Low back pain in a 23-year-old man.
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Adult↗
Biomedical subjects
N Weidner
Publications and source records attributed to N Weidner.
Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer.
Neovascularization of tumor tissue (tumor angiogenesis) is considered essential for tumor growth, proliferation and eventually metastasis. Microvessel density or count, a measure of tumor angiogenesis, correlates with clinical outcome in skin, breast, lung and prostate carcinomas. To determine whether an association of tumor angiogenesis and nodal metastasis exists in invasive bladder cancer, microvessel counts in 41 primary invasive stages (T2 to 4,NX,M0) bladder cancers were assessed. Microvessels were identified by immunostaining of endothelial cells for factor VIII-related antigen. Microvessels were scored in selected areas showing active neovascularization, either counting a 200 x field (0.74 mm.2) or by using a 10 x 10 square ocular grid (0.16 mm.2). The microvessel count correlated with the presence of occult lymph node metastases (p < 0.0001) by both techniques. The mean microvessel count in 27 patients without lymph node metastases was 56.2 microvessels per 200 x field (standard deviation [SD] 29.5, range 7 to 130) or 28.6 microvessels per grid (SD 14.4, range 4 to 65). The 14 patients with histologically proved lymph node metastases showed mean 138.1 microvessels per 200 x fields (SD 37.9, range 82 to 202) or 74.7 microvessels per grid (SD 14.4, range 43 to 115). Good correlation was noted between area and grid counting (r = 0.97). Tumor T stage, grade and the presence of vascular or lymphatic invasion did not correlate with the presence of lymph node metastases (p = 0.41, 0.59 and 0.26, respectively). Microvessel count may provide important information regarding the risk of occult metastasis in patients with invasive bladder carcinomas.
Capillaries↗
Intratumor microvessel density as a prognostic factor in cancer.
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Animals↗
Prognostic factors in breast carcinoma.
With greater public awareness and use of mammography, more breast carcinomas are detected early, before the axillary lymph nodes contain metastases. About 60% of patients will be node-negative; yet 20-30% of node-negative breast carcinoma patients will develop recurrent tumors, and they are at risk of dying of disease. These patients should be considered for adjuvant therapies, whereas the remaining 70-80% appear to be cured by surgery. Thus, accurate assessment of risk factors for recurrence provides valuable therapeutic information. This review focuses on recent reports that help identify subsets of patients at variable risk for recurrent disease.
Breast Neoplasms↗
Malignant breast lesions that may mimic benign tumors.
It has been estimated that approximately 1 in 9 women (living to age 85 years) in the United States will develop breast cancer at some time in their lives; hence the interpretation of breast biopsies has become a large and important component of the surgical pathologist's practice. Indeed, there is great pressure on surgical pathologists to make accurate diagnoses of breast lesions because of their high incidence, the increased public awareness of breast disease, the greater use of screening mammography to detect early carcinomas, the development of multiple therapeutic options (which is often determined by tumor pathology), and the harsh medical-legal climate. The focus of this article will be to define the clinicopathologic features of two malignant breast lesions that are particularly prone to simulate benign lesions, and thus pose important diagnostic problems to surgical pathologists. The two lesions include spindle-cell carcinoma and low-grade duct carcinoma in situ.
Breast↗
Endothelial cell proliferation in prostatic carcinoma and prostatic hyperplasia: correlation with Gleason's score, microvessel density, and epithelial cell proliferation.
BACKGROUND: Tumor angiogenesis is necessary for tumor growth and metastasis, and increasing intratumoral microvessel density (MVD) in prostate carcinoma has been shown in several studies to be associated with increasing tumor stage. But, the relationships of endothelial cell proliferation to intratumoral MVD, tumor cell proliferation, and Gleason's score remain unknown in prostate carcinoma. EXPERIMENTAL DESIGN: Using a double-immunolabeling technique (paraffin-reactive MIB1 Ab to determine Ki67 labeling index (Ki67LI) and anti-CD34 to quantify microvessels), we immunostained 20 prostatic carcinomas and adjacent benign prostate hyperplasia (BH) and four cases of trauma-induced granulation tissue. We correlated intratumoral endothelial cell proliferation with intratumoral MVD, tumor cell proliferation, and Gleason's score, and we compared these measurements with endothelial cell proliferation, MVD, and epithelial cell proliferation in adjacent BH. RESULTS: The intratumoral endothelial cell proliferation index (mean 0.15%) and intratumoral MVD measured 30-fold (p = 0.00007) and 1.9-fold (p = 0.000003) greater than that of adjacent BH, respectively. However, the intratumoral endothelial cell proliferation index did not correlate with intratumoral MVD, tumor cell proliferation, or Gleason's score. Nor did intratumoral MVD correlate with tumor cell proliferation. In comparison, the mean MVD and endothelial cell proliferation rates in granulation tissue were 199 and 6.50%, respectively, the latter 43-fold greater than the mean intratumoral endothelial cell proliferation index (p = 0.00023). CONCLUSIONS: Endothelial cells are actively proliferating in prostatic carcinoma, and their proliferation appears independent of intratumoral MVD and tumor cell proliferation. Yet, the relatively low intratumoral hyperplasia, suggests that endothelial cell migration and capillary remodeling play an important role in neovascularization of prostatic carcinoma, especially when compared with granulation tissue, which showed a 43-fold greater endothelial cell proliferation index. Moreover, the lack of correlation of intratumoral endothelial cell proliferation and intratumoral MVD with tumor cell proliferation suggests that tumor angiogenesis and tumor-cell proliferation are regulated by different mechanisms.
Cell Division↗
Demonstration and characterization of the angiogenic properties of cervical dysplasia.
Cervical dysplasia, or cervical intraepithelial neoplasia (CIN), is a premalignant precursor to cervical cancer. This study was designed to determine whether dysplastic lesions are angiogenic. Tissue sections from 23 surgical specimens were immunohistochemically stained for factor VIII antigen, a marker for endothelial cells. The results demonstrate that a region of neovascularization develops along the basement membrane subtending dysplastic epithelium when compared to adjacent normal epithelium. Comparison of microvessel counts underlying low grade lesions (condyloma and CIN I) with microvessel counts of CIN III lesions shows a statistically significant increase in the more advanced lesions. In a subset of the high grade lesions, large vascular structures are also noted in the upper layers of the epithelium, suggesting that a second stage of neovascularization consists of extension of stromal vascular papillae into the dysplastic lesions toward the surface of the epithelium. There is no statistical correlation between the amount of inflammation and the angiogenic ratio for each lesion, implying that angiogenesis is not secondary to the inflammatory response evoked by the lesion. The human papillomavirus type present in four CIN III lesions was determined by in situ hybridization; the amount of angiogenesis appears to be independent of the human papillomavirus type.
Epithelium↗
A multiparametric study on the prognostic value of epidermal growth factor receptor in operable breast carcinoma.
Epidermal growth factor receptor (EGFR) is a potentially useful new biological prognostic and predictive indicator in human breast cancer. Additional research on EGFR is warranted to enhance our information on: i) the method of choice for its detection and quality control issues; ii) its association with novel pathobiological markers of prognosis; iii) its prognostic value in multivariate analysis; and iv) its capability to predict response to hormone therapy and, in the future, to biological treatments using antibodies against the specific receptor or its ligands. In the present study we update previous data on EGFR status, determined immunocytochemically, by prolonging the period of observation up to 5 years and by including, in the multivariate analysis, several new biological indicators. The main results obtained are: i) EGFR is weakly associated with Ki-67 score (p = 0.073) and with p53 expression (p = 0.06); ii) EGFR is a significant indicator for recurrence (p < 0.01 and odds ratio of 2.82) but not for death (p = 0.27 and odds ratio of 1.49); iii) the prognostic power of EGFR is enhanced when combined with the knowledge of S-phase fraction; and iv) in multivariate analysis on relapse-free survival, EGFR and S-phase fraction (likelihood ratio test = 26.40; p < 0.01), c-erB-2 protein and p53 mutant protein expression (likelihood ratio test = 5.94; p = 0.05), cathepsin D (likelihood ratio test = 9.78; p < 0.01), and nodal status (likelihood ratio test = 7.32: p < 0.01) are significant and independent prognostic factors in early-stage breast carcinoma. This new information could be of help for a more rational approach in the use of EGFR as a marker in future clinical research.
Age Factors↗
Determination of epidermal growth factor receptor provides additional prognostic information to measuring tumor angiogenesis in breast carcinoma patients.
Recent studies have shown that women with invasive breast carcinoma having high microvessel density (MVD) (a measure of tumor angiogenesis) or epidermal growth factor receptor (EGFR) expression have increased risk for metastasis and/or decreased survival. To determine if MVD and EGFR expression provide additive prognostic information, we analyzed these two prognostic indicators in the primary invasive breast carcinomas from 165 consecutive patients, who were followed for a median of 51 months. Univariate analysis showed a highly significant (p < 0.001) association of MVD with overall and relapse-free survival in all patients, including both node-negative and node-positive groups (see JNCI 84:1875-1887, 1992). For EGFR, although univariate analysis suggested that women with tumors showing EGFR expression relapsed earlier and, perhaps, died earlier, the differences were not statistically significant. Multivariate analysis, in contrast, revealed that determination of EGFR did provide significant additional information to that already provided by MVD for predicting relapse-free survival in all women (p = 0.001) and in the subset of node-positive women (p = 0.007). Among node-negative women, however, the contribution of EGFR expression in predicting relapse-free survival was not significant (p = 0.12). Likewise, EGFR measurement did not provide significant additional information beyond that of MVD alone for predicting overall survival. Thus, EGFR provides additional prognostic information to determination of MVD, but only for relapse-free survival in node-positive women with invasive breast carcinoma.
Adult↗
Correlation of Ki-67 antigen expression with mitotic figure index and tumor grade in breast carcinomas using the novel "paraffin"-reactive MIB1 antibody.
Tumor proliferation is inversely associated with survival in patients with breast carcinoma. Although the proliferation marker Ki-67 antigen correlates with mitotic figure count (MFC) in breast carcinoma (number of mitotic figures per high-powered field), the more precise association of Ki-67 antigen expression with mitotic figure index (MFI) (number of mitotic figures per tumor cells) and histologic grade remains incompletely defined, especially when using the new "paraffin"-reactive monoclonal antibody MIBI to mark the Ki-67 antigen. To determine the association of Ki-67 antigen expression with mitotic figure content we immunostained 50 formalin-fixed, paraffin-embedded breast carcinomas with the MIB1 monoclonal antibody and correlated the results with MFC, MFI, and Scarff-Bloom-Richardson grade. The Ki-67 antigen-labeling index (K67LI) was the number of MIBI-positive cells/1,000 tumor cells, the MFI was the number of mitotic figures/1,000 tumor cells, and the MFC was the number of mitotic figures/10 high-powered fields. The K67LI correlated highly with the MFI (r = .76, P < .0001), MFC (r = .78, P < .0001), and Scarff-Bloom-Richardson grade (r = .73, P < .0001). In addition, analysis of variance showed that MFI was more precise than MFC in estimating K67LI and thus a more repeatable measure of tumor proliferation. Moreover, measurements made by MFI were as precise as those made by K67LI. Therefore, the correlation of K67LI with mitotic figure content was strong enough to suggest that a very carefully measured MFI provides an estimate of tumor growth fraction equivalent to the K67LI. However, which method is optimal for estimating tumor proliferation rate remains unclear.
Adenocarcinoma↗
Tumor angiogenesis, the p53 antigen, and cervical metastasis in squamous carcinoma of the tongue.
A more accurate method of detecting nodal disease in squamous cell carcinoma of the tongue is needed so that treatment of the neck with its associated morbidity can safely be reserved for patients who actually have metastatic disease. Tumor angiogenesis and the expression of the p53 antigen--which have each been shown to be predictive of metastasis in breast and colon cancer, respectively--are examined for their ability to predict neck metastasis in tongue cancer. Fifty-seven patients with T1 and T2 squamous cell carcinoma of the oral tongue, whose neck disease was examined by dissection or by 2-year follow-up, were studied. Twenty-eight patients (49%) were node positive and 29 patients (51%) were node negative. The primary tumors were immunohistochemically stained for the p53 antigen and for factor VIII, which allowed the blood vessels within the tumor to be quantitated. The mean vessel counts per x200 high-power field were 59.8 and 61.5 for node-positive and node-negative patients, respectively (p = 0.8). Node-positive patients showed overexpression of p53 43% of the time, vs. 61% for node-negative patients (p = 0.17). Multivariate analysis confirmed that no difference in tumor angiogenesis or the expression of the p53 antigen was found between tumors that had metastasized and those that had not. Therefore neither tumor angiogenesis nor the p53 tumor marker is clinically useful in determining lymph node metastasis in these patients.
Carcinoma, Squamous Cell↗
Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma.
PURPOSE: To determine the absolute and relative value of microvessel density (MVD), p53 and c-erbB-2 protein expression, peritumoral lymphatic vessel invasion (PLVI), and conventional prognosticators in predicting relapse-free (RFS) and overall survival (OS) rates in patients with node-negative breast carcinoma (NNBC). PATIENTS AND METHODS: We monitored 254 consecutive patients with NNBC for a median of 62 months. Intratumoral MVD was measured after microvessels were immunostained using anti-CD31 antibody. p53 and c-erbB-2 protein and hormone receptors were also determined immunocytochemically. Results were analyzed by both univariate and multivariate statistical analysis. RESULTS: Univariate analysis showed that MVD was significantly predictive of both RFS (odds ratio [OR], 8.30; P = .0001) and OS (OR, 4.50; P = .012) when tested as a continuous or dichotomous variable. Likewise, tumor size (OR, 3.16; P = .0012), PLVI (OR, 4.36; P = .0009), estrogen receptor (ER) status (OR, 2.35; P = .016), progesterone receptor (PR) status (OR, 2.00; P = .017), and expression of p53 protein (OR, 2.82; P = .004) were significantly associated with RFS. Tumor size (OR, 3.80; P = .0038) and expression of p53 protein (OR, 2.58; P = .024) were significantly associated with OS by univariate analysis. Multivariate analysis showed that MVD (P = .0004), p53 protein expression (P = .0063), tumor size (P = .0144), and PLVI (P = .0033) were all significant and independent prognostic factors for RFS. However, only tumor size (P = .004) and MVD (P = .047) were independent predictors for OS. c-erbB2 expression was not associated with outcome by either univariate or multivariate analysis. CONCLUSION: MVD, p53 expression, PLVI, and tumor size are independent prognostic indicators of recurrence, which are useful in selection of high-risk NNBC patients who may be eligible to receive adjuvant therapies.
Adult↗
Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma.
Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related tumors, and it can be difficult to distinguish them from other small-round-cell tumors (SRCTs). The glycoprotein p30/32MIC2 is highly, but not exclusively, expressed in both ES and PN. Although the monoclonal antibody (Mab) HBA71, which reacts with P30/32MIC2, has been reported to be relatively specific and highly sensitive for both neoplasms, it is not readily available. Yet, Mab O13 is commercially available, and it purportedly displays the same immunostaining characteristics as HBA71. Because O13 has not been studied extensively, we immunostained 21 ES/PNs and 147 other tumors or lesions that might show SRCT-like features with O13. The results were similar to those reported for HBA71. We found O13 to be 100% sensitive for ES/PN; and, no immunostaining was noted on the SRCTs often included in the differential diagnosis of ES/PN (i.e., conventional neuroblastoma, rhabdomyosarcoma, and non-lymphoblastic lymphomas). But, O13 immunoreacted with lymphoblastic lymphomas and some other tumors and normal tissues. Nonetheless, this nonspecific reactivity should not cause diagnostic problems, if an antibody panel containing anti-desmin and anti-leukocyte common antigen is used in conjunction with O13. We conclude that, within the proper diagnostic context, strong immunoreactivity of a SRCT tumor for O13 should be considered good evidence that the tumor is ES/PN.
12E7 Antigen↗
Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma.
Tumor angiogenesis is essential for tumor growth and metastasis, and intratumoral microvessel density correlates with prognosis in breast carcinoma. Yet, how intratumoral microvessel density correlates with tumor cell and intratumoral endothelial cell proliferation remains incompletely understood. To this end, we stained 57 formalin-fixed, paraffin-embedded breast carcinomas with antibody MIB1 to determine tumor cell Ki67 labeling index and with anti-CD34 to observe microvessels. We correlated the tumor cell Ki67 labeling index and mitotic figure index with intratumoral microvessel density. Using a double labeling technique combining antibody MIB1 and anti-CD34, we measured intratumoral endothelial cell proliferation in 20 of these cases and correlated these findings with tumor cell Ki67 labeling index, mitotic figure index, and intratumoral microvessel density. The intratumoral Ki67-labeling index was 45-fold greater (P < 0.000001) than that of microvessels in adjacent benign breast. Yet, endothelial cell Ki67 labeling index did not correlate with intratumoral microvessel density, tumor cell Ki67 labeling index, or mitotic figure index nor did intratumoral microvessel density correlate with tumor cell Ki67 labeling index or mitotic figure index. These findings suggest that, although endothelial cells are actively proliferating within the tumor, intratumoral microvessel density and intratumoral endothelial cell proliferation are independent of each other and of tumor cell proliferation. Thus, intratumoral microvessel density, endothelial cell proliferation, and tumor cell proliferation may be regulated by separate mechanisms.
Antigens, CD↗
Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma.
Squamous-cell carcinoma of the head and neck includes a heterogeneous group of tumours of the upper air and food passages for which prognosis is difficult to assess. In fact, patients in comparable stages may have diverse clinical courses and responses to similar treatments. In order to better define the prognosis of each patient there is therefore a need to identify novel biological markers which reflect more accurately growth rate, progression and metastatic potential of each tumour. We assessed whether metastases correlate with microvessel counts (i.e. intratumoral vascularity) using the CD-31 monoclonal antibody (MAb) and p53 mutant protein expression, determined in the primary by immunocytochemical methods in 70 patients with locally advanced head and neck cancer. Patients were treated with concurrent chemo-radiotherapy; 50 of these presented loco-regional node metastasis at diagnosis whereas 3 cases, initially node-negative, developed distant metastasis during the period of observation. No feature was predictive for objective response to treatment. The overall mean and median blood vessel density at "hot spots" was 37.42 and 36, respectively, and 57% of the tumours expressed p53 mutant proteins. These 2 biological markers were significantly associated. Patients with metastases (loco-regional and distant) had a significantly higher mean blood-vessel density than those without tumour spread. Also, patients with p53-positive (+/++) tumours had a significantly higher incidence of metastasis than those with negative ones. Multivariate analysis showed that both vascularity and stage, but not p53 expression, are significant and independent predictors of metastasis in this series.
Adult↗
Heterogeneity of mast cells at multiple body sites. Fluorescent determination of avidin binding and immunofluorescent determination of chymase, tryptase, and carboxypeptidase content.
Human mast cells (MCs) from multiple sites were studied to determine heterogeneity of expression of chymase, tryptase, and/or carboxypeptidase and the binding to avidin. Three immunophenotypes were found: MCs positive for tryptase (MCT), no immunodetectable chymase; MCs positive for tryptase and chymase (MCTC); and MCs positive for chymase (MCC), no immunodetectable tryptase. Chymase-positive MCs also bound avidin and contained carboxypeptidase. In breast skin and parenchyma and axillary lymph nodes > 95% were MCTC; a rare MC in skin and lymph nodes was MCT or MCC. In lung alveoli 91% of MCs were MCT, 8% were MCTC and 1% MCC. In bowel mucosa 58% of MCs were MCT, 35% were MCTC and 7% MCC, whereas in bowel submucosa 83% of MCs were MCTC and 17% MCC. Within esophageal epithelium 38% were MCT and 62% MCTC; whereas, in esophageal subepithelium all were MCTC. This study further documents site-dependent diversity among normal human MCs and recognizes a novel third immunophenotype rich in chymase and relatively deficient in tryptase, the MCC cell.
Avidin↗
Pure squamous cell carcinoma of the larynx with cervical nodal metastasis showing rhabdomyosarcomatous differentiation. Clinical, pathologic, and immunohistochemical study of a unique example of divergent differentiation.
We describe a unique case of pure squamous carcinoma of the larynx that developed a cervical lymph node metastasis showing rhabdomyosarcoma admixed with squamous carcinoma (that is, carcinosarcoma). The rhabdomyosarcoma showed foci immunoreactive to multiple cytokeratin monoclonal antibodies, as well as to markers for striated muscle, thus indicating true divergent epithelial and rhabdomyosarcomatous differentiation. Although the morphogenesis of carcinosarcomas remains controversial, the sequence of events for the current case favors sarcomatous transformation of the original carcinoma (that is, sarcomatous neometaplasia of the primary carcinoma clone). The possible contributory role of radiation therapy in this case in inducing such a change is noted.
Aged↗
Correlation of bromodeoxyuridine (BRDU) labeling of breast carcinoma cells with mitotic figure content and tumor grade.
Tumor proliferation is inversely associated with survival in patients with breast carcinoma. Labeling of tumor cells with bromodeoxyuridine (BRDU) correlates highly with that seen with [3H]thymidine, the current "gold standard" for measuring tumor S-phase. However, the relationship of BRDU labeling to mitotic figure content and tumor grade remains incompletely defined. To determine this, we labeled 55 breast carcinomas with BRDU in vivo and correlated the results with mitotic figure content. The BRDU labeling index was the number of BRDU-positive cells/2,000 tumor cells, the mitotic figure index was the number of mitotic figures per 1,000 tumor cells, and the mitotic figure count was the number of mitotic figures per 10 high-powered fields. BRDU labeling was also correlated with tumor grade (Scarff-Bloom-Richardson). The BRDU labeling index correlated highly with the mitotic figure index (r = 0.814, p = 7.0 x 10(-14)), mitotic figure count (r = 0.725, p = 6.0 x 10(-10)), and tumor grade (r = 0.68, p = 1.1 x 10(-8)). The correlation of BRDU labeling with mitotic figure content was strong enough to suggest that a very carefully measured mitotic figure index provides an estimate of tumor growth fraction equivalent to the BRDU labeling index. Also, analysis of variance showed that the mitotic figure index was twice as precise as the mitotic figure count in estimating BRDU labeling, and thus was a more accurate measure of tumor proliferation. Moreover, measurements made by the mitotic figure index were as precise as those made by BRDU labeling. However, which method is optimal for estimating tumor proliferation rate remains unclear. Further studies are indicated.
Adult↗