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1.  Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses 
Background
Uterine cancer is the fourth most common malignancy in women, and uterine serous carcinoma is the most aggressive subtype. However, the molecular pathogenesis of uterine serous carcinoma is largely unknown. We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer.
Methods
Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. Somatically acquired sequence mutations were further verified by Sanger sequencing. The most frequent molecular genetic changes were further validated by Sanger sequencing in 66 additional uterine serous carcinomas and in nine serous endometrial intraepithelial carcinomas (the preinvasive precursor of uterine serous carcinoma) that were isolated by laser capture microdissection. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were subjected to whole-exome sequencing.
Results
We found frequent somatic mutations in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) among the 76 uterine serous carcinomas examined. All nine serous carcinomas that had an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status between uterine serous carcinoma and the concurrent serous endometrial intraepithelial carcinoma component. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations (four tumors with point mutations, three tumors with hemizygous deletions) did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas (48%) harbored PIK3CA mutation and/or PIK3CA amplification.
Conclusion
Molecular genetic aberrations involving the p53, cyclin E–FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.
doi:10.1093/jnci/djs345
PMCID: PMC3692380  PMID: 22923510
2.  Differential Analysis of Ovarian and Endometrial Cancers Identifies a Methylator Phenotype 
PLoS ONE  2012;7(3):e32941.
Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.
doi:10.1371/journal.pone.0032941
PMCID: PMC3293923  PMID: 22403726
3.  Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers 
In this article, the authors briefly review the historical evolution of the various putative precursor lesions for Type II endometrial cancers, with an emphasis on the newly defined "Endometrial Glandular Dysplasia (EmGD)". The evidentiary basis for delineating serous EmGD as the most probable precursor lesions to endometrial serous carcinoma is reviewed in detail. An argument is advanced for the discontinuation of the term serous "endometrial intraepithelial carcinoma (EIC)" as a descriptor for a supposedly intraepithelial, precancerous lesion. Preliminary evidence is also presented that suggests that there is a morphologically recognizable "clear cell EmGD" that probably represents a precancerous lesion to endometrial clear cell carcinomas.
doi:10.1186/1746-1596-3-6
PMCID: PMC2266702  PMID: 18261213
4.  The Preclinical Natural History of Serous Ovarian Cancer: Defining the Target for Early Detection 
PLoS Medicine  2009;6(7):e1000114.
Pat Brown and colleagues carry out a modeling study and define what properties a biomarker-based screening test would require in order to be clinically useful.
Background
Ovarian cancer kills approximately 15,000 women in the United States every year, and more than 140,000 women worldwide. Most deaths from ovarian cancer are caused by tumors of the serous histological type, which are rarely diagnosed before the cancer has spread. Rational design of a potentially life-saving early detection and intervention strategy requires understanding the lesions we must detect in order to prevent lethal progression. Little is known about the natural history of lethal serous ovarian cancers before they become clinically apparent. We can learn about this occult period by studying the unsuspected serous cancers that are discovered in a small fraction of apparently healthy women who undergo prophylactic bilateral salpingo-oophorectomy (PBSO).
Methods and Findings
We developed models for the growth, progression, and detection of occult serous cancers on the basis of a comprehensive analysis of published data on serous cancers discovered by PBSO in BRCA1 mutation carriers. Our analysis yielded several critical insights into the early natural history of serous ovarian cancer. First, these cancers spend on average more than 4 y as in situ, stage I, or stage II cancers and approximately 1 y as stage III or IV cancers before they become clinically apparent. Second, for most of the occult period, serous cancers are less than 1 cm in diameter, and not visible on gross examination of the ovaries and Fallopian tubes. Third, the median diameter of a serous ovarian cancer when it progresses to an advanced stage (stage III or IV) is about 3 cm. Fourth, to achieve 50% sensitivity in detecting tumors before they advance to stage III, an annual screen would need to detect tumors of 1.3 cm in diameter; 80% detection sensitivity would require detecting tumors less than 0.4 cm in diameter. Fifth, to achieve a 50% reduction in serous ovarian cancer mortality with an annual screen, a test would need to detect tumors of 0.5 cm in diameter.
Conclusions
Our analysis has formalized essential conditions for successful early detection of serous ovarian cancer. Although the window of opportunity for early detection of these cancers lasts for several years, developing a test sufficiently sensitive and specific to take advantage of that opportunity will be a challenge. We estimated that the tumors we would need to detect to achieve even 50% sensitivity are more than 200 times smaller than the clinically apparent serous cancers typically used to evaluate performance of candidate biomarkers; none of the biomarker assays reported to date comes close to the required level of performance. Overcoming the signal-to-noise problem inherent in detection of tiny tumors will likely require discovery of truly cancer-specific biomarkers or development of novel approaches beyond traditional blood protein biomarkers. While this study was limited to ovarian cancers of serous histological type and to those arising in BRCA1 mutation carriers specifically, we believe that the results are relevant to other hereditary serous cancers and to sporadic ovarian cancers. A similar approach could be applied to other cancers to aid in defining their early natural history and to guide rational design of an early detection strategy.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Every year about 190,000 women develop ovarian cancer and more than 140,000 die from the disease. Ovarian cancer occurs when a cell on the surface of the ovaries (two small organs in the pelvis that produce eggs) or in the Fallopian tubes (which connect the ovaries to the womb) acquires genetic changes (mutations) that allow it to grow uncontrollably and to spread around the body (metastasize). For women whose cancer is diagnosed when it is confined to the site of origin—ovary or Fallopian tube—(stage I disease), the outlook is good; 70%–80% of these women survive for at least 5 y. However, very few ovarian cancers are diagnosed this early. Usually, by the time the cancer causes symptoms (often only vague abdominal pain and mild digestive disturbances), it has spread into the pelvis (stage II disease), into the space around the gut, stomach, and liver (stage III disease), or to distant organs (stage IV disease). Patients with advanced-stage ovarian cancer are treated with surgery and chemotherapy but, despite recent treatment improvements, only 15% of women diagnosed with stage IV disease survive for 5 y.
Why Was This Study Done?
Most deaths from ovarian cancer are caused by serous ovarian cancer, a tumor subtype that is rarely diagnosed before it has spread. Early detection of serous ovarian cancer would save the lives of many women but no one knows what these cancers look like before they spread or how long they grow before they become clinically apparent. Learning about this occult (hidden) period of ovarian cancer development by observing tumors from their birth to late-stage disease is not feasible. However, some aspects of the early natural history of ovarian cancer can be studied by using data collected from healthy women who have had their ovaries and Fallopian tubes removed (prophylactic bilateral salpingo-oophorectomy [PBSO]) because they have inherited a mutated version of the BRCA1 gene that increases their ovarian cancer risk. In a few of these women, unsuspected ovarian cancer is discovered during PBSO. In this study, the researchers identify and analyze the available reports on occult serous ovarian cancer found this way and then develop mathematical models describing the early natural history of ovarian cancer.
What Did the Researchers Do and Find?
The researchers first estimated the time period during which the detection of occult tumors might save lives using the data from these reports. Serous ovarian cancers, they estimated, spend more than 4 y as in situ (a very early stage of cancer development), stage I, or stage II cancers and about 1 y as stage III and IV cancers before they become clinically apparent. Next, the researchers used the data to develop mathematical models for the growth, progression, and diagnosis of serous ovarian cancer (the accuracy of which depends on the assumptions used to build the models and on the quality of the data fed into them). These models indicated that, for most of the occult period, serous cancers had a diameter of less than 1 cm (too small to be detected during surgery or by gross examination of the ovaries or Fallopian tubes) and that more than half of serous cancers had advanced to stage III/IV by the time they measured 3 cm across. Furthermore, to enable the detection of half of serous ovarian cancers before they reached stage III, an annual screening test would need to detect cancers with a diameter of 1.3 cm and to halve deaths from serous ovarian cancer, an annual screening test would need to detect 0.5-cm diameter tumors.
What Do These Findings Mean?
These findings suggest that the time period over which the early detection of serous ovarian cancer would save lives is surprisingly long. More soberingly, the authors find that a test that is sensitive and specific enough to take advantage of this “window of opportunity” would need to detect tumors hundreds of times smaller than clinically apparent serous cancers. So far no ovarian cancer-specific protein or other biomarker has been identified that could be used to develop a test that comes anywhere near this level of performance. Identification of truly ovarian cancer-specific biomarkers or novel strategies will be needed in order to take advantage of the window of opportunity. The stages prior to clinical presentation of other lethal cancers are still very poorly understood. Similar studies of the early natural history of these cancers could help guide the development of rational early detection strategies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000114.
The US National Cancer Institute provides a brief description of what cancer is and how it develops and information on all aspects of ovarian cancer for patients and professionals. It also provides a fact sheet on BRCA1 mutations and cancer risk (in English and Spanish)
The UK charity Cancerbackup also provides information about all aspects of ovarian cancer
MedlinePlus provides a list of links to additional information about ovarian cancer (in English and Spanish)
The Canary Foundation is a nonprofit organization dedicated to development of effective strategies for early detection of cancers including ovarian cancer.
doi:10.1371/journal.pmed.1000114
PMCID: PMC2711307  PMID: 19636370
5.  Induction of tumour-specific CD8+ cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer 
British Journal of Cancer  2002;86(1):151-157.
Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8+ T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccesful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8+ T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8+ T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-γ expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8+ T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8+ CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.
British Journal of Cancer (2002) 86, 151–157. DOI: 10.1038/sj/bjc/6600026 www.bjcancer.com
© 2002 The Cancer Research Campaign
doi:10.1038/sj.bjc.6600026
PMCID: PMC2746546  PMID: 11857027
serous papillary uterine cancer; CTLs; dendritic cells; tumour lysate
6.  Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers 
British Journal of Cancer  2006;94(5):642-646.
To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.
doi:10.1038/sj.bjc.6603012
PMCID: PMC2361201  PMID: 16495918
uterine; papillary serous; clear cell; survival
7.  Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies 
Purpose
Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for serous uterine carcinoma patients, focusing on Lynch syndrome malignancies.
Experimental design
Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second stage analysis was undertaken using data from GOG-210. Incidence data for cancers reported in relatives of 348 serous and mixed epithelial and 624 endometrioid carcinoma patients were compared.
Results
Nineteen of 29 (65.5%) patients in the single institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly over-represented and a high number of probands (6/29, 20.7%) reported pancreatic cancers. None of the probands’ tumors had DNA mismatch repair abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case-control study. Pancreatic cancers were, however, significantly more common in relatives of serous cancer patients (OR 2.39, 95% CI 1.06–5.38).
Conclusions
We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of serous cancer patients in a single institution study. Follow-up studies suggest only pancreatic cancers are over-represented in relatives. DNA mismatch repair defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers.
doi:10.1158/1940-6207.CAPR-11-0499
PMCID: PMC3294192  PMID: 22246618
Endometrial cancer; Uterine serous carcinoma; Lynch syndrome; Mismatch repair; Familial clustering of cancers
8.  Insights into Endometrial Serous Carcinogenesis and Progression 
Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92–100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16INKA/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called “p53 signatures”), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
PMCID: PMC2655156  PMID: 19294001
Endometrial serous carcinoma; endometrial glandular dysplasia; endometrial intraepithelial carcinoma; p53; cadherins; claudins; CDKs; MDM2 and HER2/neu (erb-B2)
9.  Serous endometrial intraepithelial carcinoma: a case series and literature review 
Background
Minimal uterine serous cancer (MUSC) or serous endometrial intraepithelial carcinoma (EIC) has been described by many different names since 1998. There have been very few cases reported in literature since EIC/MUSC was recognized as a separate entity. The World health Organization (WHO) Classification favors the term serous EIC. Although serous EIC is confined to the uterine endometrium at initial histology diagnosis, a significant number of patients could have distal metastasis at diagnosis, without symptoms. Serous EIC is considered as being the precursor of uterine serous cancer (USC), but pure serous EIC also has an aggressive behavior similar to USC. It is therefore prudent to have an accurate diagnosis and appropriate surgical staging. There are very few published articles in literature that discuss the pure form of serous EIC. The aim of this series is to share our experience and review evidence for optimum management of serous EIC.
Patients and methods
We report a series of five women treated in our institute in the last 3 years. We reviewed the relevant literature on serous EIC and various management strategies, to recommend best clinical practice.
Conclusion
Pure serous EIC is a difficult histopathological diagnosis, which requires ancillary immunohistochemical staining. It can have an aggressive clinical behavior with early recurrence and poor survival. Optimum surgical staging, with appropriate adjuvant treatment, should be discussed when treating these patients.
doi:10.2147/CMAR.S45141
PMCID: PMC3704304  PMID: 23861597
serous EIC; minimal uterine serous cancer; papillary serous endometrial cancer
10.  The novel cancer-testis antigen A-kinase anchor protein 4 (AKAP4) is a potential target for immunotherapy of ovarian serous carcinoma 
Oncoimmunology  2013;2(5):e24270.
Ovarian cancer is one of the neoplasms affecting the reproductive tract associated with high mortality rate because of limited therapeutic options and an elevated incidence of chemoresistance and recurrence. In this context, immunotherapy may constitute a promising approach to improve survival rates and clinical outcome, raising the need for specific target antigens. Cancer-testis antigens (CTAs) are considered promising candidates in this sense because they are aberrant expressed by various malignancies but not by non-transformed tissue, with the exception of testes. Here, we examined the expression and potential to promote humoral immune responses of a novel CTA, A-kinase anchor protein 4 (AKAP4), among 38 ovarian carcinoma patients. Our results reveal that AKAP4 was expressed at both the mRNA and protein levels in 89% (34/38) of ovarian carcinoma tissue specimens but not in 21 matched adjacent non-cancerous tissues. In addition, a humoral response against AKAP4 was detected in 58% (22/38) of ovarian carcinoma patients by ELISA. In particular, 65% (22/34) patients bearing an AKAP4-expressing tumor exhibited circulating anti-AKAP4 antibodies. Interestingly, the majority of specimens were categorized as ovarian serous adenocarcinoma and serous papillary carcinoma, of which 93% (28/30) and 100% (6/6), respectively, expressed AKAP4. A humoral response against AKAP4 was detected in 79% (19/24) and 67% (4/6) of ovarian serous adenocarcinoma and serous papillary carcinoma patients, respectively. The presence of circulating anti-AKAP4 antibodies suggests the AKAP4 is highly immunogenic in ovarian serous carcinoma patients. Our study lays the foundations for exploring AKAP4 as a potential target for the immunotherapy of ovarian cancer.
doi:10.4161/onci.24270
PMCID: PMC3667910  PMID: 23762804
AKAP4; cancer-testis antigen; immunotherapy; ovarian serous carcinoma; vaccine
11.  Claudin-3 and Claudin-4 expression in serous papillary, clear cell, and endometrioid endometrial cancer 
Gynecologic oncology  2008;109(2):263-269.
The tight junction (TJ) proteins claudin-3 and claudin-4 have been reported to be differentially expressed in uterine serous papillary carcinoma (USPC), a rare form of endometrial cancer characterized by a particularly high recurrence rate and poor prognosis. Preclinical experiments suggest that increased expression of both TJ proteins may in part mediate the biologically aggressive phenotype of USPC. Our aim was to determine claudin-3 and claudin-4 expression in a large cohort of surgically staged patients with USPC and clear cell endometrial cancer (n=137), and to compare the expression pattern and prognostic relevance of both claudins with that seen in patients with endometrioid endometrial cancer (n=150). The rate of claudin-3 and claudin-4 expression was significantly higher in USPC and clear cell endometrial cancer compared to endometrioid endometrial cancer (claudin-3: 78% and 61% versus 38%, p <.0001; claudin-4: 56% and 44% versus 9%, p <.0001). Furthermore, expression of both tight junction proteins was significantly associated with poor clinical outcome (claudin-3, DFS: Risk ratio (RR) 1.70, p=.0087, OS RR 1.62, p=.0247; claudin-4, DFS RR 2.66, p<0.0001, and OS RR 2.50, p<0.0001). However, claudin-3 and claudin-4 expression did not maintain prognostic independence in multivariate analyses, as their expression was tightly associated with more advanced disease stages (p <.0001 for both), and higher nuclear grade (p <.0001 for both). These clinical observations confirm the hypothesis based on preclinical evidence that increased expression of claudin-3 and claudin-4 may contribute to the aggressive phenotype of endometrial cancer of serous papillary or clear cell histology and suggest their potential utility as diagnostic biomarkers and possible targets for therapeutic intervention.
doi:10.1016/j.ygyno.2008.01.024
PMCID: PMC2453046  PMID: 18313739
Uterine serous papillary endometrial cancer; Claudin-3; Claudin-4; lapatinib; endometrium
12.  CyclinD1, a prominent prognostic marker for endometrial diseases 
Diagnostic Pathology  2013;8:138.
Purpose
Alteration of CyclinD1 was suggested to relate with development of endometrial carcinogenesis before, however CyclinD1 expression is not well defined in endometrial hyperplasia lesions. We checked the relationship between its expression and clinic-pathological variables of endometrial lesions to explore the possibility for CyclinD1 as a potential diagnostic and prognostic marker.
Methods
Cyclin D1 immunohistochemical analysis (IHC) was used to evaluate 201 fixed, paraffin-embedded endometrial samples which included simple hyperplasia (n = 27), atypical complex hyperplasia (ACH) (n = 41), endometrioid carcinoma (n = 103), endometrial serous carcinoma (ESC) (n = 21) and clear cell carcinoma (CCC) (n = 9). A breast cancer with known CyclinD1 expression was selected as a positive control in each immunohistochemistry run. We also performed follow-up study to estimate patients’ prognosis.
Results
CyclinD1 was significantly overexpressed in atypical complex hyperplasia (ACH), endometrioid carcinoma and clear cell carcinoma (CCC). The positive signaling of CyclinD1 was showed less than 40% in simple hyperplasia and endometrial serous carcinoma (ESC). The high expression of CyclinD1 was observed in metastasis carcinoma group more significantly than non-metastasis carcinoma group. Kaplan Meier analysis demonstrated that patients with high CyclinD1 expression had an obviously poor prognosis than patients without CyclinD1 staining (p < 0.05). Moreover, according to multivariate Cox regression analysis, CyclinD1 expression, as crucial as metastasis, was a risk marker for overall survival rate.
Conclusion
CyclinD1 exhibited a promising potential to predict the prognosis of patients with endometrial carcinoma. However, the statistical analysis demonstrated that CyclinD1 exhibited a poor ability to differentiate neoplastic lesions from non-neoplastic lesions; thus, the application of CyclinD1 only is not so credible for differentiation between benign and malignant lesions.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1871063048950173.
doi:10.1186/1746-1596-8-138
PMCID: PMC3846687  PMID: 23947899
Endometrial cancer; CyclinD1; Prognostic markers; Survival analysis
13.  Uterine superficial serous carcinomas and extensive serous endometrial intraepithelial carcinomas: clinicopathological analysis of 6 patients 
Uterine superficial serous carcinoma (SSC) and serous endometrial intraepithelial carcinoma (SEIC) are unique malignancies found primarily in postmenopausal women. SSC and SEIC lesions measuring 1 cm or less are categorized as minimal uterine serous carcinoma (MUSC). Less well understood, however, the clinical behavior of SSC and SEIC lesions measuring more than 1 cm. We investigated 6 postmenopausal patients, aged 69-83 years, with SSC or SEIC and without hyperestrogenism. All but 1 patient had tumors originating from the surface of polyps, including 3 patients who each had an enormous polyp occupying the entire uterine cavity. Two patients had extensive SEICs measuring more than 1 cm; the others had SSCs, including 1 MUSC. The mesenchymal cells of the cancer-bearing polyps lacked the morphologic characteristics of endometrial stroma, and the cancer glands often immunostained negatively for estrogen receptors and progesterone receptors. Diffuse immunostaining for human epidermal growth factor receptor 2 was detected in 3 patients, and p53 was detected in all. Cyclin E, a downstream molecule of the F-box and WD repeat domain-containing 7 (FBXW7), was detected in all patients. Microdissected cancer glands showed p53 mutations in 2 patients and a FBXW7 mutation in 1 patient. These findings suggest that mutations of FBXW7 and p53 may contribute to the carcinogenesis of less invasive tumor subtypes. Pathologists and physicians should carefully evaluate SSC and SEIC lesions involving large polyps but lacking myometrial invasion.
PMCID: PMC4270535  PMID: 25550841
Superficial uterine serous carcinoma; polyp; p53; F-box and WD repeat domain-containing 7 (FBXW7); cyclin E
14.  Multiple brain metastases in a patient with uterine papillary serous adenocarcinoma: Treatment options for this rarely seen metastatic brain tumor 
Background:
Uterine papillary serous adenocarcinoma (UPSAC) occurs 10-fold less frequently than endometrial carcinoma, and is referred to type 2 endometrial adenocarcinoma. The prognosis of UPSAC is worse than that of type I endometrial carcinoma. Herein we report what is only the second case of UPSAC, but it should prove to be more informative than the first reported case.
Case Description:
A 71-year-old female had three different metastases in the brain; two of the metastases were located in the posterior fossa within the cerebellar parenchyma with perilesional edema, but no mass effect, and the third metastasis was located in the right frontal lobe, and caused hemispheric edema and subfalcine herniation. The lesion that caused mass effect was completely extirpated without any surgical complications. The patient's recovery was excellent. She is able to walk independently, and use her left hand and left arm. Her Karnofsky performance score 5 months postsurgery was 80/100.
Conclusion:
Based on the outcome in the presented case, we think that in any UPSAC patient with a metastatic brain tumor causing mass effect the symptomatic metastatic tumor must be removed, regardless of disease grade, to ensure optimal quality of life.
doi:10.4103/2152-7806.117176
PMCID: PMC3768168  PMID: 24032086
Adenocarcinoma cerebrum; cerebellum; metastases; uterine
15.  The Origin and Pathogenesis of Epithelial Ovarian Cancer- a Proposed Unifying Theory 
Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53 but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, are highly aggressive, evolve rapidly and almost always present in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis, which is regarded as the precursor of these tumors. Since it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment and prevention which potentially can have a significant impact on reducing the mortality of this devastating disease.
doi:10.1097/PAS.0b013e3181cf3d79
PMCID: PMC2841791  PMID: 20154587
16.  An analysis of current treatment practice in uterine papillary serous and clear cell carcinoma at two high volume cancer centers 
Objective
Despite the rarity of uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC), they contribute disproportionately to endometrial cancer deaths. Sufficient clinical information regarding treatment and prognosis is lacking. The aim of this study is to evaluate treatment outcomes in a rare cancer cohort based on the experience at two tertiary care cancer centers.
Methods
Clinicopathologic data were retrospectively collected on 279 patients with UPSC and UCCC treated between 1995 to 2011. Mode of surgery, use of adjuvant treatment, and dissection of paraaoritc lymph nodes were evaluated for their association with overall survival (OS) and progression-free survival (PFS).
Results
40.9% of patients presented with stage I disease, 6.8% of patients presented with stage II disease and 52.3% of patients presented with stages III and IV. Median follow-up was 31 months (range, 1 to 194 months). OS and PFS at 5 years were 63.0% and 51.9%, respectively. OS and PFS were not affected by mode of surgery (open vs. robotic approach; OS: hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.28 to 1.62; PFS: HR, 0.78; 95% CI, 0.40 to 1.56). Adjuvant treatment was associated with improved OS in stages IB-II (HR, 0.14; 95% CI, 0.02 to 0.78; p=0.026) but not in stage IA disease. There was no difference in OS or PFS based on the performance of a paraaoritc lymph node dissection.
Conclusion
Minimally invasive surgical staging appears a reasonable strategy for patients with non-bulky UPSC and UCCC and was not associated with diminished survival. Adjuvant treatment improved 5-year survival in stages IB-II disease.
doi:10.3802/jgo.2015.26.1.25
PMCID: PMC4302281  PMID: 25376917
Adenocarcinoma, Clear Cell; Disease-free Survival; Endometrial Neoplasms; Lymph Node Excision; Retrospective Studies
17.  Overexpression of EpCAM in Uterine Serous Papillary Carcinoma: Implications for EpCAM-specific Immunotherapy with Human Monoclonal Antibody Adecatumumab (MT201) 
Molecular cancer therapeutics  2010;9(1):57-66.
We evaluated the expression of epithelial-cell-adhesion-molecule (EpCAM) and the potential of MT201 (adecatumumab), a human monoclonal antibody against EpCAM, in uterine serous papillary carcinoma (USPC). EpCAM expression was evaluated by real-time-PCR and immunohistochemistry (IHC) in a total of 56 USPC fresh-frozen biopsies and paraffin-embedded-tissues. EpCAM surface expression was also evaluated by flow cytometry and IHC in 6 USPC cell lines. Sensitivity to MT201 antibody-dependent-cellular-cytotoxicity (ADCC) and complement-dependent-cytotoxicity (CDC) was tested against a panel of primary USPC cell lines expressing different levels of EpCAM in standard 5-h 51Cr release-assays. EpCAM transcript was significantly overexpressed in fresh-frozen USPC when compared to normal-endometrial-cells (NEC). Median (minimum–maximum) copy number was 943.8 (31.5–1568.3) in tumor samples versus 12.9 (1.0–37.0) in NEC (P < 0.001). By immunohistochemistry, EpCAM expression was found in 96% (26 out of 27) of USPC samples with significantly higher expression compared to normal endometrial cells (P < 0.001). High surface expression of EpCAM was found in 83% (5 out of 6) of the USPC cell lines tested by flow cytometry. EpCAM-positive cell lines were found highly sensitive to MT201-mediated ADCC in vitro, while primary USPC cell lines were resistant to natural killer (NK) cell-dependent cytotoxicity. Human plasma IgG did not significantly inhibit MT201-mediated-cytotoxicity against USPC. EpCAM is highly expressed in uterine serous carcinoma at mRNA and protein levels and primary USPC are highly sensitivity to MT201-mediated cytotoxicity. MT201 might represent a novel therapeutic strategy in patients harboring advanced/recurrent or metastatic USPC refractory to standard treatment modalities.
doi:10.1158/1535-7163.MCT-09-0675
PMCID: PMC2806489  PMID: 20053761
Uterine serous papillary cancer; MT201; Adecatumumab; EpCAM; Endometrial carcinoma; Tumor markers
18.  Uterine Serous Papillary Carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody 
Cancer  2011;117(14):3163-3172.
Background
Uterine Serous Papillary Carcinoma (USPC), is an aggressive and chemotherapy resistant variant of endometrial cancer. We evaluated the expression of human –trophoblast-cell-surface-marker (Trop-2) and the potential of hRS7, a humanized anti-Trop-2 monoclonal antibody, as a novel therapeutic strategy against USPC.
Methods
Trop-2 expression was evaluated by immunohistochemistry (IHC) in a total of 23 USPC. Six primary USPC cell lines were assessed by flow cytometry and real-time-PCR for Trop-2 expression. Sensitivity to hRS7 (Immunomedics, Inc.) antibody-dependent-cellular-cytotoxicity (ADCC) and complement-dependent-cytotoxicity (CDC) was tested in standard 5-hrs-51Cr-release-assays against primary USPC cell lines.
Results
Expression of Trop-2 was found in 15 out of 23 (65%) of the tumor tissues tested by IHC and in 50% (3/6) of the USPC cell lines tested by real-time-PCR and flow-cytometry [Trop-2 expression in USPC versus normal-endometrial-cells (NEC)(p < 0.005)]. USPC cell lines overexpressing Trop-2, regardless of their intrinsic resistance to natural killer cytotoxicity, were highly sensitive to hRS7-mediated ADCC in vitro (range of killing 28.2% to 64.4%) (p< 0.001). Negligible cytotoxicity against USPC was seen in the absence of hRS7 or in the presence of Rituximab control-antibody (range of killing 1.1% to 12.4%). Incubation with interleukin-2 (50 IU/ml) in addition to hRS7 further increased the cytotoxic activity against USPC cell lines overexpressing Trop-2 (p= 0.008).
Conclusion
Trop-2 is highly expressed in uterine serous carcinoma at mRNA and protein levels. Primary USPC cell lines are highly sensitivity to hRS7-mediated-cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for USPC refractory to standard treatment modalities.
doi:10.1002/cncr.25891
PMCID: PMC3128671  PMID: 21246534
Endometrial neoplasms; Uterine Serous Papillary Carcinoma; Trop-2; trophoblast cell-surface marker; hRS7; antibody dependent cellular cytotoxicity
19.  MOLECULAR ALTERATIONS OF EGFR AND PIK3CA IN UTERINE SEROUS CARCINOMA 
Gynecologic oncology  2009;113(3):370-373.
Objectives
Uterine serous carcinoma (USC) is an aggressive endometrial cancer associated with poor prognosis despite comprehensive surgical staging and adjuvant chemotherapy and radiation therapy. Biologic targets have yet to be fully explored in this disease and research on such targets could lead to clinical trials utilizing a new class of therapeutics. This study sought to evaluate primary USC tumors for molecular alterations in epidermal growth factor receptor (EGFR) and the recently characterized oncogene PIK3CA, which encodes the catalytic p110-alpha subunit of phosphatidylinositol 3-kinase (PI3K) and thus activates the AKT-mTOR oncogenic pathway.
Methods
Paraffin-embedded archival tissue of 45 primary USC tumors was utilized in this study. Immunohistochemical analysis of EGFR was performed and cases given a score of 0 to 12 calculated as the product of staining intensity (0 to 3+) and the percentage of positively stained cells (0-4), with 1=1-25%, 2=26-50%, 3=51-75%, and 4=76-100%. For mutational analysis, neoplastic tissue was microdissected and DNA was extracted with phenol-chloroform. Exons 18 through 21 of EGFR and exons 9 and 20 of PIK3CA, the most commonly mutated exons of these genes, were amplified and directly sequenced.
Results
When EGFR was evaluated, moderate or strong EGFR membranous staining was observed in 25/45 (56%) USC cases. Thus, a mutational analysis was performed on 35 cases, including all cases with moderate and strong EGFR staining. No mutations were identified in EGFR. In contrast, PIK3CA mutations were confirmed in 5/34 (15%) of USC cases. Four cases were mutated in exon 20 and one case was mutated in exon 9.
Conclusions
Since optimal treatment of uterine serous carcinoma remains unknown, novel therapeutic approaches need to be actively pursued. In the current study of primary USC tumors, oncogenic mutations of the PIK3CA gene were seen in 15% of USC cases. This represents the first report of this gene mutation in USC. In addition, EGFR stained positively in the majority of cases, suggesting a possible target protein. These findings warrant further investigation and suggest a potential role for therapeutic agents targeting the PI3K-AKT-mTOR pathway, such as rapamycin, as well as possible targets of EGFR in the treatment of uterine serous carcinoma.
doi:10.1016/j.ygyno.2008.12.021
PMCID: PMC2745284  PMID: 19272638
Uterine serous carcinoma; PIK3CA; EGFR
20.  Nrf2 expression in endometrial serous carcinomas and its precancers 
Endometrial serous carcinoma (ESC) is the most aggressive subtype of endometrial cancer. Its aggressive behavior and poor clinical outcome may be partially attributed to lack of early diagnostic markers and unclear patho-genesis. The transcription factor Erythroid–E2-related factor 2 (Nrf2) is a recently identified protein marker, which plays a role in carcinogenesis as well as responsible for poor prognosis of many human cancers. The aim of this study is to determine the Nrf2 expression in benign endometrium (n=28), endometrial cancers (n=122) as well as their precursor lesions (n=81) trying to see whether Nrf2 has any diagnostic usage and is potentially involved in endometrial carcinogenesis. The level of Nrf2 was evaluated by immunohistochemical (IHC) and verified by using Western blots. Among the malignant cases, Nrf2 was positive in 28 (68%) of 50 ESCs, which was significantly more than in 3 (6%) of 50 endometrioid carcinomas (p < 0.001) and 2 (13%) of 15 clear cell carcinomas (p = 0.001) and other histologic types of endometrial cancers. Among endometrial precursor lesions, both serous endometrial glandular dysplasia (EmGD, 40%) and serous endometrial intraepithelial carcinoma (EIC, 44%) showed a significantly higher Nrf2 expression than that in atypical endometrial hyperplasia or endometrial intraepithelial neoplasia (0%), clear cell EmGD (10%), and clear cell EIC (25%), respectively. We conclude that Nrf2 overexpression is closely associated with endometrial neoplasms with serous differentiation. Alteration of Nrf2 expression may represent one of the early molecular events in ESC carcinogenesis and overexpression of Nrf2 may used as a diagnostic marker in surgical pathology.
PMCID: PMC3016106  PMID: 21228930
Nrf2; endometrial cancer; precancer; endometrial serous carcinoma; endometrial glandular dysplasia
21.  Evidence for a Latent Precursor (p53 Signature) that May Precede Serous Endometrial Intraepithelial Carcinoma 
Both serous intraepithelial carcinoma and endometrial glandular dysplasia are associated with uterine serous carcinoma. Recently a candidate serous cancer precursor containing p53 mutations (p53 signature) was described in the fallopian tube. We analyzed normal and neoplastic endometrium for a similar entity. Ten endometrial polyps involved by intraepithelial and/or invasive carcinoma and 137 benign polyps were studied. All were stained for p53 and MIB-1. A subset of p53 signatures and carcinomas were analyzed for γ-H2AX and p53 mutations. p53 signatures were identified in 7 of 10 cases intraepithelial carcinoma and were multicentric in 2. In one case, the signature was in continuity with intraepithelial carcinoma. Six of 137 benign polyps (4%) contained p53 signatures. The MIB-1 fraction in most signatures was less than 5%, and ranged from 50-90% in carcinomas. DNA damage (γ-H2AX) was demonstrated in both p53 signatures and adjacent carcinomas but not in benign polyps. Shared identical p53 mutations were found in paired signatures and carcinomas in two of three cases analyzed, including one case with multiple signatures. In one, a co-existent invasive serous cancer was not found to contain a p53 mutation. In a third, a p53 signature and an invasive cancer harbored two different p53 mutations. This is the first description of p53 signatures adjacent to carcinoma, suggesting a role for this entity in the genesis of serous malignancy. The significance of p53 signatures in benign conditions (polyps) remains to be determined.
doi:10.1038/modpathol.2008.197
PMCID: PMC2649686  PMID: 19151662
22.  Incidence of Serous Tubal Intraepithelial Carcinoma (STIC) by Algorithm Classification in Serous Ovarian Tumor Associated with PAX8 Expression in Tubal Epithelia: A Study of Single Institution in Japan 
Serous ovarian carcinoma is now hypothesized to originate from fallopian tube epithelium (FTE). We investigated the FTE abnormalities in the patients with epithelial ovarian tumors. Our study included 55 cases of serous tumors (24 carcinomas, 8 borderline tumors, and 23 adenomas), 14 mucinous carcinomas, 22 endometrioid carcinomas, 5 clear cell carcinomas, and 2 malignant Brenner tumors. FTE was diagnosed by the diagnostic algorithm, which combines the data of morphology, and p53, Ki-67 immunostaining, as serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive. Serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive were observed in 5, 3, 0, and 16 cases in serous carcinoma; 0, 3, 0, and 5 cases in serous borderline tumor; 0, 1, 1, and 21 cases in serous adenoma; 0, 0, 1, and 13 cases in mucinous carcinoma; 0, 0, 3, and 19 cases in endometrioid carcinoma; 0, 0, 0, and 5 cases in clear cell carcinoma; and 0, 1, 0, and 1 case in malignant Brenner tumor. Among tumors of serous histology and between carcinomas, FTE abnormalities differed significantly (P<0.05). Serous tubal intraepithelial carcinomas were only found in serous carcinoma. The incidence of secretory cell proliferation (SCP) was examined by PAX8 expression. The rate of SCP was extremely high in serous carcinoma (96%). Among tumors of serous histology and between carcinomas, an incidence of SCP differed significantly (P<0.05). Patients with SCP were significantly older (P<0.0001). Our observations were concordant with the hypothesis of serous ovarian carcinogenesis. The SCP has a meaningful association with serous ovarian cancer.
doi:10.1097/PGP.0000000000000108
PMCID: PMC4272227  PMID: 25473747
Serous ovarian tumor; Serous tubal intraepithelial carcinoma; PAX8; Immunohistochemistry; Japanese institution
23.  A case of minimal uterine serous carcinoma with distant lymph node metastasis without peritoneal dissemination 
A 61-year old woman underwent total abdominal hysterectomy and pelvic lymph node dissection under the diagnosis of endometrial cancer. Although pelvic lymph nodes were positive for adenocarcinoma with psamomma bodies, no other lesion that was a primary lesion was verified. A postoperative study revealed the existence of para-aortic lymph node and supraclavicular lymph node metastases. Therefore, the endometrial biopsy specimen was reviewed. With the findings of p53 positivity by immunohistochemistry in the papillary part, the final histopathological diagnosis was changed to endometrial serous adenocarcinoma. Postoperative chemotherapy followed by radiotherapy for supraclavicular lymph node metastasis achieved complete response. This type of tumor must be considered in a differential diagnosis when metastatic papillary serous carcinoma is detected, but the primary site remains unknown.
doi:10.3802/jgo.2011.22.1.53
PMCID: PMC3097336  PMID: 21607097
Endometrial cancer; Minimal uterine serous carcinoma; Cervical lymph node metastasis
24.  Papillary Tubal Hyperplasia. The Putative Precursor of Ovarian Atypical Proliferative (Borderline) Serous Tumors, Noninvasive Implants and Endosalpingiosis 
In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors (atypical proliferative serous tumor [APST] and serous borderline tumor [SBT]), little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube have not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of the fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated “papillary tubal hyperplasia (PTH)”, characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. Papillary tubal hyperplasia was found in 20 (91%) of the 22 cases in the Danish study. Based on this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to the primary ovarian APSTs but also to the noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tubes implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, then it can be concluded that low- and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily.
doi:10.1097/PAS.0b013e318229449f
PMCID: PMC3193599  PMID: 21997682
25.  Higher sensitivity to Patupilone versus Paclitaxel chemotherapy in primary uterine serous papillary carcinoma cell lines with high versus low HER-2/neu expression in vitro 
Gynecologic oncology  2010;119(1):140-145.
Objective
To compare the in vitro sensitivity/resistance to patupilone versus paclitaxel in uterine serous papillary carcinoma (USPC) with high versus low HER-2/neu expression.
Methods
Six primary USPC cell lines, half of which overexpress HER-2/neu at a 3+ level, were evaluated for growth rate and tested for their in vitro sensitivity/resistance to patupilone versus paclitaxel by MTS assays. Quantitative RT-PCR was used to identify potential mechanisms underlying the differential sensitivity/resistance to patupilone versus paclitaxel in primary USPC cell lines.
Results
Cell lines overexpressing HER-2/neu showed higher proliferation when compared to low HER-2/neu-expressing cell lines. Compared to low-expressing cell lines, high HER-2/neu expressors were significantly more sensitive to patupilone than to paclitaxel (P < 0.0002). In contrast, there was no appreciable difference in sensitivity to patupilone versus paclitaxel in primary USPC cell lines with low HER-2/neu expression. Higher levels of β-tubulin III (TUBB3) and P-glycoprotein (ABCB1) were detected in USPC cell lines with high versus low HER-2/neu expression (P < 0.05).
Conclusions
USPC overexpressing HER-2/neu display greater in vitro sensitivity to patupilone and higher levels of the patupilone molecular target TUBB3 when compared to low HER-2/neu expressors. Due to the adverse prognosis associated with HER-2/neu overexpression in USPC patients, patupilone may represent a promising novel drug to combine to platinum compounds in this subset of aggressive endometrial tumors.
doi:10.1016/j.ygyno.2010.06.024
PMCID: PMC2939197  PMID: 20673976
Endometrial neoplasms; uterine serous tumors; HER-2/neu; Patupilone; Paclitaxel

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