Multiple brown tumors of the ribs simulating malignancy.

Bone disease associated with primary hyperparathyroidism, known as osteitis fibrosa cystica, is now very rarely encountered, since the parathyroid disorder is most often diagnosed at the early stage of asymptomatic hypercalcemia. Here, we report the case of a patient with multiple pleural-based masses and hypercalcemia, which led to the presumptive diagnosis of malignancy. However, histological and laboratory data were consistent with the development of brown tumors of the ribs due to underlying severe hyperparathyroidism.

Increased expression of the bcl6 and CD10 proteins is associated with increased apoptosis and proliferation in diffuse large B-cell lymphomas.

There is increasing evidence that bcl6 and CD10 expression may be related to apoptosis and cell cycle progression. Therefore, 79 cases of de novo diffuse large B-cell lymphomas were studied for the expression of bcl6 and CD10 proteins in relation to 1) the apoptotic index; 2) the proliferation-associated proteins Ki67, cyclin A, and cyclin B1; and 3) the expression of the bcl2, p53, Rb, p16, and p27 proteins. Expression of bcl6, CD10, and bcl2 proteins was found in 54/79 (68%), 28/79 (35%), and 47/74 (63%) cases, respectively. The bcl6/CD10 patterns were as follows: bcl6+/CD10+ (26 cases, 32%), bcl6+/CD10- (28 cases, 33%), bcl6-/CD10- (23 cases, 31%), and bcl6-/CD10+ (2 cases, 4%). Significant positive correlations were found between bcl6/Ki67 (r =.328, P =.003), bcl6/cyclin A (r =.265, P =.018), bcl6/apoptotic index (r =.327, P =.010), CD10/Ki67 (r =.296, P =.008), and CD10/apoptotic index (r =.397, P =.001). In addition, high expression of bcl6 showed significant correlation with negative (null/low) bcl2 expression (chi(2) test, P =.002). The above findings indicate that increased expression of the bcl6 and CD10 proteins is associated with increased apoptosis and proliferation in diffuse large B-cell lymphomas. The association between increased bcl6 expression and enhanced apoptosis might be due, at least in part, to the null/low bcl2 expression because previous in vitro data showed that bcl6 overexpression induces apoptosis accompanied by bcl2 and bcl-xl downregulation. Moreover, significant correlation was found between increased apoptotic index and the bcl6+/CD10+ pattern (t test: P =.014, Mann-Whitney test: P =.046). This finding and the positive correlation of the apoptotic index with bcl6 and CD10 expression may be related to previous results showing that the expression of these proteins has favorable effects on the clinical outcome of diffuse large B-cell lymphomas.

Near-absolute expression of the bcl-2 protein identifies a subgroup of stage II breast cancer patients with a most favorable outcome. Results of a clinicopathological study.

The clinical relevance of quantitative assessment of tumor-tissue expression of the bcl-2 protein in operated stage II breast cancer was investigated in this study. Thirty-five cases were studied by immunohistochemistry for the expression of bcl-2 protein and analyzed for disease outcome. One fourth (25%) of the cases were negative and 57% demonstrated near-absolute expression of the bcl-2 protein. No association was found between immunohistochemical detection of the protein with age, hormonal receptor status and tumor grading other than between bcl-2 and estrogen receptor expression (p=0.01). An impressively positive impact of near-absolute expression of bcl-2 on clinical outcome was identified. Our results provide evidence that quantitative assessment of bcl-2 expression constitutes a new approach in early breast cancer with potential clinical implications. We consider that molecular sub-staging of patients with stage II breast cancer by level of bcl-2 expression provides additional important prognostic information and prompts for investigation of its clinical significance on the issue of adjuvant systemic therapy.

In vivo cell kinetics in breast carcinogenesis.

BACKGROUND: Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumours. In the present study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyperplasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. MATERIALS AND METHODS: A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case were analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TdT-mediated dUTP-nick end-labelling (TUNEL) and Ki-67-positive cells, respectively. The PI/AI (P/A index) was calculated for each case. RESULTS: The AIs and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypical hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P < 0.001 and P < 0.001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04) whereas it was decreased (non-significantly) from hyperplasia to preinvasive lesions. A strong positive correlation between the AIs and the PIs was found (r = 0.83, P < 0.001). CONCLUSION: These findings suggest accelerating cell turnover along the continuum of breast carcinogenesis. Atypical hyperplasias and in situ carcinomas might be kinetically similar lesions. In the transition from normal epithelium to hyperplasia and from preinvasive lesions to invasive carcinoma the net growth of epithelial cells results from a growth imbalance in favour of proliferation. In the transition from hyperplasia to preinvasive lesions there is an imbalance in favour of apoptosis.

Rectal metastases from lobular carcinoma of the breast: report of a case and literature review.

Metastatic involvement of the gastrointestinal (GI) tract secondary to breast cancer is rare. Reported herein is the case of a 74-year-old woman with metastatic lobular breast carcinoma to the rectum presenting with obstruction. The breast tumour was diagnosed nine years prior to the presentation of rectal metastases. Endoscopy was repeated twice until a diagnosis was established. Examination of endoscopy material revealed infiltration of the rectum by malignant signet ring cells identical to those of the primary breast tumour. The patient did not respond to chemotherapy and underwent laparotomy with a defunctioning colostomy. Literature review revealed only a few more cases of metastatic breast carcinoma to the rectum. Awareness of this condition may lead to accurate diagnosis and early initiation of systemic treatment, thus avoiding surgical intervention.

Immunohistochemical expression of Bcl-2 protein in breast lesions: correlation with Bax, p53, Rb, C-erbB-2, EGFR and proliferation indices.

Expression of bcl-2 protein was investigated and correlated with Bax, p53 and Rb proteins, c-erbB-2, EGFR and the proliferation indices PCNA, Ki-67 and MIB1 as well as with the conventional clinicopathological parameters in 95 cases for breast cancer tissue and 20 cases of benign hyperplastic lesions. Bcl-2 and Bax proteins immunoreactivity was detected in normal, hyperplastic and neoplastic breast epithelium. Expression of the bcl-2 protein was detected in 40% of carcinomas (> 10% positive neoplastic cells) and 85.2% of the benign hyperplastic lesions. Bax protein expression was detected in 8.1% of the carcinomas and 5.3% in the hyperplastic group. Rb and p53 proteins were detected in 75.5% and 45.5% of carcinomas. No relationship was observed between bcl-2 expression and patient's age, tumour size, tumour type and grade, lymph node status, Rb protein expression and proliferation indices. However, a strong positive relationship was detected between bcl-2 and Bax (p = 0.008), estrogen (ER) (p = 0.007) and progesterone receptors' (PgR) status (p = 0.0003). An inverse correlation with p53 protein (p = 0.004) was detected. Furthermore, a strong correlation was also observed between pRb and p53 (p = 0.001). The results indicate that in breast cancer bcl-2 protein expression may be under hormonal control. Since the expression is bcl-2 protein was inversely correlated with p53 protein expression, we suggest that bcl-2 may be related with favourable outcome in breast cancer.

Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation.

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.

Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices.

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.

Hemolytic uremic syndrome and thymic dysplasia in an infant.

A 33-day-old male infant was admitted to the neonatal intensive care nursery because of respiratory distress, grunting, cyanosis, and radiological findings of bilateral bronchopneumonia. He responded well to intensive therapy, but 11 days later developed hemolytic uremic syndrome, which was treated conservatively with prednisone and plasma transfusions with good response. The hemolytic uremic syndrome resolved, but he subsequently developed severe recurrent infections of unknown etiology and died at the age of 78 days. Necropsy findings revealed necrotizing enterocolitis as well as dysplasia of the thymus and other lymphoid tissues, compatible with the diagnosis of immunodeficiency disorder.

p53 and c-jun expression in urinary bladder transitional cell carcinoma: correlation with proliferating cell nuclear antigen (PCNA) histological grade and clinical stage.

OBJECTIVE: To investigate p53 and c-jun oncoproteins and proliferating cell nuclear antigen (PCNA) in transitional cell urinary bladder carcinomas (TCCs) and to determine their relationships to tumour grade, stage and survival. MATERIALS AND METHODS: The expression of p53, c-jun and PCNA was studied using immunohistochemistry in formalin-fixed, paraffin-embedded tissues in a series of 110 TCCs. RESULTS: 58% of our cases were positive for p53 and 88% for c-jun. A statistically very significant correlation (p < 0.0001) was observed between p53 and c-jun (r = 0.781), p53 and PCNA (r = 0.772), c-jun and PCNA (r = 0.831) as well as between each of the two oncoproteins and the histological grade and clinical stage (p < 0.001). There was no correlation of either p53, PCNA or c-jun with clinical outcome in terms of patients survival. CONCLUSION: p53 and c-jun proteins' overexpression are strongly related to rapid tumour cell proliferation and hence with aggressive growth in urinary bladder TCC. PCNA score remains an important prognostic index in transitional cell carcinoma of the bladder.

p53 DO-1 immunohistochemical overexpression in premalignant and malignant cervical lesions.

One hundred-fourteen cervical lesions, including paraffin sections from benign, premalignant and malignant cervical tissue specimens were examined immunohistochemically for overexpression of p53 protein, using the p53 DO-1 monoclonal antibody (MoAb). p53 overexpression was observed in 66% of premalignant cervical lesions and in 90% of invasive squamous cell carcinomas. The difference in p53 positive lesions of premalignant and malignant cervical lesions was statistically very significant (p < 0.001) and the difference between CIN1 and CIN2 and CIN3 statistically significant (p < 0.01). Our results indicate that p53 overexpression may be involved at an early stage in cervical carcinogenesis.

Immunohistochemical expression of cathepsin D in correlation with extracellular matrix component, steroid receptor status and proliferative indices in breast cancer.

In 87 breast cancer patients, the immunohistochemical expression of the basement membrane (BM)-degrading enzyme cathepsin D (CD) was correlated with the expression of extracellular matrix components, with growth fraction, steroid receptor content and with the other conventional prognostic variables in breast cancer. Only 6.25% of tumours had laminin-defined BM, while 86.8% showed staining for fibronectin. CD was also identified in carcinoma cells (cancer cell CD; CCCD) and in stromal cells (stromal cell CD; SCCD). Forty-five percent of tumours showed CCCD and 47.5%, SCCD expression. CCCD expression was significantly correlated with positive oestrogen receptor content, with low Ki-67 and high PCNA score and with SCCD expression. There was no correlation with collagen type IV, laminin or fibronectin. SCCD expression was positively correlated with collagen type IV, laminin expression and tumour grade. The data suggest that the CD of tumour cells and the CD of tumour-associated macrophages have different roles in breast cancer. CCCD correlates with cell proliferation and is regulated by oestrogens, while SCCD relates to cell differentiation, is oestrogen-independent, and has a proteolytic role in the breakdown of BM components.

p53 expression in hepatocellular carcinoma in Greece. Correlation with epidemiological and histopathological data.

Localization of p53 oncoprotein was investigated in 60 hepatocellular carcinomas (HCCs) from patients resident in the Northwest and Central Greece. The streptavidin-biotin complex immunoperoxidase method was performed in archival formalin-fixed, paraffin-embedded material, using the monoclonal antibody DO-1. The aim of our study was to correlate p53 expression with histological and epidemiological data. p53 overexpression in patients with serological hepatitis B or C was greater (47%) as compared to that observed in patients without these markers (p < 0.01). Morphologically normal liver tissue (NLT) and liver cell dysplasia (LCD) was recognized adjacent to HCC developing on non-alcoholic cirrhotic livers in patients with "NonA, NonB hepatitis" from between 1975-1986. NLT and LCD and p53 oncoprotein was expressed in 10% of the cases. No relationship was observed between p53 expression and tumor histological grade, patients' age and sex. These results suggest that in Northwest and Central Greece, p53 oncosupressor gene may be involved in some HCCs; it may be associated with viral chronic infection disease (HBV or HCV), and as yet with uncharacterized viruses which remain to be determined.

The prognostic significance of epidermal growth factor receptor (EGFR), C-erbB-2, Ki-67 and PCNA expression in breast cancer.

The evaluation of the immunohistochemical expression of epidermal growth factor receptor (EGFR), c-erbB-2 oncoprotein, proliferating indices Ki-67, and PCNA were determined on 68 primary breast carcinomas. These markers were correlated with each other and with other clinicopathological variables such as: age, tumor size? histotype, tumor grade and steroid receptors' content as well as nodal status. The monoclonal antibodies anti-human Epidermal Growth Factor Receptor (EGFR1), anti-human Ki67 (DAKO) and N13259 (Oncogene Science) were applied to paraffin and frozen tissue sections. All markers showed an heterogeneous pattern of staining. There was almost equally high staining intensity at the membranus for EGFR and c-erbB-2 in about 32% of the cases. The EGFR and c-erbB-2 positive cases were much less common in infiltrating lobular (2,2/13) rather than in ductal adenocarcinomas (21,20/55). The low grade carcinomas showed low expression of EGFR and c-erbB-2 oncoprotehl comparing with high grade ductal adenocarcinomas. A high index of Ki-67 was correlated with EGFR and c-erbB-2 membrane positivity. There was an inverse relationship between the expression of c-erbB-2 and EGFR, when compared with oestrogen receptors' content. A significant correlation was also demonstrated between EGFR and c-erbB-2 immunoreactivity with lymph node status. Our results provide evidence that the synchronous immunohistochemical detection of EGFR, c-erbB-2 and Ki-67 may be of useful significance in breast cancer patients, especially when combined with other clinicopathological variables. Furthermore the expression of EGFR and c-erbB-2 oncoprotein may affect the cell proliferation and differentiation.

Topographical immunohistochemical expression of bcl-2 protein in human liver lesions.

Immunolocalization of the bcl-2 protein was investigated in 60 hepatocellular carcinomas, 10 cholangiocarcinomas. 15 metastatic adenocarcinomas as well as in 37 non-neoplastic liver lesions. The three-step immunoperoxidase method was performed in archival, routinely processed material. bcl-2 protein was not identified either in neoplastic, dysplastic or normal hepatocytes, whereas it was observed in bile ductules and small bile duct epithelia, but not in the epithelium lining large bile ducts. All cases of cholangiocarcinoma and 60% of metastatic adenocarcinomas were bcl-2 positive. bcl-2 appears to be an additional marker in distinguishing hepatocellular carcinoma from cholangiocarcinoma or metastatic adenocarcinoma. Also, bcl-2 does not seem to be involved in human liver hepatocyte survival.

Immunohistochemical detection of ras P21 oncoprotein in human skin lesions.

This study was undertaken to investigate the role of the human ras family gene product [P21] in various benign, precancerous and malignant skin lesions. A streptavidin-biotin peroxidase method was performed using the monoclonal antibody (Mab)Y13259 in paraffin tissue sections of a total of 69 skin lesions (5 benign hyperplasias, 12 seborrheic keratoses, 9 solar keratoses, 20 basal cell carcinomas and 23 squamous cell carcinomas). The adjacent normal skin was also studied in all cases. The expression of ras P21 was evaluated and graded in relation to the intensity of cytoplasmic immunostaining and the percentage proportion of positive epidermal cells. The following findings were noted in this study: 1) The positivity of ras P21 increased towards the keratin layer, according to cell maturation, in all normal, hyperplastic and "borderline" lesions, and to a lower degree in the seborrheic ones. 2) Comparing B.C.C. and S.C.C., higher expression was demonstrated in the latter, probably due to the high percentage of the well differentiated component.