Pathologic findings from the national surgical adjuvant breast project. (Protocol no. 4). III. The significance of extranodal extension of axillary metastases.

One hundred fifty-eight patients with axillary nodal metastases recovered from radical mastectomy specimens for operable, invasive breast cancer were divided into those in whom such metastases were confined within the node and those in whom one or more nodes manifested extranodal extension. The relationships of these patterns to 33 pathologic and seven clinical features of these cases were investigated by contingency table analysis. Statistically significant associations (p less than .05) between extranodal extension of such metastases and short-term treatment failure, as well as the presence of four or more involved nodes, infiltrating ductal NOS histologic tumor type, stellate tumor border, and nipple involvement, were found. When the metastases were confined to the node there was a significantly greater likelihood that the cancers were either medullary or tubular histologic types. Associations with severe cell reaction and a nuclear grade of 1 were also found, but appeared to reflect the high frequency of medullary carcinomas in this group. The results suggest that evaluation of extranodal extension of axillary nodal metastases in patients with breast cancer may represent an important prognostic discriminant.     

Monitoring serum CEA in women with primary breast tumours positive for oestrogen receptor and with spread to lymph nodes.

Serum carcinoembryonic antigen concentrations (serum CEA) in 80 patients with primary breast cancer were measured preoperatively, one month after operation, and thereafter serially every third month. These data were related to histological and morphometric features of the primary breast carcinoma and the lymph node metastases and to clinical follow up data. Analysis of the serum CEA values showed significant correlations with size of tumour, the presence of lymph node metastases, oestrogen receptor, and occurrence of distant metastases. Furthermore, the results indicated that serial determination of serum CEA in the first two years after operation may be useful in monitoring for the occurrence of distant metastases in patients with metastatic spread to lymph nodes and with large (greater than or equal to 2 cm) primary breast tumours positive for oestrogen receptor. In agreement with other studies, however, it was found that the predictive value of serum CEA concentrations in general is weak and costs may prohibit the implementation of the routine assessment of CEA concentrations.     

Indicators of prognosis in node-negative breast cancer

Measures of the proliferative activity of tumor cells have prognostic value in patients with node-negative breast cancer. We studied 367 women in southern Sweden who had undergone surgical resection for such cancer. Tumor specimens were analyzed with DNA flow cytometry in order to estimate both the DNA content (ploidy) and the fraction of cells in the synthetic phase of the cell cycle (S phase). The median duration of follow-up was four years; 28 percent of the patients received adjuvant therapy, usually with tamoxifen (n = 83). A multivariate analysis based on complete data on 250 patients included the following covariates: age (greater than or equal to 75, 50 to 74, and less than or equal to 49 years), tumor size (less than or equal to 20 vs. greater than 20 mm), concentration of estrogen and progesterone receptors (less than 10 vs. greater than or equal to 10 fmol per milligram of protein), ploidy (diploid vs. nondiploid), and S-phase category (fraction of cells in S phase: less than 7.0 percent, 7.0 to 11.9 percent, and greater than or equal to 12 percent). The S-phase fraction yielded the most prognostic information, followed by progesterone-receptor status and tumor size. A prognostic model based on these three variables identified 37 percent of the patients as constituting a high-risk group with a fourfold increased risk of distant recurrence. In the remaining 63 percent of the patients, the five-year overall survival rate (92 +/- 4 [+/- SE] percent) did not differ from the expected age-adjusted rate for Swedish women. We conclude that a prognostic index that includes indicators of the proliferative activity of tumor cells may be able to identify women with node-negative breast cancer in whom the risk of recurrence is sufficiently low that adjuvant chemotherapy can be avoided.     

Factors affecting metastases to non-sentinel lymph nodes in breast cancer

AIMS: Because sentinel lymph node (SLN) biopsy for breast cancer has become well established, one of the challenges now is to determine which patients require a completion axillary dissection following a positive SLN biopsy. METHODS: A prospective database of patients who underwent SLN biopsy for invasive breast cancer from July 1999 to November 2002 (n = 180) was analysed. Fifty four patients (30%) had one or more positive SLN, and all underwent a completion axillary dissection. This subgroup was further analysed to delineate which factors predicted non-SLN metastasis. RESULTS: Twenty six of the 54 patients with a positive SLN had additional metastases in non-SLNs. Significant variables that predicted non-SLN metastasis included extranodal extension (odds ratio (OR), 17.399; 95% confidence interval (CI), 1.69 to 178.96) and macrometastasis within the SLN (OR, 6.985; 95% CI, 1.291 to 37.785). CONCLUSIONS: In patients with invasive breast cancer and a positive SLN, extranodal extension or macrometastasis within the SLN were both independent predictors of non-SLN involvement.     

Importance of hepatic artery node involvement in patients with colorectal liver metastases.

Hepatic artery lymph node (HALN) involvement is an adverse prognostic factor in patients treated for colorectal liver metastases. The prevalence of HALN positivity for mid-gut and hind-gut derived colonic tumours, for differing amounts of liver involvement, and for Dukes' A and B versus Dukes' C primary tumours was compared in 75 patients with colorectal liver metastases. All patients whose primary tumours did not invade lymph nodes (Dukes' A or B) had liver metastases that did not involve local hepatic nodes, regardless of the extent of the disease within the liver. This suggests that factors controlling metastasis are not identical with those which control lymphatic invasion in colorectal cancer. HALN positive patients may benefit less from treatment because they are significantly more likely to have both a greater burden of disease within the liver and a tumour with greater lymph invasive potential than patients with HALN negative liver metastases.     

Invasive micropapillary carcinoma of the breast: high incidence of lymph node metastasis with extranodal extension and its immunohistochemical profile compared with invasive ductal carcinoma

AIMS: Invasive micropapillary carcinoma of the breast is an aggressive and distinctive variant of breast cancer. These tumours have a characteristic histological appearance and have been associated with a high incidence of axillary lymph node metastases and a poor clinical outcome. The aims of this study were to investigate the immunohistochemical profile of invasive micropapillary carcinoma of the breast, to compare it with invasive ductal carcinoma, and to identify the morphological parameters which predict its poor outcome. METHODS AND RESULTS: Fifty-three (2.6%) invasive micropapillary carcinomas of the breast from 2022 cases of infiltrating breast carcinomas were identified by retrospective review. The patient age at presentation ranged from 33 to 78 years (mean 52.5 years). The tumour size ranged from 5 to 70 mm (mean 27 mm). Eighty-two percent (43 of 53) were of high histological grade; 69% (33 of 48) of cases with axillary lymph node dissections had positive lymph nodes; and 75.5% (40 of 53) had lymphatic invasion: 46% (22 of 48) of cases had extranodal extension. Of lymph node-positive cases, 61% had four or more metastatic lymph nodes. Of tumours with tumour size >10 mm, 77% had positive lymph nodes. The percentages of cases positive for oestrogen receptor (ER) and progesterone receptor (PR) were 68% and 61%, respectively. These values were significantly higher than the values for invasive ductal carcinomas. p53 and c-erbB-2 were detected in 48% and 54% of cases, respectively. The mean value of Ki67 was 26%. Follow-up was available in 36 patients. Eight patients had local recurrences, nine patients had distant metastases, and 10 patients died of disease within a follow-up period of 9 years. CONCLUSION: Lymphotropism and an unfavourable prognosis are the hallmarks of this distinct entity. Prognostic markers such as ER, PR, p53, and c-erbB-2 failed to provide new criteria to allow discrimination of these tumours from other breast cancers.     

Prognostic factors in lymph node metastases of prostatic cancer patients: the size of the metastases but not extranodal extension independently predicts survival

Aims: To analyse tumour characteristics and the prognostic significance of prostatic cancers with extranodal extension of lymph node metastases (ENE) in 102 node‐positive, hormone treatment‐naive patients undergoing radical prostatectomy and extended lymphadenectomy. Methods and results: The median number of nodes examined per patient was 21 (range 9–68), and the median follow‐up time was 92 months (range 12–191). ENE was observed in 71 patients (70%). They had significantly more, larger and less differentiated nodal metastases, paralleled by significantly larger primary tumours at more advanced stages and with higher Gleason scores than patients without ENE. ENE defined a subgroup with significantly decreased biochemical recurrence‐free (P = 0.038) and overall survival (P = 0.037). In multivariate analyses the diameter of the largest metastasis and Gleason score of the primary tumour were independent predictors of survival. Conclusions: ENE in prostatic cancer is an indicator lesion for advanced/aggressive tumours with poor outcome. However, the strong correlation with larger metastases suggests that ENE may result from their size, which was the only independent risk factor in the metastasizing component. Consequently, histopathological reports should specify the true indicator of poor survival in the lymphadenectomy specimens, which is the size of the largest metastasis in each patient.     

Comparative study of the histopathology of breast cancer in a screened and unscreened population investigated by mammography

The histopathology of 360 surgical resections for breast cancer in a consecutive series of patients aged 45-69 years from 1979-1983 is described. Two hundred and seventeen patients who were offered screening (screened patients) were compared with 143 patients who were referred as out-patients with breast problems and were not offered screening (unscreened patients). Both groups were investigated by mammography. Comparisons between tumour staging, grading and quadrant involvement are reported. In the screened patients 31% were in the in-situ stage or had an invasive carcinoma less than 1.0 cm in maximum diameter, compared with 7% in the unscreened patients. Conversely 26% of the screened patients had cancers greater than 2.0 cm compared with 52% in the unscreened group. The percentage of cancer patients with lymph node metastases was comparable in both 1.0-2.0 cm and greater than 2.0 cm groups of invasive carcinoma. There were more multiquadrant cancers in the unscreened patients (32%) than screened patients (17%) and this was mainly due to differences in the incidence of carcinomas 1.0-2.0 cm in diameter. This suggests that invasive tumours of comparable size are more likely to produce symptoms leading to detection if multiquadrant. Multicentric cancers were more common in unscreened patients. Differences in the histological grading related to tumour size were found within the screened and unscreened groups but not between the two groups.     

Prognostic significance of cytokeratin-positive breast cancer metastases

The most important discriminant in staging carcinoma of the breast is the presence of positive axillary lymph nodes. In this study, we determined if 45 female breast cancer patients originally classified as lymph node-negative by standard light microscopy (SLM) could be more accurately classified by immunohistochemical (IH) examination of their lymph nodes with an anticytokeratin monoclonal antibody cocktail. Identical sections of lymph nodes were sequentially examined by SLM and IH. Eight nodes (1%) in a total of five patients (11%) were positive by SLM. In comparison, 12 nodes (1.5%) in a total of nine patients (20%) were positive by IH. Five nodes were positive by IH and negative by SLM. There was no correlation between IH-detected metastases and tumor size or patient age. The survival curve for patients with IH-detected metastases was significantly worse than that of patients without IH-detected metastases. IH detection methods may be an important adjunct in staging breast cancer patients.     

Does open biopsy before mastectomy affect the prevalence of so-called axillary lymph node micrometastases detected immunohistochemically

OBJECTIVE: To determine the effect of a previous open biopsy on the presence of immunohistochemically detected micrometastases, particularly single cells, in axillary lymph nodes in patients with "node-negative" invasive breast carcinoma. METHODS: Node-negative breast cancer patients were divided into group 1 (diagnostic frozen-section biopsy with immediate mastectomy and axillary dissection) and group 2 (open surgical biopsy with temporally delayed mastectomy and axillary dissection). Archival slides of lymph nodes were examined and new sections stained with hematoxylin-eosin and immunohistochemically with a cytokeratin cocktail to detect micrometastases. RESULTS: Four (12%) of 33 patients had unequivocal lymph node metastases on additional hematoxylin-eosin sections (3 cases) or review of original material (1 case). Immunohistochemical analysis contributed additional data in only 1 group 2 patient. In this case a single strongly keratin-positive sinus-based cell was detected in 1 lymph node. CONCLUSION: The study suggests that previous surgical biopsy of the breast does not increase the incidence of immunohistochemically detected keratin positive cells in axillary lymph nodes.     

Predictive value of tumor load in breast cancer sentinel lymph nodes for second echelon lymph node metastases.

BACKGROUND: The need for routine axillary lymph node dissection (ALND) in patients with invasive breast cancer and low-volume sentinel node (SN) involvement is questionable. Accurate prediction of second echelon lymph node involvement could identify those patients most likely to benefit from ALND. METHODS: A consecutive series of 317 patients with invasive breast cancer and a tumor positive axillary SN followed by ALND was reviewed. Clinicopathologic features of the primary tumor and the SN were assessed as possible predictors of second echelon lymph node involvement. RESULTS: Second echelon metastases were found in 116/317 cases (36.6%). Frequency of second echelon lymph node involvement in patients with isolated tumor cells (ITC, N=23), micro- (N=101) and macrometastases (N=193) was 13%, 20% and 48%, respectively (p<0.001). Based on the area % of SN occupied by tumor no subgroup of patients could be selected with less than 20% second echelon lymph node involvement. However, none of the patients with SN ITC or micrometastases and a primary tumor size 相似文献   

Morphometry and breast cancer. II. Characterisation of breast cancer cells with high malignant potential in patients with spread to lymph nodes: preliminary results.

The prognostic value of clinical, quantitative, and qualitative microscopical features of both the primary tumour and also of the affected lymph nodes were investigated in 71 patients with breast cancer with spread to lymph nodes (T X N + M0). Age, tumour size, and localisation of the tumour comprised the clinical features; morphometry included assessment of the cellularity index, the mitotic activity index, and seven nuclear indices; the qualitative features investigated were histological type and grade, nuclear grade, oestrogen receptor content, number of lymph nodes affected, capsule infiltration of the nodes, presence of metastatic deposits in the efferent lymph vessels, percentage area of lymph node occupied by tumour. Immunohistochemistry was performed to show the presence of carcinoembryonic antigen and peanut agglutinin. All the patients had a minimum follow up of 24 months (maximum 48 months, mean 36 months). Analysis of the results showed that the combined results of morphometry (of the primary tumour and the axillary lymph node metastatic deposits) yielded more information than analysis of axillary lymph node state, or morphometry of the primary tumour, or the lymph node metastases alone. Patients with a nuclear axes ratio of greater than 1.41 in the primary tumour and greater than 1.36 in the lymph node metastatic deposits were less likely to develop distant metastases than patients with values below any of these thresholds (recurrence rates 5.2% and 46%, respectively). Thus the preliminary results of this prospective study indicate that morphometry provides important prognostic information in patients with breast cancer that has spread to lymph nodes.     

Intra-patient variation between breast cancer axillary lymph node metastases using quantifiable features

The intra-patient variations of some clinically relevant quantifiable features, between axillary lymph node metastases were evaluated in 44 breast cancer patients. In all lymph node metastases detected (range 2-33 per patient), the mitotic figures were counted, the volume percentage epithelium was assessed and the mean nuclear area was measured. The intra-patient variation for each quantifiable feature was expressed by the coefficient of variation (CV). Since the measurement techniques used introduce a certain, well known variation themselves because of sampling and measurement errors, the CVs found had to be greater than methodological tolerance limits (established in previous studies) to be interpreted as indicating biological variation. The CVs exceeded the methodological tolerance limits in 86% of the cases for the mitotic count, in 48% of the cases for the volume percentage epithelium, and in 47% of the cases for the mean nuclear area. This indicated that in these cases, the variation found in the quantifiable features could not be explained by sampling or measurement errors and should be regarded as real biological variation. Furthermore, the variation in the quantifiable features studied showed a significant positive correlation with the number of lymph node metastases. Thus, there may be considerable intra-patient variation in quantifiable features between axillary lymph node metastases in breast cancer. This may indicate that these lymph node metastases originate independently from different clones within the primary tumour, that they are independently formed in different stages of tumour development, or that they, as an expression of intrinsic tumour heterogeneity, may develop in different directions from the start.     

mRNA markers of breast cancer nodal metastases: comparison between mammaglobin and carcinoembryonic antigen in 248 patients

Histological detection of axillary lymph node metastases is still the most valuable prognostic parameter for breast cancer, but about 30% of node-negative patients relapse within five years, suggesting that current methods are inadequate for identifying metastatic disease. More sensitive, PCR-based methods for the detection of metastatic cells are now available, enabling the amplification of cancer cell-specific mRNA messages by the RT-PCR assay. An ideal tumour marker, consistently expressed in tumour samples and not at all in normal lymph nodes, remains to be identified. The present study first investigated the expression of seven mRNA markers, CEA, CK19, c-Met, mammaglobin, MUC-1, beta1-->GalNAc-T and p97, selected on the basis of their previously reported specificity for breast cancer cells. Eighteen lymph nodes were examined from patients without tumours. Only mammaglobin mRNA and CEA mRNA were not expressed in normal nodes. All of the other markers showed a band of expression in 17%-55% of cases, indicating that they are not breast cancer-specific. CEA mRNA and mammaglobin mRNA expression could be detected in 15/20 (75%) and 19/20 (95%) primary breast carcinomas, respectively. The expression of mammaglobin mRNA and CEA mRNA was then compared in axillary lymph nodes from 248 consecutive breast cancer patients, 89 with histologically documented lymph node metastasis and 159 without histological evidence of metastatic disease. Ninety-seven per cent of the patients with histologically involved nodes showed expression of mammaglobin mRNA, whereas CEA mRNA was expressed in 79% of these cases. In the group of patients with histologically negative lymph nodes, 46 (29%) and 32 (20%) were found to be positive for mammaglobin and CEA expression, respectively, indicating the presence of metastases not detected by routine histological examination of one lymph node section. These results show that both mammaglobin RT-PCR and CEA RT-PCR are useful tools for the detection of breast cancer metastases in axillary lymph nodes. The detection sensitivity of the mammaglobin RT-PCR is far superior to that of the CEA RT-PCR, allowing the diagnosis of occult metastases in nearly one-third of cases.     

Invasive micropapillary carcinoma of the breast: a prognostic study

Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of infiltrating ductal carcinoma that has been associated with an extremely high incidence of lymph node metastases. Follow-up studies on patients with pure IMC breast cancer histology have been limited by low patient numbers, short duration of follow-up, and a lack of multivariate analyses. Using invasive breast cancers from 1,287 patients (median follow-up, 13.8 years), histological review showed 21 cases (1.7%) with pure IMC histology. Pure IMC histology was associated with high-grade histology (P = .04), metastases to regional lymph nodes (P < .001), a high mitotic index (P = .02), and erbB-2 immunopositivity (P = .007). Univariate analyses showed a strong association between IMC histology and shortened survival (disease-free survival [DFS], P = .0052; median, 44 months for IMC and 63 months for non-IMC; disease-specific survival [DSS], P = .014; medians, 71 and 78 for IMC and non-IMC, respectively) only in an analysis of all patients. Because only 1 case of node-negative IMC histology was available, univariate analysis of IMC histology was performed only on node-positive patients without significance. Multivariate analyses comparing IMC histology with either node-positive or all other breast cancers failed to show independent prognostic significance. In summary, breast cancer patients with pure IMC histology showed survival rates similar to those of other patients with equivalent numbers of lymph node metastases.     

Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases

BACKGROUND: Insulin receptor substrate 1 (IRS-1) transmits signals from the insulin-like growth factor I receptor (IGF-IR) and insulin receptor (IR) and has been associated with the pathogenesis of cancer. IRS-1 downregulation has been suggested to play a role in breast cancer progression, but no simultaneous assessments of IRS-1 expression in primary breast cancer and metastases have been performed. AIMS: To assess IRS-1 expression in primary and metastatic breast cancer. METHODS: IRS-1 expression was analysed by means of immunohistochemistry in 109 samples of primary breast cancer and in 42 matched primary and metastatic tumours. In addition, IRS-1 expression was correlated with selected clinicopathological features, including oestrogen receptor alpha (ERalpha) and proliferation marker Ki-67 status. RESULTS: Positive cytoplasmic IRS-1 immunostaining was found in 69.7% (76 of 109) and 76.2% (32 of 42) of the primary and metastatic tumours, respectively. Both IRS-1 positive and IRS-1 negative primary tumours produced IRS-1 positive and IRS-1 negative metastases. IRS-1 expression in primary tumours correlated with poorly differentiated (G3) breast cancer (p < 0.005) and with lymph node involvement (p <0.05). In the subgroup of ERalpha positive primary tumours, IRS-1 expression positively correlated with Ki-67 (p < 0.02, r = 0.351), but in the subgroup of ERalpha negative primary tumours there was a negative correlation (p < 0.03, r = -0.509). IRS-1 expression in lymph node metastases correlated with neither ERalpha nor Ki-67. CONCLUSIONS: IRS-1 might be involved in breast cancer progression. Knowledge about differences between primary and metastatic tumours might help to understand mechanisms of breast cancer progression and lead to the development of more effective anticancer drugs.     

Angiogenesis in invasive breast carcinoma: is it associated with parameters of prognostic significance?

Recent experimental and clinical studies suggest that tumour-induced angiogenesis may be an important step in the evolution of malignant tumours, and may be related to prognosis. In our study we examined 42 cases of breast carcinoma (mean age: 56.76 ± 13.5), 21 with lymph node metastases and 21 without. Angiogenesis was evaluated after immunohistochemical staining of tumour vessels, using polyclonal antibody to factor VIII related antigen (VIIIR-Ag) and counting of the three most active areas of neovascularization. In the same manner we counted the microvessels in lymph node metastases. The mean vessel count of node-negative cases (51.16 ± 19.32) did not differ significantly from node-positive cases (45.66 ± 17.44). In contrast patients younger than 50 years had much higher mean vessel counts (54.04 ± 16.47) than did patients older than 70 years (38.03 ± 16.73) producing a P value of ≤0.05. No association was found between tumour size and mean vessel count, nor was there any significant difference between grade I (45.94 ± 16.54), grade II (53.13 ± 23.22) and grade III tumours (51.71 ± 20.64). When we compared the mean vessel count of primary tumours with those of node metastases, we found much lower counts in the latter ( P ≤0.01). The differences in our results from previous studies, probably reflect the heterogeneity which exists between different tumours in their ability to induce angiogenesis. Additionally, there is some evidence in our study that angiogenesis is possibly related to patient age and probably depends on differences in the tumour stroma.     

Genetic aberrations detected by comparative genomic hybridization predict outcome in node-negative breast cancer.

Breast cancer progression is determined by a complex pattern of multiple genetic aberrations the association of which with patient prognosis is unknown. In this study, we have undertaken a genome-wide screening to detect genetic changes associated with clinical outcome in node-negative breast cancer. Comparative genomic hybridization was used to screen for DNA sequence gains and losses across all human chromosomes in 23 tumors from node-negative breast cancer patients with no disease recurrence after at least 5 years of follow-up and in 25 node-negative patients with recurrence during the first 5 years of follow-up. The total number of genetic aberrations (copy number gains and losses) per tumor was significantly greater in the recurrence group (P = 0.019) and in the subgroup of these patients who died as a result of breast cancer (P = 0.0022). When copy number losses and gains were analyzed separately, only losses were significant (P = 0.013 for recurrence and P = 0.002 for overall survival). Of the individual loci involved, a high level gain of the long arm of chromosome 8 was significantly associated with recurrence (P = 0.01, Fisher's exact test). Furthermore, amplification of DNA sequences at chromosome 20q12-13 was found in 7 cases (15%), 6 of which had early recurrence within 32 months of diagnosis. This genome-wide overview by comparative genomic hybridization suggests that genetically advanced node-negative breast cancers having a high overall number of genetic aberrations may have a poor prognosis and that increased copy number of two specific regions, 8q and 20q13, may confer a more aggressive phenotype. Results of this pilot study suggest that determination of the total number of DNA sequence copy number aberrations may help therapeutic decision making. Specific probes should be developed to test the prognostic value of 8q and 20q12-13 amplifications in large numbers of patients.