Low-grade Serous Carcinoma of the Ovary: Clinicopathologic Analysis of 52 Invasive Cases and Identification of a Possible Noninvasive Intermediate Lesion.

Low-grade serous carcinoma (LGSC) is an uncommon but distinct histologic subtype of ovarian carcinoma. Although the histologic features and natural history of LGSC have been described in the literature, there is no robust correlative study that has specifically addressed histologic features in correlation with clinical follow-up. To refine the criteria for invasion patterns of LGSC and determine additional clinically pertinent morphologic features of LGSC predisposing to a more aggressive clinical course, the clinicopathologic features of 52 LGSCs were evaluated and compared with those of a large series of serous borderline tumors (SBT), with and without invasive implants. To qualify for LGSC, the tumor needed to demonstrate destructive invasion, nuclear atypia that was mild to moderate at most (grade 1 or 2), and a mitotic index that did not exceed 12 mitoses per 10 high-power fields. On the basis of histologic evaluation, destructive invasion was classified into 7 primary architectural patterns: (1) micropapillary and/or complex papillary; (2) compact cell nests; (3) inverted macropapillae; (4) cribriform; (5) glandular and/or cystic; (6) solid sheets with slit-like spaces; and (7) single cells. Five-year overall survival and disease-free survival for LGSC were 82% (median, 72 mo) and 47% (median, 54 mo), respectively. All the patients with fatal outcome demonstrated tumors showing invasion with predominant patterns of cribriform glands, micropapillae and/or complex papillae, or compact cell nests. Notably, 2 of 9 patients with fatal outcome had only small foci of destructive invasion (2 and 3 mm, respectively) with compact cell nests and cribriform glands as the predominant patterns. There was no statistically significant association between pattern of invasion and disease-free survival. Classic stromal microinvasion, as defined by nondestructive stromal invasion <5 mm was identified in 52% of LGSC and was statistically more frequent in LGSC than in SBT (P<0.001). In 2 LGSCs, there were areas demonstrating an intraluminal solid proliferation of tumor cells with grade 1 or 2 nuclear atypia, which we hypothesize may represent a noninvasive form of LGSC, as similar non-invasive proliferations of morphologically low-grade serous carcinomatous cells were also identified in 8 SBTs, in either solid or compact glandular/papillary formations. One patient with this isolated noninvasive pattern in SBT developed LGSC 40 months after initial operation. LGSC was typically high stage (FIGO stages II to IV, 86%) and bilateral (68%), with multiple foci of invasion (82%). Bilaterality was significantly more common in high-stage disease (P=0.009). LGSC was associated with SBT in 84% of cases, most commonly usual type (27%), followed by cribriform (18%), micropapillary (11%), or mixed cribriform and micropapillary (7%) types; focal micropapillary and/or cribriform features were present in an additional 16%. The presence of intraluminal proliferations of cells resembling LGSC occurring in SBT should prompt additional tumor sampling and assiduous evaluation of implants (if present), as this appears to represent a form of intraepithelial carcinoma, which may be associated with invasion elsewhere.

The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases.

GNAS mutations have been implicated in the development of fibrous dysplasia and multiple endocrinopathies of the Albright-McCune syndrome. To investigate the diagnostic utility of GNAS mutations in patients with fibrous dysplasia, we performed mutational analyses of histologically confirmed fibrous dysplasia and conducted a meta-analysis of the literature. We collected 48 cases of fibrous dysplasia from 3 institutions from 2002 to 2011 and performed polymerase chain reaction and direct bidirectional sequencing of exons 8 and 9 of GNAS using paraffin-embedded tissues. We searched MEDLINE, PubMed, and the KoreaMed databases from 1997 to 2011 and included an additional 155 cases of fibrous dysplasia from 8 representative studies to conduct a meta-analysis. In our sample, 28 (58.3%) of 48 cases showed point mutations of codon 201 at exon 8. Twenty-five cases had a substitution of arginine at codon 201 for histidine (p.R201H), and 3 cases had a substitution for cysteine (p.R201C). One case had a new mutation at codon 224 (p.V224A). The incidence of GNAS mutations was significantly greater in cases that involved long bones than in cases that involved flat bones (P = .017) and was higher in polyostotic cases than in monostotic cases (P = .067). In meta-analysis, 9 studies and 203 patients were included. The overall positive rate of GNAS mutation in fibrous dysplasia was 71.9% (146/203). The major types of mutations were missense mutations such as R201H (66.4%) and R201C (30.8%). As a result, the detection of GNAS mutation could be a valuable adjunct to conventional histopathologic diagnosis of fibrous dysplasia.

Sclerosing epithelioid fibrosarcoma: cytogenetic analysis of FUS rearrangement.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare but distinct variant of fibrosarcoma. A 43-year-old man presented with a lesion in his back that had been present for three years but had recently increased in size. Magnetic resonance imaging (MRI) revealed a 6-cm sized ovoid mass showing low intensities on T1 and T2 weighted images. Histologically, the tumor was of moderate cellularity, and the cells were relatively uniform in size and shape. The cells were epithelioid, round, oval and polygonal with clear and slightly eosinophilic cytoplasm, forming nests, cords, or sheet-like patterns with a dense collagenous and hyalinized matrix. The tumor was positive for vimentin, but negative for smooth muscle actin, desmin, HMB45, and CD34. Although the tumor showed nuclear overexpression of beta-catenin protein, the CTNNB1 exon3 mutation was not detected. Fluorescent in situ hybridization for FUS using dual color break-apart probes showed rearrangement of the FUS. In accordance with previous studies, our case showed positive findings of FUS rearrangement, reinforcing the notion of a close relationship between low grade fibromyxoid sarcoma and SEF.

Dermatofibrosarcoma protuberans of the breast skin.

A case of a 26-year-old woman with dermatofibrosarcoma protuberans of the breast skin is described. She had noticed a palpable mass with redness 15 years previously, but it had begun to grow rapidly with swelling and redness two months before presenting. Ultrasonography and biopsy demonstrated a possibility of sarcoma of the breast. Wide excision was performed to confirm the diagnosis. Histologically, the tumor was composed of a uniform population of fibroblasts in a distinct storiform pattern. CD34 immunostaining showed diffuse reactivity. Platelet-derived growth factor ß break-apart fluorescence in situ hybridization analysis showed a split-signal pattern which supported the diagnosis of dermatofibrosarcoma protuberans in the skin of the breast. It is important to diagnose a soft tissue lesion accurately when it occurs in the breast.

Prognostic significance of CD24 protein expression in patients treated with adjuvant radiotherapy after radical hysterectomy for cervical squamous cell carcinoma.

BACKGROUND AND PURPOSE: The CD24 marker is expressed in various carcinomas and is associated with shorter survival rates. We evaluated the prognostic significance of CD24 protein overexpression in patients treated with post-operative radiotherapy (RT) after surgery, and its prognostic significance and specific role stratified by adjuvant treatment modalities. MATERIALS AND METHODS: We determined the CD24 expression status of 140 patients with cervical squamous cell carcinoma treated with RT alone or with chemoradiotherapy (CRT) after radical hysterectomy procedures. RESULTS: CD24 expression was detected in 59 patients (42%) and was significantly associated with locoregional failure-free survival (LRFFS) (p=0.0218), distant metastasis-free survival (DMFS) (p=0.0001), and overall survival (OS) (p=0.0053). In the multivariate analysis, CD24 positivity was also significantly associated with DMFS (p=0.025) and OS (p=0.045). CD24 expression stratified by post-operative treatments (CRT or RT alone) was associated with DMFS (p=0.0001) but not with LRFFS (p=0.4423) in the CRT group. However, CD24 expression was associated with LRFFS (p=0.0198) but not with DMFS (p=0.5269) in the RT alone group. CONCLUSIONS: CD24 expression is an independent prognostic marker in patients with cervical squamous cell carcinoma, even adjuvant treatment after surgery. And this study reveals different prognostic role of CD24 expression in two subgroups treated differently after surgery. Therefore, new therapeutic strategies targeting CD24 expression stratified by subgroups might have important clinical implications.

Expression of MET in alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma which is characterized by the presence of a specific chromosomal translocation encoding the chimeric transcription factor (ASPL-TFE3) that activates expression of MET. We reviewed the clinical features and treatment outcome of 12 ASPS patients. The presence of ASPL-TFE3 fusion transcripts was assessed by reverse transcriptase polymerase chain reaction. In addition, we performed immunohistochemical studies for MET, TFE3, Ki-67, and EGFR expression. Lower extremity was the most commonly affected primary site (2 thigh, 3 lower leg, and 1 foot). Of four patients who received primary cytotoxic chemotherapy, no patient demonstrated treatment response. With follow-up duration of 94.4 months, median overall survival was 53.2 (95% C.I. 40.9-65.5) months. The immunohistochemical staining demonstrated 100% TFE3 positivity (8 of 8), 75% MET positivity (6 of 8) with a strong association between TFE3 expression and MET positivity with correlation coefficient of 0.808 (P = 0.02). The high expression of MET in ASPL-TFE3 (+) ASPS may further support the potential role of targeted agents against MET in this rare, chemoresistant tumor.

The effect of cyclooxygenase-2 expression on tumor volume response in patients treated with radiotherapy for uterine cervical cancer.

We investigated the correlation between Cyclooxygenase-2 (COX-2) expression and the tumor response in patients with cervical cancer that were treated with curative radiotherapy (RT). Fifty-seven patients with squamous cell carcinoma were treated with concurrent radiochemotherapy (CRCT, n=29) or RT alone (n=28). The response of each patient was evaluated by three serial Magnetic Resonance Imaging examinations: before the start of RT, at four weeks after the start of RT (mid-RT) and at four weeks after the completion of RT (post-RT). Forty-three patients had positive COX-2 expression. The COX-2 negative patients achieved a higher rate of complete response (CR) at mid-RT than did the COX-2 positive patients (28.6% vs. 7.0%, P=0.054), but not at post-RT (64.3% vs. 69.8%). The initial tumor volume was a significant predictor of CR at mid-RT (P=0.003) and post-RT (P=0.004). The multivariate analysis showed that the initial tumor volume (at mid-RT and post-RT) and CRCT (at post-RT) were significant predictors of CR; however, the COX-2 expression was not. In conclusion, the COX-2 expression status has no significant correlation with the tumor response. Further studies on the changes in COX-2 expression levels during RT may be helpful for determination of its role in the tumor response to treatment and patient prognosis.

Atypical leiomyomas of the uterus with long-term follow-up after myomectomy with immunohistochemical analysis for p16INK4A, p53, Ki-67, estrogen receptors, and progesterone receptors.

Atypical leiomyomas are characterized by moderately to severely pleomorphic atypical tumor cells with low mitotic counts and no coagulative tumor cell necrosis. Despite the worrisome histologic features, most tumors have shown benign behavior. However, most studied patients had total hysterectomies, and very few patients who had myomectomy alone have had long-term follow-up. The behavior of atypical leiomyomas treated with myomectomy alone is still not known. We present a study of 13 atypical leiomyomas treated with myomectomy alone with long-term follow-up results and immunohistochemical findings for p16 (p16), p53, Ki-67, estrogen receptors, and progesterone receptors. The lengths of the postoperative intervals ranged from 20 to 151 months (mean=76.1 mo). None of the patients had developed a metastasis of her atypical leiomyoma. However, 1 patient showed local recurrence at the past myomectomy site 22 months after initial myomectomy. Immunostaining for p16 showed moderate to strong diffuse immunoreactivity in 11/13 cases (84.6%) of atypical leiomyomas, and 38.5% showed immunoreactivity for p53, including 1 case with strong, diffuse positive p53. When an atypical leiomyoma is discovered in a myomectomy specimen, the patient should be carefully followed up with or hysterectomy could be recommended. Larger numbers of cases and more long-term follow-up studies are needed to confirm the safety of myomectomy for atypical leiomyomas.

Gene expression profiling for the prediction of lymph node metastasis in patients with cervical cancer.

We investigated whether gene expression profiling of primary cervical tumor tissue could be used to predict lymph node (LN) metastasis and compared this with conventional magnetic resonance imaging. We obtained 43 primary cervical cancer samples (16 with LN metastasis and 27 without LN metastasis) for microarray analysis. A prediction model for LN metastasis from the training set was developed by support vector machine methods using a 10-fold cross-validation. The 'LN prediction model' derived from the signature of 156 distinctive genes (P < 0.01) had a prediction accuracy of 77%. Correlation between mRNA expressions measured by microarray and semiquantitative reverse transcription-polymerase chain reaction was ascertained in four (RBM8A, SDHB, SERPINB13, and gamma-interferon) out of 10 genes. Magnetic resonance imaging showed accuracy (69%) for the prediction of LN metastasis. These results suggest that gene expression profiling allows reliable prediction of LN metastasis in cervical cancer.

Role of CD24 protein in predicting metastatic potential of uterine cervical squamous cell carcinoma in patients treated with radiotherapy.

PURPOSE: The protein CD24 is a cell surface protein that appears to function as an adhesion molecule; its expression has been shown to correlate with prognosis in a variety of tumors. The aim of this study was to evaluate the immunoreactivity of uterine cervical squamous cell carcinoma to CD24 and determine whether CD24 is associated with clinical and pathologic parameters, including prognosis. METHODS AND MATERIALS: The expression of CD24 protein was immunohistochemically studied in 73 cases of uterine cervical squamous cell carcinoma. All patients were treated with definitive radiotherapy alone or with concurrent chemoradiotherapy. Two pathologists independently analyzed the immunostaining; they did not have knowledge of the patient outcomes and evaluated any changes according to the percentage of tumor cells stained as follows: negative, <5% reactive; and positive, >5% reactive. RESULTS: Positive staining was found in 43 cases (58.9%). The immunoreactivity did not correlate with age, International Federation of Gynecology and Obstetrics stage, lymph node metastasis, or tumor size. For patients who were CD24 negative, the total failure and distant metastasis rates were decreased about 20% compared with the rates for patients who were CD24 positive. On univariate analysis, the 5-year distant metastasis-free survival rate of CD24-negative patients was significantly greater than that of the CD24-positive patients (84.7% vs. 66.7%, respectively, p = 0.0497). The International Federation of Gynecology and Obstetrics stage and CD24 expression were significantly associated with distant metastasis-free survival on multivariate analysis. CONCLUSIONS: CD24 expression was a significant independent prognostic factor for distant metastasis-free survival in patients with uterine cervical squamous cell carcinoma. In the future, prospective determination of CD24 expression might aid clinical practice in the selection of the appropriate therapy for individual patients.

Protein expression and mutational analysis of epidermal growth factor receptor in renal angiomyolipomas.

Renal angiomyolipoma (AML) is a benign but progressive tumor that occasionally requires non-surgical therapy and there appears to be a possibility that epidermal growth factor (EGF) is associated with pathogenesis of renal AML. The response to gefitinib, anti-epidermal growth factor receptor (EGFR) agent and a prime example of target therapy, reportedly has been correlated with the presence of mutations within the tyrosine kinase (TK) domain of EGFR or the expression of its truncated form, EGFR variant III. Therefore the purpose of the present paper was to investigate EGFR protein expression and gene mutations in exons 18, 19 and 21 in 40 renal AML. No EGFR gene mutations of TK domain were detected in any of the 40 cases studied and strong immunostaining was found in 5% of the renal AML cases. The present findings indicate that in renal AML, anti-EGFR treatment may not be promising but that there is a possibility that EGFR is associated with renal AML pathogenesis.

Immunohistochemical expression of Sonic hedgehog in intraductal papillary mucinous tumor of the pancreas.

Aberrant expression of Sonic hedgehog (Shh) has been reported in many human cancers including ductal carcinoma of the pancreas. The intraductal papillary mucinous tumor (IPMT) has been considered as one of the precursor lesions of invasive ductal carcinoma of the pancreas. Shh expression in pancreatic IPMT has not been reported. We investigated an immunohistochemical (IHC) expression of Shh in 55 cases of pancreatic IPMT. We analyzed the IHC expression of Shh in the following histologic grades of tumor: adenoma (AD), moderate dysplasia (MD), noninvasive carcinoma (NIC), and invasive carcinoma (IC), and with the following histologic subtype classification: intestinal, pancreatobiliary, null, and unclassifiable type. IHC Shh expression was noted in 6 (46.2%) of 13 AD, 5 (35.7%) of 14 MD, 12 (80%) of 15 NIC, and 11 (84.6%) of 13 IC. Shh expression was significantly increased in malignant IPMT (NIC+IC) compared with nonmalignant IPMT (AD+MD) (82.1% vs. 40.7%, P=0.0005). IHC Shh expression was found in 11 (68.8%) of 16 intestinal types, 13 (92.8%) of 14 pancreatobiliary types, 8 (38.1%) of 21 null types, and 2 (50%) of 4 unclassifiable types. Intestinal and pancreatobiliary subtypes showed a high expression of Shh compared with the null and unclassifiable type of IPMT. All 3 cases of node metastasis showed IHC Shh expression in tumor cells of metastatic lymph nodes. Therefore, Shh expression may have a critical role in the late stage of carcinogenesis of IPMT, and may impact metastatic progression to the lymph nodes in malignant IPMT.

Delayed Post-traumatic Vertebral Collapse: MR Categorization and MR-Pathology Correlation.

STUDY DESIGN: A retrospective study. PURPOSE: To categorize the MR appearance of ischemic vertebral collapse and to correlate surgical and histologic findings. OVERVIEW OF LITERATURE: X-ray and MRI findings of delayed posttraumatic vertebral collapse shows several patterns. Histopathologic signs of osteonecrosis were present only in minor portion of cases sampled for biopsy of delayed post-traumatic vertebral collapse in the literature. METHODS: Twenty-one patients (22 vertebral bodies), with surgically and histopathologically proven ischemic vertebral collapse were included. The patients were examined with a 1.5 T MR imager. Spin echo T1- and T2-weighted images were obtained in axial and sagittal planes. Two experienced musculoskeletal radiologists, who reached consensus, evaluated the MR images. Then, MR-pathology correlations were made. RESULTS: Four different MR patterns were identified. Fluid patterns, were seen in 14% (3/22) of the affected vertebral bodies, and were characterized by hypo-intense signals on T1-weighted images, and hyper-intense signals, similar to water, on T2-weighted images. Extensive bone necrosis was predominant. Compression pattern, the most common pattern, found in 41% (9/22 vertebral bodies), was characterized by a marked decrease of anterior column height. Bone necrosis, granulation tissue, marrow fibrosis, and reactive new bone formation were found in relatively equal proportion. Granulation pattern, seen in 27% (6/22 vertebral bodies), was characterized by hypo-intense signals on T1-weighted images, and intermediate signals on T2-weighted images. Extensive granulation tissue was predominant. Mixed patterns were present in 18% (4/22), of the vertebral bodies. CONCLUSIONS: Awareness of histopathologic correlation of MR patterns in patients with delayed post-traumatic vertebral collapse may facilitate effective interpretation of clinical MR images of the spine.

Prognostic significance of vascular endothelial growth factor expression and microvessel density in esophageal squamous cell carcinoma: comparison with positron emission tomography.

BACKGROUND: This study investigated whether the expression of vascular endothelial growth factor (VEGF) in a primary tumor and the intratumoral microvessel density (MVD) were independent prognostic factors in patients with an esophageal squamous cell carcinoma (SCC) in comparison with positron emission tomography (PET) by using (18)F-fluorodeoxyglucose (FDG) and stage. METHODS: Fifty-one patients with a newly diagnosed esophageal SCC who underwent preoperative FDG-PET and esophagectomy with intent to cure were enrolled in this study. The VEGF expression level, the intratumoral MVD, and the Ki-67 labeling index were evaluated by using immunohistochemical staining. Only significant variables in the univariate survival analysis were examined by multivariate survival analysis with the Cox proportional hazards model. RESULT: Cancer-related deaths occurred in 17 of 51 patients during the follow-up. Univariate survival analysis showed that the pathologic stage, pNM, maximum standardized uptake value of the primary tumor, tumor length on PET, number of PET-positive lymph nodes, PET stage, Ki-67 labeling index, intratumoral MVD, and the presence of VEGF expression were significant prognostic predictors for the overall survival. Multivariate analysis revealed that the pathologic stage, number of PET-positive nodes (0, 1, 2, or > or = 3), intratumoral MVD (cutoff, 60/mm(2)), and presence of VEGF expression were independent significant prognostic predictors for overall survival. CONCLUSION: In addition to the pathologic stage, the intratumoral MVD, the presence of VEGF expression, and the number of FDG-PET-positive nodes were independent prognostic predictors in patients with an esophageal SCC undergoing curative surgery.

Squamous cell carcinoma with sarcomatoid features of the vulva: a case report and review of literature.

BACKGROUND: A squamous cell carcinoma with sarcomatoid features of the vulva is an extremely rare malignancy of the female genital tract. This type of tumor is known to grow rapidly and associated with poorer clinical outcomes than those of squamous cell carcinoma of the vulva. CASES: A 43-year-old woman presented to our institute with a 4-month history of an aggravated vulvar mass. A radical local excision, bilateral inguinal lymph node dissection and laparoscopic assisted vaginal hysterectomy were performed. The FIGO stage of the vulvar cancer was stage II (T(2)N(0)M(0)) and the pathologic finding was consistent with a poorly differentiated squamous cell carcinoma with extensive sarcomatoid features. No further treatment was given and there was no clinical evidence of recurrence during the 2 years of follow-up. CONCLUSION: A squamous cell carcinoma with sarcomatoid features of the vulva is a tumor with aggressive biological behavior. To date, there have been only 15 cases of this disease reported in the literature. So, a collection and close study of these cases would be extremely useful in singling out and identifying the best treatment possible for this type of tumor.

Gastric syphilis mimicking adenocarcinoma: a case report.

Syphilis is an unexpected diagnosis in the stomach, and the reduced incidence of syphilis has made its clinical presentation less widely appreciated. We report a 43-yr-old man suffering from epigastric tenderness with an initial diagnosis of gastric carcinoma; gastric syphilis was confirmed by demonstrating spirochetes in a gastric biopsy specimen by silver impregnation. Excessive lymphoplasmacytic infiltration with diffuse thickening of gastric rugae should raise suspicion of gastric syphilis, which should be considered in the differential diagnosis of diffuse erosive gastritis and infiltrative lesions of the stomach.

High expression of tissue inhibitor of metalloproteinase-2 in serous ovarian carcinomas and the role of this expression in ovarian tumorigenesis.

Tissue inhibitors of metalloproteinases (TIMPs) play key roles in maintaining homeostasis of the extracellular matrix by controlling matrix metalloproteinases (MMPs). In addition to their role in regulating MMPs, TIMPs have also been shown to have pluripotential effects on cell growth, apoptosis, and differentiation. The aim of this study was to evaluate TIMP-2 level in serous ovarian tumor tissues and to understand further the role of TIMP-2 protein in ovarian tumorigenesis. The expression of TIMP-2 was assessed by immunohistochemistry in a total of 57 ovarian specimens, including 5 normal ovaries, 12 benign serous cystadenomas, 20 serous borderline tumors, and 20 serous carcinomas. In addition, we transfected a TIMP-2 plasmid into the gynecologic cancer cell lines SKOV-3, 2774, and HeLa and then assayed cell growth, apoptosis, and MMP-2 activation. We found that TIMP-2 immunostaining was significantly more frequent in serous carcinomas, mainly in tumor epithelium, compared with cells of the other tissues studied. Tissue inhibitor of metalloproteinase-2 overexpression in ovarian cancer cells did not mediate proapoptosis, inhibited cisplatin-induced apoptosis, and induced MMP-2 expression. These findings suggest that TIMP-2 may function to favor tumor growth in serous ovarian tumorigenesis. Additional research is now needed to elucidate further the role of TIMP-2 in the biologic behavior of ovarian serous tumors.

A case of colonic lymphoid tissue invasion by Gymnophalloides seoi in a Korean man.

A 65-year old Korean man, living in Mokpo-city, Jeollanam-do, Republic of Korea, visited a local clinic complaining of right upper quadrant pain and indigestion. At colonoscopy, he was diagnosed as having a carcinoma of the ascending colon, and thus, a palliative right hemicolectomy was performed. Subsequently, an adult fluke of Gymnophalloides seoi was incidentally found in a surgical pathology specimen of the lymph node around the colon. The worm was found to have invaded gut lymphoid tissue, with characteristic morphologies of a large oral sucker, a small ventral sucker, and a ventral pit surrounded by strong muscle fibers. This is the first reported case of mucosal tissue invasion by G. seoi in the human intestinal tract.

Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas.

The newly identified 3p21.3 tumor suppressor gene RASSF1A is inactivated by hypermethylation in variable solid tumors, including those of the lung, breast, prostate, kidney, and ovary. The purpose of this study was to evaluate the methylation status of RASSF1A in various types and stages of ovarian epithelial tumors. We analyzed the DNA methylation status of ovarian tumors using methylation-specific polymerase chain reaction in 54 frozen ovarian tumor tissues and in 97 cases of archival ovarian serous epithelial tumors using a microdissection procedure. Hypermethylation statuses were examined vs clinicopathologic findings. RASSF1A promoter methylation rates in the various types of fresh ovarian tissues were as follows: serous cystadenoma (1/5), serous tumor of borderline malignancy (2/7), serous adenocarcinoma (4/10), mucinous cystadenoma (0/5), mucinous tumor of borderline malignancy (2/7), mucinous adenocarcinoma (3/6), transitional-cell carcinoma (1/3), clear-cell carcinoma (3/3), and malignant müllerian mixed tumor (3/3). In archived serous tumor tissues, RASSF1A promoter hypermethylation was detected in serous cystadenoma (1/6, 16.6%), serous tumor of borderline malignancy (20/41, 48.8%), and in serous adenocarcinoma (25/50, 50%). The status of RASSF1A hypermethylation in borderline tumors was found to correlate statistically with the presence of microinvasion (p=0.002), peritoneal implant (p<0.001), and bilaterality (p=0.019). The RASSF1A promoter hypermethylation was frequently found in borderline tumors and carcinomas, suggesting that RASSF1A promoter hypermethylation may be a useful molecular marker for the early detection of ovarian tumors.

eIF-4E expression is associated with histopathologic grades in cervical neoplasia.

Translation initiation factor eIF-4E (eukaryotic initiation factor 4E) is a 25 kd messenger RNA cap-binding phosphoprotein and is involved in the initiation of protein synthesis. The expression is known to be elevated in several carcinomas as compared with normal tissues and benign lesions. In the present study, we undertook to determine whether eIF-4E expression is associated with progression in cervical neoplasia. eIF-4E expression was evaluated by immunohistochemistry in 88 formalin-fixed, paraffin-embedded cervical tissues; 10 normal cervical specimens; 19 low-grade cervical intraepithelial neoplasias (CINs); 19 high-grade CINs; and 40 invasive squamous cell carcinomas (ISCCs). In addition, eIF-4E expression was evaluated at the RNA level in fresh frozen cervical carcinoma tissues by real-time quantitative reverse transcriptase polymerase chain reaction. Immunohistochemical staining showed that eIF-4E expression was undetectable in most normal cervical squamous epithelial tissues (90%), but variable staining was observed in the basal layer of all normal endocervical glands. eIF-4E expression, which was mainly observed as cytoplasmic staining, gradually increased in accordance with histopathologic grade in the order low-grade CIN < high-grade CIN < ISCC (P < .001) and, in particular, was strongly detected in all ISCC cases. Furthermore, real-time quantitative reverse transcriptase polymerase chain reaction revealed that eIF-4E expression in tumor was significantly enhanced versus normal cervical tissues (P = .037). These results suggest that eIF-4E may play a significant role in tumor progression of cervical neoplasia and may represent useful markers for malignant transformation of cervical squamous cells.