Clive A. Wells

Predictive markers in breast cancer--the present.

Breast cancer is a heterogeneous disease and there is a continual drive to identify markers that will aid in predicting prognosis and response to therapy. To date, relatively few markers have established prognostic power. Oestrogen receptor (ER) is probably the most powerful predictive marker in breast cancer management, both in determining prognosis and in predicting response to hormone therapies. Progesterone receptor (PR) is also a widely used marker, although its value is less well established. HER‐2 status has also become a routine prognostic and predictive factor in breast cancer. Given the importance of these biological markers in patient management, it is essential that assays are robust and quality controlled, and that interpretation is standardized. Furthermore, it is important to be aware of the limitations in their predictive power, and how this may be refined through addition of further biological markers. The aim of this review is to provide an overview of the established role of ER, PR and HER‐2 in patient management, the current standards for assessing these markers, as well as highlighting the controversies that still surround their use and methods of assessment.

Telepathology: a diagnostic tool for the millennium?

Many developments in science have their origins in science fiction and telepathology is no exception. The concept was first illustrated in 1924 in the magazine ‘Radio News’. It was not until 1980, however, that the first working telepathology system was demonstrated. Although the system was shown to work, it required special hardware, dedicated software and special microwave transmission links to be installed. Little interest was shown worldwide because of the very high cost and the inability of many people to replicate such a system. Ten years later, the personal computer (PC) was able to provide more than adequate performance at low cost for both image display quality and speed, and the development of video technology had resulted in high quality images being produced by television cameras that were now easily affordable. Microscopes were also relatively cheaper. Thus, by 1993 or 1994, all the hardware necessary to produce a telepathology system was available at reasonable cost. Telepathology can now be used for remote primary diagnosis, remote referral to a specialist pathologist, remote teaching, remote presentation of post‐mortem or microscopic findings, quality assurance image circulation and feedback, and consensus diagnosis for pathological review in clinical trials. There are two residual problems. The first concerns the speed of data transmission, commonly referred to as the bandwidth. The second is that the software provided by most of the manufacturers and suppliers of these systems is not entirely suitable to the task and the systems are not interoperable. It is clear that the approach of the manufacturers is at present unlikely to produce telepathology systems which pathologists feel comfortable in using. A somewhat different approach is illustrated by the accompanying article in this issue from the Berlin group, where a relatively simple Java‐based applet and the Internet are used to allow single or multiple users to view slides on a robotic microscope. This could form the basis for a truly useful system, but still needs modification for some applications. Copyright

Metastases to the breast revisited: radiological-histopathological correlation.

Metastases to the breast from extramammary tumours are infrequent. The main challenge in diagnosis is differentiating them from primary breast cancer. Radiologically this can be difficult as there are no specific imaging characteristics for metastases to the breast. Cytopathological evaluation, as well as full radiological assessment, is vital to avoid unnecessary surgery. Sources of primary tumours include a wide variety of cancers. In this pictorial review we illustrate a number of the commonest sources of primary tumours including lymphoma, lung, ovarian and cervical carcinoma, intestinal carcinoid and rare cases of Ewings sarcoma and malignant pigmented melanocytic schwannoma (low-grade malignant melanoma).

Characterisation and cellular localisation of the immunodominant 47-Kda antigen of Candida albicans

The 47-Kda component of Candida albicans is an immunodominant antigen in the serology of systemic candidosis. Immuno-electronmicroscopy with an affinity-purified antibody to the 47-Kda antigen showed that it was present in the cytoplasm and cell wall of both yeast and mycelial cells. It was found in discrete areas on the inner and outer borders of the cell wall and was mainly located within the wall rather than exposed on the outer surface. Sometimes it appeared to be in channels across the cell wall. In the cytoplasm, it was usually near the cytoplasmic membrane and occasionally appeared in vesicular areas. It was not detected in the nucleus or mitochondria. The 47-Kda antigen did not bind to Concanavalin A, and antigenicity was lost after protease digestion. Peptide mapping suggested that the antigen was highly conserved between different strains of C. albicans.

Integrin expression in breast cancer cytology: a novel predictor ofaxillary metastasis

The integrins are heterodimeric transmembrane receptors of varying alpha and beta subunits that modulate cell adhesion to each other and to the extracellular matrix. Loss of integrin expression on primary breast cancer frozen sections measured by immunohistochemistry may be related to the presence of axillary metastasis. The clinical application of this finding would be increased if integrin expression could also be shown to be reliably measured on breast cancer cells obtained by fine needle aspiration cytology. Axillary operations may be planned as a single stage procedure from outpatients, and neoadjuvant therapy protocols may be developed without surgery to the axilla. Expression of the alpha 1, alpha 2, alpha 3, alpha 6, alpha v, beta 1, beta 3 and beta 5 integrin subunits were measured by immunohistochemistry and immunocytochemistry in 58 patients. Integrin measurement by both these methods were found to be closely associated using the kappa-test. Loss of expression of the alpha 1, alpha 2, alpha 3, alpha 6, alpha v, beta 1 and beta 5 integrin subunits measured by cytology and histology were each related to positive nodal status (chi(2) test). Measuring integrin expression on cytology is of clinical value and may prove to have prognostic significance.

Benign biopsies in the prevalent round of breast screening : a review of 137 cases

In the first round of the National Health Service Breast Screening Programme, 35,533 women attended for screening at the two breast screening units served by St Bartholomews Hospital. Further assessment was necessary in 2212 women (6.2%), of whom 412 (1%) subsequently underwent surgical biopsy. Of these 137 had benign lesions. The predominant mammographic abnormality leading to biopsy was microcalcification in 55, a mass in 48, parenchymal asymmetry in 18 and architectural distortion in 16. Histology revealed fibrocystic change in 66, fibroadenoma in 27, radial scar/complex sclerosing lesion in 23, atypical ductal hyperplasia only in eight, and a variety of unusual benign lesions in 13. In an attempt to determine criteria which would minimize unnecessary biopsy of benign lesions in future, the mammographic and cytological features of these benign lesions were reviewed and compared with the final histology. The most common diagnostic problems were clustered and variable microcalcification, the radial scar/complex sclerosing lesion, and mammographic features shown to be atypical hyperplasia on histology.

Inadequate rates are lower when FNAC samples are taken by cytopathologists

Inadequate rates (IR) in FNAC from different sources were compared. The rates were lowest when FNAC was performed by a cytopathologist (12%) and highest when done by a non‐cytopathologist (32%). These differences were mirrored in high IRs in breast cancer cases. IR was not significantly improved when non‐cytopathologist FNAC was attended by a cytotechnician.

Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: microdissection microsatellite analysis.

Loss of heterozygosity (LOH) and allelic imbalance (AI) at loci reported to show allele loss and/or imbalance in preinvasive and invasive breast cancer were examined in 41 cases of apocrine metaplasia (APM) of the breast using a microdissection technique, polymorphic microsatellite markers, and the polymerase chain reaction (PCR). Occasional examples of LOH and/or AI were identified in 2/28 (7.1%) informative cases at 1p (MYCL1), 2/14 (14.3%) at 11q (INT2), 1/15 (6.7%) at 13q (D13S267), 3/22 (13.6%) at 16q (D16S539), 2/23 (8.7%) at 17p (TP53), and 1/11 (9.1%) at 17p (D17S513) and 3/16 (18.8%) at 17q (D17S250). The finding of LOH/AI in cases of APM indicates that a subset of APM appears clonal, but the significance of allelic loss or imbalance in the pathogenesis of APM or its possible subsequent progression to carcinoma is not yet clear and requires further investigation. Clinical follow‐up of these particular cases of APM showing LOH/AI would be of further value. Copyright

c-erbB2 oncoprotein expression, gene amplification, and chromosome 17 aneusomy in apocrine adenosis of the breast.

Amplification of the c‐erbB2 oncogene and numerical aberrations of chromosome 17 occur in human breast carcinomas. Apocrine adenosis (AA) of the breast has been shown occasionally to have c‐erbB2 overexpression and a possible premalignant potential, but little is known about cellular level genetic alterations in AA of the breast. Fluorescence in situ hybridization (FISH) is a new approach to detect these. In this study, a series of AA was studied by immunohistochemistry for c‐erbB2 protein expression and by FISH using dual colour DNA probes for the c‐erbB2 gene and the centromeric region of chromosome 17. Cell membrane immunostaining was seen in 10/18 (55.6%) AA cases, but unequivocal c‐erbB2 gene amplification or chromosome 17 aneusomy was not seen. The results of this study suggest that c‐erbB2 overexpression without amplification may occur early in breast oncogenesis. Amplification and numerical chromosome aberrations may occur later in the pathogenesis of apocrine‐derived breast carcinomas. Copyright

An audit of patient acceptance of one-stop diagnosis for symptomatic breast disease.

AIMS The impetus for optimizing outpatient provision of breast-care services has come both from the patient and management in order to reduce anxiety and make full use of scarce resources. The one-stop diagnostic clinic for the investigation of symptomatic breast lesions is a relatively recent concept with well-known service benefits. However, acceptance to the patient has not been previously investigated. RESULTS The results of this prospective audit demonstrate a high level of patient satisfaction with the multi-disciplinary, one-stop breast clinic.