ONCOPOOL - a European database for 16,944 cases of breast cancer.

ONCOPOOL is a retrospectively compiled database of primary operable invasive breast cancers treated in the 1990s in 10 European breast cancer Units. Sixteen thousand and nine hundred and forty four cases were entered, with tumours less than 5 cm diameter in women aged 70 or less (mean age 55). DATA: Data were date of birth, mode of diagnosis, pathology (size, lymph node status, grade, type, lympho-vascular invasion and hormone receptor) and therapies and outcome measures: first local, regional or distant recurrences, contralateral primary, date and cause of death. TUMOUR CHARACTERISTICS: Mean diameter 1.8 cm, 66% lymph node negative, 24% 1-3 lymph nodes involved and 10% had 4 or more involved. Grade 1, 29%; Grade 2, 41%; and Grade 3, 30%. Polynomial relationships were established between grade, stage and size. Seventy-five percent were oestrogen receptor (ER) positive. ER closely related to grade. OUTCOMES: Overall Survival was 89% at 5 years from diagnosis, 80% 10 years and 73% 15 years; Breast Cancer-Specific survivals were 91%, 84% and 79%. Survival strongly related to the Nottingham Prognostic Index (NPI). Cases detected at screening had 84% 10-year survival, those presenting symptomatically 76%. ER positive cases treated with adjuvant hormone therapy had a reduction in risk of death of 13% over those not receiving adjuvant therapy (p=0.000). ER negative cases treated with chemotherapy showed a risk reduction of 23% over those not receiving chemotherapy (p=0.000).

Axillary lymph node micrometastases in invasive breast cancer: national figures on incidence and overall survival.

The purpose of this study was to estimate the incidence and prognostic value of axillary lymph node micrometastases (Nmic) of 2 mm or less in breast carcinomas. Results are based on data from the Danish Breast Cancer Cooperative Group (DBCG). The study was carried out as a nationwide, population-based trial with a study series consisting of 6,959 women under 75 years of age registered in the national DBCG data base from 1 January 1990 to 31 October 1994. All patients had contracted operable primary breast carcinoma, stage I-III, classified according to the TNM system as T1-T3, N0-N1, M0. Women with four or more metastatic axillary lymph nodes were excluded. All patients were treated systematically according to approved national guidelines and treatment protocols. Metastases were recognized microscopically on haematoxylin and eosin-stained sections. In case of doubt immunohistochemical staining for cytokeratin was performed. There was no serial sectioning. Micrometastases were tumour deposits of 2 mm or smaller, and accordingly included deposits of 0.2 mm and smaller. With a median observation time of 10 years and 2 months, women with Nmic (N=427) experienced a significantly worse overall survival (OS) compared with node-negative (Nneg) women (N=4,767) (relative risk (RR)=1.20, 95% CI: 1.01-1.43), irrespective of menopausal status. Women with macrometastases (Nmac) (N=1,765) had significantly worse final outcome than women with Nmic (RR=1.54, 95% CI: 1.29-1.85), irrespective of menopausal status. Multivariate analysis adjusted for patient-, histopathologic-, and loco-regional therapeutic variables showed that cases with Nmic had a significantly higher risk of death relative to Nneg cases (adjusted RR=1.49, 95% CI: 1.18-1.90). Interaction analysis showed that the number of nodes examined had a significant impact on adjusted relative risk of death according to axillary status. Furthermore, the number of nodes involved significantly influenced adjusted risk of death in the Nmic compared to the Nmac series. In conclusion, the results of the present study revealed worse final outcome in women with Nmic compared with Nneg, where all Nmic cases received adjuvant systemic treatment. Interaction analysis showed that the number of retrieved axillary nodes and the number of affected nodes had a different influence on survival related to axillary status. The different risk pattern in Nmic vs Nmac patients indicates that Nmic cases do not show the traditional risk pattern as revealed by the Nmac cases, in which increasing number of positive nodes is associated with an orderly increasing adjusted RR.

Guidelines on the standards for the training of specialised health professionals dealing with breast cancer.

According to EUSOMA position paper 'The requirements of a specialist breast unit', each breast unit should have a core team made up of health professionals who have undergone specialist training in breast cancer. In this paper, on behalf of EUSOMA, authors have identified the standards of training in breast cancer, to harmonise and foster breast care training in Europe. The aim of this paper is to contribute to the increase in the level of care in a breast unit, as the input of qualified health professionals increases the quality of breast cancer patient care.

[Cohort study of fracture risk before and after surgery of primary hyperparathyroidism]. / Kohortestudie af frakturrisiko før og efter operation for primaer hyperparatyreoidisme.

We studied the risk of fracture in 674 patients operated on for primary hyperparathyroidism compared to 2,021 age- and gender-matched controls, matched for age and gender, randomly drawn from the background population. Before surgery, there was an increased risk of fracture (relative risk 1.8, 9% confidence interval 1.3-2.3), but after surgery the relative risk was normalised (RR = 1.0, 0.8-1.3). The increased risk began ten years before surgery and peaked five to six years before surgery. After surgery, there was a temporary increase in the first year, but in the following years the fracture risk was normalised, with a small rise in distal forearm fractures more than ten years after surgery. Primary hyperparathyroidism may have started up to ten years before surgery, and the fracture risk is normalised after surgery.

[TPO immunostaining of the solitary, cold thyroid nodules]. / TPO-immunfarvning af den solitaere, kolde thyreoideaknude.

INTRODUCTION: The chance of malignancy in scintigraphically cold thyroid nodules is 2-24%. Differentiation between malignant and benign cytology is difficult. The aim of this study was to evaluate the ability of immunostaining (MoAB47--raised against thyroid peroxidase (TPO)) to differentiate between malignant and benign cells taken from cold thyroid nodules by fine needle aspiration biopsy (FNAB) in order to reduce the number of unnecessary thyroid operations. MATERIALS AND METHODS: One hundred and eighty-one patients (150 female) with a scintigraphically cold, solitary thyroid nodule were entered between 1993 and 1996. Fifty-seven were excluded for various reasons. Material removed by FNAB was stained with MoAB47 and routine staining. Staining of 80% or more of the cells was considered benign, less than 80% was considered malignant. Routine staining of operatively removed material was used as the final diagnosis. RESULTS: A pattern with negative TPO staining was found in all lesions that were subsequently proved to be malignant. In all but one, the lesions subsequently diagnosed as being benign stained positive for TPO. The sensitivity and specificity were respectively 1.0 and 0.99. CONCLUSION: TPO immunostaining of material removed by FNAB is a powerful tool in the differentiation between benign and malignant tumours.

Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials.

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

Carcinoma in situ of the female breast. 10 year follow-up results of a prospective nationwide study.

In a Danish nationwide prospective study of in situ carcinoma of the breast, a total of 275 women, treated with excision alone, were registered from 1982 to 1989. The series included 142 cases of ductal carcinoma in situ (DCIS), 100 cases of lobular carcinoma in situ (LCIS), 26 cases of DCIS+LCIS, and seven cases of atypical hyperplasia (AH). Within a median follow-up of 120 months, a crude recurrence rate of 28% (76 cases) was found, of which 53% (40 cases) recurred as invasive carcinomas (IC) and 47% (36 cases) as CIS. CIS recurrences appeared after median 18 months, compared to median 42 months for IC recurrences. No statistical difference was found with respect to development of IC between the three groups of DCIS, DCIS+LCIS, and LCIS. The majority of recurrences were ipsilateral, also for LCIS. Forty four of 49 recurrences following DCIS, and seven of nine recurrences following DCIS+LCIS occurred as local recurrences. Histopathologically, in DCIS a strong association was found between large nuclear size and comedonecrosis. Univariate analysis showed a significant association to recurrence for nuclear size, comedonecrosis, and size of the original lesion. Multivariate analysis showed that only comedonecrosis and size of lesion were independent predictors of recurrence, however, specimen margins were not included in the analysis, as this parameter could not be adequately evaluated in the present series. Nuclear size of original DCIS lesion was related to histologic grade of the IC recurrence. The recurrence rate for DCIS of small nuclear size increased from 6% at five years of follow-up to 16% at 10 years, possibly due to a slower growth rate and a continued but delayed risk. Similarities were found between LCIS and DCIS of small nuclear size, both showing a continued risk and comparable rate of recurrence. Further, progression to IC of similar, highly differentiated type was seen, indicating a linkage between biological behavior of the two histological types.

Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism.

OBJECTIVES: To study whether fracture risk before and after surgery was increased in patients with primary hyperparathyroidism. DESIGN: Cohort study. SETTING: Three Danish university hospitals. PARTICIPANTS: 674 consecutive patients with primary hyperparathyroidism (median age 61, range 13-89 years) operated on during the period 1 January 1979 to 31 December 1997; 2021 age and sex matched controls from national patient register. MAIN OUTCOME MEASURE: Fractures. RESULTS: The cases had an increased relative rate of fractures compared with the controls before surgery (1.8, 95% confidence interval 1.3 to 2.3) but not after surgery (1.0, 0.8 to 1.3). The risk of fracture was increased for the vertebrae (3.5, 1.3 to 9.7), the distal part of the lower leg and ankles (2.3, 1.2 to 4.3), and the non-distal part of the forearm (4.0, 1.5 to 10.6) before surgery but not after. The increase in risk of fracture began about 10 years before surgery. Risk peaked 5-6 years before surgery and remained raised, although at a lower level, in the five years immediately before surgery. A small increase in risk of fracture of the distal forearm emerged more than 10 years after surgery (2.9, 1. 3 to 6.7). CONCLUSIONS: Risk of fracture is increased up to 10 years before surgery in patients with primary hyperparathyroidism. The risk returns to normal after surgery.

Axillary surgery in breast cancer management--background, incidence and extent of nodal spread, extent of surgery and accurate axillary staging, surgical procedures.

The prime objectives of axillary surgery in the management of breast cancer are 1) accurate staging, 2) treatment to cure and 3) quantitative information of metastatic lymph nodes for prognostic purposes and allocation to adjuvant protocols. It is generally agreed that axillary node status in potentially curable breast cancer is considered the single best predictor of outcome and the main determinant of allocation to adjuvant therapy. No physical examination, no imaging techniques, and no molecular biologic markers can today replace axillary surgery for staging purposes. The objectives of axillary surgery are best obtained by carrying out a complete axillary clearance. Nonetheless, less radical surgery is generally performed by carrying out a sampling procedure with a yield of about 4 nodes or a partial axillary dissection level I-II with at least 10 nodes recovered. Understaging the axilla is detrimental to outcome and, furthermore, locoregional tumor control is important for survival. Axillary surgery should therefore be conducted in accordance with high professional standards.

Impact of axillary dissection on staging and regional control in breast tumors < or = 10 mm--the DBCG experience. The Danish Breast Cancer Cooperative Group (DBCG), Rigshisoutalet, Copenhagen, Denmark.

Data from 4771 patients with tumor diameters < or = 10 mm were analyzed. Results of surgery and pathoanatomical examinations indicated that nodal status was related to diameter, but not to number of nodes removed. More axillary metastases were found in group T1b tumors than in T1a. In 8% of tumors, at least 4 positive nodes were identified. Mean number of positive nodes was related to number of nodes removed, and when 10 or more nodes were removed a significantly lower axillary recurrence rate and better recurrence-free survival were demonstrated, confirming that axillary surgery has two goals: staging and regional disease control. Age, receptor status, grade and histological type, but not tumor location, were related to prognosis. In accordance with the classical prognostic factors, it was not possible to define a patient group where axillary surgery was superfluous. We conclude that proper staging and regional control renders a full axillary level I-II dissection necessary.

Treatment of morbidity associated with the management of the axilla in breast-conserving therapy.

The purpose of this study was to determine the impact of surgery and radiotherapy on late morbidity associated with the management of the axilla in breast cancer patients. Two hundred and sixty-six patients from a randomized breast conservation trial (DBCG-82TM protocol) were called in for a single follow-up interview and clinical examination of several functional outcome measures after a median of 6.6 years (3.5-10.5). All the patients were treated with lumpectomy and axillary dissection, followed by external beam radiotherapy to the residual breast. High-risk patients were given additional radiation to the regional lymph nodes plus adjuvant systemic treatment. Twenty-eight patients (11%) had arm edema (> or = 2 cm), which was associated with the extent of axillary node dissection as well as with age and radiotherapy (relative risk, RR = 4.5 (1.8-11.2, p = 0.001)). Impaired shoulder movement of any degree (7%) was associated with radiotherapy (RR = 4.0 (1.5-13.8, p = 0.007)) and advanced age (p = 0.002), while the extent of axillary dissection as described by the number of nodes retrieved was the only factor that predicted pain on logistic regression analysis (p = 0.02). A moderate to severe change in arm/shoulder strength and working ability was observed in 7% and 5% of patients, respectively, but no independent predisposing factor was discerned for these endpoints. It is concluded that the level of late functional morbidity several years after breast-conserving treatment is relatively low and clearly relates to age, extension of surgery, irradiation of the axilla or a combination of these factors, depending on the specific clinical outcome measure.

Thyroperoxidase (TPO) immunostaining of the solitary cold thyroid nodule.

OBJECTIVE: To evaluate the value of immunostaining using the monoclonal antibody (MoAB47) against thyroperoxidase (TPO) in distinguishing between benign and malignant tumour cells in fine needle aspiration cytology (FNAC) samples obtained from a solitary cold nodule of the thyroid gland for the purpose of strengthening the indication for thyroid surgery. DESIGN: A prospective, immunocytochemical study of FNACs taken from patients with solitary cold thyroid nodules who presented to Rigshospitalet, Copenhagen, Denmark, during the period April 1993 to May 1996. The first sample series was taken perioperatively in order to test the utility of the method. In the second part of the study samples were obtained preoperatively by ultrasonic guided aspiration. Tissue sections from the nodules obtained during a subsequent operation served as controls. PATIENTS: One hundred and eighty-one patients, 150 women and 31 men, were studied. The age range was 14-89 years with a median age of 44 years. Fifty-seven patients were excluded from the study for various reasons leaving us with a total of 124 nodules from 124 patients for final evaluation. METHODS: FNAC cells and corresponding nodular tissue were stained by immunocyto- and immuno-histochemistry using MoAb47 and by routine staining methods. Samples were considered benign if 80% or more of the epithelial-looking cells of both the FNACs and the histological tissue sections of the nodule were stained by TPO. Consequently, samples were considered malignant if more than 20% of the epithelial-looking cells failed to stain for TPO. Routinely stained tissue cells and sections served as diagnostic controls. RESULTS: A pattern with negative TPO staining was found in all lesions which, by conventional histological staining, were subsequently proven to be malignant. A universal and reliable, positive TPO staining pattern was found in all subsequently proven benign lesions, with the exception of one out of 26 follicular adenomas. This gave the method a sensitivity of 1.0 (negative TPO staining = malignancy in 27 out of 27) and a specificity of 0.99 (positive TPO staining = benign lesion, in 96 out of 97). Positive and negative predictive values were 0.96 and 1.00 respectively. CONCLUSION: Thyroperoxidase immunostaining of fine needle aspirates from solitary, scintigraphically cold nodules of the thyroid gland has proved to be an important and reliable diagnostic tool for distinguishing between benign and malignant nodules. Thus, patients might be spared further surgery if not otherwise indicated.