The recurrence of cervical intraepithelial neoplasia in HIV-positive women: a review of the literature.

The objective of this study was to assess the available evidence on the outcome of cervical intraepithelial neoplasia (CIN) in HIV-positive women after conization. We performed a literature search of Medline and Cochrane libraries to locate published articles reporting about the rate of recurrence of CIN after excisional treatment in patients with negative surgical margins. Out of 15 articles, five studies reported recurrence rate of CIN in margin negative patients. The recurrence rate of CIN after conization in HIV-infected women ranges from 20% to 75%. No conclusions can be drawn about the impact of CD4 cell counts on the recurrence rate. Available evidence suggests that standard excisional treatments for CIN are associated with high rates of recurrence in HIV-positive women. Despite the fact that the evidence is limited because of the few number of eligible studies, this issue should be considered in the management of HIV-positive patient with CIN.

Ovarian primary primitive neurectodermal tumor coexisting with endometrioid adenocarcinoma: a case report.

We report an unusual case of a 78-year-old woman with primary ovarian tumor that consisted of primitive neurectodermal tumor and endometrioid adenocarcinoma. The patient presented with abdominal pain and weight loss and had disseminated disease at her initial presentation. She was treated with debulking surgery followed by chemotherapy. The patient was still asymptomatic at the 6-month follow-up.

Mucoepidermoid carcinoma of Stensen's duct: a case report and review of the literature.

BACKGROUND: Mucoepidermoid carcinoma of Stensen's duct is a rare neoplasm, with only five cases reported in the literature. METHODS: We report another case of mucoepidermoid carcinoma of Stensen's duct and review the literature. RESULTS: Stensen's duct neoplasms tend to be symptomatic at an early stage by causing an obstruction of the parotid duct. New imaging techniques such as MR sialography and sialoendoscopy are very helpful in diagnosis and patient management. CONCLUSIONS: Although the rarity of this condition prevents definitive conclusions about the optimal treatment, we propose that Stensen's duct neoplasms should be treated like similar neoplasms occurring in the parotid gland tissue, taking into consideration clinical stage, tumor grade, and surgical margins.

14-3-3 proteins--an update.

14-3-3 is a highly conserved acidic protein family, composed of seven isoforms in mammals. 14-3-3 protein can interact with over 200 target proteins by phosphoserine-dependent and phosphoserine-independent manners. Little is known about the consequences of these interactions, and thus are the subjects of ongoing studies. 14-3-3 controls cell cycle, cell growth, differentiation, survival, apoptosis, migration and spreading. Recent studies have revealed new mechanisms and new functions of 14-3-3, giving us more insights on this fascinating and complex family of proteins. Of all the seven isoforms, 14-3-3sigma seems to be directly involved in human cancer. 14-3-3sigma itself is subject to regulation by p53 upon DNA damage and by epigenetic deregulation. Gene silencing of 14-3-3sigma by CpG methylation has been found in many human cancer types. This suggests that therapy-targeting 14-3-3sigma may be beneficial for future cancer treatment.

Immunohistochemical expression of 14-3-3 sigma protein in human urological and gynecological tumors using a multi-tumor microarray analysis.

14-3-3 sigma is an exclusive epithelial marker and data on its expression in different malignancies are very scarce. The aims of the present study are to screen its expression in the most common neoplasms occurring in the urological and gynecological tract and to evaluate its use as a diagnostic marker. A tissue microarray was constructed using 350 samples from 13 different neoplasms. Immunohistochemical analysis using a polyclonal 14-3-3 sigma antibody was performed. Overall, this protein was positive in 141 and negative in 209 tumors. The most frequent expression was seen in squamous cell carcinoma of the cervix and urothelial bladder carcinoma, followed by prostatic and endometrial adenocarcinoma. 14-3-3 sigma was able to distinguish prostate adenocarcinoma from urothelial bladder carcinoma, with an odds ratio of 0.028 (P = 0.001; 95% CI, 0.0003-0.222), and distinguish seminoma from embryonal carcinoma of the testis, with an odds ratio of 0.061 (P = 0.009; 95% CI, 0.007-0.5014). It also has a good value in differentiating renal clear cell carcinoma from papillary carcinoma, with an odds ratio 0.470 (P < 0.001; 95% CI, 0.008-0.261). 14-3-3 sigma seems to have good potential use as an epithelial marker, after confirmation with further targeted studies. Finally, as with all immunohistochemical markers, we can optimize the utility of this protein to distinguish tumor mimics by including it in an appropriate immunohistochemical panel.

MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells.

The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-kappa B signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-kappa B activity and enhanced I kappa B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-kappa B cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I kappa B alpha mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-kappa B activity. Our findings support a model in which NF-kappa B signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.

Downregulation of 14-3-3sigma in ovary, prostate and endometrial carcinomas is associated with CpG island methylation.

The 14-3-3sigma inhibitor of cell cycle progression has been shown to be target of epigenetic deregulation in many forms of human cancers; however, its role in urological and gynecological cancers has not been studied. Here, we have analyzed the expression of 14-3-3sigma, wild-type p53 and mutated p53 in over 300 cases of the most common cancers occurring in the urological and gynecological tracts and its normal counterpart tissue by immunohistochemistry using the multiple tumor tissue microarrays. 14-3-3sigma expression was detected in normal epithelia from most organs with sporadic expression in renal tubules and absence in the testis. In contrast to normal tissue, 14-3-3sigma expression was lost in 40-60% of adenocarcinomas of the breast, ovary, endometrium and prostate. There was no association between 14-3-3sigma and wild-type/mutated p53 expression. By performing methylation-specific PCR, we showed a close association of 14-3-3sigma CpG island methylation and low protein expression levels of 14-3-3sigma. In addition, a direct link of 14-3-3sigma mRNA expression levels to CpG island methylation is demonstrated in two human cancer cell lines. Loss of 14-3-3sigma expression due to promoter hypermethylation may represent the most frequent molecular aberration in ovarian, endometrial and prostate adenocarcinomas.

EB-D fibronectin expression in squamous cell carcinoma of the head and neck.

ED-B fibronectin (ED-B FN), a glycoprotein involved in cell adhesion and migration, is expressed in fetal and neoplastic tissues and absent in their normal counterparts. The aim of this study is to evaluate the expression of this glycoprotein in relation to the histological and clinical data and to determine whether it has a prognostic value in patients with head and neck squamous cell carcinoma (HNSCC). Ninety-five cases were assessed for ED-B FN expression using immunohistochemistry. Positive ED-B FN expression was significantly associated with tumor grade (p=0.06) and primary tumor site (p=0.02). The larynx was the tumor site associated with the least ED-B FN expression. In univariate analysis, there was no association with disease-free survival (p=0.48), but the mean time to progression was clearly shorter in tumors with positive ED-B FN expression than in those with negative expression (6 vs. 11 months). Patients having tumors expressing the ED-B FN had a trend to a significant lower overall survival in the multivariate analysis (p=0.06). Our study showed that ED-B FN expression might have a prognostic value in patients with HNSCC.

Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract.

Distinction of high-grade esthesioneuroblastomas from other poorly differentiated tumors arising in the nasal cavity is an important diagnostic challenge because it determines patient management and prognosis. The human achaete-scute homologue (hASH1) gene is critical in olfactory neuronal differentiation and is expressed in immature olfactory cells; therefore, it could have potential use as a diagnostic marker The aim of the present study was to determine the value of hASH1 messenger RNA (mRNA) levels in differentiating esthesioneuroblastoma from other poorly differentiated tumors. A real-time polymerase chain reaction assay was developed, permitting the comparative determination of hASH1 mRNA levels in triplicate in a double-blind pilot study including 24 frozen cases of esthesioneuroblastoma and poorly differentiated tumors. All 4 positive cases were esthesioneuroblastomas, and all 19 poorly differentiated tumors were negative. In addition, there was an inverse association between the grade of esthesioneuroblastomas and hASH1 mRNA levels. The hASH1 mRNA level might represent a useful tool for distinguishing esthesioneuroblastoma from poorly differentiated tumors of the sinonasal region.

Expression of cell cycle proteins in T1a and T1b urothelial bladder carcinoma and their value in predicting tumor progression.

BACKGROUND: Cell cycle proteins are important markers in predicting tumor behavior in urothelial carcinoma of the bladder. The objectives of this study were 1) to determine the expression levels of some of those markers in a series of patients with bladder carcinoma, 2) to define their value in distinguishing T1a (minimally invasive) from T1b (invasive) tumors, and 3) to evaluate their use as predictive factors in the progression of T1a and T1b tumors. METHODS: Tumor specimens from 101 patients were included (22 Ta specimens, 34 T1a specimens, 15 T1b specimens, and 30 T2 specimens). A tissue microarray from the 101 paraffin embedded tissue blocks was constructed. Immunohistochemistry for p16, p27, p21, p53, cyclin D1, and Ki-67 were performed. To evaluate T1a and T1b tumor progression, clinical and follow-up data were available for all 49 patients. RESULTS: Cyclin D1 and p27 were the only markers that showed a significant association with tumor stage and tumor grade (cyclin D1: P = 0.002 and P > 0.00, respectively; p27: P = 0.024 and P = 0.031, respectively). The results indicated that a combination of p21 (odds ratio, 5.7; 95% confidence interval [95% CI], 1.3-24.8 [P = 0.022]) and p16 (odds ratio, 3.7; 95% CI, 0.8-16.5 [P = 0.081]) may have potential use in distinguishing T1b tumors from T1a tumors. Finally, none of the markers examined were found to have predictive value for T1a and T1b tumor progression. CONCLUSIONS: The expression of cyclin D1 and p27 was associated with the most important prognostic factors (tumor stage and grade). The combination of p21 and p16 may have value in distinguishing T1b tumors from T1a tumors, although this finding must be evaluated in much larger series. Finally, none of the markers studied appeared to have predictive value for disease progression in patients with T1a and T1b urothelial bladder tumors.

Motility-related protein 1 (MRP-1/CD9) expression in urothelial bladder carcinoma and its relation to tumor recurrence and progression.

BACKGROUND: CD9 has been implicated in cell adhesion, motility, and proliferation, and numerous studies have demonstrated its prognostic value in different solid tumors. The objective of this study was to determine the relation of CD9 expression to tumor grade and tumor stage of urothelial carcinoma of the bladder and to define the value of CD9 in predicting the behavior of superficial papillary tumors (SPTs) (pathologic Ta [pTa] and pT1). METHODS: Three hundred twenty patients (118 patients with pTa tumors, 111 patients with pT1 tumors, and 91 patients with pT2 tumors) were examined for CD9 expression using immunohistochemistry applied on formalin fixed, paraffin embedded tissue. Patients were stratified into 3 categories, depending on CD9 expression: positive (> 50% positive cells), reduced (5-50% positive cells), or negative (< 5% positive cells). RESULTS: Loss of CD9 expression was found to be associated significantly with high-grade and high-stage urothelial tumors (P < 0.0001). A reduced/negative (altered) CD9 expression was associated with SPT progression, but not with recurrence (P < 0.001). Patients who had pTa or pT1 tumors with altered CD9 expression had a relative risk of 5.59 (P = 0.005; 95% confidence interval [95% CI], 1.69-18.48) for progression compared with patients who had tumors with positive CD9 expression. Kaplan-Meier curves showed that a lack of CD9 expression was associated significantly with progression free survival (P < 0.001; log-rank test), but not with recurrence. In patients with SPTs, multivariate Cox proportional hazards regression analysis revealed that negative CD9 expression was an independent prognostic marker for the prediction of tumor progression (P = 0.007; 95% CI, 0.11-0.70). CONCLUSIONS: In patients with urothelial bladder carcinoma, CD9 expression was associated significantly with tumor stage and grade, and a loss of CD9 expression was an independent prognostic factor for predicting progression in patients with SPTs. Thus, CD9 immunoexpression is a potential new predictor of tumor behavior in patients with SPTs of the urinary bladder.

Hepatoid adenocarcinoma with liver metastasis mimicking hepatocellular carcinoma: an immunohistochemical and molecular study of eight cases.

Hepatoid adenocarcinoma (HAC) is a special type of extrahepatic adenocarcinoma, which has a striking morphologic similarity to hepatocellular carcinoma. Seven HACs arising in the stomach and one in the lung, all with liver metastasis, were studied. They shared clinical features, such as old age, high serum alpha-fetoprotein level, aggressive behavior, and hepatic tumor in absence of risk factors for hepatocellular carcinoma (HCC). Morphologically, tumors were characterized by an admixture of tubulo-and/or papillary adenocarcinoma with hepatoid foci. In six cases, liver metastases showed an exclusive hepatoid differentiation, virtually indistinguishable from HCC with solid growth pattern. As HAC and HCC cannot be differentiated on the basis of morphology alone, differences in immunohistochemical reaction patterns would be of considerable diagnostic help. Immunostaining for CK7, CK8, CK18, CK19, CK20, alpha-fetoprotein, p-CEA, and HepPar1 revealed that hepatoid areas of both primary and metastatic HAC have a specific immunoprofile, distinctive of this entity. On the one hand, positivity of virtually all HACs for alpha-fetoprotein, CK8, CK18, and the membranous, canalicular staining for polyclonal carcinoembryonic antigen underline its hepatoid nature. On the other hand, positive staining for CK19 and CK20 and frequent negativity for HepPar1 in both primary tumors and their metastases were distinctive features of HAC. Furthermore, HAC differs from combined hepatocellular cholangiocarcinoma, being negative for CK7. In addition, for comparison of immunohistochemical results, we stained with the same antibody panel a tissue microarray of 121 HCCs. Comparative genomic hybridization study of three HAC supports their hepatoid differentiation as aberrations found in HAC are common in HCC (4q-, 8p-), and hepatoblastoma (Xq+), respectively.

Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma.

The differential diagnosis between poorly differentiated prostate adenocarcinoma (PAC) involving the bladder and high-grade urothelial bladder cancer (UC) with prostate extension can be very challenging. The aim of this study is to evaluate the use of a panel of antibodies to distinguish the poorly differentiated forms of these two tumors. We evaluated a series of 40 PAC cases (Gleason's grade >/= 8) and 45 (G3) UC cases obtained from transurethral endoscopic resection material. Immunohistochemical analysis was performed using the following antibodies: prostate acid phosphatase (PAP), prostate-specific antigen (PSA), uroplakin III (UP), thrombomodulin (TM), cytokeratin (CK) 7, and CK20. PAC expressed PSA and PAP in 34 and 38 cases, respectively. The sensitivity and specificity of expressing at least 1 marker (PSA+ or PAP+) is 95% and 100%, respectively. All UC cases were negative for both markers. UC expressed UP and TM in 27 and 22 cases, respectively. In addition, 36 of 45 cases stained positively for at least 1 marker (UP + or TM +) with specificity and sensitivity of 80% and 100%, respectively. All cases of PAC were negative for both markers. Twenty-eight UC cases were CK7+/CK20 +, and 4 PAC cases stained positively for both markers. On the other hand, 29 PAC cases and 4 UC cases were CK7-/CK20-. We concluded that PSA, PAP, UP, and TM are very useful markers in differentiating poorly differentiated UC from PAC. Finally, when all 4 markers (PAP, PSA, UP, and TM) were negative, CK7 and CK20 appeared of no major use in making the differential diagnosis.

Value of immunohistochemistry in staging T1 urothelial bladder carcinoma.

PURPOSE: The subclassification of T1 bladder tumors into T1A and T1B has an important prognostic significance and a great impact on patient management. Unfortunately, staging T1 tumors is highly subject to interpathologist variation that can be critical for patients included in randomized clinical trials. To determine the value of immunohistochemistry (IHC), such as desmin and keratin, in comparison to hematoxylin-eosin (H&E) in classifying T1 stage disease, we retrospectively examined 93 consecutive cases diagnosed at our department. MATERIALS AND METHODS: The study was conducted in two phases (H&E then IHC), each in two time periods. First H&E, and then IHC slides were reviewed independently by two experienced pathologists and discrepant cases from each phase were discussed between the two pathologists to reach a final decision. RESULTS: The two methodologies (H&E and IHC) showed total agreement in 76 out of 93 cases. IHC downstaged seven cases, that is from T1B to T1A, upstaged four cases, that is from T1A to T1B, lowered the rate of imprecision and eliminated the disagreement between the two pathologists. However, IHC failed to subclassify T1 tumors in three cases. Finally, the discussion supported by the IHC was very useful in reaching the diagnosis in some cases. CONCLUSIONS: IHC appears to be a useful tool in staging T1 bladder cancer, especially in difficult cases where specimen orientation and artifact could create a major hindrance in reaching an accurate diagnosis.

Detecting bacteria in platelet concentrates by use of reagent strips.

BACKGROUND: Iatrogenic infection of immunosuppressed or immunocompromised hosts secondary to receipt of blood components containing bacteria may result in serious adverse outcomes. Measurement of pH and glucose by use of inexpensive reagent strips has been proposed as a practical means of screening for bacteria in platelet concentrate (PC) units. STUDY DESIGN AND METHODS: Glucose and pH were measured in 3093 PC units by use of reagent strips (Multistix, Bayer Corp.) to screen for bacterial content. Any PC classified by the reagent strip method as containing bacteria was subsequently cultured to confirm the presence and quantity of bacteria present. RESULTS: Thirty of 3093 PC units were classified as containing bacteria by the reagent strip method. Two of the 30 PC units positive by the reagent strip method were also positive by standard bacterial culture technique. Bacillus cereus was isolated from both units. CONCLUSION: Screening PC units by the reagent strip method resulted in 9.7 units per 1000 being wasted, but prevented two patients from receiving a PC unit containing B. cereus.

Ovarian carcinomas in endometriosis: an immunohistochemical and comparative genomic hybridization study.

Malignant transformation of endometriosis, an uncommon phenomenon, can occur in gonadal and extragonadal sites and results in a wide histological range of tumors. Published series reporting malignant transformation of endometriosis have largely been confined to clinical and histopathological discussions with no studies reporting oncoprotein expression and genetic alterations. We report three cases of carcinomas arising in ovarian endometriosis: a serous cystadenocarcinoma, an endometrioid carcinoma with squamous differentiation, and a pure squamous cell carcinoma. Each tumor was analyzed immunohistochemically to compare oncoprotein expression (p53, bcl2, cyclin D1, and c-erb B2) between the tumors and the endometriotic tissue as well as with comparative genomic hybridization (CGH) to compare genetic alterations. All three tumors expressed nuclear p53, in contrast to the endometriotic tissue in which no p53 expression was found. Both endometrial and tumor tissue expressed bcl-2. No expression of cyclin D1 or c-erb B2 was detected in endometriotic or tumoral tissues. The CGH analysis revealed one or two chromosomal aberrations in each of the three tumors with gains on chromosomes 1q, 8q, and 13q, and losses on chromosome 10p. The endometriotic tissue, as expected, showed a normal genetic profile. These results suggest that p53 protein abnormalities and chromosomal aberrations may be involved in malignant transformation of endometriosis in the ovary. However, our results are limited by the number of cases examined and a definite conclusion on the pathogenesis of this process should be followed by future studies with a larger number of cases.