Biomedical subjects

Jaime Prat

Publications and source records attributed to Jaime Prat.

At least 19 recordsLinked to original sources

PubMed2006

PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations.

Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway are common in endometrial carcinoma. Inactivation of the tumor suppressor gene PTEN leads to a constitutively active PI3K pathway, which plays a role in the early steps of endometrial tumorigenesis. Other alterations in the PI3K/AKT pathway are mutations in the PIK3CA gene, which encode the p110alpha catalytic subunit of PI3K. PIK3CA mutations cluster to the helical (exon 9) and the kinase (exon 20) domains of the gene. In endometrial carcinomas, PIK3CA mutations have been found to coexist frequently with PTEN mutations, but it is not clear whether they occur in cells with monoallelic or biallelic inactivation of PTEN. In the present study we have evaluated PIK3CA mutational status in a series of 33 endometrial carcinomas, previously screened for microsatellite instability and mutations in PTEN, K-RAS, and CTNNB-1. The tumors were also evaluated for loss of heterozygosity on 10q23 and hypermethylation of the promoter region of PTEN/psiPTEN to assess the monoallelic or biallelic inactivation status of PTEN. PIK3CA mutations were detected in 8 (24%) of the 33 cases. Seven mutations were located in exon 20 and 1 in exon 9. PTEN alterations were found in 19 cases (57%). Biallelic inactivation of PTEN was demonstrated in 11 tumors, whereas 8 tumors exhibited alteration in only 1 of the 2 alleles. PIK3CA mutations coexisted with monoallelic alterations of PTEN in 4 cases (2 mutations and 2 allelic imbalances), with biallelic PTEN inactivation in 1 case (mutation and promoter methylation), and 3 tumors showed PIK3CA mutations in association with wild-type PTEN. PIK3CA mutations did not correlate with microsatellite instability or mutations in CTNNB-1. However, PIK3CA and K-RAS mutations (8 cases) were mutually exclusive alterations. In summary, the results confirm that PIK3CA mutations are frequent in endometrial carcinoma and support the hypothesis that PIK3CA mutations may have an additive effect to PTEN monoallelic inactivation in endometrial carcinoma.

Class I Phosphatidylinositol 3-Kinases↗

PubMed2006

Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma.

The protein kinase C (PKC) plays an important role in the activation and survival of B cells. The purpose of this study was to analyze the clinical significance of PKC-beta 2 protein expression in patients with diffuse large B-cell lymphoma (DLBCL). Tumors from 76 patients with DLBCL who received anthracycline-containing chemotherapy were examined for PKC-beta 2 protein expression by immunohistochemistry. Twenty-six cases (34%) were positive for PKC-beta 2 protein, and 50 (66%) were negative. Patients with PKC-beta-2-positive tumors showed a lower complete remission rate (31 vs 62%; P=0.015) and a lower 5-year disease-free survival (DFS) (30 vs 60%; P=0.03) than the PKC-beta-2-negative group. Overall survival (OS) was significantly lower in patients with the membranous staining pattern of PKC-beta 2 protein when compared to those with PKC-beta-2-negative tumors (14 vs 64%; P=0.005). In patients with low international prognostic index (IPI), those with tumors showing membrane expression of PKC-beta 2 had a significantly inferior DFS and OS (0 vs 79%, P=0.003; 25 vs 80%; P=0.01) compared to PKC-beta-2-negative tumors. In multivariate analysis for OS, the membrane staining of PKC-beta 2 is the strongest independent adverse prognostic factor (OR=3.4, P=0.011). Our results suggest that membrane expression of PKC-beta 2 protein on DLBCL predicts for poor survival, especially in patients with low IPI.

Adolescent↗

PubMed2006

Uterine tumors resembling ovarian sex cord tumors are polyphenotypic neoplasms with true sex cord differentiation.

In this study, we present the clinicopathologic features and immunophenotypic characteristics of five cases of uterine tumors resembling ovarian sex cord tumors and three cases of endometrial stromal tumors with sex cord-like elements, with emphasis on immunohistochemical markers of sex cord differentiation. The mean patient age was 42 years (range 19-69 years), and vaginal bleeding was the most common clinical presentation. The tumors were usually polypoid masses arising in the uterine fundus, with a mean tumor size of 6.7 cm. Sex cord patterns in uterine tumors resembling ovarian sex cord tumors, including anastomosing cords, trabeculae, small nests, tubules, and in one case, a striking retiform architecture with Leydig-like cells, comprised from 70 to 100% of the tumor volume. All uterine tumors resembling ovarian sex cord tumors were positive for two or more markers of sex cord differentiation; all five cases showed strong immunoreactivity for calretinin, with coexpression of CD99 (four cases), Melan-A (two cases), and inhibin (two cases). Endometrial stromal tumors with sex cord-like elements were less frequently positive for markers of sex cord differentiation, with each case positive for one marker (calretinin, two cases; CD99, one case). In addition, all eight cases were frequently positive for cytokeratin, CD10, vimentin, estrogen receptor, and progesterone receptor; desmin immunoreactivity, when present, was limited to minor foci of smooth muscle. Overall, the morphologic and immunohistochemical findings in uterine tumors resembling ovarian sex cord tumors strongly support that these unusual uterine tumors are polyphenotypic neoplasms with true sex cord differentiation.

12E7 Antigen↗

PubMed2005

Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors.

PURPOSE: Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior. MATERIALS AND METHODS: We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed. RESULTS: SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level. CONCLUSION: We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.

Dual-Specificity Phosphatases↗

PubMed2005

Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis.

Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior. We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites. We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for beta -catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas. Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on beta -catenin expression/mutation correlates with clinical outcome.

Adult↗

PubMed2005

Is loss of heterozygosity at 9q22.3 (PTCH gene) and 19p13.3 (STK11 gene) involved in the pathogenesis of ovarian stromal tumors?

Some ovarian fibromas and rare fibrosarcomas are associated with Gorlin syndrome, which is caused by mutation in the human homologue of Drosophila patched gene (PTCH), localized on chromosome 9q22.3. The relationship between PTCH gene and sporadic ovarian tumors in the thecoma-fibroma group has not been well characterized. On the other hand, we have recently described loss of heterozygosity (LOH) at 19p13.3 in 2 sporadic fibromas with sex-cord elements. We have analyzed DNA from 8 fibromas, 6 cellular fibromas, 2 fibrothecomas, 9 luteinized thecomas, and 2 fibrosarcomas of the ovary for LOH at 9q22.3 and 19p13.3, using polymerase chain reaction amplification for 10 microsatellite markers. LOH at 9q22.3 was detected in 4 (67%) of 6 cellular fibromas, with the highest frequency at microsatellite marker D9S15, which localizes proximal to the PTCH gene. Of 9 luteinized thecomas, 2 (22%) also exhibited LOH at 9q22.3 with 3 microsatellite markers other than D9S15. Allelic losses were not detected in any fibroma, fibrothecoma, or fibrosarcoma. LOH at 19p13.3 was found in 2 (25%) of 8 fibromas, 3 (50%) of 6 cellular fibromas, and 1 (11%) of 9 luteinized thecomas. None of the 2 fibrothecomas or 2 fibrosarcomas showed LOH at 19p13.3. LOH at both 9p22.3 and 19p13.3 was observed in 3 (50%) of 6 cellular fibromas, but not in luteinized thecomas. The results indicate that (1) LOH at both PTCH gene and STK11 gene is relatively frequent in cellular fibromas; (2) approximately a quarter of luteinized thecomas exhibited LOH of the PTCH gene; in both neoplasms, cellular fibromas and luteinized thecomas, LOH may play a role in their pathogenesis; and (3) sporadic cellular fibromas may arise through similar genetic pathways as cases of Gorlin syndrome.

AMP-Activated Protein Kinase Kinases↗

PubMed2005

Hereditary ovarian cancer.

Family history is the strongest risk factor for ovarian cancer. Three clinical manifestations of hereditary ovarian cancer have been recognized: (1) "site-specific" ovarian cancer, (2) the breast and ovarian cancer syndrome, and (3) the hereditary nonpolyposis colorectal cancer (HNPCC; Lynch II) syndrome. The first 2 groups are associated with germ line mutations in the BRCA1 and BRCA2 tumor suppressor genes, whereas HNPCC is associated with germ line mutations in the DNA mismatch repair (MMR) genes, primarily hMLH1 and hMSH2. At least 10% of all epithelial ovarian cancers are hereditary, with mutations in the BRCA genes accounting for approximately 90% of cases and most of the remaining 10% attributable to HNPCC. Hereditary ovarian cancers exhibit distinct clinicopathologic features compared with sporadic cancers. The cumulative lifetime risk of ovarian cancer is 40% to 50% for BRCA1 mutation carriers and 20% to 30% for BRCA2 mutation carriers. Both BRCA proteins participate in transcriptional regulation of gene expression as well as the recognition or repair of certain forms of DNA damage, particularly double-strand breaks. Mutations of BRCA1 and BRCA2 are mainly of the frameshift or nonsense variety. Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are high-grade and advanced-stage serous carcinomas. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumors. Hereditary ovarian cancers have a distinctly better clinical outcome with longer overall survival and recurrence-free interval after chemotherapy than sporadic cancers. Women with a family history including 2 or more first- or second-degree relatives with either ovarian cancer alone or both breast and ovarian cancers should undertake prophylactic oophorectomy immediately after childbearing has been completed to reduce the risk of ovarian cancer. The cumulative risk of ovarian cancer in HNPCC families is more than 12%. Ovarian cancer in HNPCC syndrome is diagnosed at younger age than in the general population. Most tumors are low-stage well-differentiated or moderately differentiated carcinomas. Annual follow-up is recommended for these patients.

Female↗

PubMed2005

Ovarian carcinomas, including secondary tumors: diagnostically challenging areas.

The differential diagnosis of ovarian carcinomas, including secondary tumors, remains a challenging task. Mucinous carcinomas of the ovary are rare and can be easily confused with metastatic mucinous carcinomas that may present clinically as a primary ovarian tumor. Most of these originate in the gastrointestinal tract and pancreas. International Federation of Gynecology and Obstetrics (FIGO) stage is the single most important prognostic factor, and stage I carcinomas have an excellent prognosis; FIGO stage is largely related to the histologic features of the ovarian tumors. Infiltrative stromal invasion proved to be biologically more aggressive than expansile invasion. Metastatic colon cancer is frequent and often simulates ovarian endometrioid adenocarcinoma. Although immunostains for cytokeratins 7 and 20 can be helpful in the differential diagnosis, they should always be interpreted in the light of all clinical information. Occasionally, endometrioid carcinomas may exhibit a microglandular pattern simulating sex cord-stromal tumors. However, typical endometrioid glands, squamous differentiation, or an adenofibroma component are each present in 75% of these tumors whereas immunostains for calretinin and alpha-inhibin are negative. Endometrioid carcinoma of the ovary is associated in 15-20% of the cases with carcinoma of the endometrium. Most of these tumors have a favorable outcome and they most likely represent independent primary carcinomas arising as a result of a Mullerian field effect. Although the criteria for distinguishing metastatic from independent primary carcinomas rely mainly upon conventional clinicopathologic findings, loss of heterozygosity and gene mutation analyses can be helpful. Transitional cell carcinomas are distinguished from undifferentiated carcinomas by the presence of thick, undulating papillae with smooth luminal borders, microspaces, and tumor cells with distinctive 'urothelial' appearance. Krukenberg tumors are metastatic adenocarcinomas traditionally perceived as composed of mucin-filled signet-ring cells associated with a striking proliferation of the ovarian stroma but many variations on this pattern occur.

Base Sequence↗

PubMed2005

Immunohistochemical analysis of PTEN in endometrial carcinoma: a tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities.

The tumor suppressor gene PTEN/MMAC1 is located on chromosome 10q23.3. Inactivation of PTEN, either by mutations, deletions, or promoter hypermethylation, has been identified in a wide variety of tumors. Inactivation of the two alleles of PTEN is required, because it is a tumor suppressor gene. Immunohistochemical staining may be an effective screening method to demonstrate the absence of the protein in tumors exhibiting PTEN inactivation. We studied a tissue microarray, constructed from paraffin-embedded blocks of 95 endometrial carcinomas, 38 of them previously evaluated for alterations in PTEN. We also studied cell blocks obtained from one PTEN-defective endometrial cancer cell line, after transfection with either a plasmid encoding wild-type PTEN or the empty vector. The tumor samples were tested with four different anti-PTEN commercial antibodies: a polyclonal antibody, the monoclonal antibody 28H6, the monoclonal antibody 10P03, and the monoclonal antibody 6.H2.1. Results were correlated with the presence of abnormalities in PTEN, as well as with the immunohistochemical expression of phosphorylated AKT. Antibody 28H6 produced a predominant nuclear staining, while the other three antibodies produced a predominant cytoplasmic staining. There was no significant correlation between the results obtained with the four antibodies. The monoclonal antibody 6.H2.1 was the only one that exhibited a correlation with the presence of molecular alterations in PTEN, and a statistically significant association with immunostaining for phosphorylated AKT (r=-0.249, P=0.037). The monoclonal antibody 10P03 exhibited an association with phospho-AKT that did not have statistical significance. Both 6.H2.1 and 10P03 antibodies stained PTEN-transfected cells, and were negative in the PTEN-deficient cell line blocks. The polyclonal antibody and the monoclonal antibody 28H6 produced positive staining in PTEN-deficient cell line blocks, suggesting nonspecific staining. The results indicate that monoclonal antibody 6.H2.1 may be a suitable alternative for tumors with inactivation of PTEN.

Antibodies, Monoclonal↗

PubMed2005

Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules).

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease. In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.

Adult↗

PubMed2005

Survivin expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3.

Evasion of apoptotic cell death plays a key role in cancer development. Survivin is a member of the inhibitor of apoptosis proteins, which also has a role in the control of cell division. Survivin may be overexpressed in some tumors and has been suggested to be related to PTEN, beta-catenin, p53 [all of them frequently abnormal in endometrial carcinomas (ECs)], and STAT-3. A tissue microarray was constructed from paraffin-embedded blocks of 95 ECs, previously studied for microsatellite instability and for alterations in PTEN, k-RAS, and CTNNB-1. Immunohistochemical evaluation included 1) survivin, 2) markers of cell proliferation and apoptosis (Ki67-MIB1 and M 30-neoepitope cytokeratin 18), and 3) proteins involved in cell signaling pathways (PTEN, phospho-AKT, beta-catenin, p53, and STAT-3). Survivin expression was frequent in ECs (75.95%) but did not show any statistical significant correlation with histological type and grade, stage, overall survival, or mitotic and apoptotic indexes. Survivin expression had a statistical significant correlation with decreased PTEN expression (r = -0.383, p = 0.001), increased phospho-AKT (r = 0.70, p < 0.001), and positive STAT-3 immunostaining (r = 0.6, p < 0.001). Survivin expression did not show statistical correlation with either beta-catenin or p53 alterations. The results suggest that increased survivin expression is frequent in ECs and may be dependent on STAT-3 and PI3 K/AKT activation. Because PTEN abnormalities are very frequent in ECs, the results from this study indicate that PTEN may interfere with the process of apoptosis and cell proliferation by promoting survivin expression.

Apoptosis↗

PubMed2004

Abnormalities in the NF-kappaB family and related proteins in endometrial carcinoma.

The NF-kappaB family of transcription factors regulates a wide variety of cellular processes including cell growth, differentiation, and apoptosis. A tissue microarray was constructed from paraffin wax-embedded blocks from 95 endometrial carcinomas (EC), previously studied for microsatellite instability, as well as for alterations in PTEN, k-RAS and beta-catenin. Immunohistochemical evaluation included members of the NF-kappaB (p50, p65, p52, c-Rel, Rel-B) and the IkappaB (IkappaBalpha, IkappaBbeta, IkappaBepsilon, Bcl-3) families, as well as putative targets of NF-kappaB such as Flip, Bcl-xL, Cyclin D1, and oestrogen and progesterone receptors. Results were correlated with the clinical and pathological data. Nuclear immunostaining for members of the NF-kappaB family was frequent in EC (p50, 20%; p65, 16.5-21.9%; p52, 9.3%; c-Rel, 48.9%; Rel-B, 15.7%); and it correlated with negativity for members of the IkappaB family in some cases. There was a statistically significant association between immunoreaction for p50 and p65 (p = 0.006), suggesting activation of the so-called 'classic form' of NF-kappaB, similar to that described in breast cancer. Bcl-3 nuclear immunostaining was detected in 60.7% of cases. The vast majority of p52-positive tumours showed Bcl-3 nuclear immunoreaction (p = 0.038). Immunostaining for putative targets of NF-kappaB was as follows: Bcl-xL, 76.2% (p = 0.001); Flip 43.0%; Cyclin D1, 64.79%. p65 immunostaining correlated with increased immunoreaction for steroid hormone receptors. No correlation was found between NF-kappaB nuclear pattern and the presence of microsatellite instability, or alterations in PTEN, k-RAS, or beta-catenin. These results suggest that the NF-kappaB and IkappaB families of genes may be important in endometrial carcinogenesis, by controlling apoptosis and cell proliferation.

Adenocarcinoma↗

PubMed2004

Prognostic parameters of endometrial carcinoma.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the Western world. Approximately 80% of cases are well- to moderately differentiated (endometrioid) adenocarcinomas, which are confined to the uterine corpus at diagnosis, and thus most can be cured. Conversely, high-grade (ie, clear cell and serous) carcinomas account for only 15% to 20% of cases and show marked nuclear atypia. These tumors usually invade the myometrium and may extend beyond the uterus at the time of hysterectomy. In addition to clinical and morphological differences, these 2 groups of endometrial carcinomas differ in their pathogenesis. Whereas prognosis in the latter group is generally poor, the pathologist's role in establishing the outcome in the former group is crucial. Furthermore, it has become progressively apparent that both groups overlap to some extent, making the dualistic model a guideline at best. Over the last 2 decades, several studies have demonstrated the prognostic importance of various key surgical and pathological parameters, including histological type, histological grade, surgical-pathological stage, depth of myometrial invasion, vascular invasion, and cervical involvement. This review presents the most important prognostic factors of endometrial carcinomas from the pathologist's viewpoint, and attempts to clarify existing conflicts in the classification and diagnosis of these tumors.

Adenocarcinoma↗

PubMed2004

Borderline ovarian tumors: key points and workshop summary.

This article documents major points of agreement and disagreement among experts invited to participate in a Borderline Ovarian Tumor Workshop held in Bethesda, MD, on August 27-28, 2003. It is suggested that controversies related to the diagnosis and management of these tumors are often related to lack of data in the literature (small numbers of cases, unreported or unclear criteria for diagnosis and follow-up, insufficient length of follow-up, etc), and specific recommendations are made for further investigation and for reporting of data in future studies.

Female↗

PubMed2004

Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: workshop perspectives.

Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature.

Cystadenocarcinoma, Serous↗

PubMed2004

The STK11/LKB1 Peutz-Jegher gene is not involved in the pathogenesis of sporadic sex cord-stromal tumors, although loss of heterozygosity at 19p13.3 indicates other gene alteration in these tumors.

Germ line mutations in the STK11/LKB1 tumor-suppressor gene (chromosome 19p13.3) are responsible for the Peutz-Jeghers syndrome (PJS). PJS patients frequently develop neoplasms of various organs. Ovarian sex cord-stromal tumor (SCST) with annular tubules, which shows a characteristic morphology intermediate between granulosa cell and Sertoli cell tumors, is distinctively associated with PJS. Although somatic mutations of STK11 are reportedly rare in sporadic forms of common cancers linked to PJS, there are no available studies assessing STK11 alterations in larger series of sporadic ovarian tumors with granulosa, Sertoli or combined differentiation. We examined 29 sporadic SCSTs for loss of heterozygosity (LOH) at 19p13.3, mutation, and promoter methylation of STK11. LOH at 19p13.3 was detected in 12 of 29 (41%) SCSTs, with the highest frequency at chromosome marker D19S894, which localizes approximately 3 mb centromeric to STK11, and it was more frequent in granulosa/Sertoli-stromal cell tumors (10 of 19; 52%) than in thecoma-fibroma tumors (2 of 10; 20%). The 2 fibrothecomas harboring LOH contained sex cord elements. None of the LOH-positive SCSTs demonstrated mutations or promoter methylation of STK11. Our results indicate that LOH at 19p13.3 in sporadic SCSTs targets a gene different from STK11, and may play a role in the pathogenesis of sporadic SCSTs, especially in tumors containing sex cord derivatives.

AMP-Activated Protein Kinase Kinases↗

PubMed2004

Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas.

Endometrioid carcinomas of the ovary closely resemble their uterine counterparts. It has been suggested that the former tumors have the same molecular alterations (microsatellite instability [MSI], PTEN, and beta-catenin) described in endometrioid carcinomas of the uterus. We analyzed 55 ovarian carcinomas, including 22 endometrioid, 18 clear cell, and 15 mixed types. MSI was detected in 5 of 39 cases (13%). MLH1 promoter hypermethylation was identified in 2 of the 5 MSI-positive tumors. PTEN was mutated in 5 of 54 cases (9%); of these, 3 had MSI and exhibited frameshift mutations in short-coding mononucleotide repeats. Beta-catenin nuclear expression was detected in 11 of 54 cases (20%) by immunostaining; of these, 7 exhibited CTNNB1 gene mutations. These alterations were found more frequently in endometrioid carcinomas than in tumors of the other 2 groups. Among the former tumors, MSI was detected in 3 of 17 cases (17.5%); PTEN mutations, in 3 of 21 (14%); and beta-catenin, in 8 of 21 (38%). The molecular alterations were found more often in tumors associated with endometriosis than in tumors without endometriosis. Six endometrioid tumors demonstrating matrix metalloproteinase-7 (MMP-7) immunoreactivity with nuclear accumulation of beta-catenin had good outcomes, in contrast to poor outcomes in 7 of 9 predominantly nonendometrioid tumors demonstrating expression of MMP-7 only. We found a similar frequency of beta-catenin abnormalities but lower rates of MSI and PTEN alterations than in uterine endometrioid carcinomas. Alterations in beta-catenin and PTEN genes, as well as MSI, are frequent in low-stage ovarian carcinomas of endometrioid type that have a favorable prognosis.

Adult↗

PubMed2004

Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases.

Nine malignant mesonephric tumors were obtained from the consultation files of one of the authors (J.P.) over a 13-year period (1988-2001). There were 4 adenocarcinomas (ACs) and 5 malignant mixed mesonephric tumors (MMMTs). The ACs were found in the cervix (3) and vagina (1). The MMMTs involved the uterus (1), cervix (3), and vagina (1). Most patients presented with abnormal vaginal bleeding. The 4 patients with mesonephric AC ranged in age from 24 to 54 years (mean, 41 years). The tumors measured 2 to 6 cm (mean, 3.7 cm). Two ACs were stage I and two were stage II. Two of the three patients with follow-up information were alive without clinical evidence of disease at 3 and 11.5 years, and the other was alive with recurrent tumor 8.5 years postoperatively. The 5 patients with MMMTs ranged in age from 37 to 62 years (mean, 49 years). The mean size of four tumors was 5.2 cm (range, 3.5-8 cm). The uterine MMMT infiltrated the entire myometrial wall extending to the endometrial cavity where it resembled an endometrial polyp. Although the most common histologic pattern in the current series was the glandular (ductal) pattern, retiform, tubular, and solid growth patterns were also encountered. Among the MMMT subgroup, the sarcomatous component was homologous in 3 cases (endometrial stromal or spindle cell) and heterologous in the other 2 cases (skeletal muscle and cartilage). Of the 4 patients with follow-up information available, 1 (stage II) died of disease 7 months after surgery, another (stage IV) was alive with bone metastases at 3.3 years, and the other 2 patients (stages IB and IC) had no clinical evidence of disease at 1 and 3.7 years, respectively. Evidence of mesonephric hyperplasia was found in 5 (42%) cases. The MMMT that arose in the corpus presented as an endometrial polyp. In this case, histologic differential diagnosis includes serous carcinoma, endometrial stromal sarcoma, and uterine tumor resembling ovarian sex cord-stromal tumor. Immunostainings are not helpful. Mesonephric ACs often present in early stage and have better prognosis than their müllerian counterparts. Surgery alone appears to be the treatment of choice. In contrast, MMMTs may present in advanced stage and are aggressive tumors, similar to malignant mixed müllerian tumors.

Adenocarcinoma↗