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1.  Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma 
Introduction: BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways. Methods: A prospective study of 47 HR women (40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy and 48 LR controls undergoing salpingo-oophorectomy was performed. Ovarian/tubal tissues were harvested. Immunohistochemical analysis of candidate proteins CSF-1, CSF-1R, ErbB4 is presented, with scores separately analyzed in epithelium and stroma, in ampulla, fimbria, ovary, and ovarian endosalpingiosis (ES). Comparison was performed between HR and LR groups. Results: Elevated levels of CSF-1 (p=0.005) or ErbB4 (p=0.005) in the ovarian epithelium, or ErbB4 (p=0.005) in the ovarian stroma, were significantly associated with both the HR status and carrying a BRCA mutation, as was nuclear ErbB4 staining. Ovarian ES, an entity which likely derives from the tubal mucosal epithelium, was also associated with HR (p=0.038) and BRCA mutation status (p=0.011). Among the BRCA carriers only, markers also found association when present in the tube as well as in ovarian ES (p < 0.05). ROCs were generated including in the regression model both CSF-1 and ErbB4 expression levels. A model including CSF-1 in ovarian epithelium, ErbB4 in ovarian stroma, and younger age achieves AUC=0.87 (73% sensitivity, 93% specificity) of detection of the HR status. In BRCA carriers, CSF-1 in ovarian epithelium alone achieves AUC=0.85. Conclusions: Our data suggest that elevated levels of CSF-1/ErbB4 in the adnexae correlate with HR/BRCA carrier status. CSF-1/CSF-1R signaling is active in ovarian cancer progression; our data suggests a role in its initiation. ErbB4, in particular nuclear ErbB4, may have a role in tumor initiation as well. Ovarian ES, an entity which may represent a latent precursor to low-grade pelvic serous carcinomas, was surprisingly associated with both HR status and the BRCA carrier cohort. In line with these findings, both ErbB4 and CSF-1R expression in ovarian ES correlated with carrying a BRCA mutation. This analysis, which needs to be validated, indirectly suggests a potential link between ovarian ES and the development of pelvic serous carcinoma in women who are BRCA mutation carriers.
PMCID: PMC3902233  PMID: 24482739
CSF-1; ErbB4; endosalpingiosis; high-risk
2.  Expression of the Oncofetal Protein IGF2BP3 (IMP3) in Endometrial Clear Cell Carcinoma: Assessment of Frequency and Significance 
Human pathology  2013;44(8):1508-1515.
Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms, including ovarian clear cell carcinoma. In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial clear cell carcinomas (CCC). Cases with scores of 0-100, 101-200, and 201-300 were classified as negative/mildly positive (n=17), moderately positive (n=20) and strongly positive (n=13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (p=0.01). Increasing levels of IMP3 expression showed a trend towards decreasing RFS (median survival 75.6, 81.3 and 48.4 months for the negative/mildly, moderately and strongly positive groups respectively (p=0.09). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend towards reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggests that IMP3 expression may be involved in the pathogenesis of CCC, and is worthy of further exploration.
PMCID: PMC3888088  PMID: 23465280
3.  Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells 
Nature communications  2013;4:1909.
CD25, the alpha chain of the interleukin-2 receptor, is expressed in activated T cells and plays a significant role in autoimmune disease and tumorigenesis; however, the mechanisms regulating transcription of CD25 remain elusive. Here we identify the Src-associated substrate during mitosis of 68kDa (Sam68) as a novel non-Rel component in the nuclear factor-kappaB (NF-κB) complex that confers CD25 transcription. Our results demonstrate that Sam68 plays an essential role in the induction and maintenance of CD25 in T cells. T cell receptor engagement triggers translocation of the inhibitor of NF-κB kinase alpha (IKKα) from the cytoplasm to the nucleus, where it phosphorylates Sam68, causing complex formation with NF-κB in the nucleus. These findings reveal the important roles of KH domain-containing components and their spatial interactions with IKKs in determining the binding targets of NF-κB complexes, thus shedding novel insights into the regulatory specificity of NF-κB.
PMCID: PMC3684077  PMID: 23715268
4.  Cytologic changes of ovarian epithelial cancer induced by neoadjuvant chemotherapy 
Objective: Neoadjuvant chemotherapy (NACT) followed by cytoreduction has now become a part of standard care for patients with advanced ovarian cancer. Cytologic changes of the cancer cells induced by NACT, however, sometimes may cause confusion in terms of pathologic diagnosis and therefore inappropriate management. The objective of this study was to characterize the histologic or cytologic features of the ovarian cancers from those patients who received NACT in order to improve the diagnostic accuracy and reduce unnecessary clinical workup. Methods: Specimens from 120 patients with advanced ovarian cancer who received NACT were studied. All 120 cases had either cytologic samples from ascites (n=108) or fine needle aspiration (n=12) and the diagnosis of consistent with cancers of ovarian origin was made prior to NACT. There were 70 (58.3%) patients received subsequent tumor debulking surgery after NACT. The time frame between NACT and debulking surgery ranged from 28 to 65 with an average of 45 days. Among the 70 cases with cytoreductive surgery, 48 cases containing both pre-NACT cytology/histology and subsequent debulking specimens were suitable for the study. All 48 post-NACT ovarian cancers were reviewed and the characteristic pathologic features in gross were summarized. Microscopic evaluation and immunohistochemical stainings with antibodies against ER, PR, p53, WT1, PAX8, CK7, CK20, and CDX2 were performed to confirm the primary site and histologic type of the cancers. Results: Grossly, tumor size within the ovaries from those debulking specimens ranged from 2.3 to 6.5 cm in greatest dimension. The cancers were mainly solid (average of 65%) and cystic areas had more or less hemorrhagic appearance. Extensive tumor necrosis and some with fibrosis were present. Microscopically, the non-necrotic cancer cells were arranged in cords, islands and sometimes as scattered single large cells with large amount of eosinophilic cytoplasm with vacuoles. The viable cancer cells contained more or less vacuolated cytoplasm in almost all post chemotherapy cases. Multinucleated tumor giant cells were noted in close to half of the cases. The cancer cells commonly had large hyperchromatic bizarre nuclei with coarse chromatin clumping and sometimes prominent nucleoli. Due to the unusual cytologic changes after NACT, there was a concern of non-ovarian origin or the different histologic type of the cancers. Therefore, immunohistochemical (IHC) staining with the antibodies against ER, PR, PAX8, WT1, CK7, CK20, and CDX2 was performed in all 48 pairs of the cases. The 48 paired samples showed identical immunophenotype in pre- and post-NACT cancers, confirming there was no metastatic or new primary cancer involved in the study. Conclusions NACT can apparently induce significant cytologic/histologic changes in ovarian cancer. Aware of such NACT induced changes will be useful to make correct diagnosis for those patients who have received NACT. IHC with appropriate panels of the antibodies will be helpful to aid the diagnosis, particularly when nuclear change is dramatic and the clinical history of ovarian cancer is not available.
PMCID: PMC3796234  PMID: 24133590
Ovarian cancer; cytological changes; chemotherapy; immunohistochemical
5.  PAX8: a sensitive and specific marker to identify cancer cells of ovarian origin for patients prior to neoadjuvant chemotherapy 
Neoadjuvant chemotherapy followed by cytoreduction surgery has been used where an accurate cytologic or pathologic diagnosis is usually required before the initiation of neoadjuvant chemotherapy. However, it is difficult to make definitive diagnosis of presence of cancer cells, particularly gynecologic versus non-gynecologic origin, from those ascites specimens due to the absence of specific biomarkers of gynecologic cancers. In the present study, we evaluated if, in addition to the routine morphologic diagnosis, the biomarker PAX8 could be useful in recognition of ovarian epithelial cancer cells prior to the neoadjuvant chemotherapy.
Two hundred and two cytology specimens including 120 pretreatment ovarian cancer samples, 60 benign controls, and 22 malignant non-gynecologic cases were studied. All cytology slides were morphologically reviewed in a blinded fashion without knowing corresponding pathology diagnosis, if present. A total of 168 cytology specimens with a cell block were stained with PAX8 and Calretinin. These included patients with potential for ovarian cancer neoadjuvant chemotherapy (n = 96), metastatic cancers (n = 22), and benign controls (n = 50).
Among the 96 ascitic samples prior to neoadjuvant chemotherapy, 76 (79%) showing morphologic features consistent with cancers of ovarian primary were all PAX+/Calretinin-. The remaining 20 (21%) cases were positive for adenocarcinoma, but morphologically unable to be further classified. Among the 22 metastatic cancers into the pelvis, one case with PAX8+/Calretinin- represented a renal cell carcinoma and the remaining 21 PAX8-/Calretinin- metastatic cancers were either breast metastasis (n = 4) and the metastasis from gastrointestinal tract (n = 17). Among the 50 benign control pelvic washing cases, 5 PAX8+/Calretinin-cases represented endosalpingiosis (n = 4) and endometriosis (n = 1), 25 PAX8-/Calretinin + cases showed reactive mesothelial cells, and the remaining 20 specimens with PAX8-/Calretinin- phenotype typically contained inflammatory or blood cells without noticeable diagnostic epithelia.
PAX8 identifies all Müllerian derived benign or malignant epithelia. When combining with Calretinin, PAX8 is a sensitive marker to diagnose the carcinomas of ovarian origin, which will be ideal to be used for those patients with a possible advanced ovarian cancer prior to receiving neoadjuvant chemotherapy.
PMCID: PMC3751714  PMID: 23958394
PAX8; Ascitic fluid; Ovarian cancer; Neoadjuvant chemotherapy; Origin; Marker
6.  Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium 
Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.
PMCID: PMC3623651  PMID: 23531335
7.  Struma ovarii simulating ovarian sertoli cell tumor: a case report with literature review 
Struma ovarii, as a monodermal variant of ovarian teratoma, constitutes about less than 3% of ovarian teratomas. It is difficult to be macroscopically recognized. Multiple appearances under microscope serve as another reason to mislead the accurate pathologic evaluation. Here, we report an unusual case of struma ovarii occurred in a 77 years old woman, which is currently known as the oldest age for this disease. The frozen section morphologically showed sex cord like elements and was suspicious for a sex-cord stromal tumor, probably a Sertoli cell tumor. Final pathological diagnosis was confirmed as struma ovarii based on the typical morphologic thyroid follicles and immunohistochemical staining results.
PMCID: PMC3563194  PMID: 23412916
Struma ovarii; sertoli cell tumor; ovary
8.  Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases 
Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC.
PMCID: PMC3555196  PMID: 23359866
Clear cell carcinoma; endometrium; morphologic features
11.  Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis 
Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.
PMCID: PMC3328281  PMID: 22405464
Ovarian cancer; Fallopian tube; Carcinogenesis; Serous carcinoma; p53 signatures
12.  High levels of Nrf2 determine chemoresistance in type II endometrial cancer 
Cancer research  2010;70(13):5486-5496.
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.
PMCID: PMC2896449  PMID: 20530669
Nrf2; chemoresistance; and endometrial cancer
13.  Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis 
Oncology Letters  2011;2(4):643-647.
The present study aimed to examine the combined effects of oxaliplatin (L-OHP) and rapamycin (RAPA) in the HCT116 colon cancer cell line. The growth inhibitory effect was evaluated by MTT assay as a monotherapy or combination therapy. IC50 values were determined using CalcuSyn 2.0 software. To determine the interaction of the drugs, the combination index (CI) was calculated using the Chou-Talalay method. Apoptosis was investigated using flow cytometry and Western blotting. Acridine orange staining was employed to observe morphological changes. The results showed the IC50 values of L-OHP and RAPA to be 8.35±0.78 μM (r=0.99) and 223.44±38.10 nM (r=0.94), respectively. CI was ≤1 when L-OHP was used at doses ranging from 1 to 5 μM plus RAPA at a dose of 10 nM, suggesting synergistic or additive effects. CI was ≥1 when 100 nM RAPA was used in combination with low-dose L-OHP, showing additive to antagonistic effects. The combination of L-OHP (1 μM) and RAPA (10 nM) induced 19.76% Annexin V-positive cells, which was found to be higher than L-OHP (11.45%, p<0.01) or RAPA (6.89%, p<0.01) alone. The cleaved PARP protein expression levels were highest after 48 h of combination treatment. Acridine orange staining showed typical bright red Acidic vesicular organelles in the RAPA group, whereas the green condensed chromatin in the apoptotic bodies was found in both the L-OHP and combination groups. In conclusion, at a cytostatic concentration, RAPA was found to potentiate the anti-tumor effects of low-dose L-OHP in the HCT116 colon cancer cell by inducing enhanced apoptosis.
PMCID: PMC3406438  PMID: 22848242
rapamycin; oxaliplatin; colon cancer; apoptosis; autophagy
14.  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
15.  Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2 
Carcinogenesis  2008;29(6):1235-1243.
Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a ‘good’ transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2–small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.
PMCID: PMC3312612  PMID: 18413364
16.  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)
17.  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.
PMCID: PMC2266702  PMID: 18261213
18.  E-cadherin and β-catenin expression in early stage cervical carcinoma: a tissue microarray study of 147 cases 
The disruption of intercellular adhesions is an important component of the acquisition of invasive properties in epithelial malignancies. Alterations in the cell-cell adhesion complex, E-Cadherin/β-Catenin, have been implicated in the oncogenesis of carcinomas arising from various anatomic sites and have been correlated with adverse clinico-pathologic parameters. In this study, the authors investigated the immunohistochemical expression of E-Cadherin and β-Catenin in a cohort of early stage cervical cancers to determine its prognostic significance and to investigate differences between the three major histological subtypes.
Patients and methods
A tissue microarray of 147 cases of FIGO stage 1A and 1B cervical carcinomas [96 squamous cell carcinomas (SCC), 35 adenocarcinomas (AC), 12 adenosquamous carcinomas (ASQ), 4 miscellaneous types] was constructed from our archived surgical pathology files and stained with monoclonal antibodies to E-Cadherin and β-Catenin. Cases were scored by multiplying the intensity of staining (1 to 3 scale) by the percentage of cells stained (0–100%) for a potential maximum score of 300. For both markers, "preserved" expression was defined as bright membranous staining with a score of 200 or above. "Impaired" expression included any of the following: negative staining, a score less than 200, or exclusively cytoplasmic or nuclear delocalization.
Impaired expression of β-Catenin was found in 85.7%, 66.7%, & 58.3% of AC, SCC & ASQ respectively. Impaired expression of E-Cadherin was found in 94.3%, 86.5% & 100% of cases of AC, SCC, & ASQ respectively. The differences between the histologic subtypes were not significant. For the whole cohort, a comparsion of cases showing impaired versus preserved of E-Cadherin and β-Catenin expression showed no significant differences with respect to recurrence free survival, overall survival, patient age, histologic grade, and frequency of lymphovascular invasion or lymph node involvement. There was no correlation between the status of both markers for all three histological subtypes (overall spearman correlation co-efficient r = 0.12, p = 0.14)
Impairment of E-Cadherin and β-Catenin expression is very frequent in early stage cervical cancers, and alterations in the E-Cadherin/β-Catenin cell adhesion complex are therefore likely involved in the pathogenesis of cervical carcinomas even at their earliest stages. None of the three major histological subtypes of cervical carcinoma (SCC, ADCA, ADSQ) is significantly more likely than the others to show impairment in E-Cadherin and β-Catenin expression. Overall, the expression of both markers does not significantly correlate with clinico-pathological parameters of prognostic significance.
PMCID: PMC1183253  PMID: 15969753
19.  Role of osteopontin in amplification and perpetuation of rheumatoid synovitis 
Journal of Clinical Investigation  2005;115(4):1060-1067.
Osteopontin (OPN) is an extracellular matrix protein of pleiotropic properties and has been recently recognized as a potential inflammatory cytokine. In this study, we demonstrate, for the first time to our knowledge, that overexpression of OPN in synovial T cells is associated with local inflammatory milieu and that OPN acts as an important mediator in amplification and perpetuation of rheumatoid synovitis. The study revealed that mRNA expression of OPN was highly elevated in CD4+ synovial T cells derived from patients with RA, which correlated with increased OPN concentrations in synovial fluid (SF). The pattern of OPN overexpression was confined to rheumatoid synovium and correlated with coexpression of selected OPN receptors in synovial T cells, including integrins αv and β1 and CD44. RA-derived SF stimulated the expression of OPN in T cells, which was attributable to IL-10 present in SF and abrogated by anti–IL-10 antibody. Among the more than 300 autoimmune and inflammatory response genes examined, OPN selectively induced the expression of proinflammatory cytokines and chemokines known to promote migration and recruitment of inflammatory cells. Furthermore, it was evident that OPN activated transcription factor NF-κB in mononuclear cells. The study has important implications for understanding the role of OPN in rheumatoid synovitis and other inflammatory conditions.
PMCID: PMC1059449  PMID: 15761492
20.  Age dependent association of endometrial polyps with increased risk of cancer involvement 
Endometrial polyps (EMPs) are commonly encountered in routine surgical pathology practice, but opinions differ on whether they are intrinsically a marker for concurrent or subsequent malignancy. The objectives of the present study are 1) to investigate the age-group in which EMP are most commonly encountered 2) to document the age-group in which EMP are most commonly associated with malignancies 3) To investigate whether the age of diagnosis of the various carcinoma subtypes in EMPs is congruent with published data on similar malignancies arising in non-polypoid endometrium and 4) To investigate whether the histologic subtype distribution of malignancies associated with EMPs are similar or different from the distribution of malignancies arising from non-polypoid endometrium based on published data.
Patients and methods
All cases of EMPs were retrieved from the files of Yale-New Haven Hospital for the period 1986–1995. The patients were divided into 5 age groups: Each group was further subclassified based on an association (or lack thereof) of EMPs with endometrial carcinoma. Chi-square test was used to compare the proportion of malignancy associated EMPs between the age groups.
We identified 513 EMPs, of which 209 (41%) were from biopsy specimens and 304 (59%) from hysterectomy specimens. Sixty six (13%) of all EMPs were malignant. The 66 malignant EMPs included 58 endometrioid, 6 serous, 1 carcinosarcoma, and 1 clear cell carcinoma. In age group >35, only 1(2.5%) of 40 EMPs was associated with endometrial malignancy. In contrast, 37(32%) of 115 EMPs were associated with malignancy in the age group > 65. The frequency of malignant EMPs increased with age and reached statistical significance in the age group >65 (p < 0.001). The most common histologic type of malignancy was endometrioid adenocarcinoma.
EMPs show statistically significant age dependent association with malignant tumor involvement. Careful search for malignancy, particularly in women with multiple risk factors is advised in daily practice. Additional studies are needed to address the histological features and immunohistochemical profiles in the context of association between endometrioid and high-grade endometrial carcinoma and endometrial polyps.
PMCID: PMC549519  PMID: 15703068

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