Biomedical subjects

C Blake Gilks

Publications and source records attributed to C Blake Gilks.

At least 19 recordsLinked to original sources

PubMed2006

Stromal CD10 expression in invasive breast carcinoma correlates with poor prognosis, estrogen receptor negativity, and high grade.

CD10 is a zinc-dependent peptidase (metalloproteinase), which degrades a variety of bioactive peptides. Earlier studies suggested that CD10 expression in tumor stroma is associated with biological aggressiveness of the tumor. To date, only one study has addressed the clinical significance of stromal CD10 expression in invasive carcinoma of the breast. The aim of this confirmatory study is to evaluate stromal CD10 expression in breast carcinoma and to examine associations between CD10, clinicopathological variables, and patient outcome. Tissue microarrays, containing 438 cases of invasive breast carcinoma and 15 cases of ductal carcinoma in situ with 15 years median follow-up time, were assembled. CD10 expression was assessed by immunohistochemistry and scored as negative, weak and strong. Nonparametric correlational tests, univariate and multivariate survival analyses were performed. Stromal CD10 was preferentially expressed in invasive compared to noninvasive breast cancers (P=0.003). There were correlations between stromal CD10 expression and higher tumor grade (P=0.01) and estrogen receptor (ER) negative status (P=0.002). There was no correlation between CD10 and lymph node status, tumor size, histological subtype, progesterone receptors, and Her2 status. Stromal CD 10 expression was associated with decreased long-term disease-specific and overall survival in the entire cohort (P<0.01), and in lymph node negative (P<0.05), but not lymph node positive subset of patients. It approached prognostic significance in multivariate analysis (P=0.06) when lymph node status, tumor size, ER and Her2 were considered in the same model; and was associated with a relative risk of death of 2.8, compared to relative risk of 2.4 for lymph node positive status. Thus, stromal CD10 expression in invasive carcinoma of the breast is associated with ER negativity, higher tumor grade and decreased survival and constitutes a potential prognostic marker and a target for development of novel therapies.

Adult↗

PubMed2006

Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival.

PURPOSE: Estrogen receptor (ER) expression predicts improved breast cancer-specific survival and reduced risk of recurrence and is targeted in breast cancer therapy. A high-quality antibody to identify ER-positive patients plays an important role in clinical decision making for women with breast cancer. This study evaluates immunohistochemistry using two anti-ER antibodies, a new rabbit monoclonal antibody (SP1) and the mouse monoclonal antibody (1D5), in relation to biochemical ER assay results and clinical data on survival and adjuvant systemic therapy. PATIENTS AND METHODS: A population-based tissue microarray series of 4,150 invasive breast cancers was constructed. All patients had staging, pathology, treatment, and follow-up information. The median follow-up was 12.4 years and the median age at diagnosis 60 years. Survival analysis and log-rank tests were used to evaluate the prognostic value of ER status and correlations with clinical data. RESULTS: Among the 4,105 samples interpretable for both antibodies, SP1 detected ER positivity in 69.5% and 1D5 in 63.1% of cases. Both monoclonal antibodies are demonstrated to be good prognostic indictors for breast cancer-specific and relapse-free survival. In multivariate analysis, including age, tumor size, grade, and lymphovascular and nodal status, SP1 was a better independent prognostic factor than 1D5. Among patients with discrepant ER results, the 8% of patients who were SP1 positive/1D5 negative showed good outcomes, and the 2% SP1-negative/1D5 positive had poor outcomes. Maintaining the same 92% specificity and 98% positive predictive value, SP1 is 8% more sensitive than 1D5 using biochemical assay as gold standard. CONCLUSION: SP1 represents an improved standard for ER immunohistochemistry assessment in breast cancer.

Animals↗

PubMed2006

Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts.

PURPOSE: Published reports suggest that DNA microarrays identify clinically meaningful subtypes of lung adenocarcinomas not recognizable by other routine tests. This report is an investigation of the reproducibility of the reported tumor subtypes. METHODS: Three independent cohorts of patients with lung cancer were evaluated using a variety of DNA microarray assays. Using the integrative correlations method, a subset of genes was selected, the reliability of which was acceptable across the different DNA microarray platforms. Tumor subtypes were selected using consensus clustering and genes distinguishing subtypes were identified using the weighted difference statistic. Gene lists were compared across cohorts using centroids and gene set enrichment analysis. RESULTS: Cohorts of 31, 72, and 128 adenocarcinomas were generated for a total of 231 microarrays, each with 2,553 reliable genes. Three adenocarcinoma subtypes were identified in each cohort. These were named bronchioid, squamoid, and magnoid according to their respective correlations with gene expression patterns from histologically defined bronchioalveolar carcinoma, squamous cell carcinoma, and large-cell carcinoma. Tumor subtypes were distinguishable by many hundreds of genes, and lists generated in one cohort were predictive of tumor subtypes in the two other cohorts. Tumor subtypes correlated with clinically relevant covariates, including stage-specific survival and metastatic pattern. Most notably, bronchioid tumors were correlated with improved survival in early-stage disease, whereas squamoid tumors were associated with better survival in advanced disease. CONCLUSION: DNA microarray analysis of lung adenocarcinomas identified reproducible tumor subtypes which differ significantly in clinically important behaviors such as stage-specific survival.

Adenocarcinoma↗

PubMed2006

Immunolocalization of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and type I GnRH receptor during follicular development in the human ovary.

CONTEXT: GnRH and its receptor have been detected at the mRNA level in different ovarian cell types, implicating an autocrine role of the GnRH system in the human ovary. However, the expression at the protein level of GnRH and its receptor in specific cell types during follicular development has not been documented in humans. OBJECTIVE: We evaluated the immunohistochemical expression of GnRH-I (the classical form of mammalian GnRH), GnRH-II (the novel isoform), and the type I GnRH receptor (GnRHR) that is known to bind both forms of GnRH, in ovaries of premenopausal women. MAIN OUTCOME MEASURES: Immunohistochemistry, immunofluorescence, immunoblot assay, and real-time RT-PCR were performed. RESULTS: GnRH-I, GnRH-II, and GnRHR were not immunostained in the follicles from the primordial to the early antral stage. In preovulatory follicles, both forms of GnRH and their common receptor were localized predominantly to the granulosa cell layer, whereas the theca interna layer was weakly positive. In the corpus luteum, significant levels of GnRH-I, GnRH-II, as well as GnRHR were observed in granulosa luteal cells, but not in theca luteal cells. Both GnRH isoforms and the type I GnRHR were localized also to the ovarian surface epithelium from which over 85% of ovarian cancers are thought to be derived. CONCLUSION: The expression of GnRH-I, GnRH-II, and GnRHR protein in the human ovary is temporally and spatially specific and further supports the physiological role of an autocrine regulatory system involving GnRH-I, GnRH-II, and GnRHR in follicular development and corpus luteal function.

Adult↗

PubMed2006

Disruption of the Y-box binding protein-1 results in suppression of the epidermal growth factor receptor and HER-2.

The overexpression of the epidermal growth factor receptor (EGFR) and HER-2 underpin the growth of aggressive breast cancer; still, it is unclear what governs the regulation of these receptors. Our laboratories recently determined that the Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, induced breast tumor cell growth in monolayer and in soft agar. Importantly, mutating YB-1 at Ser(102), which resides in the DNA-binding domain, prevented growth induction. We reasoned that the underlying cause for growth attenuation by YB-1(Ser(102)) is through the regulation of EGFR and/or HER-2. The initial link between YB-1 and these receptors was sought by screening primary tumor tissue microarrays. We determined that YB-1 (n = 389 cases) was positively associated with EGFR (P < 0.001, r = 0.213), HER-2 (P = 0.008, r = 0.157), and Ki67 (P < 0.0002, r = 0.219). It was inversely linked to the estrogen receptor (P < 0.001, r = -0.291). Overexpression of YB-1 in a breast cancer cell line increased HER-2 and EGFR. Alternatively, mutation of YB-1 at Ser(102) > Ala(102) prevented the induction of these receptors and rendered the cells less responsive to EGF. The mutant YB-1 protein was also unable to optimally bind to the EGFR and HER-2 promoters based on chromatin immunoprecipitation. Furthermore, knocking down YB-1 with small interfering RNA suppressed the expression of EGFR and HER-2. This was coupled with a decrease in tumor cell growth. In conclusion, YB-1(Ser(102)) is a point of molecular vulnerability for maintaining the expression of EGFR and HER-2. Targeting YB-1 or more specifically YB-1(Ser(102)) are novel approaches to inhibiting the expression of these receptors to ultimately suppress tumor cell growth.

Breast Neoplasms↗

PubMed2006

A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.

Cell Movement↗

PubMed2006

MDM2 protein expression is a negative prognostic marker in breast carcinoma.

The protein encoded by the MDM2 oncogene inhibits the function of p53, leading to increased cell growth, avoidance of apoptosis, tolerance of genetic instability, and resistance to chemotherapy. The present study was performed to evaluate the relationship between MDM2 protein expression and survival in breast carcinoma. Two series of cases were used in this study: the first to identify the cutoff to be used in the interpretation of MDM2 immunostaining and perform preliminary survival analysis, and a second, independent series, to validate the findings from the first series and to perform multivariate analysis. For both series, archival sections of tissue microarrays were stained with anti-MDM2 antibody (NeoMarkers, Fremont, CA, USA) and MDM2 staining intensity was scored semiquantitatively. In the first series, 49 of 362 (14%) interpretable cases were positive for MDM2 expression, with 35 (10%) showing weak positivity and 14 (4%) strong positivity. Patients with MDM2-positive tumours had a significantly worse disease-specific survival than patients with MDM2-negative tumours (P=0.0022, 10-year DSS 61% (95% CI: 45-73) vs 73% (95% CI: 67-77)). No significant difference in survival was observed between patients with strongly and weakly MDM2-positive tumours (P=0.3). Accordingly, in the independent validation series weak and strong MDM2 positivity were combined and considered to be MDM2 positive. MDM2 expression was seen in 230/1747 (13%) interpretable cases in this series, with a significant difference (P<0.0001) in DSS between MDM2-negative and MDM2-positive cases (10 year DSS 58% (95% CI: 51-64) vs 73% (95% CI: 70-75)). MDM2 was an independent prognostic marker (HR=1.35, P=0.02) in a Cox regression model including MDM2 expression, tumour grade, nodal status, ER status and tumour size. Immunohistochemical studies of MDM2 in more than 2000 breast carcinomas show that MDM2 is an independent negative prognostic marker.

Biomarkers, Tumor↗

PubMed2006

Cell type- and stage-specific changes in HOXA7 protein expression in human ovarian folliculogenesis: possible role of GDF-9.

Homeobox (HOX) genes are important transcriptional regulators in development and in adult tissues. A major obstacle to the understanding of their roles in humans has been the lack of well-defined anti-human HOX antibodies. We generated a thoroughly characterized polyclonal rabbit antibody against human HOXA7 and used it to study the distribution, role, and regulation of HOXA7 in human ovarian folliculogenesis and in granulosa cell tumors. Immunohistochemically, follicles were strongly HOXA7-positive compared with stroma. Oocytes expressed little HOXA7. Granulosa cells were predominantly negative in primordial follicles, had uniformly HOXA7-positive nuclei in primary follicles, and, as follicles matured, the subcellular localization of HOXA7 changed from nuclear to predominantly cytoplasmic. HOXA7 was mainly cytoplasmic in theca interna, but completely absent in theca externa. Granulosa cell tumors were mainly HOXA7 positive and, like in preovulatory follicles and theca interna, staining was predominantly cytoplasmic. The change in HOXA7 expression from negative primordial to positive primary follicles suggested a relationship with granulosa cell proliferation. To test this hypothesis, SV40 Tag-immortalized human granulosa cells (SVOG) were double stained with anti-HOXA7 antibody and with Ki-67 as proliferation marker. HOXA7 expression was highest in mitotic cells. In addition, growth differentiation factor-9 (GDF-9), known to be secreted by oocytes in primary human follicles, up-regulated HOXA7 protein, and stimulated proliferation of SVOG, while TGF-beta1 inhibited HOXA7 expression and proliferation. This is the first report on the expression of any HOX gene in human ovarian follicles and granulosa cell tumors. It shows that HOXA7 undergoes cell type- and stage-specific changes during ovarian folliculogenesis, likely regulates granulosa cell proliferation, and in subcellular location differs between proliferating and secretory cells. The increase in HOXA7 protein in response to GDF-9 represents the first demonstration of a possible regulatory role of oocytes in ovarian follicular HOX gene expression.

Animals↗

PubMed2005

NRG1 gene rearrangements in clinical breast cancer: identification of an adjacent novel amplicon associated with poor prognosis.

Rearrangements of the neuregulin (NRG1) gene have been implicated in breast carcinoma oncogenesis. To determine the frequency and clinical significance of NRG1 aberrations in clinical breast tumors, a breast cancer tissue microarray was screened for NRG1 aberrations by fluorescent in situ hybridization (FISH) using a two-color split-apart probe combination flanking the NRG1 gene. Rearrangements of NRG1 were identified in 17/382 cases by FISH, and bacterial artificial chromosome array comparative genomic hybridization was applied to five of these cases to further map the chromosome 8p abnormalities. In all five cases, there was a novel amplicon centromeric to NRG1 with a minimum common region of amplification encompassing two genes, SPFH2 and FLJ14299. Subsequent FISH analysis for the novel amplicon revealed that it was present in 63/262 cases. Abnormalities of NRG1 did not correlate with patient outcome, but the novel amplicon was associated with poor prognosis in univariate analysis, and in multivariate analysis was of prognostic significance independent of nodal status, tumor grade, estrogen receptor status, and human epidermal growth factor receptor (HER)2 overexpression. Of the two genes in the novel amplicon, expression of SPFH2 correlated most significantly with amplification. This amplicon may emerge as a result of breakpoints and chromosomal rearrangements within the NRG1 locus.

Breast Neoplasms↗

PubMed2005

Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumours.

INTRODUCTION: Phosphorylated Akt (P-Akt) is an attractive molecular target because it contributes to the development of breast cancer and confers resistance to conventional therapies. Akt also serves as a signalling intermediate for receptors such as human epidermal growth factor receptor (HER)-2, which is overexpressed in 30% of breast cancers; therefore, inhibitors to this pathway are being sought. New celecoxib analogues reportedly inhibit P-Akt in prostate cancer cells. We therefore examined the potential of these compounds in the treatment of breast cancer. The analogues were characterized in MDA-MB-453 cells because they overexpress HER-2 and have very high levels of P-Akt. METHODS: To evaluate the effect of the celecoxib analogues, immunoblotting was used to identify changes in the phosphorylation of Akt and its downstream substrates glycogen synthase kinase (GSK) and 4E binding protein (4EBP-1). In vitro kinase assays were then used to assess the effect of the drugs on Akt activity. Cell death was evaluated by poly(ADP-ribose) polymerase cleavage, nucleosomal fragmentation and MTS assays. Finally, tumour tissue microarrays were screened for P-Akt and HER-2 expression. RESULTS: OSU-03012 and OSU-O3013 inhibited P-Akt and its downstream signalling through 4EBP-1 and GSK at concentrations well below that of celecoxib. Disruption of P-Akt was followed by induction of apoptosis and more than 90% cell death. We also noted that the cytotoxicity of the celecoxib analogues was not significantly affected by serum. In contrast, the presence of 5% serum protected cells from celecoxib induced death. Thus, the structural modification of the celecoxib analogues increased P-Akt inhibition and enhanced the bioavailability of the drugs in vitro. To assess how many patients may potentially benefit from such drugs we screened tumour tissue microarrays. P-Akt was highly activated in 58% (225/390) of cases, whereas it was only similarly expressed in 35% (9/26) of normal breast tissues. Furthermore, HER-2 positive tumours expressed high levels of P-Akt (P < 0.01), supporting in vitro signal transduction. CONCLUSION: We determined that Celecoxib analogues are potent inhibitors of P-Akt signalling and kill breast cancer cells that overexpress HER-2. We also defined an association between HER-2 and P-Akt in primary breast tissues, suggesting that these inhibitors may benefit patients in need of new treatment options.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models.

OBJECTIVE: To evaluate subrenal capsule xenografting of primary ovarian tumor tissues in mice for development of new ovarian cancer models. METHODS: Pieces (1 x 3 x 3 mm) of ovarian tumor specimens from patients were meticulously grafted under renal capsules of female NOD/SCID mice within 2 h of surgical removal. Tumor types included papillary serous adenocarcinomas, borderline and benign mucinous cystadenomas, granulosa cell tumors, a serous borderline tumor and a grade 3 mixed surface epithelial tumor of transitional and undifferentiated types. After 1-2 months, grafts were retrieved for comparison with original tissues. Hematoxylin and eosin (H&E) and immunohistochemical staining was carried out using tissue micro-arrays and CEA, B72.3, WT-1, OC125, keratin, inhibin, CK7, CK20, Cam5.2, and MIB-1 as markers. RESULTS: Tumor tissue engraftment rate was > 95%. Comparison of donor and post-graft tissues showed highly similar histopathological features; 91 +/- 5% concordance in immunostaining indicated major preservation of immunophenotypes in the xenografts for 30-60 days. There was a small, but significant, increase in MIB-1 proliferative index in xenografts compared to original specimens. CONCLUSIONS: Subrenal capsule xenografts of primary human ovarian tumors in SCID mice can retain major histopathological and immunohistochemical characteristics of the original tissues. The achievable, consistently high engraftment rate allows use of such xenografts as tools for studying a wide range of ovarian tumors, including granulosa cell tumors and benign, borderline, and malignant surface epithelial neoplasms. Potential applications include preclinical testing of patients' tumor responses to various chemotherapeutic regimens, evaluation of novel therapeutic agents, analysis of tumor progression at cellular and molecular levels, and identification of new therapeutic targets.

Animals↗

PubMed2005

Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling.

OBJECTIVES: The molecular pathogenesis of ovarian serous tumors of low malignant potential (S-LMP) is not well understood, although the collective data suggest that they arise through molecular mechanisms distinct from those leading to conventional serous carcinomas (S-Ca). To further examine the molecular differences between these two diseases, we studied the gene expression pattern of ovarian S-LMP and S-Ca using high-density spotted cDNA and tissue microarrays. METHODS: Total RNA from 23 ovarian S-LMP and S-Ca was analyzed on 43,200 spot cDNA microarrays and the differential expression of proteins encoded by differentially expressed genes was validated using tissue microarrays. RESULTS: Unsupervised hierarchical clustering analysis of filtered data showed a complete separation between S-LMP and S-Ca, based predominantly on a small set of genes expressed at higher levels in S-LMP than in S-Ca. Many genes previously identified as up-regulated in ovarian carcinoma relative to normal ovarian tissue were expressed at even higher levels in S-LMP. These genes included mucin-1, mesothelin, HE4, PAX 8, and apolipoprotein J/clusterin. Immunohistochemical staining of tissue microarrays confirmed higher expression of selected proteins encoded by these genes in the S-LMP. Few genes were expressed at a higher level in S-Ca; these included E2F1, topoisomerase IIalpha, and cyclin E, with higher levels of cyclin E protein confirmed by immunohistochemistry. CONCLUSIONS: S-LMP and S-Ca are distinguished at the molecular level by a relatively small gene set, suggesting the pathogenesis of S-LMP as well as S-Ca may involve molecular pathways that escape detection by global gene expression profiling. In order to obtain biologically and clinically relevant information about the mechanisms involved in ovarian carcinogenesis, future studies based on molecular profiles of ovarian cancer should include analyses of low malignant potential tumors. Inclusion of such tumors is also critical to the evaluation of the efficacy of potential new diagnostic and/or therapeutic biomarkers.

Adult↗

PubMed2005

An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line.

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.

Aged↗

PubMed2005

Description of a novel system for grading of endometrial carcinoma and comparison with existing grading systems.

The most widely used system for grading of endometrial carcinoma is the International Federation of Gynecology and Obstetrics (FIGO) grading system. This grading system requires evaluation of histologic features that are difficult to assess reproducibly. Two hundred and two cases of endometrial carcinoma, treated by hysterectomy, were retrieved from the archives of Vancouver General Hospital (1983-1998). For each tumor, the architectural pattern, nuclear grade, and mitotic index were assessed. The tumor architectural pattern, nuclear grade, and mitotic index were significant predictors of patient outcome (P < 0.0001 for each, by univariate analysis). There were no prognostic differences between patients having predominantly solid versus papillary tumors, or tumors with mild versus moderate nuclear atypia. The tumors were then classified into high and low grade based on assessment of these three features. The presence of at least two criteria of these three: 1) predominantly papillary or solid growth pattern, 2) mitotic index > or =6/10 high power fields, or 3) severe nuclear atypia, resulted in a tumor being considered high grade. Low-grade tumors satisfied at most one of those criteria. The proposed grading system was found to be an independent predictor of patient outcome when patient survival was adjusted for FIGO stage, patient age, and tumor cell type. It also had more prognostic power than other grading systems tested when it was applied to all tumors, regardless of their cell type; however, the FIGO grading system was superior for prognostication when only carcinomas of endometrioid type were considered. With the FIGO grading system, no significant difference in survival was observed between patients with grade 1 and grade 2 tumors. Combining FIGO grades 1 and 2 results in a binary system (grades 1 and 2 vs. grade 3) that was the most prognostically significant grading system tested, with the additional advantages of being highly reproducible and familiar to practicing pathologists.

Adult↗

PubMed2005

Synchronous and metachronous endocervical and ovarian neoplasms: evidence supporting interpretation of the ovarian neoplasms as metastatic endocervical adenocarcinomas simulating primary ovarian surface epithelial neoplasms.

The vast majority of endocervical adenocarcinomas are high-risk human papillomavirus (HPV)-related neoplasms, characterized by p16 expression and frequent loss of hormone receptor expression, which infrequently metastasize to the ovaries. We report 10 cases of endocervical adenocarcinomas with ovarian metastases in which the ovarian tumors simulated primary ovarian surface epithelial neoplasms. The presence of HPV DNA was assessed to determine whether the ovarian neoplasms were metastases or independent neoplasms. Immunohistochemistry for hormone receptors and p16 was also performed. The ovarian metastases presented concurrently with the primary endocervical tumors in 5 cases, subsequent to the endocervical tumors in 3 cases, and prior to diagnosis of the endocervical tumors in 2 cases. The ovarian tumors ranged in size from 2 to 30 cm, with tumors in 7 cases measuring 10 cm or greater. The ovarian tumors were unilateral in 8 cases and bilateral in 2. In all cases, the ovarian tumors were initially diagnosed as or thought to represent independent primary ovarian surface epithelial tumors (atypical proliferative [borderline] tumors or well-differentiated carcinomas of endometrioid or mucinous type). The endocervical tumors ranged in size from microscopic foci to 3 cm, with depth of invasion ranging from 0.2 to 1.5 cm; in 2 cases, the invasive foci qualified as microinvasive according to Federation Internationale de Gynecologie et d'Obstetrique staging criteria for cervical carcinoma. Adenocarcinoma in situ was identified in all tumors. In all cases, the paired endocervical and ovarian tumors contained identical HPV types. All evaluable tumors were diffusely positive for p16; and in 8 cases, there was absent or only limited expression of hormone receptors. Two of the minimally invasive endocervical tumors were initially interpreted as adenocarcinoma in situ and not recognized as unequivocally invasive even when evaluated in conjunction with the histologically identical ovarian tumors. HPV DNA detection in the ovarian tumors of 2 patients without known cervical disease led to discovery of occult cervical adenocarcinomas in those patients. Endocervical adenocarcinomas, including some qualifying as microinvasive, can metastasize to the ovaries and simulate primary ovarian surface epithelial neoplasms. The presence of HPV DNA in these ovarian tumors confirms that they are metastatic endocervical adenocarcinomas.

Adenocarcinoma↗

PubMed2005

Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma.

The human epidermal growth factor receptor (Her) family of receptor tyrosine kinases includes Her-1, Her-2, and Her-3. The overexpression of Her-1 and Her-2 have been reported previously in surface epithelial ovarian cancer. Although up to one-third of ovarian carcinomas have been found to have amplification or overexpression of Her-2, responses to trastuzumab therapy in these patients have been disappointing. In this study, we examined Her-1, Her-2, and Her- 3 protein expression as well as the frequency of Her-2 amplification in a series of 103 high-grade, advanced-stage (FIGO stage III or IV) ovarian surface epithelial carcinomas. Immunohistochemical staining using commercially available antibodies against Her-1-3 and fluorescence in situ hybridization (FISH) using probes against Her-2 and chromosome 17 centromere (CEP) were performed on a tissue microarray containing cores of tumor from 103 surface epithelial carcinomas (85 serous, 6 mixed surface epithelial, 5 clear cell, 3 endometrioid, 3 undifferentiated, 1 mucinous). Nine of 99 (9.1%) tumors were positive for Her-1 expression and 5 of 102 (4.9%) tumors were positive for Her-2 expression, with 1 showing strong immunoreactivity. None of the Her-1 positive tumors exhibited Her-2 immunoreactivity. There was no correlation between Her-1 or Her-2 expression and survival. Using Her-2:centromere fluorescence ratios of 2.0 or 1.5 as cutoffs in assessment of Her-2 amplification, 8 of 75 (10.7%) and 25 of 75 (33.3%) tumors, respectively, showed Her-2 amplification. Two of eight tumors that showed higher level (>2) Her-2 amplification by FISH also were positive for Her-2 by immunohistochemistry. Only 3 of 103 tumors expressed Her-3. Immunoreactivity for Her-1 and Her-2 was less frequently observed in this series than has been previously reported. The strong correlation between Her-2 immunostaining and amplification characteristic of breast carcinoma is not seen in ovarian carcinoma. These results indicated that few patients with ovarian carcinoma have tumors that would benefit from therapy targeted specifically against Her-1, Her-2, or Her-3.

Biomarkers, Tumor↗

PubMed2005

Aggressive behavior of stage I ovarian mucinous tumors lacking extensive infiltrative invasion: a report of four cases and review of the literature.

Previous studies have indicated that mucinous carcinomas of the ovary associated with extraovarian spread at the time of presentation or follow-up almost always have extensive infiltrative invasion within the primary tumor. We present four cases of stage I ovarian mucinous tumors that lacked extensive infiltrative invasion but were associated with an unexpectedly aggressive behavior. The patients were 18, 20, 41, and 45 years of age at presentation. All four of them presented with an abdominal mass or increased abdominal girth. The tumors were all stage Ia, 17 to 37 centimeters in maximal dimension, and typically multicystic with solid areas. The number of blocks per centimeter of tumor diameter was 0.65, 0.88, 0.92, and 1.0 in the four tumors, respectively, a degree of sampling within that recommended in previous studies. Clinical findings supported that they were primary tumors rather than metastatic from an occult primary tumor. On microscopic examination, the tumors all contained foci of intraepithelial carcinoma and foci of invasion as follows: expansile invasion only (two cases), expansile invasion and microinvasive carcinoma (one case), and microinvasive carcinoma only (one case). The expansile invasion was extensive in each of the three cases in which it was present. On follow-up, each patient experienced recurrent disease 7 months to 4.5 years after diagnosis, including hematogenous spread to lung and/or bone and liver in three patients. Three of four patients developed intraperitoneal spread. Three of four patients died of disease, and one patient is alive with persistent disease. Although ovarian mucinous tumors with only expansile invasion or only microinvasive carcinoma are usually associated with an excellent prognosis, this study indicates that these tumors can rarely behave in an aggressive fashion with hematogenous spread and a fatal outcome. Some of these tumors may have contained unsampled foci of infiltrative invasion. Although the optimum level of sampling in mucinous tumors remains to be determined, we recommend additional sampling of tumors in which the initial sections reveal intraepithelial carcinoma, microinvasive carcinoma, expansile invasion, or combinations thereof.

Adenocarcinoma, Mucinous↗

PubMed2004

Gain of OGP, an estrogen-regulated oviduct-specific glycoprotein, is associated with the development of endometrial hyperplasia and endometrial cancer.

PURPOSE: Lesions in the endometrium are difficult to differentially diagnose. The present study examined whether oviduct-specific glycoprotein is differentially expressed in normal, hyperplastic, and malignant endometrium. EXPERIMENTAL DESIGN: The expression of oviduct-specific glycoprotein was characterized by immunohistochemical methods with whole sections of endometrium from 90 women. An endometrial cancer tissue microarray with 200 cases of endometrial cancer was also assessed for oviduct-specific glycoprotein, estrogen receptor, and PTEN expression. RESULTS: In normal endometrium, there was focal oviduct-specific glycoprotein expression in the basalis layer, where the stem cells reside, in 10 of 15 cases. On average, atypical hyperplastic endometria stained more intensely than hyperplastic endometria (P = 0.017), whereas the percentage of positively stained cells was not significantly different. The mean staining indices (intensity x percentage of positive cells score) for hyperplasia and atypical hyperplastic were 4.7 and 5.5 and were significantly higher than staining indices seen in normal cycling endometria or well-differentiated endometrioid endometrial carcinomas (P < 0.0001 and P < 0.001, respectively). The endometrial cancer tissue microarray showed that of 139 endometrioid endometrial carcinomas, 11 cases were strongly oviduct-specific glycoprotein positive, whereas the other 128 cases were negative or weakly positive. Analysis of Kaplan-Meier curves with log-rank statistics showed a trend toward significance, with strong oviduct-specific glycoprotein staining serving as a predictor of good prognosis (P = 0.1). There was a significant positive correlation between oviduct-specific glycoprotein staining and loss of PTEN in the cases of endometrial cancer (P = 0.004). CONCLUSIONS: Oviduct-specific glycoprotein may be a useful diagnostic adjunct to more accurately classify premalignant and early malignant change in the endometrium, improving on the current irreproducible histologic classification system.

Adenocarcinoma↗