The significance of lobular neoplasia on needle core biopsy of the breast.

The management of a core biopsy diagnosis of lobular neoplasia is controversial. Detailed radiological-pathological review of 47 patients with cores showing classical lobular neoplasia was performed (patients with pleomorphic lobular carcinoma in situ (LCIS) or associated risk lesions were considered separately). Immediate surgical excision in 25 patients showed invasive carcinoma in 7, ductal carcinoma in situ (DCIS) in 1 and pleomorphic LCIS in 1; radiological-pathological review showed that the core biopsy missed a mass in 5, missed calcification in 2 and that calcification appeared adequately sampled in 2. Nineteen patients had follow-up of at least 2 years. Four patients developed malignancy at the site of the core biopsy (invasive carcinoma in three, DCIS in one); one carcinoma was mammographically occult, one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core. In conclusion, most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion, emphasising the importance of multidisciplinary review and investigation of any discordance. Some carcinomas were found after apparently adequate core biopsy, raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia.

Reading the prognosis of the individual with breast cancer.

AIM: To obtain better survival estimates for the individual than is provided by placement in an NPI group. METHOD: Consecutive primary operable breast cancers treated at Nottingham City Hospital 1990-1999. Ten year % actuarial survivals plotted for 10 ranges of NPI from 2.0 to 6.9. There is an excellent inverse correlation between median NPI value for each range and survival at 10 years. To enable estimation of survival for all individual values of NPI, a curve fitting technique applied to these results (by G.B.) gave the formula to estimate survival from the individual's NPI score: 10 year % survival for the individual=-3.0079 x NPI(2)+12.30 x NPI+83.84. This gave an r(2) of 0.98. RESULTS AND CONCLUSION: Greater accuracy in individual survival prediction is obtained by dividing women into 10 groups by NPI scores than in the originally described six groups; rank order of survival in relation to NPI score is preserved. A curve fitting technique has been applied to these data to give a formula for the prediction of 10 year survival for every 0.1 value of NPI.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990-1999.

UNLABELLED: The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. AIMS: Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. METHODS: The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980-1986 (n=892) and 1990-1999 (n=2,238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. RESULTS: Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. CONCLUSION: The updated survival figures overall and for each Prognostic group for the NPI are presented.

Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma.

This study aimed to test the hypothesis that lymphovascular invasion adds prognostic information to histological grade and tumour size in node-negative invasive carcinoma of the breast. Lymphovascular invasion was assessed in haematoxylin and eosin tumour sections from 2760 patients with node-negative invasive breast carcinoma treated with definitive surgery. Patients were divided into two groups: 990 in the no adjuvant therapy series (diagnosed in 1974-1988) with median follow-up of 13 years; and 1765 in the selective adjuvant therapy series (1988-2000) with median follow-up of 6.8 years. Lymphovascular invasion was identified in 19% of tumours and was associated with larger tumour size, higher histological grade and younger age. Overall, survival was associated on multivariate analysis with lymphovascular invasion, histological grade and tumour size in both patient series, and with histological type in the no adjuvant therapy series. In conclusion, lymphovascular invasion is an independent prognostic factor in node-negative breast cancer and should be considered in decisions about adjuvant treatment in this group of women.

Estrogen receptor assay in primary breast cancer and early recurrence of the disease.

Estrogen receptor assays of primary breast tumors have been related to early recurrence of the disease. A significantly longer disease-free interval was found in women whose primary tumor was estrogen receptor positive. Although there was no relationship of receptor content to stage of disease at mastectomy, the greatest difference between recurrence rates was found when the tumor had spread to the lymph nodes, especially to those in the apex of the axilla or in the internal mammary chain. Presence of estrogen receptor is closely related to histologically well-differentiated tumors, but it was found that poorly differentiated estrogen receptor-negative tumors recurred earlier than poorly differentiated receptor-positive tumors and had a very unfavorable prognosis.

Immunocytochemical localization of estrogen receptor in human breast tissue.

An immunocytochemical assay for the measurement of estrogen receptor (ER-ICA; Abbott Diagnostics) has been evaluated in 163 human breast carcinomas. Specific binding was observed in the nuclei of 111 of 163 (68%) tumors. An excellent correlation was observed between the ER-ICA and the estrogen receptor enzyme immunoassay. A significant relationship was observed between ER-ICA status and percentage of ER-ICA negative cells, histological grade of malignancy, and mitotic activity of the tumors. A significant correlation was also observed between ER-ICA status and age at mastectomy with 50% of patients with ER-ICA positive breast tumors presenting with their disease over 60 years of age. No association was observed with either tumor size or patient nodal status. Examination of the proportion of negative cells within tumors revealed a trend for the acquisition of poor prognostic features to be associated with an increase in the negative cell population. Data on the recurrence free interval of these patients showed a significant recurrence free advantage in ER-ICA positive patients, particularly those whose tumors contained low numbers of negative cells.

Evaluation of an enzyme immunoassay for estrogen receptors in human breast cancers.

An estrogen receptor enzyme immunoassay kit (ER-EIA) has been evaluated in 70 human breast carcinomas against a routine cytoplasmic [3H]estradiol binding assay (ERU). A linear correlation between the ER-EIA and the ERU was observed for binding values up to 400 fmol/mg of cytosol protein. Above this value, the ERU underestimates the concentration of receptor. The ERU gave a lower number of estrogen receptor-positive tumors (50 of 70) than did the ER-EIA assay (59 of 70). In the ERU-negative ER-EIA-positive tumors, receptor values as determined by the ER-EIA assay all fell below 50 fmol/mg of protein (mean, 19.9 +/- 4.2 fmol/mg of protein). Application of an exchange procedure which estimates the total steroid binding capacity of the cytosol gave positive results in 7 of 9 ERU-negative ER-EIA-positive tumors (mean, 16.9 +/- 2.95 fmol/mg of protein). Subdivision of the binding data according to the menopausal status of the patient indicates low receptor values in premenopausal women by each assay. A correlation between the ER-EIA assay and the histological grade of tumors was observed; Grade I well-differentiated tumors were all positive, while Grade II and III tumors were 86% and 75% positive, respectively. No correlation between the ER-EIA assay and tumor lymph node stage or tumor size was observed.

Sections of the nipple and quadrants in mastectomy specimens for carcinoma are of limited value.

AIM: To assess the value of nipple and quadrant sections in mastectomy specimens for carcinoma in detecting Paget's disease and multifocal carcinoma. METHODS: Two hundred and forty eight consecutive mastectomies performed for carcinoma were reviewed. The presence of Paget's disease of the nipple and mode of identification of any multifocal carcinoma was recorded. RESULTS: Nipple sections showed Paget's disease in eight specimens: in five the diagnosis had been made on previous biopsy and in three (1%) this was a new diagnosis. In the 220 specimens in which all four quadrants were sampled, multifocal disease was identified more often in specimens with invasive carcinoma (39 of 186; 21%) than in those with only ductal carcinoma in situ (0 of 34). In specimens with invasive carcinoma, multifocality was identified macroscopically in 20: on microscopy of tumour sections in four, on microscopic examination of quadrant sections in 11, in the nipple in three, and in both quadrant and nipple sections in one. Overall, multifocality was found on microscopic examination of quadrant or nipple sections in 15 of 220 specimens (7%). CONCLUSIONS: The low frequency of detection of multifocality or Paget's disease in nipple and quadrant sections from mastectomy specimens, combined with the fact that such findings do not affect patient management, suggest that nipple and quadrant sections should only be taken if resources permit.

Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up.

135 consecutive patients aged over 70 years with operable primary breast cancer (clinically maximum diameter 5 cm) were randomised to either wedge mastectomy or tamoxifen 20 mg twice daily as initial therapy. The mean time from randomisation is now 65 months. There was no difference between the two groups in terms of overall survival or cause of death. Likewise, the groups were similar for site of initial metastatic disease and the probability of developing metastatic disease. However, failure of locoregional control was significantly greater in the tamoxifen group. The optimum treatment for elderly patients with operable breast cancer includes mastectomy.

Safe selection criteria for breast conservation without radical excision in primary operable invasive breast cancer.

In a previous series from this unit of 263 women with primary operable breast cancer treated by macroscopic lumpectomy and breast irradiation, local recurrence was high. An audit at a median follow up of 36 months showed 56 (21%) ipsilateral breast recurrences. Eighteen of these recurrences were aggressive and uncontrolled. Multivariate analysis shows patient age, lymphovascular invasion, tumour size and nodal status to be predictive of local recurrence (Locker AP, et al., Br J Surgery 1989, 76, 890-894). New selection criteria for breast conservation were defined based on these data and also on securing an adequate clear margin of excision. In a subsequent prospective series of 275 women fulfilling these criteria, 6 women (2.2%) developed ipsilateral breast recurrence at the same median follow up of 36 months. In none was this uncontrolled and aggressive. Breast conservation, without radical excision, is safe as long as the selection criteria described are followed.

Screening women aged less than 50 years with a family history of breast cancer.

Family history is an important breast cancer risk factor and is a common reason for referral to specialist breast clinics for consideration of breast screening. The aims of this study were to determine cancer detection rates and prognostic features of breast cancers identified in women aged less than 50 years at increased risk of breast cancer who attend a Family History Breast Screening Clinic (FHC). Between January 1988 and December 1995, 1371 asymptomatic women aged less than 50 years underwent annual clinical breast examination and biennial mammography due to a family history of breast cancer. A total of 29 cancers (23 invasive and 6 in situ) were detected or presented as interval cancer during a mean follow-up of 22 months (range 0-96 months). This gave a relative risk for invasive breast cancer in this high-risk group of 5 when compared with an age-matched female population in the U.K. The cancer screening detection rates were similar to those of women aged 50 years or over undergoing population screening in the NHS Breast Screening Programme (NHSBSP)--FHC prevalent screen 8 per 1000 screening visits versus NHSBSP 6.5 per 1000, FHC incident screen 3.3 per 1000 screening visits versus NHSBSP 3.8 per 1000. A higher proportion of in situ cancers were detected in the FHC screened group compared with cancers identified in symptomatic patients from an age-matched risk group (21% versus 4%). No differences were demonstrated for invasive tumour size, grade or lymph node stage between symptomatic and screened women. The early results of this study suggests that young women at risk of breast cancer due to a family history may benefit from regular breast screening due to the early detection of in situ lesions.

The prognosis of small primary breast cancers.

The Nottingham Prognostic Index (NPI) is an integrated prognostic index used to predict patient survival for women with invasive breast cancer. The index is based on invasive tumour size, histological lymph node stage and tumour grade. The value of such an index has been questioned in small invasive breast cancers and it has been suggested that size is the only necessary prognostic determinant. The aims of this study were to determine the extent of regional lymph node involvement and survival in women with small invasive breast cancers and to assess the value of the NPI. Between 1976 and 1994, 2684 women aged < or = 70 years were treated for primary operable invasive breast cancers of < or = 5 cm in maximum diameter, of which 318 measured < or = 1 cm. Follow-up data were evaluated to determine histological factors important in predicting survival outcomes in women with cancers < or = 1 cm in diameter and comparing their survival according to the NPI with all women treated for primary operable breast cancers < or = 5 cm in maximum diameter. Histological lymph node involvement was demonstrated in 56/318 (18%) of cancers of < or = 1 cm in diameter. Significant survival differences were demonstrated for small breast cancers according to lymph node stage, vascular invasion and histological tumour grade. Only lymph node stage and histological tumour grade were independent prognostic indicators using a multivariate Cox model. The survival curves for small tumours stratified by the NPI were similar to those of cancers up to 5 cm in diameter. The results indicate that lymph node staging and histological grading are still important prognostic determinants for breast cancers < or = 1 cm in diameter. An axillary node staging procedure should be performed for all invasive breast cancers < or = 1 cm in diameter. The NPI remains relevant for small breast cancers.

Oestrogen-regulated genes in breast cancer: association of pLIV1 with lymph node involvement.

In order to isolate markers of oestrogen responsiveness in breast cancer, we have cloned a number of oestrogen-regulated genes. Two of these, pLIV1 and pLIV2 (pS2), have been shown to be predominantly expressed in oestrogen receptor (ER)+ tumours. In this study, we examined their expression in relation to various clinical and histopathological features of breast cancer, and showed that pLIV1, but not pS2, is significantly associated with lymph node involvement (P < 0.01), while pS2 is more frequently observed in premenopausal patients (P < 0.05). Subdivision of the pLIV1 data by ER and nodal status of the tumour identified a highly significant association between pLIV1 expression and lymph node involvement in ER-positive disease, with 15/24 (63%) ER+ pLIV1+ tumours showing nodal involvement. Conversely, 20/23 (87%) ER+ pLIV1- patients were lymph node-negative (P < 0.001). Subdivision of the pS2 data by ER status did not reach significance. The application of pLIV1 as a marker of lymph node involvement was further exemplified in small tumours (< < 2 cm), where 11/12 (92%) lymph node-positive patients expressed pLIV1, while 17/22 (77%) node-negative patients were pLIV1 negative (P < 0.001). Similarly, pLIV1 expression identified lymph node involvement in moderately differentiated tumours (P < 0.01), but was independent of vascular invasion. pLIV1 may, therefore, represent a candidate gene for metastatic spread in ER+ breast cancer.

Consistency of histopathological reporting of breast lesions detected by screening: findings of the U.K. National External Quality Assessment (EQA) Scheme. U. K. National Coordinating Group for Breast Screening Pathology.

The aim of the scheme was to determine consistency of histopathological reporting in the United Kingdom National Breast Screening Programme. This external quality assessment scheme involved 51 sets of 12 slides which were circulated to 186-251 pathologists at intervals of 6 months for 3 years. Participants recorded their diagnoses on standard reporting forms, which were submitted to the U.K. National Cancer Screening Evaluation Unit for analysis. A high level of consistency was achieved in diagnosing major categories of breast disease including invasive carcinoma and the important borderline lesions, radial scar and ductal carcinoma in situ (DCIS), the latter exceeding a national target set prior to the onset of the scheme. Atypical hyperplasia (AH) was reported with much less consistency although, where it was the majority opinion, over 86% of diagnoses were of benign disorders and only 14% were of DCIS. Inconsistency was encountered in subtyping and measuring DCIS, the former apparently due to current uncertainties about classification and the latter to poor circumscription, variation in size in different sections and merging with zones of AH. Reporting prognostic features of invasive carcinomas was variable. Measurement of size was achieved with adequate consistency except in a small number of very poorly circumscribed tumours. Grading and subtyping were inconsistent although the latter was not specifically tested and will be the subject of future study. Members of the National Coordinating Group achieved greater uniformity than the remainder of the participants in all diagnostic categories, but both groups experienced similar types of problem. Our findings suggest that participation in the scheme improves diagnostic consistency. In conclusion, consistency in diagnosing invasive carcinoma and radial scar is excellent, and good in DCIS, but improvements are desirable in diagnosing atypical hyperplasia, classifying DCIS and reporting certain prognostic features of invasive tumours. Such improvements will require further research, the development of improved diagnostic criteria and the dissemination of clearer guidelines.

Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. European Commission Working Group on Breast Screening Pathology.

It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Routine diagnosis of mammary Paget's disease. A modern approach.

This study compares the diagnostic reliability of conventional mucin histochemistry and immunocytochemical techniques in distinguishing mammary Paget's disease from superficial spreading malignant melanoma and primary intraepidermal carcinoma. Formalin-fixed, paraffin-embedded archival tissue was used and comprised 13 cases of mammary Paget's disease, five cases of superficial spreading melanoma, and six cases of intraepidermal carcinoma. Sections from each case were stained for the presence of mucin using diastase periodic-acid-Schiff (d-PAS) with and without an alcian blue counterstain as well as immunocytochemistry for cytokeratin (CAM 5.2), epithelial membrane antigen (NCRC-11) and c-erb B-2 (21N). Mucin staining in intraepidermal carcinoma and malignant melanoma was consistently negative. Diastase-resistant PAS positivity was seen in six of 13 cases of mammary Paget's disease and eight of 13 cases using an alcian blue counterstain. NCRC-11 showed positive immunoreactivity in four of six cases of intraepidermal carcinoma, one in five cases of melanoma, and five of 13 cases of mammary Paget's disease. Positive immunoreactivity using CAM 5.2 and 21N was seen in all cases of mammary Paget's disease, with consistent negative immunoreactivity in the other tumor types. We conclude that CAM 5.2 and 21N should be used in the investigation of mammary Paget's disease in preference to conventional mucin stains.

Traffic of lymphocytes in the thoracic duct and renal lymph after allotransplantation and in immunosuppression.

A marked rise is seen in the number of white blood cells in the lymph leaving the sheep kidney after allografting; the number of lymphocytes leaving the kidney rising in direct relation to the degree of damage from acute rejection. No such rise is demonstrable in the number of lymphocytes in the thoracic duct lymph of sheep with rejecting kidney allografts. Indeed, there is an apparent decrease in the number of lymphocytes in the thoracic duct lymph of sheep with rejecting kidney allografts. Indeed, there is an apparent decrease in the number of circulating lymphocytes in the body when acute rejection is fully developed. Animals on immunosuppressive regimens show no alteration in the number of lymphocytes collected on thoracic duct cannulation, but immunosuppression appears to reduce the lymphocyte traffic through the kidney.

Hydatidiform mole in Nottingham: a 12-year retrospective epidemiological and morphological study.

The results of a 12-year retrospective study on the epidemiology of hydatidiform mole (HM) in Nottingham are presented. We have reviewed the histology of our cases of HM, tried to minimize selection bias, and have used the most reliable data available. Using data from two different sources we have calculated the frequency of HM as 1 in 1400 deliveries. The frequency of HM in this study is one quarter of that reported in an excellent study from Japan. We suggest that, with accurate epidemiological studies, the difference in frequency of HM between 'high risk' and 'low risk' areas is less than previously accepted. The present study also shows a lower incidence of persistent trophoblastic disease than previously generally accepted. We confirm that partial HM is a distinct clinicopathological entity and that two forms are distinguishable histologically. The malignant potential of partial HM is uncertain, and we suggest that the clinical management of partial HM should be no different from that of complete HM until further studies dictate otherwise.

A new immunohistochemical antibody for the assessment of estrogen receptor status on routine formalin-fixed tissue samples.

We describe a method for the immunocytochemical assessment of estrogen receptor (ER) status on routinely processed, formalin-fixed tissue using a recently developed commercially available monoclonal antibody (Dako 1D5) with a microwave antigen retrieval technique. A series of 90 cases of human breast carcinoma was analyzed and the staining was assessed using a semiquantitative microscopic scoring method and by assessment of the percentage of nuclei showing positive staining. The results were compared with assessment using another commercially available antibody (Abbott H222) and with clinical response to tamoxifen therapy. Direct comparison of the paired sets of H scores and the percentage of positively stained nuclei using the two different techniques showed a significant correlation. By assigning an arbitrary cut-off for positivity of H score = 50, assessment of ER status using DAKO 1D5 antibody was found to correlate with response to tamoxifen therapy with a sensitivity of 90% and a specificity of 51%, similar to values in previous studies using other methods. We conclude that assessment of ER status using this new antibody and technique gives accurate results on routinely processed, formalin-fixed tissue and may be used as an alternative to other methods.