Prognostic role of immunohistochemical analysis of 5 mc in myelodysplastic syndromes.

BACKGROUND: Aberrant DNA methylation at CpG islands within promoters is increasingly recognised as a common event in human cancers and has been associated with the silencing of important tumour suppressor genes. Epigenetic therapy using hypomethylating agents has demonstrated clinical effectiveness; the drugs azacitidine and decitabine have been approved for the treatment of MDS. METHOD: We investigated the association between global DNA methylation and clinical outcome in MDS. We evaluated 134 MDS bone marrow trephine biopsies (BMTB) by immunohistochemistry and compared the results with those from an age-matched group of normal BMTB. Immunohistochemistry was performed on paraffin-embedded sections using the anti-5-methylcytosine (5mc) antibody. RESULTS: Our results showed that the 5mc immunostaining score (M-score) of patients with MDS was higher than those of normal controls and that overall survival significantly correlated with global DNA methylation, age and IPSS score. Therefore, we found that patients with high levels of methylation had a shorter median overall survival (OS) compared with patients with lower levels. These immunohistochemistry results were confirmed by analysing global DNA methylation on LINE-1 sequences using the COBRA method and pyrosequencing. CONCLUSION: This study reports that global DNA methylation detected by immunohistochemistry predicts OS in MDS.

Immunohistochemical expression of vascular endothelial growth factor (VEGF) in different types of odontogenic cysts.

The objective of the present study was to evaluate vascular endothelial growth factor (VEGF) expression in different types of odontogenic cysts. A total of 25 parakeratotic odontogenic keratocysts (POKCs), 16 orthokeratotic odontogenic keratocysts (OOKCs), and 28 follicular cysts (FCs) were evaluated semiquantitatively for immunohistochemical analysis of VEGF in epithelial cells, endothelial cells of blood vessels, inflammatory cells and focally stromal cells. A significant different expression of VEGF in all cell components was found in keratocysts compared to FCs. The POKCs (80%) and OOKCs (68%) showed more than 50% VEGF positive epithelial cells, whereas the majority of FCs (71%) were either negative in the epithelium or showed less than 10% positive cells. Similarly, the POKCs (88%) and OOKCs (68%) showed more than 50% positive endothelial cells, whereas the FCs (75%) were either negative or showed less than 10% VEGF positive endothelial cells. The highest percentage of cases with score 2 positivity in the stromal cells was observed in POKCs (68%); OOKCs showed a score 2 positivity in 44%, score 1 in 31% and score 0 in 25%, whereas 68% of FCs showed a score 0, 25% a score 1 and only 7% of cases showed a score 2. No statistically significant differences were observed between POKCs and OOKCs in VEGF expression in the epithelial and endothelial cells, whereas the positivity score in stromal cells was significantly higher in POKCs compared to OOKCs. The present results can support the hypothesis that angiogenesis is an active mechanism in the invasive growth of the OKC.

Immunohistochemical expression of somatostatin receptor subtypes in prostate tissue from cystoprostatectomies with incidental prostate cancer.

OBJECTIVE: To examine immunohistochemically the expression of the five somatostatin receptors (SSTRs) in cystoprostatectomies (CyPs) with incidental prostate cancer. MATERIALS AND METHODS: The five SSTRs (SSTR1-5) were evaluated in 'normal-looking' epithelium (NEp), high-grade prostatic intraepithelial neoplasia (HGPIN) and pT2a Gleason score 6 adenocarcinoma in 20 CyP specimens with incidental prostate cancer and 20 radical prostatectomy (RP) specimens with clinically detected prostate cancer. RESULTS: For cytoplasm expression, the mean percentage of positive secretory cells with strong cytoplasmic staining increased from NEp to HGPIN and prostate cancer, being slightly lower in the CyP than in the RP specimens. Both in the CyP and RP specimens SSTR4 was found in the highest percentage of cells. There was membrane staining in the secretory cells for SSTR3 and SSTR4. There was nuclear staining in the secretory cells for SSTR4 and SSTR5. For SSTR1 and SSTR3 the mean proportions of positive basal cells were higher than for the other three subtypes, and greater in NEp than in HGPIN. There were positive smooth muscle and endothelial cells for all five SSTR subtypes, the highest proportions being SSTR1 and the lowest SSTR5. CONCLUSIONS: This immunohistochemical study expands our knowledge of the expression and localization of SSTRs in the various tissue components in the prostate with incidental cancer, compared with clinically detected cancer. Such information might be useful in developing further non-invasive strategies for the prevention and treatment of pre-neoplastic and neoplastic lesions of the prostate.

Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), and microvessel density in endometrial tissue in women with adenomyosis.

Adenomyosis is a disease with a mysterious pathogenesis, defined by an abnormal displacement of the eutopic endometrium deeply and haphazardly inside the myometrium. Angiogenesis has been indicated to play an important role and our aim was to investigate whether vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha) expression and microvessel density (MVD) were different in women with and without adenomyosis. Immunohistochemistry was performed in endometrial tissues in 23 patients who underwent radical hysterectomy for adenomyosis (14) and for ovarian cysts and fibroids (9) at an Academic Hospital. Compared to women without the disease, VEGF expression was increased in endometrium with a normal location in patients with adenomyosis, although not associated to a significant increase of HIF-1alpha and MVD. Moreover, the endometrium with an abnormal location in patients with adenomyosis showed an increased VEGF and HIF-1alpha expression, particularly in the epithelial cells, associated to an increase of MVD, compared with the endometrium in a normal location in the same group of patients. Our present findings suggest that VEGF-mediated angiogenesis might be associated with the development of adenomyosis. In the ectopic foci the abnormal location might contribute to increased HIF-1a expression, stimulation of VEGF production, and increased vessel formation. In endometrium with a normal location, instead, where VEGF increased expression seems not to be correlated with HIF-1alpha increased expression nor with an increased MVD, other mechanisms might be reasonably postulated. Additional studies are required to explore new targeted and more effective treatment modalities.

HER-2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy.

In this prospective study, we determined HER-2 status in primary breast invasive carcinomas and in the paired lymph node metastases (synchronous and metachronous), local recurrence and metachronous distant metastases, to verify the percentage of discordant cases. HercepTest and Fluorescence in situ hybridization (FISH) were used to determine HER-2 status on 119 cases of primary infiltrating breast carcinoma and paired metastases (45 cases with synchronous lymph node metastases, 9 cases with metachronous lymph node metastases, 30 cases with local recurrence, and 35 cases with metachronous distant metastases). A therapeutically significant HER-2 status discordance was demonstrated between primary carcinoma and synchronous lymph node metastases (6.7%), local recurrence (13.3%) and metachronous distant metastases (28.6%). In the first comparison, there was a normal HER-2 status in primary tumours and HER-2 amplification in paired metastases, in the second the opposite phenomenon was present, and both types of discordance were evident in the third comparison. Considering the cases of local recurrences and metachronous distant metastases all together, 14 out of 65 cases (21.5%) showed a therapeutically significant discordance of HER-2 status between the primary tumour and the paired metachronous recurrence or metastasis (p < 0.001), the 15.4% of cases showing normal HER-2 status in the primary tumour and HER-2 amplification in the neoplastic relapse. For the treatment of metastatic patients, the evaluation of HER-2 status should be performed in neoplastic tissue from metastatic site, whenever possible. This procedure could be also suggested in the patients that are metastatic at the time of diagnosis.

Immunohistochemical detection and localization of somatostatin receptor subtypes in prostate tissue from patients with bladder outlet obstruction.

BACKGROUND AND AIM OF THE STUDY: Scant information on the cellular distribution of the five somatostatin receptor (SSTR) subtypes in the normal prostate and in neoplasms of the prostate has been reported in very few studies in which techniques, such as in situ hybridization histochemistry, autoradiography, and more recently immunohistochemistry, have been applied. The aim of the study was to examine immunohistochemically the distribution and localization of these 5 subtypes in the various tissue components in normal prostate. MATERIALS: The study was conducted in 14 surgical specimens of normal prostate tissue from adenomectomy specimens from patients with bladder outlet obstruction. The distribution and localization of the 5 somatostatin receptor (SSTR) subtypes was investigated with an immunohistochemical technique. Specificity of the antibodies against the 5 receptor subtypes was preliminarily investigated. RESULTS: Close to 90% of secretory cells showed a weak positivity in the cytoplasm, the proportion ranging from 86.3% (SSTR4) to 89.9% (SSTR5). Strong immunoreactivity was seen in a small proportion of cells, ranging from 0.8% (SSTR3) to 3.2% (SSTR1). For the subtypes 1 and 3 the greatest proportion of basal cells showed a moderate intensity (42.5 and 41.4%, respectively), strong immunoreactivity being observed only in 18.1 and 15.8% of cells, respectively. For the subtypes 2, 4 and 5, the majority of cells showed a weak intensity (72.3, 65.7 and 65.1%, respectively). Subtype 1 showed a strong immunoreactivity in the cytoplasm in 60% of the smooth muscle cells. With subtypes 2, 3 and 4 the greatest proportion of cells showed a weak intensity (63.4, 89.8 and 81.7%, respectively). With the subtype 5 the majority of cells (59.8%) were negative. Subtype 1 showed a strong immunoreactivity in the cytoplasm in 98.6% of the endothelial cells. With subtypes 3 and 4 the greatest proportion of cells showed a weak intensity (73.5 and 56.4%, respectively). With the subtype 2 and 5 the majority of cells were negative (59.1 and 50.7%, respectively).

Clinicopathological features of primary cutaneous B-cell lymphomas from an academic regional hospital in central Italy: no evidence of Borrelia burgdorferi association.

We reviewed the clinico-pathological features of 73 primary cutaneous B-cell lymphomas (PCBCLs), diagnosed in 10 years in Marche region in central Italy, which included 16 marginal zone lymphomas (MZL), 33 follicle centre lymphomas (FCL) and 24 diffuse large B cell lymphomas (DLBCL). We also investigated the presence of Borrelia burgdorferi in tissues by polymerase chain reaction. Differences in age, sex, location site, response to therapy, disease recurrence and 5-year disease-specific survival were observed among the 3 histological groups. Specific DNA sequences of Borrelia burgdorferi were not detected in any of the 73 cases of PCBCL. We conclude that PCBCLs in Marche region behave according to the literature data and do not seem to be associated with Borrelia burgdorferi. Additional investigations should be performed on other possible etiologies, at least in our geographical area.

HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent cancer.

Previous studies have demonstrated HER2 protein overexpression and/or gene amplification in a subset of patients with clinically significant prostate cancer (PCa), especially in the androgen-independent phase of the disease. There are no studies on incidentally detected PCa. The aim of the study was to analyze HER2 expression and gene amplification in PCa incidentally detected in cystoprostatectomies. High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. Comparison was made with clinically detected PCa, both untreated and hormonally treated, and with androgen-independent PCa. Nineteen cystoprostatectomy (CyP) and 44 radical prostatectomy specimens (25 untreated and 19 hormonally treated) with pT2a Gleason score 6 cancer and HGPIN were used in this study. It also included 9 specimens of transurethral resection of the prostate with hormone-independent cancer and 8 cases of normal prostate tissue from CyP specimens without PCa and prostatic intraepithelial neoplasia. HER2 protein and Ki-67 were investigated immunohistochemically. Patients with immunohistochemical scores of 2+ and 3+ were considered to have HER2 overexpression (HercepTest method). Dual-color fluorescence in situ hybridization analysis was performed using the CEP-17/HER dual probe combination. High-grade prostatic intraepithelial neoplasia showed HER2 overexpression in 26% of the CyP cases and in 40% and 83% of the untreated and treated cases, respectively. Prostate cancer showed HER2 overexpression in 16% of cases in the CyP group and in 36% and 47.5% in the untreated and treated groups, respectively. HER2 overexpression was present in 78% of androgen-independent cancers. HER2 gene amplification was seen in a small proportion of nuclei and some of the cases. In HGPIN, it ranged from 1.1% (in 5 cases) in the CyP group to 2.1% (in 10 cases) and 1.9% (in 6 cases) in the untreated and treated groups, respectively. In PCa, the proportion of nuclei with gene amplification was 0.7% (in 3 cases) in the CyP group, 2.6% (in 10 cases) and 2.5% (in 12 cases) in the untreated and treated groups, respectively, and 9% (in 6 cases) in the androgen-independent PCa. Ki-67 expression in HGPIN and PCa in CyP specimens was lower than in the radical prostatectomies and cases of transurethral resection of the prostate. Our findings in the current HER2-related study indicate that incidentally detected cancer has features of less aggressiveness than clinically detected cancer. This may contribute to a better understanding of the results obtained in screening programs where insignificant cancers are detected along with clinically significant cancers.

Maspin expression is a favorable prognostic factor in non-small cell lung cancer.

OBJECTIVE: To evaluate prognostic impact of maspin expression in patients with resected non-small cell lung cancer (NSCLC). STUDY DESIGN: From 1996 to 2001, 439 patients underwent radical surgery for NSCLC at the Polytechnic University of the Marche Region. Maspin expression was detected as cytoplasmic and nuclear staining of neoplastic cells. For cytoplasmic staining, cases were classified as negative, low positive, and high positive. In positive cases, intensity of staining was also considered and scored. A similar classification was used for nuclear staining, but intensity was not considered. RESULTS: The analysis showed that smoking history, pathologic stage of disease, N status, histologic grading, sex, and Eastern Cooperative Oncology Group performance status had a prognostic impact on overall survival (OS). Expression of maspin was also found to be an independent prognostic factor. A statistically significant longer OS was seen in patients with higher compared with lower expression of nuclear maspin, and poorer OS was present in patients with a higher intensity of cytoplasmic staining. Nuclear expression of maspin was also found to be an independent prognostic factor at multivariate analysis. CONCLUSION: Results suggest that overexpression of maspin correlates with favorable prognosis in NSCLC. and may be a useful clinical marker.

Comparison of germinal center markers CD10, BCL6 and human germinal center-associated lymphoma (HGAL) in follicular lymphomas.

BACKGROUND: Recently, human germinal center-associated lymphoma (HGAL) gene protein has been proposed as an adjunctive follicular marker to CD10 and BCL6. METHODS: Our aim was to evaluate immunoreactivity for HGAL in 82 cases of follicular lymphomas (FLs)--67 nodal, 5 cutaneous and 10 transformed--which were all analysed histologically, by immunohistochemistry and PCR. RESULTS: Immunostaining for HGAL was more frequently positive (97.6%) than that for BCL6 (92.7%) and CD10 (90.2%) in FLs; the cases negative for bcl6 and/or for CD10 were all positive for HGAL, whereas the two cases negative for HGAL were positive with BCL6; no difference in HGAL immunostaining was found among different malignant subtypes or grades. CONCLUSIONS: Therefore, HGAL can be used in the immunostaining of FLs as the most sensitive germinal center (GC)-marker; when applied alone, it would half the immunostaining costs, reserving the use of the other two markers only to HGAL-negative cases.

Epidermal growth factor receptor status in stages of resected non-small cell lung cancer: implications for treatment with epidermal growth factor receptor inhibitors.

OBJECTIVE: To verify whether epidermal growth factor receptor (EGFR) status could be considered a prognostic factor and assessment of it an effective tool for planning therapy in patients with non-small cell lung cancer (NSCLC). STUDY DESIGN: From 1996 to 2001, 439 patients underwent radical surgery for NSCLC at the Polytechnic University of the Marche Region. EGFR expression was detected as membranous and/or cytoplasmic staining of neoplastic cells with various intensity and was considered positive when > or = 1% of the tumor cells had membranous staining. RESULTS: Samples from 423 patients were available for EGFR analysis. EGFR expression and a stronger intensity of staining were associated with a trend for a worse prognosis in the analysis of all of the patients. The subgroup analysis showed no prognostic significance in stages I and II but a significantly longer survival in patients with advanced disease (stage III and particularly N2) overexpressing EGFR. CONCLUSION: The results of our study, showing a significantly longer survival in patients with advanced disease (stage III, particularly N2) overexpressing EGFR, present a new perspective, both for prognostic evaluation of patients with radically resected NSCLC and for the management of adjuvant treatment also employing targeted therapy.

Immunostaining for nucleophosmin in bone marrow trephine biopsy specimens in acute myeloid leukemias.

OBJECTIVE: To evaluate the technicalfeasibility of nucleophosmin (NPM) staining and the problems of interpretations by pathologists in an academic regional hospital in Italy. STUDY DESIGN: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells that presents genetic abnormalities in several genes, including NPM. Mutations of the NPM gene occur in 35% of patients with AML with normal karyotype, causing cytoplasmic rather than nuclear localization of the protein. Because the NPM antibody recently became commercially available, we immunostained a series of diagnosed AML samples. We performed NPM immunostaining in 48 AML cases. NPM immunostaining was correlated with phenotypic and cytogenetic data. RESULTS: Reactivity for NPM was exclusively nuclear in 31 cases (64.6%) and nuclear and cytoplasmic in 17 cases (35.4%). The distribution of NPM cytoplasmic staining was more frequently observed in cases with monocytic differentiation and with normal karyotype or with minor cytogenetic abnormalities (p < 0.05). CONCLUSION: NPM immunostaining is a feasible test, without problems of interpretation for pathologists, when the sections are optimally prepared and can be considered predictive of peculiar phenotypic and karyotype subtypes of AML, in addition to the well-known prognostic role.

Diffuse large B-cell lymphoma with Homer-Wright rosettes, sinusoidal growth pattern, and CD30 expression: a possible overlap between microvillous lymphomas and sinusoidal CD30-positive large B-cell lymphomas.

Rosette formation is an unusual finding in malignant lymphomas. We herein report another case of a diffuse large B-cell lymphoma (DLBCL) with ultrastructural evidence of cellular projections, sinusoidal growth pattern, and strong CD30 expression. A literature review of the DLBCL cases showing all these features was also performed.

Lesional skin chemokine CTACK/CCL27 expression in mycosis fungoides and disease control by IFN-alpha and PUVA therapy.

Recruitment of neoplastic T cells to skin is a critical step in the pathogenesis of mycosis fungoides (MF) lesions. Cutaneous T-cell attracting chemokine (CTACK)/CCL27 attracts memory T cells to skin, resulting in increased cutaneous expression. The interactions between neoplastic cells and skin immune system require further elucidation. CTACK/CCL27 expression and density of dendritic cells (DC), CD8+ and CD4+ lymphocytes were investigated in skin lesions of 52 early-stage MF patients treated by interferon (IFN)-alpha in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA). Skin lesion biopsies obtained at diagnosis and after treatment were studied by immunohistochemistry. Initial CTACK/CCL27 expression was abnormal/suprabasal in 36 patients. Normal/basal CTACK/CCL27 expression tended to correlate with a high DC density and low CD4+ cell density in the neoplastic infiltrate. Treatment induced a significant increase in CTACK/CCL27 expression (chi(2) test: P=0.004). Overall, 33 patients relapsed [median event-free survival (EFS), 46 months] during follow-up (median, 92.5 months, range, 43-165). Normal/basal CTACK/CCL27 expression at the end of treatment correlated with lower rates of recurrence and a longer median EFS (111 months vs. 39 months with suprabasal expression; log rank test: P=0.031). CTACK/CCL27 overexpression in early-stage MF might thus be related to a balance between neoplastic cells and immunomodulant DC. Normal CTACK/CCL27 expression after treatment designates a subset of patients with favorable disease behavior. The mechanisms underpinning CTACK/CCL27 overexpression after therapy in the remaining patients, who are at greater risk of recurrence, warrant further investigation.

Immunohistochemical expression of endothelin-1 and endothelin-A and endothelin-B receptors in high-grade prostatic intraepithelial neoplasia and prostate cancer.

OBJECTIVES: To analyze the expression of endothelin-1 (ET-1), endothelin-A receptor (ET-A-R), and endothelin-B receptor (ET-B-R) in incidental prostate cancer in cystoprostatectomies (CyPs), clinically detected hormonally untreated and hormonally treated prostate cancer in radical prostatectomies (RPs), and hormone-independent prostate cancer in transurethral resections of the prostate (TURPs). High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. METHODS: Nineteen CyPs and 44 RPs (25 untreated, 19 treated) with pT2a Gleason score 6 cancer and HGPIN were examined. The study included 9 TURPs with hormone-independent cancer and 8 normal cases from CyPs without prostate cancer and HGPIN. ET-1, ET-A-R, ET-B-R, and the proliferation marker Ki67 were investigated immunohistochemically. RESULTS: The mean proportion of prostate cancer cells with strong ET-1, ET-A-R, and ET-B-R expression in CyPs was lower (18.5%, 28.0%, and 14.7%, respectively) than in the untreated group (40.7%, 39.7%, and 25.1%) and higher than in treated group (5.0%, 13.9%, and 11.3%). The highest values were in the hormone-independent cancer group (53.9%, 48.9%, 33.3%). The trend in the proportion of HGPIN cells overexpressing ET-1, ET-A-R, and ET-B-R was similar to that in the cancer groups. The values in HGPIN lesions were always slightly greater than those in the cancers. Ki67 expression in HGPIN and prostate cancer in CyPs was lower than in RPs and TURPs. CONCLUSIONS: Our study showed for the first time that ET-1, ET-A-R, and ET-B-R expression is not limited to the late prostate cancer phases. It is also seen in HGPIN as well as in prostate cancers considered to be clinically insignificant, such as those seen in CyP specimens. Although the series of cases in each group was small, our data may have clinical significance.

Expression of motility-related molecule Cdc42 in endometrial tissue in women with adenomyosis and ovarian endometriomata.

OBJECTIVE: To evaluate Cdc42 expression in eutopic and ectopic endometrial tissue in patients with adenomyosis and ovarian endometriotic cysts compared with patients without endometriosis. DESIGN: Experimental retrospective study. SETTING: University hospital. PATIENT(S): Twenty-four patients with adenomyosis, 19 with ovarian endometriomata, and 9 with fibroids or benign ovarian cysts. INTERVENTION(S): Hysterectomy and bilateral oophorectomy. MAIN OUTCOME MEASURE(S): Immunostaining for Cdc42 of eutopic and ectopic endometrial tissues. RESULT(S): In eutopic endometrium of patients with adenomyosis and with fibroids or benign ovarian cysts, the intensity of Cdc42 immunostaining was weaker, especially in the specialized stromal cells, compared with cases with ovarian endometriosis (chi(2) test, P=.003). Expression of Cdc42 in eutopic endometrium showed a trend to be higher in the secretory than in the proliferative phase and in patients with ovarian endometriotic cysts compared with patients with adenomyosis (unpaired t test, P=.005), especially in the proliferative phase. CONCLUSION(S): An abnormally high expression of Cdc42 in eutopic endometrium in the secretory phase may contribute to the development of ovarian endometriosis, but it does not seem to be involved in the pathogenesis of adenomyosis.

Chromosomal abnormalities in macroscopically normal urothelium in patients with bladder pT1 and pT2a urothelial carcinoma: a fluorescence in situ hybridization study and correlation with histologic features.

OBJECTIVE: To analyze chromosomal abnormalities in macroscopically normal urothelium in patients with bladder pT1 and pT2a urothelial carcinoma and correlate the changes with histologic features. STUDY DESIGN: Cytologic touch preparations of the tumors and of the adjacent and distant urothelium were obtained from 8 bladders with urothelial carcinoma. Fluorescence in situ hybridization (FISH) was used to detect abnormalities of chromosomes 3, 7, 9 and 17 and of the 9p21 locus. RESULTS: The macroscopically normal urothelium adjacent to and distantfrom neoplastic foci was either normal looking microscopically or showed histologic changes ranging from hyperplasia to dysplasia and carcinoma in situ. FISH analysis detected chromosome gains and 9p21 deletion similar to those present in the urothelial carcinoma even though the percentage of altered nuclei was lower, especially in hyperplasia. The microscopically normal urothelium showed minor abnormalities in terms of gain for all the chromosomes investigated. CONCLUSION: Even though urothelium looks normal from the macroscopic point of view, it frequently harbors histologic changes and chromosomal abnormalities. These findings are of clinical significance since they might represent genetic alterations involved in recurrence and/or progression of urothelial carcinoma.

Molecular mechanisms in prostate cancer. A review.

Genetic studies have provided remarkable clues to the causes of prostate cancer (PCa). For example, in addition to the expected role of androgens in facilitating the development of PCa, the possibility that infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate cancer genes; that insight will profoundly affect future studies and may ultimately lead to new approaches to the prevention of prostate cancer. The identification of key molecular alterations in prostate cancer cells implicates carcinogen defenses, including GSTP1, growth factor signaling pathways (such as NKX3.1, PTEN and p27) and androgens as critical determinants of the phenotype of PCa cells and defines specific targets for detection, diagnosis and treatment of PCa.

Immunohistochemical evaluation of HER-2/neu expression in infiltrating breast carcinoma: a study of reproducibility.

OBJECTIVE: To determine interobserver and intraobserver reproducibility in the assessment of the HercepTest- and TAB250-immunostained slides. STUDY DESIGN: Three independent expert pathologists (two with and one without training in HercepTest assessment) evaluated the HercepTest and TAB250-immunostained slides of 108 infiltrating breast carcinomas with a triple-blind method. The evaluation was repeated, with the same method and sequence of view, after 60 days. RESULTS: Expert pathologists, after adequate training in HercepTest evaluation, could reach excellent interobserver (K=.911, P<.001) and intraobserver reproducibility (K of .863-.926; P <.001 for all). The percentage of disagreement in intraobserver reproducibility ranged from 0.9% to 3.7%. Interobserver and intraobserver reproducibility in the evaluation of TAB250-immunostained slides was good (K = .658, P < .001) and from good to excellent (K of .600-.895, P < .001 for all), respectively. CONCLUSION: Optimization of the level of accuracy in HercepTest evaluation is mandatory because the decision to initiate therapy with Herceptin depends on the result. Moreover, considering that the percentage of disagreement in intraobserver reproducibility ranges from 0.9% to 3.7%, it is advisable that two expert pathologists evaluate all HercepTest slides with a double-blind method. If there are discordant results, they must be discussed by the same pathologists.