ABSTRACT
Ovarian carcinoma is the most lethal type of gynecologic malignancy in the Western world. Majority of early stage ovarian cancers are asymptomatic and this is the main reason that more than two-thirds of patients are diagnosed with advanced disease. Ovarian tumors are heterogeneous and the different histologic subtypes are further classified as benign, borderline (low-grade) and malignant (high-grade) to reflect their behavior. The aim of the study was to analyze gene expression profiles in three histologic types of ovarian carcinoma in an attempt to find the molecular differences among serous, endometrioid and clear cell subtypes. The analysis of gene expression was performed on 57 samples of ovarian carcinoma. RNA was isolated from the ovarian cancer tissues. The gene expression changes were determined by microarray analysis and quantitative real time polymerase chain reaction (qRT-PCR). Measurement of relative gene expression levels was used to identify molecular differences among three histologic types of ovarian carcinoma (clear-cell, endometrioid and serous). Unsupervised statistical analysis revealed four biological subtypes among three histotypes under study. The endometrioid ovarian carcinoma was divided into two molecular subtypes. The biggest molecular differences were observed between clear-cell and serous carcinomas (1070 genes, FDR 0.05), the smallest between endometrioid and serous carcinomas (81 genes, FDR 0.05). The biggest group of differentially expressed genes was involved in transport and metabolism. This finding can explain the differences in the response to chemotherapy observed among different histologic types of ovarian carcinomas. In conclusion, we found TCF2 (HNF1B) gene as a suitable marker for ovarian clear cell carcinoma. Gene expression profiling also shed light on the molecular mechanisms of different chemoresistance among the analyzed histotypes.
Subject(s)
Adenocarcinoma, Clear Cell/genetics , Carcinoma, Endometrioid/genetics , Cystadenocarcinoma, Serous/genetics , Ovarian Neoplasms/genetics , Transcriptome , Cell Movement , Female , Hepatocyte Nuclear Factor 1-beta/genetics , Humans , Neoplasm Invasiveness , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain ReactionABSTRACT
Ovarian tumors from two patients, compatible by histological and immunohistochemical criteria with small cell carcinoma of hypercalcemic type (SCCHT) (WT1+, EMA dispersed+, synaptophysin+ or dispersed+), were extensively sampled in order to find clues to their histogenesis. Subsequently, small foci of immature teratoma were found in both of them (in 1/122 and in 3/80 tumor sections). In one case, microfoci of yolk sac tumor were also present within the teratoma area as well as in the background of the small cell tumor population - in the primary tumor and in omental metastasis. We found a resemblance of the microscopic patterns of SCCHT and atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system, and this prompted us to evaluate INI-1 and SMARCA4 immunohistochemical expression, because their alternative loss is regarded as a molecular hallmark of AT/RT. INI-1 expression was retained, while that of SMARCA4 was lost. We therefore analyzed tumor DNA by PCR amplification and sequencing for mutations in the SMARCA4 gene (NG_011556.1), which were identified in both tumors (c.2184_2206del; nonsense c.3277C>T - both in one tumor; nonsense c.3760G>T in another tumor). These data suggest that SCCHT is most likely an embryonal tumor originating from immature teratoma and related to malignant rhabdoid tumor. Further analyses are necessary to determine whether the tumors diagnosed as SCCHT constitute a homogeneous group or represent more than one entity.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Small Cell/genetics , DNA Helicases/genetics , Gene Expression Regulation, Neoplastic , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adult , Biomarkers, Tumor/metabolism , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , Carcinoma, Small Cell/surgery , DNA Helicases/metabolism , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Diagnosis, Differential , Female , Gene Silencing , Germ-Line Mutation , Humans , Nuclear Proteins/metabolism , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Pilot Projects , Pregnancy , Prospective Studies , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , Sequence Analysis, DNA , Teratoma/genetics , Teratoma/pathology , Transcription Factors/metabolismABSTRACT
It has been reported that a highly conserved human protein PUMILIO2 forms a complex with NANOS1 in human male germ cells, as does the Drosophila ancestor Pumilio, which binds Nanos to regulate translation of specific mRNAs. Here, we found that PUMILIO2 interacts also with SNAPIN, a modulator of SNARE complex assembly, which is involved in vesicle trafficking. We demonstrated that SNAPIN interacts additionally with NANOS1 protein. This is the first report demonstrating that the N-terminal region of NANOS1 is necessary for protein binding. In human testis, SNAPIN co-localizes with PUMILIO2 and NANOS1 in prenatal and also in spermatogenic germ cells of the adult. We describe for the first time the expression of SNAPIN in germ cells which raises possibility that SNAPIN plays an extra role in mammals which is germ cell specific. The presence of a coiled-coil domain responsible for protein-protein interaction could enable SNAPIN to be an adaptor of PUMILIO2 and NANOS1, binding other factors to regulate translation in the development of the human germ cells.
Subject(s)
Germ Cells/metabolism , RNA-Binding Proteins/metabolism , Vesicular Transport Proteins/metabolism , Amino Acid Sequence , Animals , Cell Line , Humans , Immunohistochemistry , Immunoprecipitation , In Vitro Techniques , Male , Mice , Molecular Sequence Data , Protein Binding , Seminiferous Tubules/metabolism , Sequence Homology, Amino Acid , Two-Hybrid System Techniques , Vesicular Transport Proteins/chemistryABSTRACT
Cervical cancer incidence and mortality in Poland is among the highest in Europe. To investigate infection with different human papillomaviruses (HPV) in Warsaw, Poland, we obtained cervical cell specimens from 834 women aged 18-59 years from the general population, and 88 cervical cancers. DNA of 44 HPV types was detected using a GP5+/6+-based PCR assay. HPV prevalence was 16.6% in the general female population, being highest (24.2%) in women aged 25-34 years, notably among unmarried women (37.3%). HPV prevalence fell to 8.6% at ages 55-59. High-risk HPV prevalence was 11.3%, with HPV16 being the most common type (3.7%). All but one cervical cancer were high-risk HPV-positive, although the importance of HPV16 (73%) was much greater, and multiple infections fewer (1%), than among HPV-positive women in the general female population. In summary, we report a relatively high burden of HPV infection in Warsaw, Poland, where 79% of cervical cancers are theoretically preventable by HPV16/18 vaccines.
Subject(s)
Papillomavirus Infections/epidemiology , Uterine Cervical Dysplasia/epidemiology , Uterine Cervical Neoplasms/epidemiology , Adolescent , Adult , Age Distribution , Alphapapillomavirus/isolation & purification , Female , Humans , Marital Status/statistics & numerical data , Middle Aged , Neoplasm Invasiveness , Poland/epidemiology , Prevalence , Risk Factors , Sexual Partners , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/virologyABSTRACT
The TP53 gene mutational spectrum in human tumours shows variations related to tissue of origin, carcinogen exposure or molecular background. We have compared TP53 mutations in ovarian carcinomas from different geographical regions; this study was based on data extracted and verified from the IARC database (R10, 2005), and on our results from 127 carcinomas. In total 873 mutations were evaluated. Tumours from Japan and Korea had a higher frequency of exon 7 mutations (38%vs 25%, p = 0.011) and lower frequency of exon 8 mutations (11%vs 29%, p = 0.0003) than those from Western countries; they were particularly different from Norwegian tumours which showed the lowest proportion of exon 7 (19%, p = 0.001) and highest proportion of exon 8 (37%, p < 0.0001) mutations. There were also differences in the profile of TP53 hotspots. The third hotspot in tumours from Poland was amino acid (AA) 176 (8.2% of substitutions vs 1.7% in other countries, p < 0.001), while in tumours from the UK it was AA 220 (8.9%vs 2.3%, p < 0.001). Codon 273 was the only apparent hotspot in the Norwegian tumours, while it was rarely mutated in Polish and Asian tumours. In contrast to other data tumours from Norway presented with 273(HIS) codon (82% of mutations at AA 273, p = 0.002), while tumours from the UK shared the 273(CYS) codon (80%, p < 0.001). Further analysis of TP53 gene mutations in ovarian cancer by geography could provide greater insights.
Subject(s)
Genes, p53/genetics , Genetic Variation , Mutation/genetics , Ovarian Neoplasms/genetics , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Mucinous/genetics , Adenocarcinoma, Mucinous/pathology , Amino Acid Substitution/genetics , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/pathology , Codon/genetics , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/pathology , Exons/genetics , Female , Geography , Humans , Ovarian Neoplasms/pathology , Polymorphism, Single-Stranded ConformationalABSTRACT
OBJECTIVE: We aimed to evaluate frequency of PTEN mutation, LOH and expression in ovarian tumors. In search for a molecular pathway, we confronted PTEN gene mutations with TP53, K-RAS and BRCA1 gene status in the same tumors. We also evaluated clinical significance of PTEN expression in a subgroup of patients uniformly treated with platinum-based regimens. METHODS: Molecular analysis was performed on 105 ovarian tumors (100 carcinomas) with the use of the SSCP and sequencing. Seventy-six tumors were analyzed for LOH at 10q23 locus with the use of six polymorphic markers. Immunohistochemical PTEN expression was done on paraffin-embedded material. Multivariate and univariate analysis was performed with the STATA program. RESULTS: PTEN mutations occurred in 5/100 (5%) of all carcinomas and in 3/15 (20%) of endometrioid carcinomas (EC). Low-grade EC that developed in borderline tumors had PTEN and/or K-RAS mutation (4/5, 80%), while high-grade EC had TP53 mutations only. There was a reverse association between PTEN and TP53 mutations (P = 0.005). LOH at PTEN locus was found in 60% of endometrioid and in 28% of serous and clear cell carcinomas. PTEN expression did not associate with PTEN mutations or LOH. Strong PTEN expression diminished risk of death in a TP53 positive group only (HR = 0.35, P = 0.029). CONCLUSION: Our results suggest that PTEN mutations may play a role in a development of low-grade endometrioid tumors. PTEN haploinsufficiency caused by LOH or epigenetic events may possibly contribute to development of other histological types and may be an adverse prognostic factor.
Subject(s)
Genes, BRCA1 , Genes, p53 , Genes, ras , Loss of Heterozygosity , Mutation , Ovarian Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/metabolism , Female , Humans , Immunohistochemistry , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , PTEN Phosphohydrolase/biosynthesisABSTRACT
ERBB2 expression has been found in 19 to 44% of ovarian carcinomas; however, its predictive value has not been demonstrated, and trastuzumab has not found clinical application in ovarian cancer patients. We evaluated clinical significance of ERBB2 expression in relation to TP53 accumulation in ovarian carcinoma patients treated with platinum-based regimens. Immunohistochemical analysis with CB11 and a novel NCL-CBE356 antibody (against the internal and external domains of ERBB2, respectively) was performed on 233 tumours (FIGO stage IIB-IV); the US Food and Drug Administration-approved grading system with 0 to 3+ scale was used for evaluation, and the results were analysed by the Cox and logistic regression models. In all, 42% of the tumours expressed (category 1+, 2+ or 3+) either CB11 or CBE356 or both (CB11/CBE356 parameter). Associations between ERBB2 expression and clinical factors were observed only if tumours with staining category 1+ were grouped together with tumours showing staining categories 2+ and 3+. CB11/CBE356 parameter had a better predictive value than CB11 alone. CB11/CBE356 expression was negatively associated with platinum sensitivity (PS) in the TP53(-) group (P=0.022) and with disease-free survival (DFS) in the TP53(+) group (P=0.009). Our results may suggest that trastuzumab should be given postoperatively to patients with TP53(-)/ERBB2(+) ovarian carcinomas to enhance PS, and after completion of chemotherapy to patients with complete remission and TP53(+)/ERBB2(+) carcinomas to extend DFS time (in total to 30.4% of all patients analysed). Thus, novel criteria for ovarian cancer patient inclusion for clinical trials with trastuzumab should be considered and tested.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Tumor Suppressor Protein p53/metabolism , Adult , Aged , Antibodies, Monoclonal , Epitopes/immunology , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/immunology , Prognosis , Receptor, ErbB-2/immunologyABSTRACT
BACKGROUND: The prognostic and predictive value of cell cycle regulatory proteins in ovarian cancer has not been established. We evaluated the clinical and biological significance of P21(WAF1), P27(KIP1), C-MYC, TP53 and Ki67 expressions in ovarian cancer patients. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 204 ovarian carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV treated with platinum-based chemotherapy. Multivariate analysis with Cox and logistic regression models was performed in the whole group, and in the TP53-negative and TP53-positive subgroups. RESULTS: High P21(WAF1) labeling index (LI) was an independent positive predictor of platinum-sensitive response (P = 0.02). Overall survival was positively influenced by P21(WAF1) LI (P = 0.02) or by P21(WAF1) plus P27(KIP1) LI (P = 0.004) in the TP53-negative group only. Ki67 LI showed borderline association with disease-free survival (P = 0.05). Growth fraction was negatively associated with P21(WAF1) and P27(KIP1) indices in the TP53-negative group (P = 0.023 and 0.008, respectively), and these associations were borderline or lost in the TP53-positive group. Endometrioid and clear cell carcinomas differed from other carcinomas by having a low incidence of TP53 accumulation, a high incidence of C-MYC overexpression (70%) and a low median Ki67 LI (all with P <0.001). CONCLUSIONS: We have shown an independent predictive value of P21(WAF1) LI in ovarian carcinoma patients. The prognostic value of P21(WAF1) and P21(WAF1) plus P27(KIP1) LI was determined by TP53 status. A high frequency of C-MYC overexpression in endometrioid and clear cell carcinomas may suggest its role in the development of these tumor types.
Subject(s)
Carcinoma/drug therapy , Carcinoma/genetics , Cell Cycle Proteins/biosynthesis , Cyclins/biosynthesis , Gene Expression Regulation, Neoplastic , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Proto-Oncogene Proteins c-myc/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Proteins/biosynthesis , Adult , Aged , Carcinoma/pathology , Cell Cycle Proteins/analysis , Cyclin-Dependent Kinase Inhibitor p21 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclins/analysis , Enzyme Inhibitors , Female , Genes, Tumor Suppressor , Humans , Middle Aged , Ovarian Neoplasms/pathology , Prognosis , Proto-Oncogene Proteins c-myc/analysis , Retrospective Studies , Treatment Outcome , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Proteins/analysisABSTRACT
In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatin-based chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB-IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P=0.005) or the only (in FIGO IIIC, P=0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(-) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P=0.047) and by BCL2 expression in the TP53(-) group (P=0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P=0.049); its loss was found with advancing FIGO stage (P=0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Gene Expression Regulation, Neoplastic , Mitogen-Activated Protein Kinase Kinases/biosynthesis , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Protein Serine-Threonine Kinases/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Adult , Aged , Cisplatin/administration & dosage , Disease-Free Survival , Female , Humans , Immunohistochemistry , MAP Kinase Kinase 1 , Middle Aged , Mitogen-Activated Protein Kinase Kinases/analysis , Neoplasm Staging , Ovarian Neoplasms/pathology , Predictive Value of Tests , Prognosis , Protein Serine-Threonine Kinases/analysis , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins c-bcl-2/analysis , Regression Analysis , Treatment Outcome , Tumor Suppressor Protein p53/analysis , bcl-2-Associated X ProteinABSTRACT
We looked for NBS1 gene (602667) alterations and changes in nibrin expression in 162 human gynaecological tumours, mostly ovarian. Exons 6-8 and 10 of the NBS1 gene were evaluated by the SSCP and direct sequencing method. Nibrin expression was detected immunohistochemically with the use of the p95NBS1 (Ab-1) antibody. The 657del5 mutation (Slavic mutation) was found in two of 117 carcinomas studied (1.7%) - in both cases it was present in the germline; one of these tumours showed loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. We have found three types of novel germline intron variants: (1) two concomitant transitions (G to A) at bases 14009 and 14256; (2) C to T transition at base 13998; (3) G to C transversion at base 20035. Among the carcinomas studied, the intron variants were associated with a clear cell histological type (p = 0.004). Our results may suggest that NBS1 gene alterations contribute to the development of rare ovarian carcinomas. LOH for 657del5 in tumour tissue may support the hypothesis that the NBS1 gene functions as a tumour suppressor.
Subject(s)
Abnormalities, Multiple/genetics , Cell Cycle Proteins/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , Abnormalities, Multiple/pathology , Antibodies/metabolism , Base Sequence , Carcinoma/pathology , Cell Cycle Proteins/metabolism , Exons , Female , Gene Deletion , Humans , Introns , Loss of Heterozygosity , Molecular Sequence Data , Nuclear Proteins/metabolism , Ovarian Neoplasms/pathology , Polymorphism, Single-Stranded ConformationalABSTRACT
Changes in cell survival contribute to tumour development, influence tumour biology and its response to chemotherapy. p53 gene alterations should negatively affect apoptosis by impaired p53-dependent apoptotic response. We looked for associations between spontaneous apoptosis, p53 gene mutation, p53 protein accumulation, growth fraction, bcl-2 expression and histological parameters in 64 ovarian, four tubal and three peritoneal carcinomas. Apoptotic cells were detected with the TUNEL method. p53 gene variants were detected by the single-strand conformation polymorphism and were sequenced directly. P53, Ki-67 and bcl-2 protein expressions were detected immunohistochemically. A weighed multiple logistic regression model was applied. Apoptotic index (AI) ranged 0.02-0.18 (mean 0.11); proliferation index (PI) ranged 3-90% (mean 54%). p53 gene mutations were present in 51, p53 protein accumulation in 46, and diffuse bcl-2 expression in 29 of 71 tumours. The AI was positively associated with the presence of p53 gene mutation (P = 0.011). However, the PI included into the analysis did positively influence the AI (P = 0.02) and diminished the association with p53 gene mutation (P = 0.082). The AI was negatively associated with good histological differentiation (P = 0.0006), the serous tumour type (P = 0.002), and diffuse bcl-2 expression (P = 0.025). Strong bcl-2 expression was associated with endometrioid tumour type (P = 0.002). FIGO stage and p53 protein accumulation were the only parameters that influenced overall survival time. Thus, our results suggest that histological tumour type and grade are major determinants of spontaneous apoptosis in ovarian carcinomas; p53 alterations do not adversely but rather positively affect spontaneous apoptosis by increasing growth fraction. This, in turn, suggests p53-independency of spontaneous apoptosis in ovarian carcinomas.
Subject(s)
Apoptosis/genetics , Cell Division/genetics , Genes, p53 , Ovarian Neoplasms/pathology , Adolescent , Adult , Aged , Female , Genes, bcl-2 , Humans , Middle Aged , Ovarian Neoplasms/genetics , Survival AnalysisABSTRACT
Desmin is a marker of smooth and striated muscle, but evidence is accumulating that it may be expressed by human mesothelium. The aim of this study was to describe desmin expression in normal, reactive, and hyperplastic peritoneal mesothelium, and to evaluate its potential use as a marker for differentiating between epithelial and mesothelial proliferations. We immunohistochemically studied 27 tissue specimens (from 22 patients) with reactive mesothelium, including omentum (n = 14), fallopian tubes (n = 7), ovaries (n = 3), ascitic fluid (n = 1), and peritoneal washings (n = 2). Ovarian surface epithelium (OSE) from 9 cases and 28 ovarian surface epithelial tumors was evaluated for comparison. The desmin expression pattern in the mesothelium, which was similar to but less consistent than that of cytokeratins, was evident in flat and reactive mesothelium, including hyperplastic mesothelial sheets and mesothelium entrapped in clefts. Mesothelial pseudoglandular structures, present in three cases, were predominantly negative for desmin. Desmin expression was observed in the OSE in 4 of 9 cases but not in any mullerian-derived epithelium or mullerian type tumor. Thus, in contrast to cytokeratins, desmin discriminated mesothelial cells from mullerian type epithelia. Compared with vimentin, desmin discriminated mesothelial cells from other tissues except muscle cells. We conclude that desmin may be used in addition to cytokeratins and vimentin as a marker of peritoneal mesothelium.
Subject(s)
Desmin/analysis , Fallopian Tubes/chemistry , Ovary/chemistry , Peritoneum/chemistry , Ascitic Fluid/chemistry , Epithelium/chemistry , Epithelium/pathology , Female , Humans , Hyperplasia , Immunohistochemistry , Keratins/analysis , Omentum , Peritoneum/pathology , Vimentin/analysisABSTRACT
Twenty three old male patient was diagnosed as a pineal gland tumor and was operated in neurosurgical ward. He died four weeks later due to pneumonia and respiratory failure. Clinical diagnosis was based on computer tomography (CT) and magnetic resonance image (MRI) examination. Histological study of a biopsy and autopsy specimens showed embryonal carcinoma with yolk sac tumor differentiation. The diagnosis was supported by positive cytokeratin, placental alkaline phosphate and alpha-fetoprotein immunostainings.
Subject(s)
Brain Neoplasms/pathology , Carcinoma, Embryonal/pathology , Endodermal Sinus Tumor/pathology , Neoplasms, Multiple Primary/pathology , Pineal Gland/pathology , Adult , Fatal Outcome , Humans , MaleABSTRACT
Neuroendocrine tumors are a heterogeneous group of separate clinico-pathological entities which have a common characteristic i.e. expression of endocrine differentiation potential. In the ovary, the term "neuroendocrine" relates mainly to widely known carcinoids, but it may also be applied to rare neuroendocrine carcinomas of non-small-cell type and small cell carcinomas of pulmonary type. Ovarian carcinoids develop in pure form or in association with other tumors, mainly teratomas. They originate from endocrine cells, either of teratomatous origin or possibly also indigeneous. Ovarian neuroendocrine carcinomas belong most probably to surface epithelial neoplasms, which express endocrine pathway of differentiation. The neuroendocrine carcinomas of non-small-cell type are characterized by the presence of islands, sheets, and trabeculae with little intervening stroma (organoid growth pattern) and cellular homogeneity. However, they are higher-grade than carcinoids. To date, eight ovarian neuroendocrine carcinomas have been described, and all developed in association with glandular müllerian type component. The neuroendocrine differentiation was confirmed by presence of at least two specific markers (argyrophilia and/or argentaffinity, chromogranin A). Initial observations suggest that the presence of neuroendocrine differentiation carries bad prognosis. Primary ovarian small cell carcinomas of the pulmonary type do not differ histologically from their counterparts in other organs. They are composed of small cells with scanty cytoplasm and oval to spindle-shaped nuclei. About 13 cases of this tumor type in the ovary have been reported. Some of them developed in pre-existing benign or malignant ovarian tumors. Argyrophilia and positive chromogranin A staining were seen in two cases only. The prognosis for this tumor type is poor.
Subject(s)
Neuroendocrine Tumors/classification , Neuroendocrine Tumors/pathology , Ovarian Neoplasms/classification , Ovarian Neoplasms/pathology , Carcinoid Tumor/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Small Cell/pathology , Female , Humans , Lung Neoplasms/pathologyABSTRACT
The clonality of disseminated serous carcinoma involving the ovary, peritoneum, and, occasionally, the endometrium is controversial. Histopathologic examination alone cannot unequivocally distinguish between a monoclonal origin and a multicentric origin. Two patients with peritoneal serous carcinoma with minimal ovarian involvement (one with endometrial serous carcinoma), nine patients with stage III bilateral ovarian carcinoma, and one patient with stage III bilateral carcinosarcoma were studied for clonality. One patient with ovarian carcinoma that recurred after chemotherapy was also studied. Previous analyses of single frozen tumor specimens from these patients had identified different p53 gene mutations in each patient. To test the hypothesis that the disseminated cancers had a monoclonal origin, we assayed DNA from numerous foci from each patient to determine whether the known p53 mutation was present in each specimen. Identical mutations were detected in the tumor foci from each patient with peritoneal dissemination and minimal ovarian involvement, including one patient with an endometrial serous carcinoma as well. In all the patients with bilateral ovarian cancer, the genetic change in p53 was identical in both ovarian tumors. Genetic progression was observed in two patients, one of whom showed a loss of heterozygosity involving the p53 gene in a recurrent tumor. In the second patient, a p53 mutation not present in either ovarian tumor was detected in a metastatic tumor from the omentum. These results strongly suggest that disseminated serous carcinomas, whether primary in the ovary, endometrium, or peritoneum, are of monoclonal rather than multicentric origin; that bilateral stage III ovarian cancers are typically of monoclonal origin; and that additional genetic events involving p53 might occur during progression of these tumors.
Subject(s)
Cystadenocarcinoma, Serous/pathology , Endometrial Neoplasms/pathology , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Aged , Cystadenocarcinoma, Serous/genetics , Endometrial Neoplasms/genetics , Female , Humans , Middle Aged , Mutation , Ovarian Neoplasms/genetics , Peritoneal Neoplasms/genetics , Polymorphism, Single-Stranded ConformationalABSTRACT
Mutations of the p53 gene are common in human ovarian carcinomas; however, their role in the early development of ovarian cancer is unclear. Twelve ovarian borderline tumors (BTs; eight of them p53 immunopositive) and 10 stage I carcinomas (four of them p53 immunopositive) were studied for genetic alterations in the p53 gene. The study was based on single-strand conformation polymorphism (SSCP) analysis and DNA sequencing of exons 2 through 11 of the p53 gene using DNA preparations from microdissected tumors. Mutations were found in 40% of the carcinomas (including a borderline component adjacent to carcinoma in one lesion) but in none of the pure BTs. These findings suggest that p53 mutations may not be commonly associated with the borderline phenotype of ovarian epithelial tumors but may occur during malignant transformation.
Subject(s)
Genes, p53 , Mutation , Ovarian Neoplasms/genetics , Tumor Suppressor Protein p53/analysis , Adult , Aged , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/pathology , Polymorphism, Single-Stranded ConformationalABSTRACT
Seventy-nine ovarian serous and mucinous borderline tumors, 36 stage I carcinomas and 39 stage II-IV carcinomas were studied for p53 protein accumulation with monoclonal antibody PAb1801.p53 protein was expressed in 14% of borderline tumors, 36% of stage I carcinomas, and 64% of higher stage carcinomas. All immunopositive carcinomas accumulated p53 protein in the primary tumor, and 95% of them showed concordance in staining among different tissue blocks. A difference in frequency of p53 protein accumulation between stage I and higher stage serous carcinomas was not statistically significant. p53 positivity was associated with microinvasion, microcarcinoma and coexistent carcinoma in mucinous borderline tumors (P = .025). An association between p53 protein expression and poor tumor differentiation in Stage I carcinomas as statistically significant (P = .03). p53 positivity was observed in a poorly differentiated endometrioid carcinoma as well as in adjacent benign endometriotic tissue. These results suggest that p53 abnormalities may be early events in ovarian cancer, possibly contributing to malignant transformation of some borderline tumors, endometriosis and other carcinoma precursors.
Subject(s)
Adenocarcinoma, Mucinous/genetics , Carcinoma/genetics , Genes, p53/genetics , Ovarian Neoplasms/genetics , Adenocarcinoma, Mucinous/pathology , Carcinoma/pathology , Female , Gene Expression , Humans , Immunohistochemistry , Neoplasm Staging , Ovarian Neoplasms/chemistry , Ovarian Neoplasms/pathology , Tumor Suppressor Protein p53/analysisABSTRACT
Mutations of the p53 gene on chromosome 17p are a common genetic change in the malignant progression of many cancers. We have analyzed 38 malignant tumors of ovarian or peritoneal müllerian type for evidence of p53 variations at either the DNA or protein levels. Genetic studies were based on single-strand conformation polymorphism analysis and DNA sequencing of exons 2 through 11 of the p53 gene; mutations were detected in 79% of the tumors. These data show a statistically significant association between mutations at C.G pairs and a history of estrogen therapy. Two of 20 patients whose normal tissue could be studied carried germ-line mutations of p53. Immunohistochemical analysis of the p53 protein was carried out using monoclonal antibody PAb1801. Ninety-six percent of the missense mutations were associated with abnormal accumulation of p53 protein, but nonsense mutations, a splicing mutation, and most deletions did not result in p53 protein accumulation. A statistically significant association between p53 protein accumulation in poorly differentiated stage III serous carcinomas and small primary tumor size at diagnosis was found, perhaps suggesting that p53 protein accumulation accelerates the metastatic spread from a primary tumor. Overall, our findings indicate that alterations of p53 play a major role in ovarian cancer, including predisposition to the disease in some patients, and suggest a possible mechanism for somatic mutations leading to this cancer.
Subject(s)
Chromosomes, Human, Pair 17 , Genes, p53 , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Point Mutation , Tumor Suppressor Protein p53/metabolism , Amino Acid Sequence , Base Sequence , Codon/genetics , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Exons , Female , Humans , Immunohistochemistry , Neoplasm Metastasis , Neoplasm Staging , Ovarian Neoplasms/surgery , Polymerase Chain Reaction , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/geneticsABSTRACT
Two cases of cervical carcinoma and two cases of normal ectocervical epithelium with a squamous signet-ring cell component are presented. In one carcinoma the vacuolization was so prominent that it partially obliterated the epithelial pattern of the tumor. Paraffin specimens were studied with a panel of histo- and immunohistochemical stains and by electron microscopy. The vacuoles of the squamous signet-ring cells did not contain glycogen, mucopolysaccharides or masses of intermediate filaments. The findings are discussed in relation to possible human papillomavirus and Chlamydia trachomatis infection. The true nature and possible clinicopathologic implications of the squamous carcinoma with signet-ring cells remain to be established, but the phenomenon may cause diagnostic difficulties, especially in biopsy specimens.
ABSTRACT
Progesterone receptor (PR) expression was studied in human cervix uteri from 21 cases. The study was performed on fresh frozen material with application of mouse anti-rabbit PR antibody and the immunoperoxidase method. Most cervical PR-s were present in the glandular epithelium and in smooth muscle cells. The results suggest that PR expression in the cervical glands is hormone-dependent; it was strongest in the presence of estrogen-stimulated endometrium, weaker with progesterone stimulation and absent in atrophy. The ectocervical epithelium contained relatively few progesterone receptors.