immunohistochemistry [c-erbB-2, p53, oestrogen receptor (ER) and progesterone receptor (PR)], DNA flow cytometry and S-phase fraction. BRCA1 mutations were found in 40 breast and 15 ovarian tumours. The BRCA1 positive breast tumours were significantly more often of ductal type, histological grade III and manifested a heavy lymphocyte infiltration. Additionally, as compared to BRCA1 negative tumours, the BRCA1 positive tumours were significantly more often ER, PgR and c-erbB-2 negative. Furthermore, they were significantly more often DNA non-diploid, as well as being characterised by higher S-phase fraction values. These results suggest that BRCA1-induced breast cancers may manifest distinct tumour biological features of clinical importance.

Cell biological factors in ductal carcinoma in situ (DCIS) of the breast-relationship to ipsilateral local recurrence and histopathological characteristics

All cases of ductal carcinoma in situ (DCIS) diagnosed from 1987 to 1991 in the Southern Health Care Region of Sweden, and operated upon with breast conserving treatment (BCT) with (n=66) or without (n=121) postoperative radiation (RT) were clinically followed, morphologically re-evaluated and analysed for cell biological factors (immunohistochemical assays or DNA flow cytometry). Median age at diagnosis was 58 years (range 29--83 years) and median follow-up was 62 months. Oestrogen (ER)- and progesterone receptor (PR)-negativity, c-erbB-2 overexpression, low bcl-2 expression, p53 accumulation, DNA non-diploidy and high Ki67, were strongly associated with high grade DCIS, and comedo-type necrosis. In contrast, significant associations to growth pattern (not diffuse versus diffuse) were seen only for c-erbB-2 and PgR. There was also a strong relationship between the cell biological factors, and a summary cell biological index based on principal component analysis was introduced (CBI-7). In the group that had not received postoperative RT, 31 ipsilateral local recurrences occurred (13 invasive, 18 DCIS). Ipsilateral recurrence-free interval (IL-RFI) was in univariate analyses significantly, or almost significantly, shorter for patients showing p53 accumulation, high Ki67 or low bcl-2, compared with patients with normal p53, low Ki67 and high bcl-2. The prognostic importance of the remaining cell biological factors was less pronounced. On the other hand, the index CBI-7, was a strong predictor for recurrence.

Clinical multi-colour fluorescence imaging of malignant tumours - initial experience

Purpose: the detection of malignant tumours relies on a variety of diagnostic procedures including X-ray images and, for hollow organs, endoscopy. the purpose of this study was to present a new technique for non-invasive tumour detection based on tissue fluorescence imaging Material and Methods: A clinically adapted multi-colour fluorescence system was employed in the real-time imaging of malignant tumours of the skin, breast, head and neck region, and urinary bladder. Tumour detection was based on the contrast displayed in fluorescence between normal and malignant tissue, related to the selective uptake of tumour-marking agents, such as haematoporphyrin derivative (HPD) and δ-amino levulinic acid (ALA), and natural chromophore differences between various tissues. in order to demarcate basal cell carcinomas of the skin, ALA was applied topically 4–6 h before the fluorescence investigation. for urinary bladder tumour visualisation (transitional cell carcinoma of different stages including carcinoma in situ), ALA was instilled into the bladder 1–2 h prior to the study. Malignant and premalignant lesions in the head and neck region were imaged after i.v. injection of HPD (Photofrin). Finally, the extent of in situ and invasive carcinomas of the breast was investigated in surgically excised specimens from patients that received a low-dose injection of HPD 24 h prior to the study. the tumour imaging system was coupled to an endoscope. Fluorescence light emission from the tissue surface was induced with 100-nslong optical pulses at 390 nm, generated from a frequency-doubled alexandrite laser. with the use of special image-splitting optics, the tumour fluorescence, intensified in a micro-channel plate, was imaged in 3 selected wavelength bands. These 3 images were processed together to form a new optimised-contrast image of the tumour. This image, updated at a rate of about 3 frames/s, was mixed with a normal colour video image of the tissue Results: A clear demarcation from normal surrounding tissue was found during in vivo measurements of superficial bladder carcinoma, basal cell carcinoma of the skin, and leukoplakia with dysplasia of the lip, and in in vitro investigations of resected breast cancer Conclusions: the initial clinical experience of using multi-colour fluorescence imaging has shown that the technique has the potential to reveal malignant tumour tissue, including non-invasive early carcinoma and also precancerous tissue. Further investigations are needed to fully develop the method

Histologic grading in breast cancer--reproducibility between seven pathologic departments. South Sweden Breast Cancer Group

Histologic grade, including tubular formations, nuclear grade, and mitotic activity, is a well-documented prognostic factor in breast cancer. In comparison with other prognostic parameters, the evaluation of histologic grade is cheap and can be performed, in principle, in all cases of breast cancer. One possible disadvantage is that the evaluation may vary between different pathological departments. The aim of the present work was therefore to study the reproducibility of the histologic grading system by distributing haematoxylin-erythrosin-stained slides from 93 invasive breast cancers to the seven pathology departments within the southern healthcare region of Sweden. The evaluation was performed blindly and without any knowledge of other clinical parameters. In 31% of the cases the same histologic grade was obtained for all departments. The overall mean kappa was 0.54, indicating a moderate reproducibility. Of the three factors included in histologic grade, the agreement was best for tubular formations and poorest for nuclear grade and mitotic activity. The overall moderate reproducibility should be considered when the clinical usefulness of histologic grading is compared with other prognostic instruments.Histologic grade, including tubular formations, nuclear grade, and mitotic activity, is a well-documented prognostic factor in breast cancer. In comparison with other prognostic parameters, the evaluation of histologic grade is cheap and can be performed, in principle, in all cases of breast cancer. One possible disadvantage is that the evaluation may vary between different pathological departments. The aim of the present work was therefore to study the reproducibility of the histologic grading system by distributing haematoxylin-erythrosin-stained slides from 93 invasive breast cancers to the seven pathology departments within the southern healthcare region of Sweden. The evaluation was performed blindly and without any knowledge of other clinical parameters. In 31% of the cases the same histologic grade was obtained for all departments. The overall mean kappa was 0.54, indicating a moderate reproducibility. Of the three factors included in histologic grade, the agreement was best for tubular formations and poorest for nuclear grade and mitotic activity. The overall moderate reproducibility should be considered when the clinical usefulness of histologic grading is compared with other prognostic instruments.

S-Phase Fraction and Urokinase Plasminogen Activator Are Better Markers for Distant Recurrences Than Nottingham Prognostic Index and Histologic Grade in a Prospective Study of Premenopausal Lymph Node–Negative Breast Cancer

PURPOSE Histologic grade, Nottingham Prognostic Index (NPI), estrogen receptor (ER) and progesterone receptor (PgR) status, and tumor size have previously been shown to be important prognostic indicators for distant recurrence of breast cancer. The purpose of this study was to compare the prognostic value of these factors with flow cytometric S-phase fraction (SPF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) in premenopausal patients with lymph node-negative breast cancer. PATIENTS AND METHODS In 237 consecutive premenopausal patients with lymph node-negative breast cancer and freshly frozen tumor material available, SPF, ER and PgR status, uPA and its inhibitor PAI-1, histologic grade, and NPI were evaluated. RESULTS SPF was univariately the most powerful prognostic factor for distant recurrence, followed by uPA, histologic grade, PgR, age, ER, NPI, and PAI-1, the latter being nonsignificant. Multivariate analysis revealed that neither NPI nor histologic grade was significant after adjustment for SPF, a fact that may be explained by the strong association between these factors. uPA was, however, an independent prognostic factor in addition to SPF, NPI, or histologic grade. CONCLUSION In this prospective study, SPF and uPA were found to be independent prognostic factors in premenopausal women with lymph node-negative breast cancer. We suggest that SPF, if performed under standardized conditions, can replace histologic grade as a selection instrument for adjuvant medical treatment. The value of the combination of SPF and uPA needs to be confirmed in an independent prospective trial.

Comparison of immunohistochemical and biochemical assay of steroid receptors in primary breast cancer--clinical associations and reasons for discrepancies.

The main aim was to investigate risk perception and psychological distress in individuals attending genetic counselling. A consecutive series of 86 individuals with a diagnosis and/or family history of breast, ovarian or colorectal cancer was included. Risk assessments were performed before and immediately after genetic counselling and at a one-year follow-up. Psychological distress was assessed 1 week before, and 6 weeks, 6 months and 1 year after genetic counselling. The number of individuals who correctly estimated the general risk in the population increased significantly from 35% before to 82% after counselling (p<0.001). One year later, data on general risk estimates showed a significant reduction of the number of correct estimations to 51%, compared with directly after the counselling (p<0.005). In total, 54% estimated their own lifetime risk correctly after the counselling, compared with 17% before (p<0.001) (those with a cancer diagnosis estimated the risk of their children developing cancer). One year later, the number of correct estimations had dropped to 28%. Before the counselling, the majority of the participants overestimated both the general risk and their own/childrens risk. The participants experienced moderate levels of psychological distress before the counselling and a decrease of anxiety afterwards (p<0.02). However, half of the participants reported moderate or high distress. There were no differences in psychological distress between those who estimated their risk/childrens risk as low, moderate or high or between those who over-, under- or correctly estimated their own/childrens risk. Further investigations are needed to develop and adjust the risk information provided to the individual in order to avoid misunderstanding, especially as this information is going to be revealed to family members. Counselling support should be offered to those individuals who experience psychological distress.

Correlation between karyotypic pattern and clinicopathologic features in 125 breast cancer cases

A correlation analysis was performed on 125 cytogenetically characterized breast cancer cases to assess the relationship between the tumor karyotype and clinicopathologic features. The carcinomas of young women had a higher modal chromosome number than those of older women. The number of chromosomal aberrations and modal chromosome number were also found to correlate with the histologic type, grade and mitotic activity of the tumor. Whereas all lobular carcinomas were karyotypically normal or near‐diploid, more than 3 aberrations and sometimes near‐triploid or near‐tetraploid karyotypes were common findings in ductal carcinomas, especially in grade‐III tumors and in tumors showing high mitotic activity in vivo. Karyotypes with cytogenetically unrelated clones and unbalanced structural chromosomal rearrangements were more frequent in infiltrating than in in situ carcinomas but, at least as far as the second of these 2 characteristics is concerned, especially in infiltrating carcinomas that also had an in situ component. The presence of cytogenetic polyclonality correlated with tumor grade. Although recurrent chromosome aberrations were significantly more common in ductal than in lobular carcinomas, none of these breast cancer‐associated anomalies seemed to be specific for any particular clinicopathologic parameter. The associations between modal chromosome number and mitotic activity and between cytogenetic polyclonality and tumor grade were found to be statistically significant in multivariate models. No correlation was seen between the karyotypic findings and tumor size or the presence of axillary‐lymph‐node metastases.

Cytodiagnosis of soft tissue tumors and tumor-like conditions by means of fine needle aspiration biopsy

SummaryIn the evaluation of soft tissue tumors primary sarcomas must be differentiated from other malignancies, such as cancer metastases, malignant lymphomas, as well as benign tumors and tumor-like conditions. As far as possible this should be done without open biopsy to avoid local spread.Fine needle aspiration biopsy as opposed to thick needle biopsy utilizes smaller needle diameters up to 0.8 mm with assumed negligible risks of local or distant tumor spread. Such a fine needle aspiration biopsy for cytodiagnosis was supposed to increase the reliability of the preoperative diagnosis.In a consecutive series of 187 patients referred to an orthopedic oncology group because of suspected malignancy fine needle aspiration biopsy was made. In 129 cases with histology and in 49 non-operated cases with at least 2 years of clinical follow-up the reliability of the method is analyzed. In 163 cases the aspirated material was sufficient for a diagnosis and 152 cytological reports were correct regarding the diagnosis of a malignancy contra a benign tumor or tumor-like condition. Thirty-five of 43 malignancies were primary soft tissue sarcomas, 28 of these with a correct cytologic diagnosis of sarcoma. Eight were malignant lymphomas or carcinomas. Fourty-nine patients with 48 benign and one malignant cytological diagnosis were not operated upon. At least 2 years of clinical follow-up confirmed a benign diagnosis in these cases. The total reliability is thus around 85%.Fine needle aspiration biopsy is considered to be a very valuable complement to other investigations in the diagnostic work-up of soft tissue tumors.

Cytogenetic findings in phyllodes tumors of the breast: Karyotypic complexity differentiates between malignant and benign tumors☆

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3)(p21p23),were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.

Karyotypic abnormalities in fibroadenomas of the breast

Short‐term cultures of 50 fibroadenomas of the breast were cytogenetically analyzed. Nine tumors were found to display clonal chromosome aberrations. One had multiple, cytogenetically unrelated clones, whereas the others had a single abnormal clone each. Four cases had one balanced translocation as the sole anomaly, and one had a complex intrachromosomal rearrangement of chromosome 3, leading to loss of 3p material. One fibroadenoma had a single numerical aberration, and one had supernumerary ring chromosomes. The remaining 2 cases had both numerical and structural aberrations. The only recurrent alterations were trisomy 20 and rearrangement of chromosome arm 1p. The finding of similar chromosomal aberrations in fibroadenomas and carcinomas suggests that women with karyotypically abnormal fibroadenomas may have an increased risk of developing subsequent breast cancer. If so, different chromosome anomalies might have different pathogenetic and/or prognostic significance. Int. J. Cancer, 70:282–286, 1997.