Mitotic indexes as prognostic predictors in female breast cancer

Summary A series of 688 women with breast cancer were followed-up for a mean of 13 years. Tumour size, axillary lymph node status, histological grade, histological type and two mitotic indexes (M/V; MAI) were assessed and related to disease outcome. Primary tumour size (P<0.0001), the volume-corrected mitotic index (M/V) (P<0.0001), the mitotic activity index (MAI) (P=0.0001), and histological grade (P=0.0074) predicted axillary lymph node status. Recurrence as well as recurrence-free survival was significantly related to the axillary lymph node status (P<0.0001), M/V index (P<0.0001), MAI (P<0.0001), tumour size (P=0.0031) and histological grade (P=0.0208). Multivariate analyses disclosed the tumour size and M/V index as independent predictors of axillary metastasis at diagnosis. Recurrence was related independently to M/V index, axillary metastasis and tumour size. Independent predictors of recurrence-free survival in Cox's analysis were M/V index and axillary lymph node status. Axillary lymph node status (P<0.0001), tumour size (P<0.0001), M/V index (P<0.0001), MAI (P<0.0001) and histological grade (P=0.0009) predicted survical in that order. Cox's analysis showed that axillary lymph node status was the most important independent predictor of survival followed by tumour size and M/V index. In a separate Cox's analysis of axillary-lymph-node-negative patients the M/V index and tumour size were independently related to survival. In conclusion the M/V index is an important prognostic factor in breast cancer and also in axillary-lymph-node-negative breast tumours.Abbreviations MAI mitotic activity index - M/V index volume-corrected mitotic index     

Prognostic value of epidermal growth factor expression in breast cancer

A series of 198 female breast cancer biopsies were analysed immunohistochemically for the expression of epidermal growth factor (EGF), with special emphasis on its prognostic significance. A total of 67/198 tumours (33.8%) were EGF-positive, 24 (12%) of which showed strong expression of EGF. EGF was usually expressed in the cytoplasm of the cancer cells but, in 22 cases, the normal ducts adjacent to the cancer showed positive staining as well. Strong EGF expression was related to distant metastases at diagnosis (P=0.04). Oestrogen(ER)- and progesterone-receptor(PR)-negative tumours showed EGF positivity with equal frequency (P=0.05 in both). Axillary lymph node status, histological type, tumour size, histological grade, S-phase fraction, mitotic index or cancer recurrence did not show any statistical correlation with EGF expression. Tumour size (P=0.007), axillary lymph node involvement (P=0.003) and ER content (P=0.03) were independent prognostic factors in multivariate survival analysis, whereas EGF positivity, as an independent factor, had no effect on survival. In univariate analysis, however, EGF positivity predicted a more favourable outcome in axillary-lymph-node-positive tumours (P=0.04). The results suggest that immunohistochemical assessment of EGF expression has hardly any clinical significance in addition to the well-established prognostic factors in breast cancer.Abbreviations EGF epidermal growth factor - EGFR EGF receptor     

Ki-67 expression as a prognostic marker in patients with hepatocellular carcinoma

Ki-67 expression in tumours has been shown to be associated with prognosis in patients with hepatocellular carcinoma (HCC). In this study, primary HCC samples were obtained from 67 patients undergoing surgical resection. None of these patients had been subjected previously to any other form of therapy, such as arterial embolization or chemotherapy. Histologically normal liver tissues from liver resection for metastatic colon cancer were taken as controls (n= 8). Monoclonal antibody against Ki-67 was used for immunostaining and ?ow cytometry was used to measure tumour DNA ploidy. The mean Ki-67 labelling index (percentage of Ki-67-positive cells) of the HCC (26 ± 22%; range 0.1–89%) was signi?cantly higher than that of the normal controls (39 ± 0.8%, P < 0.05). The mean Ki-67 labelling index (19 ± 15%; n= 28) of the tumours with diploid DNA pattern was signi?cantly lower than those with aneuploid DNA pattern (32 ± 25%, n= 39; P= 0.01). Hepatocellular carcinoma patients (n= 47) with Ki-67 index >10% had a signi?cantly lower disease-free and overall survival than those (n= 20) with Ki-67 index ≤10% (P= 0.0009 and P= 0.02, respectively). Multivariate analysis showed that Ki-67 expression and tumour node metastasis stage were two independent prognostic factors for disease-free and overall survival rates. Our results suggest that the expression of Ki-67 is an independent prognostic indicator for patients with HCC after resection and could be of assistance in the decision-making of adjuvant therapy.     

Proliferating-cell nuclear antigen (PC10) immunolabelling and other proliferation indices as prognostic factors in breast cancer

Proliferating cell nuclear antigen, PCNA (PC10), immunolabelling was determined in 175 women with breast carcinomas and related to other established prognostic factors: flow-cytometric data, volume-corrected mitotic index, sex steroid receptor content and clinical outcome during the mean follow-up of 9 years. The maximum fraction of PCNA-positive nuclei (PCNA_max), the average fraction of positive nuclei (PCNA_tot) and the number of intensely stained nuclei per microscope field (PCNA_count) were significantly related to histological grade (P<0.001), DNA ploidy ((P<0.001), S-phase fraction (P<0.001), mitotic index (P<0.001) and sex steroid receptor content (P=0.002). PCNA_max (P=0.015) predicted survival in univariate analysis; PCNA_tot (P=0.025), PCNA_max (P=0.007) and PCNA_count (P=0.019) predicted the recurrence-free survival. In axillary-lymph-node-negative tumours, PCNA_tot (P=0.092), PCNA_max (P=0.036) and PCNA_count (P=0.006) predicted survival and recurrence-free survival (P=0.011), (P=0.012) and (P=0.006) respectively. In multivariate analysis including clinical, histological, flow-cytometric and biochemical variables, PCNA_tot (P=0.004) predicted the recurrence-free survival independently. In axillary-lymph-node-negative breast cancers, PCNA_tot predicted accurately the patient survival (P=0.002) and the recurrence-free survival (P=0.002). The results indicate that PCNA immunolabelling has independent prognostic value particularly in local breast cancer.Abbreviation PCNA proliferating-cell nuclear antigen     

Prognostic value of cell cycle regulatory proteins in muscle-infiltrating bladder cancer

Purpose The aims of this study were to investigate the expression levels of proteins involved in cell cycle regulation in specimens of bladder cancer and to correlate them with the clinicopathological characteristics, proliferative activity and survival.Methods Eighty-two specimens obtained from patients affected by muscle-invasive bladder cancer were evaluated immunohistochemically for p53, p21 and cyclin D1 expression, as well as for the tumour proliferation index, Ki-67. The statistical analysis included Kaplan–Meier curves with log-rank test and Cox proportional hazards models.Results In univariate analyses, low Ki-67 proliferation index (P = 0.045) and negative p21 immunoreactivity (P = 0.04) were associated to patient’s overall survival (OS), but in multivariate models p21 did not reach statistical significance. When the combinations of the variables were assessed in two separate multivariate models that included tumour stage, grading, lymph node status, vascular invasion and perineural invasion, the combined variables p21/Ki-67 or p21/cyclin D1 expression were independent predictors for OS; in particular, patients with positive p21/high Ki-67 (P = 0.015) or positive p21/negative cyclin D1 (P = 0.04) showed the worst survival outcome.Conclusions Important alterations in the cell cycle regulatory pathways occur in muscle-invasive bladder cancer and the combined use of cell cycle regulators appears to provide significant prognostic information that could be used to select the patients most suitable for multimodal therapeutic approaches.     

Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence

BackgroundMicroscopic venous and lymphatic invasion is a known prognostic factor for various cancers, but its prognostic relevance for pancreatic neuroendocrine tumors (PNETs) is unclear.MethodsThirty-two consecutive patients with PNET who had complete resection were included in this study. Venous and lymphatic invasion was identified on elastic tissue or immunohistochemical staining, and correlated with other clinicopathological factors, including recurrence-free survival.ResultsVenous and lymphatic invasion was identified in nine (28%) and three (9%) patients, respectively. Tumors with venous invasion were of significantly larger size, higher Ki-67 index, and higher mitotic counts. Patients with venous invasion showed significantly worse prognosis than those without venous invasion (P = 0.001). Five of nine patients (56%) with venous invasion had tumor recurrence, while a relapse was found in one case in patients without venous invasion (n = 23). Lymphatic invasion was not correlated with any other clinicopathological parameters including lymph node metastasis and recurrence-free survival. Predictive factors for recurrence in univariate analysis included microscopic venous invasion, tumor size ≥ 20 mm, non-functionality, and WHO grades. In multivariate analysis where WHO grades and microscopic venous invasion were applied, venous invasion remained a significant predictor of poor recurrence-free survival (P = 0.021).ConclusionsMicroscopic venous invasion may serve as a predictive factor for tumor recurrence in patients with resectable PNET. The combination of WHO grades and microscopic venous invasion may assist in the stratification of the patients for risk of tumor recurrence.     

PPARγ and Wnt/β-Catenin pathway in human breast cancer: expression pattern, molecular interaction and clinical/prognostic correlations

Purpose

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor expressed in a large number of human cancers and plays important roles in breast cancer cell proliferation. Its association with clinicopathologic features and Wnt/β-Catenin signaling pathway, a crucial factor in embryonic and malignant development, in breast cancer has not been reported systematically. In the present study, expression patterns, interaction and the correlations with clinical/prognostic factors of PPARγ and β-Catenin were investigated among patients with breast cancer.

Methods

Using immunohistochemistry, we performed a study on 70 patient-derived human breast tumors and compared the protein expression levels of PPARγ, β-Catenin and Ki-67. Correlations were then analyzed between IHC-assessed level of these molecules and major clinicopathologic variables and survival. Furthermore, western blot (WB) analysis before and after immunoprecipitation with PPARγ and β-Catenin were performed on breast cancer tissues and cell lines to evaluate their protein level and molecular interaction.

Results

We showed that PPARγ expression was of significant prognostic value in the outcome of breast carcinomas, which positively correlated with ER status (P = 0.012) and inversely associated with histologic grade (P = 0.012), tumor size (P = 0.007), axillary lymph node status (P = 0.044), TNM stage (P = 0.026), Ki-67 (P = 0.006) and abnormal β-Catenin expression (P = 0.023), whereas no correlation was seen between PPARγ and age (P = 0.513), histology (P = 0.764), PR (P = 0.099) or HER-2 status (P = 0.175). Kaplan–Meier survival curves of the study population showed that high expression level of PPARγ significantly correlated with long-term survival. Molecular interaction could also be demonstrated between PPARγ and β-Catenin both in breast cancer cell lines and tissue samples.

Conclusions

On the basis of these results, we suggested that PPARγ might serve as a future target for the development of novel treatments in breast cancer.     

A prospective study on the prognostic significance of urokinase-type plasminogen activator levels in breast cancer tissue

Urokinase-type plasminogen activator (u-PA), which cleaves plasminogen to yield plasmin, is a serine protease of fibrinolysis and is presumed to play a key role in extracellular proteolysis and facilitate the migration of cancer cells. This study was conducted prospectively to evaluate the prognostic significance of u-PA antigen level in breast cancer tissues. u-PA concentrations in the cytosol of 226 breast cancer tissues were determined prospectively by enzyme-linked immunosorbent assay using cytosol fractions prepared for steroid hormone assay. The median follow-up period of the patients was 60 months. Various prognostic factors were evaluated by univariate analysis or multivariate analysis using the Cox proportional-hazards method. Patients with primary breast cancer containing high levels of u-PA had a significantly shorter disease-free survival than patients with low levels of u-PA antigens. In multivariate analysis, a high level of u-PA was an independent risk factor for disease-free survival, being independent of age, axillary node status, and estrogen receptor status. Among the major prognostic factors, a high u-PA antigen level, lymph node involvement, and a positive estrogen receptor status were the most important for predicting relapse-free survival (P=0.044, P<0.0001, P=0.0039). This first prospective study confirmed the prognostic significance of the u-PA antigen level in association with other major prognostic factors. The results of our present study suggest that u-PA in breast cancer tissue might be involved in breast cancer invasion and metastasis. Received: 20 November 1996 / Accepted: 9 June 1997     

Telomerase activity significantly correlates with cell differentiation, proliferation and lymph node metastasis in colorectal carcinomas

Telomerase activity was examined by the telomeric repeat amplification protocol assay, in a total of 37 colorectal adenocarcinomas, including stages A, B and C according to the Astler and Collier classification, and correlated with clinicopathological features. Of 17 stage C lesions, 13 were positive (76.5%; P<0.01), demonstrating a significant correlation with lymph node metastasis. In contrast, only 6 of 20 stage A and B␣carcinomas were positive (30.0%), this being significantly lower (P<0.05). Moderately or poorly differentiated subtypes were more predominant in the telomerase-positive than in the telomerase-negative groups (P<0.05) with greater elevation of mitotic and Ki-67 labeling indices (P<0.0001). No significant relation was found between telomerase activity and p53 protein accumulation or Bcl-2 protein expression. The good correlation with tumor staging, lymph node metastasis, differentiation, and mitotic and Ki-67 labeling indices suggests that this parameter might have potential application in estimation of prognosis. Received: 28 February 1998 / Accepted: 30 April 1998     

Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis

Purpose The objective of this study was to evaluate breast carcinomas for the expression of cyclooxygenase-2 (Cox-2) using a tissue microarray (TMA) and to determine its clinical and prognostic relevance.Methods We analyzed Cox-2 expression in 600 samples from 200 breast carcinomas immunohistochemically performing TMA technology and semiquantitative analysis. Results were correlated with various clinicopathological variables and follow-up data. Expression of estrogen receptor, progesterone receptor, Ki-67, and Her-2/neu-oncogene was analyzed and correlated with Cox-2 status.Results We observed a moderate or strong cytoplasmic staining for Cox-2 in 78 (40.6%) of breast carcinomas. Increased Cox-2 expression corresponded to higher pT stage (P=0.038), amplification of Her-2/neu (P=0.032), lymphovascular invasion (P=0.006), a high MIB-1 labeling index (LI) (P<0.001), and histological grading (P=0.013). We also observed an inverse relationship between strong Cox-2 expression and estrogen and progesterone receptor content of tumors (P=0.037 and P=0.010). However, we could not demonstrate a significant association between Cox-2 staining and overall survival or disease free survival time.Conclusions These results suggest that Cox-2 expression is significantly associated with less differentiated and more aggressive breast carcinomas and might therefore be a useful prognostic indicator as well as a target for therapy.     

Intra-mammary tumor location does not influence prognosis but influences the prevalence of axillary lymph-node metastases

Background The number of axillary lymph-node metastases is not only a function of disease progression in primary breast cancer, but is also influenced by the intra-mammary location of the tumor. Nevertheless, the prognostic role of the tumor site is discussed controversially. The objective of this study was to analyze the impact of primary-tumor location on axillary lymph-node involvement, relapse, and mortality risk by univariate and multivariate analysis, in patients both with and without systemic and loco-regional treatment.Method Retrospective analysis was conducted on 2,414 patients at the I. Frauenklinik, Ludwig-Maximilians University, Munich and Berlin-Charlottenburg, who underwent R₀ resection of the primary tumor and systematic axillary lymph-node dissection (at least five lymph nodes resected) for UICC I-III-stage breast cancer. Patients with unknown tumor site, multifocal tumor spread, central tumor location, or tumor location within 15° of the border between outer and inner quadrants were excluded from the study. Median observation time was 6.7 years.Results The primary tumor site was within or between the medial quadrants of the breast in 33.6% of the patients (n=810) and in the lateral hemisphere of the breast in 66.4% (n=1,604). Tumor size, histopathological grading, and estrogen receptor status were balanced between patients with lateral and medial tumor location. Metastatic axillary lymph-node involvement was significantly associated with a lateral tumor location (P<0.0001). The mean number of axillary lymph-node metastases was increased by 29% in cases with lateral tumor location (2.2 vs 1.7, P=0.003). In a multivariate logistic regression analysis allowing for tumor location, estrogen receptor status, grading and tumor size, tumor location was confirmed as a significant risk factor (P=0.02) for axillary lymph-node involvement. Tumor location, however, did not correlate with either disease-free survival (DFS) or overall survival (OS), by univariate (DFS: P=0.41; OS: P=0.57) or by multivariate analysis (DFS: P=0.16; OS: P=0.98).Conclusion We conclude that there is no sufficient evidence to support any independent prognostic significance of intra-mammary tumor location in early breast cancer. However, medial tumor location may lead to the underestimation of axillary lymph-node involvement.     

Matched pair analysis of survival after chest-wall recurrence compared to mammary recurrence: a long-term follow up

Background: Local recurrence remains a major concern after primary treatment of breast cancer and has a major impact on subsequent survival. While most studies report a poorer survival rate in patients with a local recurrence after mastectomy than after breast conservation, it remains controversial whether different risk profiles at the time of primary diagnosis may account for this difference. Method: Matched pair analysis of 134 patients with newly diagnosed locoregional recurrence of breast cancer without evidence of systemic disease. Matching criteria included the primary surgical treatment, tumor size, nodal status, and age. The significance of various prognostic parameters at the time of primary diagnosis and at the time of recurrence were evaluated, by univariate and multivariate analyses, with respect to survival after recurrence. The median follow-up was 8.4 years. Results: Risk factors at the time of presentation, such as tumor size and lymph node status, were comparable between both groups. Local recurrence occurred on an average 9 months earlier in patients after mastectomy (P=0.08). Univariate analysis showed that lymph node status (P=0.0001) and disease-free interval from primary treatment to local recurrence (P=0.0002) were the most significant single prognostic factors for subsequent survival after local recurrence. The primary surgical treatment modality was shown to be of marginal statistical influence (only P=0.05). Conclusion: Local recurrence after mastectomy seems to be associated with worse survival than after breast-conserving therapy. Early onset of chest-wall recurrence, moreover, represents the highest independent risk for cancer-associated death. Received: 22 November 2000 / Accepted: 3 January 2001     

Expression of retinoblastoma gene (Rb) protein in T12MO prostatic adenocarcinoma

The expression of Rb protein was analysed by immunocytochemical methods in 118 patients with T12M0 prostatic adenocarcinoma who were followedup for more than 12 years. Rb protein was expressed in 117/118 (99%) tumours. The fraction of positive nuclei was (mean±SD, 92±19%) and only one tumour was completely negative for Rb protein. Abnormal expression of the Rb protein (in fewer than 90% of cells) was independent of the T category while there was a significant relationship between DNA ploidy (P=0.0138), S-phase fraction (P=0.0042) and expression of the Rb protein. Abnormal expressin of the Rb protein had no prognostic value while T category (P=0.0017), Gleason score (P=0.0097), DNA ploidy (P=0.0034), S-phase fraction (P=0.0179) and mitotic index (P=0.0001) were significant prognostic factors. In multivariate analysis the only independent predictor was the mitotic index [Risk ratio (RR) (95%CI)=7.4(2.4–22.5),P=0.004]. The results show that Rb protein immunohistochemistry has hardly any prognostic significance in prostatic adenocarcinoma whereas direct measurement of cell proliferative activity contains significant prognostic information.     

Relationship of DNA ploidy to hormone receptor status and proliferation in invasive breast carcinoma

Purpose: In 247 primary invasive breast carcinomas, DNA ploidy was related to hormone receptor status, proliferation, and clinical/histopathologic factors. Methods: DNA ploidy analysis was performed by image analysis using imprints. Estrogen (ER) and progesterone (PR) receptor status was determined immunohistochemically. The proliferative activity of the tumours was assessed by Ki-67 antigen labelling. Total observation time was 3.5 years. Results: DNA ploidy analysis revealed a high fraction of tumours with non-peridiploid patterns (78%). Significant correlations between DNA ploidy and ER/PR receptor status (P < 0.01) were found with increased frequencies of peridiploid DNA results in receptor positive tumours. A significant relationship became manifest between DNA ploidy and Ki-67 index showing high frequencies of non-peridiploid DNA patterns in tumours with Ki-67 index >20% (P < 0.01). There was a strong correlation (P < 0.001) between DNA ploidy and histopathologic grading, while tumour size and lymph node status were not correlated to DNA ploidy. Conclusions: The results of our study on invasive breast carcinoma demonstrate that DNA ploidy measured by image analysis is predominantly associated with markers of cell differentiation. Preliminary outcome data reveal a risk-indicating potential of DNA ploidy primarily in cases with favourable results for other prognostic factors. Received: 18 February 2000 / Accepted: 9 May 2000     

Nomogram based on tumor-associated neutrophil-tolymphocyte ratio to predict survival of patients with gastric neuroendocrine neoplasms

AIM To assess the predictive value of the tumor-associated neutrophil-to-lymphocyte ratio in terms of the clinical outcomes of patients with gastric neuroendocrine neoplasms after radical surgery.METHODS Data were retrospectively collected from 142 patients who were diagnosed with gastric neuroendocrine neoplasms and who underwent radical gastrectomy at our department from March 2006 to March 2015. These data were retrospectively analyzed, and a receiver operating characteristic curve analysis was used to identify the optimal value of the tumorassociated neutrophil-to-lymphocyte ratio. Univariate and multivariate survival analyses were used to identify prognostic factors. A nomogram was then applied to predict clinical outcomes after surgery.RESULTS The tumor-associated neutrophil-to-lymphocyte ratio was significantly associated with tumor recurrence, especially with liver metastasis and lymph node metastasis(P 0.05 for both), but not with clinical characteristics(P 0.05 for all). A multivariate Cox regression analysis identified the tumor-associatedneutrophil-to-lymphocyte ratio as an independent prognostic factor for recurrence-free survival and overall survival(P 0.05 for both). The concordance index of the nomograms, which included the tumorassociated neutrophil-to-lymphocyte ratio, Ki-67 index, and lymph node ratio, was 0.788(0.759) for recurrence-free survival(overall survival) and was higher than the concordance index of the traditional TNM staging system [0.672(0.663)].CONCLUSION The tumor-associated neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with gastric neuroendocrine neoplasms. Nomograms that include the tumor-associated neutrophil-to-lymphocyte ratio, Ki-67 index, and lymph node ratio have a superior ability to predict clinical outcomes of postoperative patients.     

Prognostic significance of the endoscopic ultrasound defined lymph node metastasis count in esophageal cancer

The key prognostic factor which predicts outcome after esophagectomy for cancer is the number of malignant lymph node metastases, but data regarding the accuracy of endoscopic ultrasound (EUS) in determining and predicting the metastatic lymph node count preoperatively are limited. The aim of this study was to assess the prognostic significance of EUS defined lymph node metastasis count (eLNMC) in patients diagnosed with esophageal cancer. Two hundred and sixty‐seven consecutive patients (median age 63 years, 187 months) underwent specialist EUS followed by stage directed multidisciplinary treatment (183 esophagectomy [64 neoadjuvant chemotherapy, 19 neoadjuvant chemoradiotherapy], 79 definitive chemoradiotherapy, and 5 palliative therapy). The eLNMC was subdivided into four groups (0, 1, 2 to 4, >4) and the primary measure of outcome was survival. Survival was related to EUS tumor (T) stage (P < 0.0001), EUS node (N) stage (P < 0.0001), EUS tumor length (p < 0.0001), and eLNMC (P < 0.0001). Multivariable analysis revealed EUS tumor length (hazard ratio [HR] 1.071, 95% CI 1.008–1.138, P= 0.027) and eLNMC (HR 1.302, 95% CI 1.133–1.496, P= 0.0001) to be significantly and independently associated with survival. Median and 2‐year survival for patients with 0, 1, 2–4, and >4 lymph node metastases were: 44 months and 71%, 36 months and 59%, 24 months and 50%, and 17 months and 32%, respectively. The total number of EUS defined lymph node metastases was an important and significant prognostic indicator.     

Apoptosis in breast cancer: relationship with other pathological parameters

Apoptosis is a frequent phenomenon in breast cancer and it can be detected by light microscopy in conventional histopathological sections or by special staining techniques. The number of apoptotic cells as a percentage of cells present, or the number of apoptotic cells per square millimetre of neoplastic tissue, is usually described as the apoptotic index (AI). In breast cancer, the AI is not related to tumour size, axillary lymph node metastasis or distant metastasis at diagnosis. It is greater in invasive ductal carcinomas than in other histological types. High AI is also related to high histological grade, high nuclear grade, comedo-type necrosis, lack of tubule formation, and dense infiltration of the tumour by lymphocytes. Sex steroid receptor-negative tumours have greater AIs than the sex steroid receptor-positive ones. Aneuploid breast cancers with high S-phase fractions (SPFs) also have high AI values compared with diploid tumours with low SPFs. p53-Positive breast cancers have high AIs, whereas tumours that are Bcl-2 positive have low AIs. The AI shows a strong positive correlation to all direct or indirect indicators of cell proliferation, such as mitotic index and Ki67 immunolabelling. Univariate survival analyses show that a high AI is linked with unfavourable disease outcome in axillary lymph node-negative and -positive breast cancer, but multivariate analyses indicate that AI is not an independent prognostic factor. In conclusion, a high AI is related to malignant cellular features and indicators of invasiveness and cell proliferation in breast cancer.     

Clinical relevance of p53 index and expression of proliferating cell nuclear antigen and Ki-67 in gastric cancer

The prognostic value of the immunohistochemical expression of p53 protein, proliferating-cell nuclear antigen (PCNA) and Ki-67 antigen was evaluated in a series of 116 stage I–II gastric cancer patients. The staining for p53 protein (staining frequency and intensity) in malignant cells was expressed as a p53 index. Similarly, the staining frequency and intensity for PCNA and Ki-67 were evaluated. The p53 index was independent of the stage and differentiation grade, but significantly related to DNA ploidy, S-phase fraction and mitotic activity. A high p53 index was a sign of inferior survival, compared to a low or intermediate index. p53-negative tumours were also associated with poor survival. In a multivariate analysis, only the depth of tumour infiltration and the presence of nodal metastases were independent prognostic factors in stage I–II gastric cancer. PCNA expression and Ki-67 antigen expression were not related to the stage, ploidy, proliferative activity or p53 expression, and they had no impact on survival. The results indicate that p53 protein expression may be of prognostic significance in gastric cancer, while PCNA and Ki-67 antigen expression have no predictive value. Received: 2 February 1998 / Accepted: 16 June 1998     

Reduced expression of retinoblastoma (Rb) gene protein is related to cell proliferation and prognosis in transitional-cell bladder cancer

Archival biopsy specimens from transitional-cell bladder cancers (n=222) were analysed immunohistochemically for expression of retinoblastoma (Rb) gene protein. The intensity of staining for Rb protein and the fraction of positive nuclei were analysed and related to several other prognostic factors and survival. Six per cent of the tumours were totally negative for Rb protein and abnormal (weak) expression was found in 40% of cases. The fraction of positive nuclei and abnormal expression (weak) were highly significantly interrelated (P<0.0001). A low value for the fraction of Rb-protein-positive nuclei was related to a large fraction in S phase (P=0.001), high mitotic index (P=0.016) and overexpression of epidermal growth factor receptor (P=0.034) and p53 protein (P=0.019). A normal Rb protein expression pattern was related to low S-phase values (P=0.0001) whereas over-expression of p53 was related to high S-phase values (P=0.0077). Morphometrically measured nuclear atypia and the fraction of Rb-protein-positive nuclei were negatively correlated (P<0.05). In univariate survival analysis altered expression of Rb protein (P=0.07) and low frequency (≤50%) of Rb-protein-positive nuclei (P=0.0128) predicted a poor outcome. In a multivariate analysis, reduced expression of Rb protein had no independent prognostic value over T category, papillary status and the size of the S-phase fraction. The results show that tumour-suppressor genes Rb and p53 participate in the growth regulation of human bladder cancer cells in vivo and accordingly modify the prognosis.     

细胞角蛋白19和人乳腺球蛋白在乳腺癌阴性前哨淋巴结中的表达及临床意义

目的研究乳腺癌常规病理检查阴性的前哨淋巴结中细胞角蛋白19(cytokerantin-19,CK19)和人乳腺球蛋白(human mammaglobin,hMAM)的表达及临床意义。方法采用免疫组化SP法检测60例乳腺癌阴性前哨淋巴结中CK19和hMAM的表达,并分析两者表达差异及与临床病理因素的关系。结果 60例乳腺癌阴性前哨淋巴结经免疫组化SP法检测hMAM表达2例,阳性检出率为3.3%。CK19除了hMAM阳性2例外,另外检出6例,阳性检出率为13.3%。CK19表达与肿瘤T分期有关(P<0.05),与患者的年龄、月经状况、定位方法、肿瘤位置、病理类型、雌激素受体表达、孕激素受体表达、CerbB-2表达、Ki-67表达和肿瘤分子分型均无相关(P>0.05);hMAM表达与以上临床病理因素均无相关(P>0.05)。结论 CK19和hMAM均可作为检测乳腺癌阴性前哨淋巴结微转移的指标,但CK19是检测乳腺癌阴性前哨淋巴结微转移的敏感指标。