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Small integrin-binding ligand N-linked glycoproteins (SIBLINGs) constitute a family of extracellular matrix proteins involved in bone homeostasis. Their pattern of expression has been primarily reported in bone and tooth and, more recently, in several cancer types. Dentin matrix protein 1 (DMP1), a SIBLING family member, expression was investigated by immunohistochemistry in a retrospective series of 148 primary human breast cancers. Correlations between DMP1 expression levels in the tumors and clinicopathologic features, bone metastases development and relapse of the disease were examined. DMP1 was expressed by 63.5% of the breast tumors analyzed. Significant inverse associations were found between DMP1 expression levels and the size and grade of the tumors (both, P < 0.0001). High DMP1 expression levels in the primary breast lesions were associated with a lower risk of subsequent development of skeletal metastases (P = 0.009). Patients with tumors expressing high levels of DMP1 had a significantly higher disease-free survival rate than those with low DMP1-expressing tumors (P = 0.0062). When DMP1 expression was examined in breast cancer cell lines, we found that non invasive MCF-7 and T47-D cells expressed higher levels than highly invasive MDA-MB-231 and Hs578T cells. Moreover, the specific inhibition of DMP1 expression in MCF-7 cells using siRNAs promoted significantly their migratory capability. Our data implicate for the first time DMP1 expression in breast cancer progression and bone metastases development.

Purpose: Tumors with p53 overexpression have been associated with enhanced resistance to cisplatin-based chemotherapy in a few and small studies involving non-small cell lung cancer. The relationships and interactions between p53, Rb and bcl-2 immunostaining, clinical parameters and response to cisplatin-based chemotherapy were evaluated in the present study. Experimental design: Histological specimens obtained by bronchial or fine-needle biopsy from patients who underwent cisplatin-based chemotherapy between 1992 and 1999 were evaluated by immunostaining. Results: There were 102 patients, 88 men. Median age was 63 years; 47 had stage III and 55 stage IV disease. Forty-six tumor samples (45%) had positive immunostaining for p53, 61 (59%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for bcl-2. The response rate of the group with p53 positive immunostaining was 26% versus 57% of the p53 negative group ( P =0.004). In multivariate analyses p53 positive immunostaining was identified as an independent predictive factor for resistance to cisplatin-based chemotherapy ( P =0.006). Conclusions: Our study confirmed an association of p53 immunostaining and response rate of patients treated with cisplatin-based chemotherapy.

DNA ploidy image analysis in breast carcinomas has occasionally revealed cases with a diploid DNA content but with a single hypertetraploid element, the so-called single cell aneuploidy (SCA). To identify the biologic significance of this little known phenomenon, we selected 40 cases with SCA from a series of 599 consecutive operable breast carcinomas. The clinical, pathological and biological characteristics of SCA cases were compared with those of a control group of 40 pure diploid breast carcinomas. Hormonal receptor status, proliferative indexes (Ki-67) and p53 overexpression were determined immunohistochemically and quantitatively evaluated by image analysis. The overexpression of c-erbB-2 was determined semiquantitatively. SCA was observed in 6.6% of cases (40 of 599) and in 17% of otherwise diploid cases (40 of 236). Breast cancers with SCA occur in younger women (mean age 54.75 y vs 61.12 y, P

We present a case of multiple amyloidomas occurring in the calves of a 61-year-old woman, without systemic amyloidosis or plasma cell dyscrasia. The disappearance of Congo red positivity after potassium permanganate treatment and immunohistochemical results showed that this was a case of reactive AA amyloidosis. True soft tissue amyloidomas are extremely rare, and this is the first case of AA amyloidoma in the soft tissues of the legs.

Aims and background Giant cell tumor of tendon sheath (GCTTS) is a common tumor occurring on the tendon sheaths of the fingers. The nature of this lesion is still controversial: some researchers consider it a reactive process arising from chronic inflammation while others regard it as a tumor of presumed synovial cell or monocytic macrophage system origin. In an effort to clarify the histogenesis we decided to further investigate the immunophenotypic profile of this tumor. Study design We studied 20 GCTTS of the fingers using a panel of 18 antibodies, 13 monoclonal and 5 polyclonal. Results The immunohistochemical investigation revealed that the mononuclear cells of this lesion can be divided into two groups. The cells of the first and more numerous group were positive for vimentin, PG-M1 and KP1 but also for muscle actin (HHF35 monoclonal antibody) and neuron-specific enolase. A second population of mononuclear cells, usually arranged around the giant cells, were positive for PG-M1, KP1, LCA and occasionally for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Multinucleated giant cells were also positive for KP1, PG-M1 and LCA monoclonal antibodies. A variable but usually weak positivity for al-pha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme was also observed. Conclusions Our results suggest a synovial cell origin for GCTTS and do not support the hypothesis that it could be a neoplasm with a true histiocytic origin. The positivity of some cells for the HHF35 antibody, together with electron microscopic evidence of filament bundles with focal dense bodies, suggests that at least part of the mononuclear cells may have a myofibroblastic differentiation.

Cutaneous cysts lined by ciliated epithelium are very rare, benign tumors predominantly occurring on the lower extremities of young women. We describe a ciliated cyst found in the perineum of a 60-year-old man. The location and histological features led us to attribute a primitive tailgut origin to this cyst, probably from the embryonic remnants of cloacal membrane. Only two previous examples of similar cysts were found in the literature.

Image cytometric analysis of DNA ploidy status of 40 fresh primary breast carcinomas was performed in a comparative study on cytologic preparations stained directly by the Feulgen method and smears from the same tumors Feulgen-stained after Papanicolaou staining. There was a 0.82 overall concordance in diploid and aneuploid tumor classification and a good correlation (r = 0.736, P < 0.001) between the DNA indices determined by the two methods. Discordances are probably due to tumor heterogeneity. This study demonstrates that image cytometric DNA analysis on previously routine-stained cytologic preparations is feasible and reliable for pretreatment DNA analysis and suggests potential applications in retrospective studies with cytologic material from archives.

Summary We describe a case of spontaneous dissecting aneurysm of the circumflex coronary artery in a 44-year-old primigravida at term with no vascular risk factors. Spontaneous coronary artery dissection is a very rare condition with a greater prevalence in women, postpartum in particular. The left anterior descending artery is the most frequently affected. Histologically, the most common finding is a hematoma occupying the outer third of the media, resulting in complete compression of the true lumen. Arterial wall changes during pregnancy together with hemodynamic factors, a lytic action of protease released from eosinophils, and intimal tears are the main hypotheses considered to explain the etiology of spontaneous coronary artery dissection.

The assessment of HER-2/neu status is a prerequisite in the clinical management of patients with breast cancer in order to obtain prognostic and predictive information, including Herceptin sensitivity. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are the techniques recommended to detect HER-2/neu alterations and considerable attention is currently being focused on the standardization of these techniques. Intrinsic limitations of IHC, such as antigen preservation and antibody specificity, may make it difficult to score the membrane staining thereby resulting in inconclusive results.In this study, 65 invasive breast carcinomas, with doubtful IHC results using the monoclonal antibody CB11, were reanalyzed with two recently licensed assays, the Hercep Test (IHC) and the Path Vision (FISH).IHC with Hercep Test detected HER-2 protein overexpression in 72% of cases, including nine (14%) strongly positive (3+), 13 (20%) medium positive (2+) and 25 (38%) weakly positive (1+) specimens. FISH testing, with interpretable results in 48 cases, showed a moderate HER-2 gene amplification in only 22% of carcinomas with 2+ or 3+ overexpression.These data indicated an excessive sensitivity of the Hercep Test and suggested that, in the case of indeterminate results after standard IHC, the FISH technique is the best approach to establish HER-2 status.

Background HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. Patients and Methods HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest®. Results Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest® was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. Conclusion HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

For breast cancer management biopathologic profile and particularly the expression of estrogen receptor (ER) and progesterone receptor (PR) is considered essential. In advanced cases, core biopsy results are the only data available. To evaluate reliability of data, results of ER, PR, MIB1, p53 and c-erbB2 on core biopsy were compared with those on surgical specimens. Results showed a statistically significant concordance for ER and PR in pT1 but not in pT2 tumors, possibly due to breast cancer heterogeneity. MIB1 results were worse with no significant concordance even for pT1 group. There was statistically significant concordance in pT1 and pT2 groups for p53 and c-erbB 2, probably due to the high number of negative cases for these markers. We recommend more core biopsies for larger tumors since core biopsy has a high probability for giving unreliable data in these cases. In conclusion, this study showed that core biopsy has a high probability for not very reliable data in bigger tumors where the results obtained might be the only data available. A higher number of core biopsy is recommended in those cases.

Primary cutaneous leiomyosarcomas are rare tumors, few series being reported in the current literature. A retrospective study of 7 cases was undertaken to understand the clinicopathological characteristics of these neoplasms and some of their molecular mutations. Histologically, a well-differentiated proliferation of cells of smooth muscle derivation was evident in all cases. The number of mitoses was considered the most important criterion of malignancy (more than 2 for 10 HPF). Smooth muscle actin, desmin, and vimentin were positive in all cases. Immunohistochemical analysis also revealed a positivity for p53 in 3 cases and no reaction for retinoblastoma protein. Research for Epstein-Barr virus was negative in all cases. Three patients developed local recurrences owing to incomplete surgical excision. Recurrent tumors were more atypical and located deeper. No distant metastases were observed. Our results emphasize that cutaneous leiomyosarcomas have an indolent biological course if treated by surgical excision with wide margins. Molecular abnormalities involving tumor suppressor genes are probably involved.

The search for single independent prognostic factors in breast cancer has often produced conflicting results. Therefore, prognostic indexes have been compiled by combining several parameters. In this study we compare the Nottingham Prognostic Index (NPI), which is based on traditional prognostic factors (diameter of the neoplasm, lymph node status and histological grade) with the Adelaide Prognostic Index (API), which is based on the tumour diameter and two biological parameters: oestrogen receptors and cell kinetics. We considered 82 cases of breast cancer observed over the period 1987-1990 with a minimum follow-up of 60 months. The NPI gives a better definition of the prognostic profile for each patient. Our results indicate three prognostic groups (good, moderate, unfavourable), which differ with respect to disease-free survival (DFS; P=0.0024) and overall survival (OS; P=0.0033). In contrast, the API scores showed no significant correlation with OS or DFS. The use of prognostic indexes, especially when compiled using traditional parameters, is a useful aid to the clinician, since they can provide a reliable indication of how individual tumours will evolve.

The aim of this study was to evaluate the impact of Bcl-2, retinoblastoma (Rb) and p53 proteins on overall survival of 102 patients with locally advanced and metastatic NSCLC who underwent cisplatin-based chemotherapy.Paraffin-embedded bronchial biopsy and fine-needle biopsy specimens were evaluated by an immunostaining method.Median age of analyzed patients was 61 years. Male/female ratio was 88/14. There were 10 (10%) patients with stage IIIA, 37 (36%) with stage IIIB and 55 (54%) with stage IV NSCLC. Only 15 (15%) tumor specimens had no detectable alterations for analyzed factors. Forty-six samples (45%) had positive immunostaining for p53, 61 (60%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for Bcl-2. Median and 5-year survival of analyzed population was 12 months and 6%, respectively. In univariate analysis Bcl-2 overexpression, stage (III versus IV) and normal lactate dehydrogenase (LDH) serum levels were associated with better overall survival (P0.02, 0.001 and 0.03). In multivariate analysis, only stage was identified as an independent predictive factor.High frequency of Rb and Bcl-2 loss was detected in patients with advanced NSCLC. P53, Rb and Bcl-2 have not been shown to be independent predictors of survival even if Bcl-2 might have a particular relevance in patients with advanced NSCLC and should be better explored in this setting.

In this study, we retrospectively evaluated the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in 228 and 213 specimens, respectively, from stages I and II breast cancer patients (pts) enrolled in a randomized phase III adjuvant chemotherapy trial comparing epirubicin to CMF, while tamoxifen was given to all postmenopausal pts. The expression of VEGF and MVD was assessed on tissue sections formalin-fixed and paraffin-embedded by immunohistochemical staining using anti-VEGF antibody of human origin and anti-CD34 monoclonal antibody. Univariate and multivariate analysis were performed using chi squared test, log-rank test and Cox's regression model. Sixty four of 228 pts were classified as VEGF positive (28%) with no significant difference in the two treatment arms. In 213 pts evaluated for CD34, 103 pts (48%) were classified as MVD high. No significant association between VEGF and MVD was found, and neither were they correlated with many known prognostic factors such as age, tumor size, nodal status, and histological grade. The only significant correlations observed were between VEGF and estrogen receptor (ER) status (p = 0.013) and between MVD and HER2 overexpression (p = 0.023). At a median follow up of 96 months VEGF and MVD were not correlated with relapse-free survival (RFS) and overall survival (OS) in all pts and in pts assigned to one of the two treatment arms. In conclusion, VEGF and MVD retrospectively evaluated, cannot be considered prognostic factors in node negative (N−) high risk and node positive (N+) breast cancer pts treated with two different regimens of adjuvant chemotherapy.

Background and Objectives: The different and unpredictable outcomes in early-stage non-small cell lung cancer patients requires urgent research concerning the biological pathway of this neoplasm. Our study investigated the frequency of expression and the clinicopathologic and prognostic significance of a series of biological markers in stage I and II resected non-small cell lung cancer. Methods: A total of 99 cases of pathologic stage I and II were analyzed. The mean follow-up of surviving patients was 41 months. The expressions of the following biological markers were tested: bcl-2, p53, Ki-67, angiogenesis, and tumor vessel invasion. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biological markers using Cox's model for multivariate analysis. Results: Tumoral vessel invasion was present in 22 (22%) pathologic samples, the angiogenesis mean value was 37 ± 13, and median was 35; 13 (13%) patients showed positive immunostaining for bcl-2 oncoprotein. P53 oncoprotein expression was present in 48 patients (48.5%). All samples presented Ki-67 expression (mean value = 25.3 ± 19.3, median = 20). The pathologic staging of the tumor was the most important independent prognostic factor for survival (P = 0.037) and for recurrence of disease (P = 0.040). Tumoral vessel invasion was the only marker with an independent predictive factor for survival and recurrence of disease in the group of patients without lymph node involvement (P = 0.02). Conclusion: Our data do not support a relevant prognostic role for p53, bcl-2, or Ki-67 immunohistochemical markers in non-small cell cancer. Tumor vessel invasion was an independent predictive factor of poor outcome in the group of patients without lymph node involvement. Pathological stage was confirmed as the most important independent prognostic factor.

BACKGROUND Due to the widespread use of fine needle aspirate biopsy the practice of determining estrogen (ER) and progesterone (PR) receptors in breast carcinoma from cytological smears (CS) is becoming very common. The aim of this study was to determine concordance between ER and PR assessed by immunocytochemical assay (ICA) on CS and FS both evaluated by image analysis since we have found no data in literature on this. METHODS 104 breast carcinoma cases were selected. For all cases ER and PR determination was performed on CS, obtained by light scraping of the freshly cut surface of the excised surgical tumors at the time of frozen section diagnosis, and FS using the same monoclonal antibodies. Computer-assisted image analysis was performed in all cases using CAS 200. Results were expressed as percent positive area of neoplastic nuclei compared with total nuclear area of the examined neoplastic cells. RESULTS Good correlation was demonstrated between percent positive nuclear neoplastic area by ER-ICA on CS and FS (r = 0.759; P < 0.0001). Concordance of results was 90.19% (P < 0.001). Good correlation was also demonstrated between percent positive nuclear neoplastic area by PR-ICA in CS and FS (r = 0.889; P < 0. 0001). Concordance of results was 97.02% (P < 0.0001). CONCLUSIONS Our data suggest that ICA on CS with automated image analysis is efficient in evaluating ER and PR content in human breast cancer, especially when CS is the only method pathologists have to evaluate receptor status e.g. in advanced breast cancer cases when neoadjuvant therapy is necessary before surgery or when surgery is impossible.

BACKGROUND A strong positive correlation exists between the breast cancer tissue content of either urokinase-plasminogen activator (uPA) or plasminogen activator inhibitor type 1 (PAI-1), quantified in the tissue extracts by immunoassays, and the survival of patients with breast cancer. Furthermore, several studies assign to the urokinase-type plasminogen activator receptor (uPAR) a pivotal role in triggering the proteolytic activity of the urokinase pathway involved in tumor stroma degradation, tumor spread and metastasis. However, the pattern of distribution of uPAR in normal and cancerous human tissue and the pattern of coexpression of activators and inhibitors that occurs in breast cancer tissues is not completely known. METHODS The immunohistochemical localization of uPAR, uPA, tPA) and PAI-1 was evaluated by using the avidin-biotin immunoperoxidase technique and affinity-purified monoclonal antibodies from American Diagnostica Inc. Studies were performed in formalin fixed, paraffin-embedded tissue prepared from 23 surgically excised non-neoplastic breast tissues and 18 ductal breast carcinomas. RESULTS While the expression of uPAR protein represents a constant feature of invasive ductal breast cancer, it was also observed in most of the breast tissue samples, including the normal breast tissues. The staining for uPAR was mainly localized on normal or tumoral epithelial cells, even if the co-expression of uPAR in stromal cells was frequently observed in adjacent slides. A semiquantitative analysis of immunohistochemical results showed that uPAR and PAI-1 were overexpressed in invasive breast cancer in comparison with normal and benign breast tissues. In addition, uPA was higher in both invasive breast carcinomas and benign breast lesions with respect to normal breast tissues. CONCLUSIONS We showed that overexpression of uPAR, uPA, and its main inhibitor, PAI-1, is a constant feature of invasive ductal breast carcinomas. However, the expression of the above fibrinolytic reactants is not specific for breast cancer since positive staining for these molecules was frequently observed in benign breast lesions as well as in normal breast tissues. The combined increased expression of uPA and its cellular receptor, uPAR on the surface of tumor epithelial cells may account for the activation of the proteolytic system which occurs in breast cancer. Cancer 1996;77:1079-88.

Two cases of intralobular carcinoma of the breast showing myoepithelial cell differentiation are reported. One was an in situ lesion localized within a fibroadenoma; the second was predominantly in situ, but areas of invasion were present. The neoplastic cells had round to ovoid nuclei and were polygonal to spindle in shape displaying glycogen rich clear cytoplasm. Alpha-smooth muscle actin was present in the cytoplasm of the neoplastic cells in both cases. In one case the same cells displayed cytoplasmic microfilaments at electron microscopic level. Intralobular growth of neoplastic myoepithelial cells has never been described in the literature, and this line of differentiation has to be added to the endocrine and apocrine features occasionally observed in in situ lobular carcinomas of the breast.

Prognosis for locoregionally advanced NSCLC patients is poor. Five year survival rates of less than 10 % are reported for patients with mediastinal lymph-node involvement [1]. Efforts to improve this poor prognosis have recently focused on multiple therapeutic modalities including neo-adjuvant chemotherapy [2–6] and give the best reproducible response rates. Since 1988 a phase II trial of this neo-adjuvant chemotherapy combination has been used in patients with clinically apparent N2 to assess response rate, complete resection by surgery and the feasibility of combined treatment.

We describe a case of leiomyoma in the breast in a 48-year-old woman. The main clinical–pathologic features together with the differential diagnosis, and the pertinent literature reviewed.

A case of bilateral primary malignant lymphoma of the breast in a 30 year old woman is described. The tumors were first discovered during a self-examination of the breast at the 7th month of pregnancy. Thereafter they rapidly increased in size. The patient underwent simple bilateral mastectomy, and histological examination revealed a centroblastic/centro-cytic lymphoma. The patient is alive and well 9 months after mastectomy.

A case is reported of undifferentiated metastatic lung carcinoma in which both a supraclavicular lymph node and bone marrow were infiltrated by anaplastic tumor cells which had engulfed erythrocytes and nucleated elements. The possibility of a histiocytic origin for the phagocytizing neoplastic cells was excluded by ultrastructural, cytochemical, and immunoperoxidase studies. This investigation shows that epithelial tumor cells may, at times, develop phagocytizing activity, a phenomenon observed in certain experimentally induced tumors. The mechanism responsible for this phenomenon is not clear.

Male and female noninbred Sprague-Dawley rats 30-36 days of age were given single iv injections of 10 or 5 mg adriamycin (Ad)/kg or 10 mg daunomycin (DM)/kg. Multiple mammary tumors (MT), mostly adenocarcinomas, were observed in 29 and 67% of the females given 10 and 5 mg Ad/kg, respectively, and in 64% of those given 10 mg DM/kg. The mean induction time for females receiving 10 mg Ad/kg was 135 days, for those receiving 5 mg/kg it was 114 days, and for those receiving DM it was only 80 days. Single MT, also mostly adenocarcinomas, were observed an average of 279 days from injection in 31% of the males given 5 mg Ad/kg and an average of 91 days from injection in 37% of the males given 10 mg DM/kg. No tumors were observed in the males given 10 mg Ad/kg, but these survived for only 79 days after treatment.

Aims and Background Amplification/overexpression of HER-2/neu and inactivation of p53 may be reliable parameters for the prognostic assessment of breast carcinomas. Several studies have addressed the prognostic significance of simultaneous expression of these gene abnormalities with controversial results. Methods In this study we analyzed the biopathological profile of 45 breast cancers with both HER-2/neu and p53 overexpression and compared their features with those of 45 randomly selected cases negative for these gene products. Results Tumors with HER-2/neu and p53 coexpression were found in younger patients, were more often multifocal and/or multicentric, were poorly differentiated in 55% of cases and lymph node-positive in 57%, showing a statistically significant difference compared to tumors with neither alteration (11% and 28%, respectively). Moreover, they were prevalently negative for estrogen (71% vs 22%) and progesterone receptors (78% vs 40%) and showed a higher proliferative activity. Conclusions Our data demonstrate that the coexpression of p53 and HER-2/neu is an additive effect in terms of genetic instability reflected by both morphological and biological adverse features; patients with such coexpression should be assigned to specific therapeutic and follow-up protocols.

The presence of cytoplasmic structures, apparently inside the nuclei of neoplastic cells, has been observed repeatedly in the electron microscope (1). These structures, designated "nuclear pseudoinclusions" (1), are the result of cross-sections of cytoplasmic invaginations of the nuclear membrane. Their extranuclear origin is evident, since these structures are surrounded by a well defined, double, nuclear membrane. A situation different from these "nuclear pseudo-inclusions" is reported here.