Should endometrial clear cell carcinoma be classified as Type II endometrial carcinoma?

Endometrial clear cell carcinomas (ECCCs) are considered to be Type II endometrial carcinomas, like uterine serous adenocarcinoma (SCA), and therefore aggressive clinical management is indicated. However, according to the limited clinical, immunohistochemical, and molecular data available in the literature, ECCCs show overlapping features of SCA and endometrioid adenocarcinomas. Therefore, questions regarding their designation as the Type II carcinomas have been raised. We performed immunohistochemical staining for hepatocyte nuclear factor-1ß and napsin A for the histologic confirmation of clear cell carcinoma (CCC), and analyzed immunohistochemical findings for estrogen receptor, progesterone receptor, HER2/neu, p53, p16, ARID1A, PTEN, DNA mismatch-repair proteins along with other prognostic factors. We performed DNA sequencing for the K-RAS, BRAF, PIK3CA, and PTEN genes for 16 pure CCCs. No patients with pure CCC experienced recurrent disease or died of the disease (0/16, 0%). ECCCs had SCA-like features with rare expression of estrogen receptor/progesterone receptor (18.8%/6.3%) and no K-RAS mutations, intermediate features regarding expressions of p53 (37.5%) and p16 (25%), and endometrioid adenocarcinoma-like features regarding losses of PTEN (81.3%), ARID1A (25%) and mismatch-repair protein (68.8%), expression of microsatellite instability-high (25%), HER2/neu (12.5%), and PIK3CA mutations (18.8%). Pure ECCC should not be regarded as Type II carcinoma, because it shares the immunohistochemical and molecular characteristics of Type I endometrioid adenocarcinoma and Type II SCA.

Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice.

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

Risk factors for recurrence and prognosis of low-grade endometrial adenocarcinoma; vaginal versus other sites.

Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.

MicroRNA expression profiling and Notch1 and Notch2 expression in minimal deviation adenocarcinoma of uterine cervix.

BACKGROUND: MicroRNA (miRNA) expression is known to be deregulated in cervical carcinomas. However, no data is available about the miRNA expression pattern for the minimal deviation adenocarcinoma (MDA) of uterine cervix. We sought to detect deregulated miRNAs in MDA in an attempt to find the most dependable miRNA or their combinations to understand their tumorigenesis pathway and to identify diagnostic or prognostic biomarkers. We also investigated the association between those miRNAs and their target genes, especially Notch1 and Notch2. METHODS: We evaluated miRNA expression profiles via miRNA microarray and validated them using.real-time PCR assays with 24 formalin-fixed, paraffin-embedded tissue blocks of MDA and 11 normal proliferative endocervical tissues as control. Expression for Notch1 and 2 was assessed by immunohistochemistry. RESULTS: MiRNA-135a-3p, 192-5p, 194-5p, and 494 were up-regulated, whereas miR-34b-5p, 204-5p, 299-5p, 424-5p, and 136-3p were down-regulated in MDA compared with normal proliferative endocervical tissues (all P<0.05). Considering the second-order Akaike Information Criterion consisting of likelihood ratio and number of parameters, miR-34b-5p showed the best discrimination power among the nine candidate miRNAs. A combined panel of miR-34b-5p and 194-5p was the best fit model to discriminate between MDA and control, revealing 100% sensitivity and specificity. Notch1 and Notch2, respective target genes of miR-34b-5p and miR-204-5p, were more frequently expressed in MDA than in control (63% vs. 18%; 52% vs. 18%, respectively, P<0.05). MiR-34b-5p expression level was higher in Notch1-negative samples compared with Notch1-positive ones (P<0.05). Down-regulated miR-494 was associated with poor patient survival (P=0.036). CONCLUSIONS: MDA showed distinctive expression profiles of miRNAs, Notch1, and Notch2 from normal proliferative endocervical tissues. In particular, miR-34b-5p and 194-5p might be used as diagnostic biomarkers and miR-494 as a prognostic predictor for MDA. The miR-34b-5p/Notch1 pathway as well as Notch2 might be important oncogenic contributors to MDA.

Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3.

Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1ß, Wilms' tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient's survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%, respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival (P<0.05). High Galectin-3 (≥80%) expression was seen in 59.7% of CCCs, and associated with FIGO stages III and IV, and high Ki-67 labeling index. High Ki-67 labeling index (≥50%) and p53 expression (≥50%) were seen in 27.1% and 18.6% of CCCs, respectively, but there was no clinicopathologic and prognostic significance. On the basis of the fact that the expression of Emi1 in CCC was correlated with a high histologic grade and worse overall survival, target therapy using inhibitors of Emi1 may be tried in the management of CCC patients with Emi1 expression.

Chromosomal aberrations detected by chromogenic in situ hybridization in abdominal wall endometriosis after cesarean section.

The goal of this study is to evaluate the chromosomal loss in abdominal wall endometriosis by chromogenic in situ hybridization (CISH). Twenty-four cases of abdominal wall endometriosis that developed after cesarean section at the Korea University Medical Center between January 1997 and December 2006 were selected. CISH was performed in the sections of tissue microarray block using the Zymed CISH centromeric probes for chromosomes 3, 7, 8, 9, 10, 11, 17, and 18. Monosomy was defined when the percentage of the nuclei with a single dot was more than mean+3 SD of the respective probe in normal control endometrium. CISH study was possible in more than half of the endometriosis samples, except for chromosome 9, and was most successful for chromosome 17. The frequency of monosomy was high for chromosomes 9 (75.0%) and 17 (73.9%), moderate for chromosomes 10 (57.1%) and 18 (56.3%), and low for chromosomes 3 (12.5%), 7 (22.2%), 8 (10.5%), and 11 (10.5%). Monosomy for >2 and 3 chromosomes occurred in 66.7% and 42.9% of the cases, respectively. It is concluded that CISH method may be considered a useful laboratory technique in detecting chromosomal loss, and multiple chromosomal loss is involved in the formation of ectopic endometrium in abdominal wall endometriosis.

Corticosteroid treatment of pure red cell aplasia in a patient with hepatitis A.

Secondary pure red cell aplasia (PRCA), as an extrahepatic manifestation of hepatitis A virus infection, has been reported on rare occasions. We report herein an unusual case of hepatitis A complicated by PRCA. In addition, we reviewed nine cases reported in the English literature. Our case of nonfulminant hepatitis A complicated by PRCA and hemolytic anemia was successfully treated with initial transfusion and corticosteroid therapy for 18 weeks. The patient's hematologic abnormalities and liver function tests re-normalized completely. We review clinical features and effective therapeutic strategies for this disease entity.

Effect of different forms of anionic nanoclays on cytotoxicity.

Anionic nanoclays, so-called layered double hydroxide (LDH) nanoparticles, have been extensively applied as drug delivery systems, since they efficiently enter cells via endocytosis pathway and possess controlled release property. However, the stability of LDHs varies, depending on the type of interlayer anions, which can also affect their toxicity. In this study, we investigated the effects of two different forms of LDH, carbonate form (MgAl-LDH-CO3) and chloride form (MgAl-LDH-Cl), on cytotoxicity in human lung epithelial cells. The result showed that MgAl-LDH-Cl was more easily dissolved into metal ions under simulated lysosomal (pH 4.5) and body fluid (pH 7.4) conditions than did MgAl-LDH-CO3. According to cytotoxicity evaluation, MgAl-LDH-CO3 exhibited high toxicity compared with MgAl-LDH-Cl in terms of induction of oxidative stress, apoptosis and membrane damage. These results suggest that easily dissoluble MgAl-LDH-Cl has low cytotoxicity, while high stability of MgAl-LDH-CO3 is correlated to elevated cytotoxicity.

Giant melanotrichoblastoma.

Trichoblastomas are benign skin tumors composed mostly of follicular germinative cells recapitulating the differentiation of hair follicles. Several variants of trichoblastomas have been reported, including pigmented trichoblastomas, melanotrichoblastomas, subcutaneous trichoblastomas, or giant trichoblastomas. We report a rare case of a pigmented trichoblastoma with abundant dendritic melanocytes. A 51-year-old Korean man had a round soft tissue mass on his back. The tumor was 6 cm in size and located in the subcutaneous fatty layer. On immunohistochemical stain for Melan A, numerous dendritic melanocytes were demonstrated in both pigmented and nonpigmented epithelial cell components. These cells were also positive for HMB45, and some of the dendritic melanocytes were positive for S-100 protein. With the aid of immunohistochemical staining, we diagnosed the tumor as a giant melanotrichoblastoma.

Comparative cytotoxicity of Al2O3, CeO2, TiO2 and ZnO nanoparticles to human lung cells.

The increased applications of nanoparticles in a wide range of industrial fields raise the concern about their potential toxicity to human. The aim of this study was to assess and compare the toxicity of four different oxide nanoparticles (Al2O3, CeO2, TiO2 and ZnO) to human lung epithelial cells, A549 carcinoma cells and L-132 normal cells, in vitro. We focused on the toxicological effects of the present nanoparticles on cell proliferation, cell viability, membrane integrity and oxidative stress. The long-term cytotoxicity of nanoparticles was also evaluated by employing the clonogenic assay. Among four nanoparticles tested, ZnO exhibited the highest cytotoxicity in terms of cell proliferation, cell viability, membrane integrity and colony formation in both cell lines. Al2O3, CeO2 and TiO2 showed little adverse effects on cell proliferation and cell viability. However, TiO2 induced oxidative stress in a concentration- and time-dependent manner. CeO2 caused membrane damage and inhibited colony formation in long-term, but with different degree depending on cell lines. Al2O3 seems to be less toxic than the other nanoparticles even after long time exposure. These results highlight the need for caution during manufacturing process of nanomaterials as well as further investigation on the toxicity mechanism.

Pseudomelanosis ilei associated with ingestion of charcoal: case report and review of literature.

Melanosis or pseudomelanosis of the gastrointestinal tract refers to an accumulation of pigment deposits in the gastrointestinal mucosa. Pigmentation can affect the entire gastrointestinal tract. Melanosis of the colon is not uncommon, but black pigmentation of the small intestine is extremely rare. We report a case of pseudomelanosis of the terminal ileum in a 52-year-old woman who had ingested a tablespoon of charcoal powder daily for 2 years. Numerous small and medium-sized irregular grayish black pigmentations mostly on the background of geographic light grayish discolored mucosa and some on the normal-looking mucosa were seen on the terminal ileum. The finding was similar to a cut surface of a dragon fruit and we named the lesion 'dragon fruit ileum'. Follow up endoscopy 10 months later revealed no significant change in the pigmentation. We could not search any English literature on this lesion. However, we could find three cases from two papers from Korea describing similar lesions after chronic charcoal ingestion and the papers were reviewed with a report of our case.

Glomeruloid peritoneal implants in ovarian serous borderline tumours--distinction between invasive and non-invasive implants and pathogenesis.

AIMS: To determine whether or not the glomeruloid implants (GI) composed of papillary cores within clear spaces lined by mesothelial cells or tumour cells located in superficial or deep peritoneal tissue in ovarian serous borderline tumours (SBTs) are invasive. METHODS AND RESULTS: We examined the differences in incidence, histological and immunohistochemical findings among three groups: 100 GI with mesothelial cells lining clear space (type I), 100 GI with tumour cells lining clear space (type II), and 100 invasive implants with clefts but no lining cells from 30 cases of SBT with peritoneal implants. The type I lesion had characteristics of non-invasive implants with a tendency for smooth contours (100/100), superficial location (71/100), absence of desmoplasia (100/100) and absence of surrounding destructive invasion (100/100), In contrast, type II GI had irregular contours (67/100), deep location (93/100), presence of desmoplastic reaction (100/100) and presence of destructive invasion (12/100). Immunohistological studies suggested intermediate forms between the two types of lesions. CONCLUSIONS: Type I GI are non-invasive implants, whereas type II GI are invasive implants and it is important to evaluate the presence and nature of cells lining the clear space in determining whether implants associated with ovarian SBTs are invasive or not.

Borderline-like mucinous tumor arising in mature cystic teratoma of the ovary associated with pseudomyxoma peritonei.

SUMMARY: Pseudomyxoma peritonei (PMP) is now considered to originate from appendiceal mucinous neoplasms in almost all cases. However, a mucinous neoplasm arising in a mature cystic teratoma is rarely responsible for PMP. We herein report 2 cases of PMP associated with borderline mucinous tumors arising in mature cystic teratoma. Both ovarian borderline mucinous tumors were morphologically and immunohistochemically similar to the secondary tumors from appendiceal origin, and PMP was histologically similar to peritoneal adenomucinosis.

Identification of Pax5 as a target of MTA1 in B-cell lymphomas.

Previously, we have shown that metastasis-associated protein 1 (MTA1) overexpression in transgenic mice was accompanied by high incidence of spontaneous B-cell lymphomas including diffuse large B-cell lymphomas (DLBCL). To understand the molecular basis of lymphoma in MTA1-transgenic (MTA1-TG) mice, we wished to identify a putative MTA1 target with a causal role in B-cell lymphogenesis. Using chromatin immunoprecipitation assays, we identified paired box gene 5 (Pax5), a molecule previously implicated in B-cell lymphogenesis, as a potential downstream effector of MTA1. Lymphomas from MTA1-TG mice also showed up-regulation of Pax5. We also found that MTA1 acetylated on Lys(626) interacted with p300 histone acetyltransferase, and that acetylated MTA1 was recruited to the Pax5 promoter to stimulate Pax5 transcription. Global gene profiling identified down-regulation of a set of genes, including those downstream of Pax5 and directly implicated in the B-cell lymphogenesis. Significance of these murine studies was established by evidence showing a widespread up-regulation of both MTA1 and Pax5 in DLBCL from humans. These observations provide in vivo genetic evidence for a role of MTA1 in lymphomagenesis.

Metastasis-associated protein 1 transgenic mice: a new model of spontaneous B-cell lymphomas.

Metastasis-associated protein 1 (MTA1), a component of the nuclear remodeling complex and the founding homologue of the MTA family, has been implicated in metastasis, but definitive causative evidence in an animal model system is currently lacking. Here, we show that MTA1 overexpression in transgenic mice is accompanied by a high incidence of spontaneous B cell lymphomas including diffuse large B cell lymphomas (DLBCL). Lymphocytes and lymphoma cells from MTA1-TG mice are hyperproliferative. Lymphomas were transplantable and of clonal origin and were characterized by down-regulation of p27Kip1 as well as up-regulation of Bcl2 and cyclin D1. The significance of these murine studies was established by evidence showing a widespread up-regulation of MTA1 in DLBCL from humans. These findings reveal a previously unrecognized role for the MTA1 pathway in the development of spontaneous B cell lymphomas, and offer a potential therapeutic target in B cell lymphomas. These observations suggest that MTA1-TG mice represent a new model of spontaneous DLBCL associated with high tumor incidence and could be used for therapeutic intervention studies.

Intraoperative consultation for ovarian tumors.

The primary function of intraoperative frozen consultation is to provide an as accurate and prompt diagnosis as possible during surgery and to guide the surgeon in further management. However, the evaluation of frozen section (FS) is sometimes difficult because of suboptimal tissue quality and frozen artifacts compared with routinely processed tissue section. The pathologist responsible for the FS diagnosis requires experience and good judgment. Ovarian tumors are a heterogeneous group of tumors including primary surface epithelial tumors, germ cell tumors and sex cord-stromal tumors, secondary tumors, and other groups of tumors of uncertain histogenesis or nonspecific stroma. Intraoperative FS is a very important and reliable tool that guides the surgical management of ovarian tumors. In this review, the diagnostic key points for the pathologist and the implication of the FS diagnosis on the operator's decisions are discussed.

FOXP1 abnormalities in lymphoma: translocation breakpoint mapping reveals insights into deregulated transcriptional control.

Deregulation of FOXP1 expression plays an important role in lymphoma development although the underlying molecular mechanism is poorly understood. FOXP1 is targeted by chromosome translocations in MALT lymphoma and diffuse large B-cell lymphoma, where high-level protein expression is associated with poor prognosis. Nonetheless, the incidence and nature of FOXP1 abnormalities at both the genetic and protein levels, and their correlation in these lymphomas are not well established. We investigated FOXP1 translocation, copy number change and protein expression in MALT lymphoma (n=321), MALT lymphoma with a diffuse large B-cell lymphoma component (59), nodal diffuse large B-cell lymphoma (64) and extranodal diffuse large B-cell lymphoma (151) by interphase fluorescence in situ hybridization and immunohistochemistry. FOXP1 translocation was found in eight MALT lymphomas and three MALT lymphomas with diffuse large B-cell lymphoma, with all positive cases originating in the stomach. In diffuse large B-cell lymphoma, the translocation was seen in 5 cases originating in the stomach (2), tonsil (1), large intestine (1) and lymph node (1). Immunoglobulin heavy chain gene was the translocation partner in 11 of the 16 positive cases. Fluorescence in situ hybridization mapping revealed FOXP1 breakpoints within the 5' untranslated region of the gene (upstream of exon 6, the first coding exon of full-length FOXP1) in 14 cases, but downstream of exon 6 (most likely upstream of exon 8) in the remaining 2 cases. Three copies of the FOXP1 gene were observed in MALT lymphoma (17%), MALT lymphoma with diffuse large B-cell lymphoma (12%) and diffuse large B-cell lymphoma (32%), including cases with FOXP1 translocation (19%). Immunohistochemistry showed strong/moderate FOXP1 staining in all the cases with FOXP1 translocation. However, FOXP1 expression was independent of FOXP1 translocation or copy number changes. Our findings suggest that (1) FOXP1 translocation may disrupt the full-length FOXP1 transcript and lead to expression of FOXP1 transcript variants with alternate 5' ends and (2) mechanisms other than translocation and copy number changes are also responsible for FOXP1 overexpression in lymphoma.

Correlated expression of erbB-3 with hormone receptor expression and favorable clinical outcome in invasive ductal carcinomas of the breast.

The prognostic impact of epidermal growth factor receptor (EGFR) family members in breast carcinoma was evaluated through the analysis of 378 cases of invasive ductal carcinoma to determine the relationship between EGFR family members and clinical outcome. It was found that 13.8% of the cases were positive for erbB-3. Expression of erbB-3 was inversely correlated with EGFR and erbB-4 expression (P = .012 and P = .046). Expression of erbB-3 was correlated with positive estrogen and progesterone receptor status and inversely correlated with histologic grade. Expression of erbB-3 was correlated with longer disease-free survival (DFS; P = .028). Within the erbB-3-expressing group, there was a tendency for the coexpressing group to have shorter DFS compared with the single-expressing group. This study revealed that erbB-3 expression was associated with better prognosis. In an era of personalized targeted therapy, erbB-3 expression and its coexpressive pattern with other EGFR family members could be an important determinant for therapeutic plans for breast cancer treatment.