C.W. Elston

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up

Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedur mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features–the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables; three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P<0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.

A prognostic index in primary breast cancer

From a multiple-regression analysis of prognostic factors and survival in a series of 387 patients with primary breast cancer, a prognostic index has been constructed, based on lymph-node stage, tumour size and pathological grade. This index is more discriminating than lymph-node stage alone, and enables a larger group of patients to be identified with a very poor prognosis.

Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up

The histological tumour type determined by current criteria has been investigated in a consecutive series of 1621 women with primary operable breast carcinoma, presenting between 1973 and 1987. All women underwent definitive surgery with node biopsy and none received adjuvant systemic therapy. Special types, tubular, invasive cribriform and mucinous, with a very favourable prognosis can be identified. A common type of tumour recognized by our group and designated tubular mixed carcinoma is shown to be prognostically distinct from carcinomas of no special type; it has a characteristic histological appearance and is the third most common type in this series. Analysis of subtypes of lobular carcinoma confirms differing prognoses. The classical, tubulo‐lobular and lobular mixed types are associated with a better prognosis than carcinomas of no special type; this is not so for the solid variant. Tubulo‐lobular carcinoma in particular has an extremely good prognosis similar to tumours included in the ‘special type’ category above. Neither medullary carcinoma nor atypical medullary carcinoma are found to carry a survival advantage over carcinomas of no special type. The results confirm that histological typing of human breast carcinoma can provide useful prognostic information.

Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

PURPOSE The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings. MATERIALS AND METHODS This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system. RESULTS Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups. CONCLUSION Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.

Confirmation of a prognostic index in primary breast cancer

A prognostic index, previously derived in a group of 387 patients with primary breast cancer, has been recalculated for the same patients with over 5 years further follow-up and shown to be unchanged. The prognostic index has also been applied prospectively to a further group of 320 patients and shown to be similarly effective in identifying patients with either a very good or a very poor prognosis. It has been verified that the index applies to patients with primary breast cancer. Patients have now been divided into 5 prognostic groups, predicting 11% of patients with an almost normal survival and a further 10% with a very poor prognosis. The index is used to stratify patients to study the effects of treatment regimes within groups of similar patients.

Pathological prognostic factors in breast cancer. III: Vascular invasion : relationship with recurrence and survival in a large study with long-term follow-up

The invasion of vascular spaces (lymphatic and/or blood vessel) by tumour, as assessed on routine haematoxylin and eosin sections, was investigated in a consecutive series of 1704 women with primary operable invasive breast carcinoma. Strict morphological criteria were used. Patients were under 70 years of age and received definitive surgery with no adjuvant systemic therapies. Information from regular follow‐up (range 3–17 years) was recorded on to a computer database. Definite vascular invasion was seen in 22.8% of cases and concurrence between pathologists was high. In univariate analyses, vascular invasion was strongly associated with lymph node stage (P≤ 0.0001), tumour size (P≤ 0.0001), histological grade (P≤ 0.0001) and type of tumour (P≤ 0.0001). In multivariate analyses vascular invasion was of independent prognostic significance for both survival and for local recurrence of tumour; patients with tumours showing no vascular invasion had a significant survival advantage and a reduced risk of local recurrence. No association with oestrogen receptor status or menopause status was seen. The results confirm that histological assessment of vascular invasion provides independent prognostic information in primary operable breast carcinoma which may be helpful in making clinical decisions.

Ki67 immunostaining in primary breast cancer: pathological and clinical associations.

Ki67 immunostaining has been performed on 136 primary breast cancers and related to various clinical and pathological features of the disease. Staining was most frequently seen in poorly differentiated tumours showing high rates of mitotic activity, but was independent of tumour size, lymph-node status and ER expression. A high level of Ki67 immunostaining was often associated with early recurrence of breast cancer after mastectomy. These data are consistent with the concept of the Ki67 antibody detecting an antigen that is closely related to cell proliferation and thus provides a clinically useful marker for this important characteristic of the tumour.

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long‐term follow‐up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403–410

The Nottingham Tenovus Primary Breast Cancer Study (NTPBCS) was set up by Professor Roger Blamey in 1974 and the main objective was to evaluate a wide range of potential prognostic factors in a single cohort of patients. Multivariate analysis soon established that the three most powerful factors were tumour size, lymph node stage and histological grade and these were incorporated into the Nottingham Prognostic Index (NPI). These results were greeted initially with considerable scepticism; the breast cancer research community was more interested in biochemical and molecular markers and the utility of histological grade was questioned because of alleged problems with consistency and reproducibility. The original method used was that developed from the Scarff-BloomRichardson system by one of us (C. W. Elston) in the Cancer Research Campaign Trial of the Treatment of Early Breast Cancer but we realized that even greater objectivity was required if the method was going to become more widely accepted. Accordingly we introduced more specific criteria for assessing the three elements of the method, tubule formation (glandular differentiation), nuclear pleomorphism and mitotic counting and have since provided further clarification and reporting guidelines. The Nottingham method has been validated in several other studies and has been adopted for use in the breast cancer pathological data sets of the United Kingdom, the rest of Europe, the United States and is the system recommended by the International Union Against Cancer and the World Health Organization. World-wide acceptance of the importance of histological grading is emphasized further by the fact that our definitive paper is currently the 8th most cited publication in the whole field of breast cancer research for the decade 1990–99 (www.esi-topics.com/breast-cancer/papers/a1.html). It is clear that the most important prognostic factors in breast cancer remain the traditional histopathological features of tumour size, lymph node stage and histological grade and the NPI, which has also been validated in other series is being used increasingly to stratify patients for therapeutic purposes. It is considered by many to be the gold standard by which novel prognostic factors are judged. The challenge for the future is not to search for further prognostic factors but to identify those, which in addition to hormone receptor and c-ErbB-2 status, can be used to predict response to specific therapies. Given the current obsession with citation indices and the acquisition of large research grants, it is perhaps pertinent to record that this work on histological grading was carried out in a routine NHS department by diagnostic histopathologists without the benefit of external funding.

c-erbB-2 oncoprotein expression in primary and advanced breast cancer.

Immunoreactivity for c-erbB-2 oncogene product expression has been investigated in patients with breast cancer using the polyclonal antibody 21N. Three series of patients were studied, 602 presenting with primary operable cancer, 57 with stage 3 and 123 with stage 4 disease. Representative tissue sections of each primary tumour were stained using a standard immunoperoxidase technique. Invasive tumour membrane immunoreactivity was assessed and identified in 15% of patients with primary operable cancer and 20% in the advanced breast cancer group. The results demonstrate a relationship between poorer survival and oncogene expression in all three patient groups. Patients in the primary operable cancer group with membrane oncoprotein expression had a poorer outcome, 35% 10-year survival, compared with those in which membrane expression was absent, 55% 10-year survival. The median survival of patients with stage 3 disease with c-erbB-2 membrane positivity was 17 months compared to 24 months with membrane negativity. In stage 4 disease median survival with membrane expression was 8.8 months compared to 19.7 months with no membrane expression. In addition in the series of primary cancers a correlation existed between histological grade and membrane immunoreactivity. Multivariate analysis showed histological grade to be a more powerful prognostic factor than c-erbB-2 protein expression. In conclusion, this study demonstrates, in a large series of patients presenting to one centre, that c-erbB-2 protein expression is a prognostic indicator in patients with primary operable and advanced breast disease.

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.