Gábor Cserni

Meta-analysis of non-sentinel node metastases associated with micrometastatic sentinel nodes in breast cancer.

The need for further axillary treatment in patients with breast cancer with low‐volume sentinel node (SN) involvement (micrometastases or smaller) is controversial.

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.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

Aims: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. Methods: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. Results: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. Conclusions: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Ratios of involved nodes in early breast cancer

IntroductionThe number of lymph nodes found to be involved in an axillary dissection is among the most powerful prognostic factors in breast cancer, but it is confounded by the number of lymph nodes that have been examined. We investigate an idea that has surfaced recently in the literature (since 1999), namely that the proportion of node-positive lymph nodes (or a function thereof) is a much better predictor of survival than the number of excised and node-positive lymph nodes, alone or together.MethodsThe data were abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results (SEER) program of women diagnosed with nonmetastatic T1–T2 primary breast carcinoma between 1988 and 1997, in whom axillary node dissection was performed. The end-point was death from breast cancer. Cox models based on different expressions of nodal involvement were compared using the Nagelkerke R2 index (R2N). Ratios were modeled as percentage and as log odds of involved nodes. Log odds were estimated in a way that avoids singularities (zero values) by using the empirical logistic transform.ResultsIn node-negative cases both the number of nodes excised and the log odds were significant, with hazard ratios of 0.991 (95% confidence interval 0.986–0.997) and 1.150 (1.058–1.249), respectively, but without improving R2N. In node-positive cases the hazard ratios were 1.003–1.088 for the number of involved nodes, 0.966–1.005 for the number of excised nodes, 1.015–1.017 for the percentage, and 1.344–1.381 for the log odds. R2N improved from 0.067 (no nodal covariate) to 0.102 (models based on counts only) and to 0.108 (models based on ratios).DiscussionRatios are simple optimal predictors, in that they provide at least the same prognostic value as the more traditional staging based on counting of involved nodes, without replacing them with a needlessly complicated alternative. They can be viewed as a per patient standardization in which the number of involved nodes is standardized to the number of nodes excised. In an extension to the study, ratios were validated in a comparison with categorized staging measures using blinded data from the San Jose–Monterey cancer registry. A ratio based prognostic index was also derived. It improved the Nottingham Prognostic Index without compromising on simplicity.

Metastases in axillary sentinel lymph nodes in breast cancer as detected by intensive histopathological work up

AIM: To assess the value of the intensive histological work up of axillary sentinel lymph nodes (SLN) to demonstrate regional metastatic disease. METHODS: From a series of 58 successful lymphatic mapping procedures, 78 SLN were analysed by serial sections (mean of 49 levels/SLN) and by immunostaining to cytokeratin and epithelial membrane antigen, and the results compared with those obtained by assessing the central cross section. RESULTS: The central cross section would have failed to detect metastases in eight of 26 lymph nodes (31%) in patients with breast cancer metastasising to the SLN only. This would have led to a false negative node status in six of 21 patients (29%). Two micrometastases were detected with the aid of immunostains. CONCLUSIONS: The results suggest the need to examine SLN at multiple levels and to use immunohistochemistry in negative cases. Serial sections are also useful in the case of micrometastases, as some of these may convert to macrometastases at deeper levels. Multiple level investigation of SLN and immunohistochemistry in the event of the negativity of standard stains would result in improved staging and an increase in the proportion of node positive disease detected.

Complete sectioning of axillary sentinel nodes in patients with breast cancer. Analysis of two different step sectioning and immunohistochemistry protocols in 246 patients

Aims: To evaluate two detailed step sectioning protocols for sentinel lymph nodes (SLNs). Methods: After vital dye or combined dye and radiocolloid guided biopsy, SLNs were fixed in formalin and embedded in paraffin wax. In protocol A, SLNs from 123 patients were sectioned in steps of 50–100 μm, whereas in protocol B, SLNs from 123 patients were sectioned at steps of 250 μm. Epithelial marker immunohistochemistry (IHC) was performed on multiple levels in cases with negative haematoxylin and eosin findings. Results: In groups A and B, 74 and 47 patients were found to have tumour cells in their axillary SLNs, and 19 (28%) and 18 (19%) patients, respectively, were upstaged as compared with the standard histological assessment. Nodal involvement detected by deeper sections was often micrometastatic or in isolated tumour cells Conclusions: Serial sectioning and IHC are recommended for the evaluation of SLNs. The optimal extent of the histopathological work up should be studied further.

Brain and core temperatures and peripheral vasomotion during sleep and wakefulness at various ambient temperatures in the rat.

Changes in brain, core and tail skin temperatures (Tbr, Tc and Tt) associated with transitions in the arousal states were recorded in rats throughout the 24-h diurnal cycle at 10 °C, 21 °C and 29 °C. Falling asleep was accompanied by decreases in both Tbr and Tc and vasodilation at 10 δC and 21 °C. At 29 °C, tail vessels were permanently dilated, and further dilation was not found on sleep onset. Tbr and Tc, however, continued to decrease during non-rapid-eye-movement sleep (NREMS); these changes are likely to result from reductions in heat production and increased conductive heat loss. The changes in Tbr, Tc and Tt on awakening mirrored those on falling asleep. It is suggested that the suppression of sleep in the cold and the enhancement of NREMS in the heat promote thermoregulation. Rapid-eye-movement sleep (REMS) was associated with sharp rises in Tbr. The rise in Tbr was the largest in the cold and was attenuated at 29 °C. Tc decreased and Tt increased in the cold, whereas Tc tended to increase and Tt to decrease in the heat. The paradoxical peripheral vasomotion during REMS supports previous suggestions on severe thermoregulatory impairment during REMS in other species.

Prognostic value of histopathology and trends in cervical cancer: a SEER population study

BackgroundHistopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial.MethodsWomen under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973–2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria.ResultsThere were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20–0.39), carcinoma not otherwise specified 0.91 (0.79–1.04), non-mucinous adenocarcinoma 1.06 (0.98–1.15), adenosquamous carcinoma 1.35 (1.20–1.51), mucinous adenocarcinoma 1.52 (1.23–1.88), small cell carcinoma 1.94 (1.58–2.39).ConclusionSmall cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk.

The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer

BACKGROUND To evaluate the prognostic impact of the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes on survival in women diagnosed with nodal micrometastatic breast cancer before the era of widespread sentinel lymph node biopsy. METHODS Subjects were 62,551 women identified by the Surveillance Epidemiology and End Results database, diagnosed with pT1-2pN0-1 breast cancer between 1988 and 1997. Kaplan-Meier breast cancer-specific survival (BCSS) and overall survival (OS) were compared between three cohorts: node-negative (pN0, n=57,980) nodal micrometastasis all <or=2mm (pNmic, N=1818), and macroscopic nodal metastasis >2mm but <2 cm (pNmac, n=2753). Nodal subgroups were examined by the number of positive nodes (1-3 versus >or= 4) and the LNR (<or=0.25 versus >0.25). RESULTS Median follow-up was 7.3 yr. Ten-year BCSS and OS in pNmic breast cancer were significantly lower compared to pN0 disease (BCSS 82.3% versus 91.9%, p<0.001 and OS 68.1% versus 75.7%, p<0.001). BCSS and OS with pNmic disease progressively declined with increasing number of positive nodes and increasing LNR. OS with pNmic was similar to pNmac disease when matched by the number of positive nodes and by the LNR. Both pN-based and LNR-based classifications were significantly prognostic of BCSS and OS on Cox regression multivariate analysis. CONCLUSION Nodal micrometastasis is associated with poorer survival compared to pN0 disease. Mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR. The number of positive nodes and the LNR should be considered in risk estimates for patients with nodal micrometastatic breast cancer.

Intraoperative analysis of sentinel lymph nodes in breast cancer by one-step nucleic acid amplification

One-step nucleic acid amplification (OSNA) is a novel method introduced for the lymph node staging of breast cancer and has been tested in multiple series. The present review summarises current literature and concerns related to the new method. The results of this automated molecular assay based on the quantification of cytokeratin 19 mRNA show a 96% concordance rate with detailed histopathology complemented with immunohistochemistry when alternative slices of the same lymph node are used for the two tests. The low false-negative rate makes OSNA suitable for the intraoperative evaluation of sentinel lymph nodes. The false-positive rate also seems very low. Most discordant cases are explainable by low volume metastases (micrometastases), which may be missing from the material submitted for one test, but not from the different part used for the other test. It is tempting to change the gold standard for comparisons between the methods, and if this is done, histology seems to come out as a weaker test for the identification of metastases. OSNA detects more low volume nodal involvement, but it is uncertain whether these require further axillary treatment, and this will be a subject for future investigations. Therefore, it is also uncertain whether the advantage of OSNA of detecting practically all metastases due to complete sampling of lymph node tissue is clinically more important than the exclusion of metastases greater than micrometastasis that can be reliably done by intraoperative microscopy followed by permanent section histology.