Primary Epithelial Tumors Research Articles

Acinar Cell Carcinoma versus Solid Pseudopapillary Tumor of the Pancreas in Children: A Comparison of Two Rare and Overlapping Entities with Review of the Literature

Primary epithelial tumors of the pancreas are extremely uncommon in children, and among these, acinar cell carcinoma (ACC) is the most rare. Here we describe our recent observations in the case of a 10-year-old boy with one of these exceptional examples. The histologic diagnosis of ACC was supported by both immunohistochemistry and electron microscopy. Despite its rarity, ACC should be kept in the differential diagnosis of pediatric pancreatic exocrine tumors. We also provide a comparison with an example of solid pseudopapillary tumor, another relatively infrequent epithelial tumor of the pancreas in the young. We review the relevant literature addressing the clinical and pathologic features of ACC and its distinction from other pancreatic neoplasms.

Primary epithelial submandibular salivary gland tumours – Review of management in a district general hospital setting

Primary epithelial submandibular gland (SMG) tumours are uncommon, accounting for 8-12% of all salivary gland neoplasms, and most studies come from large specialised centres. There is little published about the relative frequency and outcome of SMG tumours treated in general hospitals. A retrospective study from two district general hospitals over a 10 year period (1996-2005). Seventeen benign (68%) and eight malignant (32%) tumours were included. A painless mass was the most common presentation. Pain and paraesthesia were not pathognomonic of malignancy. Pleomorphic adenoma accounted for all 17 benign tumours and adenoid cystic carcinoma was the commonest malignant tumour. Fine needle aspiration cytology (FNAC) accurately identified 78% of the benign tumours but none of the malignant tumours. Pre-operative imaging was also unable to distinguish malignant from benign tumours. Incomplete excision was reported in 20% of cases and was more common for malignant tumours. It may be difficult to distinguish benign from malignant SMG tumours on clinical examination and pre-operative investigations. Any suspected submandibular tumour should be considered for early treatment even when FNAC is suggestive of a benign tumour.

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma

Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (2 7/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (1 7/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.

Nowotwory złośliwe jam nosa i zatok przynosowych w materiale własnym – charakterystyka epidemiologiczna i kliniczna

Summary Introduction Sinonasal malignances (SNM) usually present as a difficult diagnostic and therapeutic problem. In the paper presented, the epidemiological and clinical characteristics of SNM, diagnosed in Holy Cross Cancer Center in Kielce (Dept. of Otolaryngology, Head and Neck Surgery), from 2001 to 2007, as well as a calculated survival rates are discussed. Material and methods From the hospital data and current clinical observations of 87 patients with SNM the age, sex, localization, stage of the disease, pathology and treatment applied, was taken for analysis. In cases with at least 3 year observation, the Kaplan-Meier survival curves were calculated. Results In the analyzed group of 87 cases, ranging from 8 to 82 years of age (average 62,3 years), there was 48 male, and 39 female patients (M : F = 1,2 : 1). 59,8% of all group was in the age above 60 years, with the most common age group 71–80 years (33,3%). The most common defined localization was a maxillary sinus (33,3%), but due to very advanced stage at time of diagnosis in 37,9% of cases, the precise localization within the region was not possible to define. The primary epithelial tumors were diagnosed in 52,9% (n = 46), of all SNM, the non epithelial malignant tumors in 42,5% (n = 37), and metastatic tumors to the nose and paranasal sinuses in 4,6% (n = 4). In the group of epithelial SNM the Squamous cell carcinoma dominated (26/46–56,5%), and in the non epithelial SNM the most common group was a malignant lymphoma (10/37–27,0%). At time of diagnosis the majority of patients with epithelial SNM (80,4%) presented with advanced local stage of the disease (T3 + T4a + T4b). The combined modality treatment was applied in the most of patients in the analyzed group (79,3%). The probability of 3 years disease free survival, calculated with Kaplan-Meier method was 64,0%, and 5-years survival – 45,0%. Conclusions 1. The SNM present as a very heterogeneous group of tumors 2. The most common SNM are a Squamous cell carcinoma, and malignant lymphoma. 3. The majority of SNM are diagnosed at then advanced stage of local disease. 4. The calculated probability of 3-years survival was 64,0%, and 5-years survival 45,0%. 5. The diagnostic, as well as therapeutic approach to SNM requires a multidisciplinary cooperation.

Expression of MTA1 and nm23-H1 protein in ovarian carcinomas in relation to lymph node metastasis

Objective：Cancer metastasis is a complex process involving a sequential series of multi-step genetic events, which produces an imbalance between stimulatory and inhibitory genes for metastasis. Presently, we examined the expression of metastatic tumor antigen 1 (MTA1) and nonmetastatic protein 23 homologue H1 (nm23-H1) proteins in metastasized epithelial ovarian cancer cells. Methods：Fifty-one primary epithelial ovarian tumors and corresponding lymph nodes (LNs) were examined immunohistochemically for expression of MTA1 and nm23-H1. Expression of these proteins was statistically evaluated. Results：The frequency of MTA1 expression was 30.3% (10/33) in stage III/IV LNs but was absent (0/18) in stage I/II LNs (p=0.01). MTA1 expression was observed in 50% (6/12) of metastasizing LNs but in only 10.3% (4/39) of non-metastasizing LNs (p=0.01). In contrast with MTA1, nm23-H1 expression was evident in 16 of 18 (88.9%) stage I/II ovarian cancer tissue samples but only in 20 of 33 (60.6%) stage III/IV tissues (p=0.05), and nm23-H1 production was also observed in 75.6% (34/45) of ovarian cancer tissue with residual tumors under 2 cm in diameter, but in 2/6 (33.3%) of cancer tissue with residual tumors exceeding 2 cm in diameter (p=0.03). Conclusion：The degree of expression and imbalance of MTA1 and nm23H1 are correlated with ovarian cancer LN metastasis.

Expression of DNA Damage Checkpoint Protein Hus1 in Epithelial Ovarian Tumors Correlates With Prognostic Markers

Hus1 and Rad9 are proteins involved in DNA damage checkpoint regulation, which is required for the maintenance of genomic stability. In addition to checkpoint activation, mammalian cells also use apoptosis to eliminate cells with severe DNA damage. Interestingly, Rad9 was shown to be directly involved in apoptosis as well. Despite the knowledge of molecular mechanisms on how Hus1 and Rad9 act in response to DNA damage, little is known about the role of these 2 proteins in cancer progression. In this study, we analyzed the expression of Rad9 and Hus1 in epithelial ovarian tumors and correlated them to clinopathological parameters and apoptotic biomarkers (p53, Bcl-2, and Bax). Histological sections from 114 primary ovarian epithelial tumors were stained with antibodies using the streptavidin-biotin method. In addition, mitotic and apoptotic indices (both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling assay) were also measured. We found that Rad9 expression correlated closely to significance only with the apoptotic and mitotic indices (P = 0.056 and 0.059, respectively). Hus1 levels correlated significantly with the clinicopathologic factors of bad prognosis, including FIGO (International Federation of Gynecology and Obstetrics) stage (P < 0.002) and with the p53 expression (P < 0.001), Bax expression (P < 0.008), mitotic index (P < 0.001), and apoptotic index (P < 0.003).

Expression and activity of taxane-metobolizing enzymes in ovarian tumors

Objective. Current firstline chemotherapy for ovarian cancer consists of carboplatin combined with either paclitaxel or docetaxel. Disposition of carboplatin is determined by renal clearance, while the taxanes are metabolized by cytochrome P450 (CYP450) enzymes. Although the majority of taxane metabolism occurs in the liver, recent data have shown that some solid tumors express CYP450 enzymes in the tumors themselves. The objective of this study was to determine whether ovarian tumors express genes regulating cellular efflux and subsequent metabolism, and whether any clinico-pathologic features correlated with expression. Methods. Gene expression of CYP2C8, CYP3A4/A5 and the ABC transporter ABCB1 was determined in 56 primary epithelial ovarian tumors. Cells were grown from seven different tumors and exposed ex vivo to paclitaxel (PAC) and docetaxel (DOC) for up to 24 h. PAC and DOC concentrations were measured in the media by an LC-MS assay. Results. Results from this analysis demonstrate that ovarian cancer cells do express functional taxane-metabolizing enzymes. Such expression appeared to enhance the ability of cancer cells to metabolize DOC. Specifically, the PK of DOC was correlated with the ratio of CYP4A5 to ABCB1 gene expression, thus representing a novel mechanism of chemotherapy resistance. There was no relationship between PAC PK parameters and gene expression. Conclusions. Knowledge of inter-individual variation in CYP450 enzyme and ABC transporter tumor expression and activity may influence the individualization of chemotherapy, by avoiding agents that are rapidly metabolized and selecting agents that are not.

Deletion of PSCA increases metastasis of TRAMP‐Induced prostate tumors without altering primary tumor formation

Prostate stem cell antigen (PSCA) is expressed in normal epithelium of various tissues, in embryos and adult animals. PSCA expression is upregulated in up to 70% of prostate tumors and metastases, and a subset of bladder and pancreatic cancers. However, its function is unknown. We studied the effect of targeted gene deletion of PSCA on normal organ development and prostate carcinogenesis. PSCA +/+, PSCA +/-, and PSCA -/- mice were bred and aged to 22 months. A cohort of animals was treated with gamma-irradiation at 2 and 6 months of age. PSCA knockout mice were crossed to TRAMP mice and TRAMP+ PSCA +/+, TRAMP+ PSCA +/-, and TRAMP+ PSCA -/- mice and offspring aged to 10 months of age. Tissues were analyzed by RT-PCR, histology, and immunohistochemistry for markers of proliferation, apoptosis, angiogenesis, and tumor progression. PSCA knockout animals were viable, fertile and indistinguishable from wild-type littermates. Spontaneous or radiation-induced primary epithelial tumor formation was also similar in wild-type and PSCA knockout mice. We observed an increased frequency of metastasis in TRAMP+ PSCA heterozygous and knockout mice, compared to TRAMP+ wild-type mice. Metastases were largely negative for PSCA and androgen receptor. Cleaved-caspase 3 and CD31 staining was similar in all genotypes. Aurora-A and Aurora-B kinases were detected in the cytoplasm of PSCA heterozygous and knockout tumors, suggesting aberrant kinase function. These data suggest that PSCA may play a role in limiting tumor progression in certain contexts, and deletion of PSCA may promote tumor migration and metastasis.

Hepatozelluläres Karzinom und Cholangiokarzinom - Unterschiedliche Prognose, Pathogenese und Therapie

Primary liver cancer is one of the most common cancer worldwide. Beside hepatocellular carcinoma (HCC), accounting for more than 80%, cholangiocarcinoma (CC) is the second most frequent primary malignant epithelial liver tumor. Combined hepatocellular-cholangiocarcinoma (HCC/CC) is a rare form of liver cancer with a frequency of 1%. Both, hepatocellular carcinoma and cholangiocarcinoma, show a wide geographical variation with low-incidence areas in North America and Europe and high incidence areas in Africa and Asia. Whereas hepatocellular carcinomas develop by malignant transformation of hepatocytes, cholangiocarcinomas arise from the small intrahepatic bile duct epithelium. The UICC-TNM classification of malignant liver tumors is applied for both tumor entities. 70-80% of hepatocellular carcinoma occur in cirrhotic liver. In high incidence areas, such as Asia and Africa, HCC is strongly associated with chronic viral hepatitis B and C and liver cirrhosis. Nutritional factors, toxins and metabolic diseases contribute also to hepatocarcinogenesis. The etiology of cholangiocarcinoma remains unclear, most occur in absence of known etiological factors. But several risk factors including hepatolithiasis, liver fluke infection, and anatomical abnormalities associated with inflammation of the biliary tract have been described.

DUSP7 and DUSP8 promoter hypermethylations: Predictors of clinical outcomes in advanced epithelial ovarian carcinoma

5501 Background: The Dual specificity phosphatases (DUSPs) are a subclass of the protein tyrosine phosphatase (PTP) gene family which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within the mitogen-activated protein kinases (MAPKs) leading to inactivation. MAPK activation is a downstream target of several oncogenes and may give rise to oncogenic transformation, and hence DUSPs are potential tumor suppressor genes. The aim of this study was to investigate if DUSPs are subject to methylation-dependent silencing in epithelial ovarian cancer. Methods: In this study, promoter methylation and gene expression of the DUSPs genes (DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8 and DUSP10) were investigated in 9 ovarian cancer cell lines and in 74 primary epithelial ovarian tumors (Stage III/IV), using methylation specific PCR (MSP) and Reverse- transcription PCR (RT-PCR). The 74 clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/NCIC OV10) with clinical follow-up in excess of 6.5 years. Results: Ovarian Cancer Cell lines: Aberrant CpG methylation detected in DUSP1, DUSP2, DUSP4, DUSP6, DUSP7 and DUSP8. DUSP7 promoter methylation was associated with downregulation of mRNA expression. Primary Ovarian Tumors: Methylation of DUSP1, DUSP2, DUSP7 and DUSP8 was observed in 15–38% of the primary tumors. DUSP7 methylation is a predictor of adverse PFS in both univariate (median PFS 10.6 m versus 13.3m, p=0.002) and multivariate (Cox Regression HR 2.76, p&lt;0.001) analyses, and is associated with a trend for poorer OS (22.1 m versus 29.3 m, p=0.07). In contrast, DUSP8 methylation is an independent predictor of favorable PFS (median 23.7m versus 11.5m; Cox Regression HR 0.30, p=0.006) and OS (HR 0.31, p=0.013). 5-year OS for DUSP8 methylated patients was 58.3% compared with 16.1% for DUSP8 unmethylated (HR 0.277, p=0.005). Conclusion: This is the first report of DUSP methylation in epithelial ovarian cancer. The study suggests that methylation-dependent transcriptional silencing of DUSP7 in advanced epithelial ovarian cancer may represent an independent predictor of adverse PFS. DUSP8 methylation, on the other hand, is a favorable clinical outcome marker. No significant financial relationships to disclose.

Immunohistochemical Expression of Cyclooxygenase‐2 in Canine Ovarian Carcinomas

Ovarian tumours among domestic animals are frequently encountered in bitch. Cyclooxygenase-2 (COX-2) expression has been evaluated in different kind of canine primary epithelial neoplasms. Eleven canine ovarian carcinomas and two normal samples were evaluated immunohistochemically for COX-2 expression. Nine of 11 carcinoma samples (81%) expressed COX-2 enzyme isoform. The immunoreactivity was intracytoplasmically recorded and the intensity ranged from faint to strong. Our results show that COX-2 is expressed in canine ovarian carcinoma, suggesting a potential role of COX-2 in canine ovarian carcinogenesis.

P16 Expression in Primary Ovarian Mucinous and Endometrioid Tumors and Metastatic Adenocarcinomas in the Ovary

Distinction of primary ovarian epithelial tumors from metastatic adenocarcinomas is challenging for tumors exhibiting mucinous, endometrioid, or mixed endometrioid/mucinous differentiation. Metastatic carcinomas with these types of differentiation can be derived from several sites, including the gastrointestinal tract and the uterus. Most endocervical adenocarcinomas exhibit mucinous and/or endometrioid differentiation; they infrequently metastasize to the ovaries but may simulate primary ovarian tumors [both atypical proliferative (borderline) and carcinoma]. Most are high-risk human papillomavirus (HPV)-related and demonstrate diffuse p16 over-expression due to complex molecular mechanisms by which high-risk HPV transforming proteins interact with cell cycle regulatory proteins. The performance of this expression pattern for identifying metastatic endocervical adenocarcinomas in the ovaries among primary ovarian tumors and other metastatic adenocarcinomas having mucinous and/or endometrioid/endometrioidlike differentiation has not been evaluated. Immunohistochemical expression of p16 was assessed in 195 tumors, including 98 primary ovarian tumors (51 mucinous, 47 endometrioid, and 4 mixed mucinous-endometrioid tumors), 93 metastatic adenocarcinomas of known primary sites (colorectum: 34, endocervix: 19, pancreaticobiliary tract: 17, appendix: 7, stomach: 5), 11 metastatic adenocarcinomas of unknown origin (7 established as noncervical), and 4 adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin. The HPV status of the endocervical adenocarcinomas was determined by in situ hybridization and polymerase chain reaction (when in situ hybridization was negative). Expression was assessed based on the percentage of moderately to strongly positive cells, estimated to the nearest 10%. Mean and median expression values for HPV-positive endocervical adenocarcinomas (99%, 100%; range 90% to 100%) were substantially higher than those for primary ovarian mucinous (5%, 0%; range 0% to 70%) and endometrioid (20%, 10%; range 0% to 100%) tumors, HPV-unrelated endocervical adenocarcinomas (0%, 0%; range 0% to 60%), metastatic adenocarcinomas of unknown origin (11%, 0%; range 0% to 30%), and adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin (40%, 35%; range 0% to 90%); only the 15 HPV-positive endocervical adenocarcinomas and 6 other tumors had values of 80% or greater. Diffuse (>75% positive tumor cells) moderate to strong p16 expression is a sensitive (100%) and specific (97%) marker for identifying HPV-related endocervical adenocarcinomas metastatic to the ovary among the primary ovarian tumors and metastatic adenocarcinomas from other sites that are in the differential diagnosis of ovarian tumors having mucinous and/or endometrioid/endometrioidlike differentiation. p16 is useful as part of a panel of immunohistochemical markers for distinguishing primary ovarian tumors from metastases and, when diffusely positive, can suggest the cervix as a potential primary site for metastatic adenocarcinomas of unknown origin.

Metastatic colorectal adenocarcinoma involving the ovary with elevated serum CA125: A potential diagnostic pitfall

Elevated serum levels of CA125 are observed not only in association with primary ovarian epithelial neoplasms but also in a variety of other clinical settings, including ovarian involvement by metastatic disease. There is considerable overlap in gross and histologic features between primary ovarian tumors and metastatic colorectal adenocarcinoma, which can make diagnosis particularly challenging in the setting of an increased CA125 level. The aims of this study were to determine how frequently serum CA125 is elevated in women with ovarian involvement by metastatic colorectal adenocarcinoma and to compare the features of cases with and without associated elevations of serum CA125. Eighty-nine cases of histologically confirmed ovarian involvement by metastatic colorectal adenocarcinoma were identified by retrospective review. Clinicopathologic data were analyzed, including preoperative serum CA125 level (available in 42 cases). Features of cases with an associated increase in serum CA125 were compared with those of cases with no such elevation. Twenty-nine patients had an elevated serum CA125 level (>35 U/mL) preoperatively (range 39.0-556.3, median 143.0, mean 199.1). Thirteen patients had a serum CA125 level within the reference range, while forty-seven patients had no preoperative testing for serum CA125. Clinical, gross, and histologic features of cases with an associated increase in serum CA125 were generally similar to those of cases with a non-elevated serum CA125 concentration. In three cases, the tumor was initially diagnosed as an ovarian primary. At least 32.6% of women with ovarian involvement by metastatic colorectal adenocarcinoma have an elevated serum CA125 level prior to oophorectomy. Such cases do not differ significantly from cases lacking such an association with respect to a variety of clinicopathologic features. The possibility of metastasis from a colorectal carcinoma merits consideration in the formation of the differential diagnosis for a woman with an adnexal mass and elevated serum CA125, even in the absence of an established history of gastrointestinal malignancy.

Increased risk of concurrent primary malignancies in patients diagnosed with a primary malignant epithelial ovarian tumor

AbstractOvarian cancer and second malignant neoplasms are found to occur rather frequently in the same patient. From a clinical perspective, it is important to have quantitative information on concurrent malignancies in the same year of diagnosis of the epithelial ovarian cancer. In this population-based study, we used data from the Netherlands Nationwide Network for Registry of histo- and cytopathology (PALGA) and the Netherlands Cancer Registry (NCR). Data of the ovarian cancer as well as data on previous or later cancers were obtained. Age-specific cancer rates from the NCR were used to calculate expected numbers of cancer. Between 1987 and 1993, histopathology reports were identified of 4577 patients with primary epithelial malignant or primary borderline malignant ovarian cancers and its longitudinal data. As the database may lack detailed information on histopathology, a recent sample of 789 patients diagnosed with ovarian cancer in 1996–2003 was comprehensively studied as well. In the eventual data analysis of 5366 patients, 244 cases (4.5%) of concurrent primary malignancy were reported in the same year that the malignant epithelial ovarian tumor had been diagnosed against 51 expected. The observed vs expected ratio was 4.8 and the 95% confidence interval (CI) (4.3–5.5). For cancer of the uterus/endometrium the observed vs expected ratio was 62.3 (95% CI 52.5–73.5). For skin, breast, colorectal, urinary bladder, renal and cervical cancer the ratio was also larger than unity. The elevated risk of concurrent cancer may lead to clinical screening protocols. The findings on endometrial cancer may prompt research on common etiologies and biomarkers.

Tumor promoting properties of the ETS protein MEF in ovarian cancer

We have previously shown that MEF (myeloid ELF1-like factor, also known as ELF4) functions as a transcriptional activator of the interleukin (IL)-8, perforin, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-3 genes in hematopoietic cells. MEF is also expressed in non-hematopoietic tissues including certain ovarian cancer cells. To define the function of MEF in these cells, we examined primary human ovarian epithelial tumors and found that MEF is expressed in a significant proportion of ovarian carcinomas, and in the CAOV3 and SKOV3 ovarian cancer cell lines, but not in normal ovarian surface epithelium. Manipulating MEF levels in these cell lines altered their behavior; reducing MEF levels, using short hairpin RNA expressing vectors, significantly inhibited the proliferation of SKOV3 and CAOV3 cells in culture, and impaired the anchorage-independent growth of CAOV3 cells. Overexpression of MEF in SKOV3 cells (via retroviral transduction) significantly increased their growth rate, enhanced colony formation in soft agar and promoted tumor formation in nude mice. The oncogenic activity of MEF was further shown by the ability of MEF to transform NIH3T3 cells, and induce their tumor formation in nude mice. MEF is an important regulator of the tumorigenic properties of ovarian cancer cells and could be used a therapeutic target in ovarian cancer.

Analysis of the relationship between pathology and recurrence of primary lacrimal epithelial tumors

To analyze the relationship between pathology and recurrence of primary lacrimal epithelial tumors. 128 cases of primary lacrimal epithelial tumors including benign mixed tumor (74 cases, 57.8%), adenoid cystic carcinoma (22 cases, 17.2%) and malignant mixed tumor (18 cases, 14.1%) were subjected in the study. Pathological features were analyzed and compared with their recurrence. The recurrent rate of benign mixed tumor, adenoid cystic carcinoma and malignant mixed tumor was 23.0%, 18.2% and 27.8%, respectively. The recurrence of benign mixed tumor was statistically related to pathological classification and encapsulates. Primary lacrimal epithelial tumors show variant types and high recurrent rate. The pathological features were decisive in diagnosis, selection of treatment and the time of follow-up.

Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: An independent prognostic factor for tumor progression

Objectives. Chemokine CXCL12 and its unique receptor CXCR4 have been recently implicated in cancer metastasis. Our goal was to explore expression of CXCL12 and CXCR4 protein in normal ovarian surface epithelium, primary tumors and paired metastases of epithelial ovarian cancer as well as its association with clinicopathological features. We also wanted to test if expression of CXCR4 has prognostic value in epithelial ovarian cancer patients. Method. Sections from 6 normal ovarian surface epithelium, 44 primary epithelial ovarian tumors and 30 paired metastatic tumors in omentum were evaluated for CXCL12 and CXCR4 expression using immunohistochemistry (IHC). Results. All samples of normal ovarian surface epithelium were negative for CXCL12 and CXCR4 protein. Ovarian cancer cells mainly showed cytoplasmic staining of CXCL12 and CXCR4. CXCL12 and CXCR4 staining were detected in 40/44 (91%) and 26/44 (59%) patients with primary epithelial ovarian tumors respectively. CXCR4 expression in primary tumors had no significant correlation with lymph nodes metastasis. However, if we combined CXCR4 expression in primary tumors with metastatic tumors, a significant correlation with lymph nodes metastasis was found ( P = 0.018). The intensity of CXCL12 staining correlated with ascites ( P = 0.014). The rate of CXCR4 expression in refractory and recurrent group (81% versus 28%, P = 0.0008) was significantly higher than that in no-recurrent group. After a median follow-up of 37 months, CXCR4 expression was found associated with an unfavorable prognosis with significantly reduced median disease progression-free survival and overall survival of 15 and 27 months ( P = 0.0004, P = 0.017) respectively. Median time-to-event was not reached in patients with negative CXCR4 staining. In multivariate analysis, CXCR4 expression and residual tumor size emerged as independent prognostic factors in epithelial ovarian cancer patients. Conclusions. This article provides the first evidence that CXCR4 expression could be an independent prognostic factor for epithelial ovarian cancer patients.

MDA-7/IL-24-Based Cancer Gene Therapy: Translation from the Laboratory to the Clinic

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.

Ovarian Involvement by Metastatic Colorectal Adenocarcinoma

Ovarian involvement by metastatic colorectal adenocarcinoma, although not an uncommon occurrence, remains a diagnostic challenge. The gross and histologic features of such metastases overlap those of primary ovarian epithelial neoplasms such as endometrioid or mucinous adenocarcinoma. The clinical and pathologic features of 86 cases of metastatic colorectal adenocarcinoma involving the ovary were reviewed. Patients ranged in age from 19 to 85 years (median, 51 years); 24% were younger than 40 years. Presenting symptoms included abdominal or pelvic pain (45 cases), rectal bleeding (13 cases), change in bowel habits (20 cases), and vaginal bleeding (5 cases). In 23 cases, an ovarian mass was the first manifestation of the disease. Ovarian involvement was bilateral in 49 cases and unilateral in 33 (including 20 cases in which the only involved ovary measured at least 10 cm in greatest dimension). Involved ovaries ranged from 2 to 24 cm (mean, 10.1 cm), and most featured both solid and cystic areas. Many involved ovaries featured smooth capsules without gross evidence of surface involvement by tumor. In general, the tumors had typical histologic features of metastatic colorectal adenocarcinoma, including a garland pattern and dirty necrosis. In 23 cases, foci with a benign or low malignant potential appearance were seen. Immunohistochemical studies showed that 29 of 29 tumors (100%) were positive for CK20; focal CK7 positivity was seen in 5 of 30 cases (17%). In 9 of the cases, an ovarian primary was diagnosed or favored initially, and 5 of these cases were initially treated as ovarian primaries. Metastatic colorectal adenocarcinoma should be considered in the differential diagnosis of an ovarian mass, even if the mass is large and unilateral or in a young patient, to secure proper treatment of these patients.

The influence of aquaporin-1 and microvessel density on ovarian carcinogenesis and ascites formation

This study aimed at investigating aquaporin-1 (AQP1) distribution and expression in primary ovarian epithelial tumors, correlating with clinicopathologic variables and intratumoral microvessel density (IMD). The AQP1 expression and IMD in 105 cases with primary epithelial ovarian tumors were measured by semiquantitative immunohistochemical technique. AQP1 was located mainly in microvessels and small vessels but seldom in tumor cells. Expression of AQP1 and IMD in ovarian malignant tumors was significantly higher than that in borderline tumors (P= 0.000,P= 0.001, respectively), and that in borderline tumors was higher than in benign tumors (P= 0.008,P= 0.028, respectively). The expression of AQP1 in FIGO stage III–IV was more than that in stage I–II (P= 0.001), and cases with ascites volume greater than 1000 mL were more than cases with ascites volume less than 1000 mL (P= 0.000). There is a positively correlated relationship between expression of AQP1 and IMD (correlation coefficient 0.60,P= 0.000) and between expression of AQP1 and ascites volume (correlation coefficient 0.57,P= 0.000). These data implicate that high AQP1 expression may play an important role in the ovarian carcinogenesis, progression, and ascites formation. Further studies into the mechanism of AQP1 regulation and the relationship between AQP1 expression and tumor angiogenesis may lead to novel therapies for ovarian carcinoma.