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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.

Tight junction proteins claudin 3 (CLDN3) and claudin 4 (CLDN4) are frequently altered in several human cancers, including ovarian carcinomas. Here, we examined the gene expression of CLDN3 and CLDN4 in various tumors, including 19 normal ovaries and 47 ovarian carcinomas by analyzing Affymetrix HG-U133 array data. Furthermore, a total of 114 ovarian serous tumors, including 10 adenomas, 20 borderline tumors and 84 carcinomas, were analyzed immunohistochemically to confirm the expression of two proteins and we assessed the association of their expression with the clinicopathological characteristics and survival of the patients. The microarray experiment revealed CLDN3 and CLDN4 transcripts were significantly up-regulated by 5-fold or more in most subtypes of ovarian epithelial carcinomas while the immunohistochemical analyses indicated that each protein was expressed in 68 (81.0%) and 72 (85.7%) of 84 serous adenocarcinomas, respectively. Borderline serous tumors and adenomas showed significantly lower expression of these proteins than the adenocarcinomas. Kaplan-Meier survival analysis showed that serous adenocarcinoma patients with high CLDN3 expression had substantially shorter survival (P=0.027). Multivariate analysis demonstrated that CLDN3 overexpression is an independent negative prognostic factor. Our findings suggest that CLDN3 overexpression can be used as a prognostic indicator in ovarian serous carcinomas. Moreover, CLDN3 may be a promising target for antibody-based therapy of ovarian carcinomas.

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.

We studied the immunoexpression of p14ARF, MDM2, and p53, in addition to relationships between those protein expressions and estrogen receptor (ER)alpha in ovarian serous tumors including benign (n= 23), borderline (n= 41), and malignant (n= 94). The aberrant expressions of p14ARF, MDM2, and p53 were observed in 19.6% (31/158), 47.5% (75/158), and 39.9% (63/158) of cases, respectively. The expression of MDM2 was significantly higher in borderline tumors compared to benign (P= 0.04) and malignant (P < 0.01) tumors. p53 expression in borderline tumors was uncommon, and p14ARF expression loss was mainly observed in carcinomas. Altered expression of p14ARF, MDM2, and p53 shows significant relationship with stage. Overexpression of MDM2 (P= 0.01) and loss of p14ARF expression (P= 0.04) were significantly associated with ER expression. Our results suggest that alteration of p14ARF-MDM2-p53 pathway proteins may contribute significantly to the tumorigenesis of ovarian serous neoplasms, and ER is involved in cellular regulation of p14ARF-MDM2-p53 pathway in ovarian serous neoplasms.

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.

Objectives: CD24, originally described as a B-cell marker, has been revealed as one of the candidate molecular markers of epithelial ovarian cancer. We aimed to determine the pattern and extent of CD24 expression in ovarian serous tumors and to clarify its relationship with pathological parameters, especially those associated with the early events of tumor progression in serous tumors of borderline malignancy., Methods: A total of 114 ovarian serous tumors, including 9 adenomas, 34 borderline, and 71 carcinomas, were analyzed immunohistochemically using a CD24 monoclonal antibody on paraffin blocks., Results: In normal epithelium and serous cystadenomas, the CD24 expression was localized to the apical membranous portion. In some of borderline tumors (26.4%), additional cytoplasmic expression was observed. The cytoplasmic expression of CD24 in borderline tumors was associated with microinvasion (P = 0.001) and omental implants (P = 0.033) with statistical significance. Serous adenocarcinomas showed strong diffuse cytoplasmic expression of CD24, which was significantly associated with shortened survival rate both in univariate (P = 0.011) and multivariate (P = 0.009) analysis., Conclusion: The loss of apical localization with the acquisition of the cytoplasmic staining of CD24 protein is a surrogate marker of stromal invasion in ovarian serous tumors of borderline malignancy. Furthermore, the increase in the cytoplasmic expression of CD24 protein is a strong independent molecular marker for shortened survival rate of patients with ovarian serous adenocarcinomas.

We report a case of mullerianosis of the mesosalpinx, the appearance of which simulated metastatic adenocarcinoma. The patient was a 37-year-old woman with a mixed epithelial cystadenoma of borderline malignancy associated with endometriosis in both ovaries. The left mesosalpinx contained a firm, 2.2-cm, gray-white mass that on microscopic examination consisted of glands lined mostly by endocervical-type epithelium with admixed tubal-type glands and foci of endometriosis. Rupture of glands with extravasation of mucin into the surrounding stroma was observed, but there was no desmoplastic stromal reaction. Awareness of this relatively uncommon lesion is critical to avoid misdiagnosis and overly aggressive treatment.

Benign peritoneal melanosis is extremely rare and traditionally occurs in association with ovarian dermoid cysts, but rarely with peritoneal cyst, enteric duplication cyst or gastric triplication. The pathogenesis of peritoneal melanosis, in particular, the origin of the pigment-producing cells is unclear. We describe a case of peritoneal melanosis that was associated with ovarian serous cystadenoma in a young woman. Ovarian serous cystadenoma has not been previously described as a combined lesion of peritoneal melanosis. Based on the extremely rare incidence of this lesion and heterogeneous combined lesions, the possibility of an incidentally found, coexisting lesion couldn't be excluded. Here, we suggest that peritoneal mesothelial cells pinched off during the developmental period might be a source of pigment-producing cells.

Objective: Anti-inhibin alpha and inhibin/activin betaA subunit and anti-CD99 monoclonal antibodies (mAbs) have recently been demonstrated to be able to label ovarian granulosa cells; thus, they may be of value in the diagnosis of granulosa cell tumors. The present study aimed to determine what combination of these mAbs may be useful for the differential diagnosis of sex cord-stromal tumors of ovary., Design: Immunohistochemical analyses with anti-inhibin alpha and inhibin/activin betaA subunit antibody and anti-CD99 mAb were performed on 42 ovarian tumors, including sex cord-stromal tumors (29), ovarian epithelial cancers (10), and Krukenberg tumors (3)., Results: All sex cord-stromal tumors were positive for inhibin alpha subunit, and 17 cases (58.6%) of sex cord-stromal tumors were immunoreactive for inhibin/activin betaA subunit. Epithelial tumors and Krukenberg tumors were all negative for inhibin/activin betaA subunit except mucinous carcinoma, which showed strong cytoplasmic immunoreactivity. All sex cord-stromal tumors except one granulosa cell tumor showed membranous staining for CD99. A case of serous carcinoma and a case of mucinous carcinoma were positive for CD99, and the remaining epithelial tumors and Krukenberg tumor were all negative for CD99., Conclusions: The results of immunohistochemical analysis, together with literature review, suggest that inhibin alpha subunit may be a useful diagnostic marker for sex cord-stromal tumor of the ovary. In addition, anti-CD99 antibody may be useful for the differential diagnosis between ovarian tumors. Inhibin/activin betaA subunit has a limited usefulness in the differential diagnosis of ovarian tumor because of its wider immunoreactivity for both sex cord-stromal tumors and mucinous carcinomas. The differential diagnosis of sex cord-stromal tumors of the ovary would be better made with a combined use of both anti-inhibin alpha subunit and anti-CD99 mAbs.

A case of a monodermal teratoma of the ovary composed solely of mature neuroglial elements is described. The cyst lining comprised ependymal cells surrounded by white matter which itself was resting on mesothelial cells. Astrocytes, oligodendrocytes, microglia and neurofilament-positive fibres were seen, but no neuron cell bodies were present. Immunohistochemical stains showed positivity for glial fibrillary acidic protein in ependymal, subependymal and the white matter regions while S-100 protein positivity was restricted to the white matter. Vessels within neuroectodermal tissue, but not those within the mesodermal tissue, stained positively for anti-glucose transporter protein, a marker shown to be present in vessels with barrier functions. We conclude that this is a rare case of monodermal teratoma consisting of purely mature brain tissue with a microvasculature exhibiting blood-brain barrier characteristics.

A pathologic study was done on four cases of ovarian sex cord tumor with annular tubules. All four tumors occurred in young women (11-24 years of age) and were not associated with the Peutz-Jeghers syndrome. Two patients had evidence of hyperestrinism. One patient who had metastasis to the retroperitoneum, left supraclavicular lymph node, and liver confirmed the malignant potential of this tumor. Gross examination revealed tumors that were solid, yellowish, and unilateral, with varying degrees of cystic degeneration. Microscopic examination showed simple or complex annular tubules with prominent basement membranes. Many tumor cells contained lipid in the cytoplasm. Ultrastructural study showed Charcot-Bottcher filaments in all four cases, indicating Sertoli cell differentiation. True lumens and microvilli were identified in one case. The classification of the sex cord tumor with annular tubules as a Sertoli cell tumor, annular tubular type was proposed on the basis of ultrastructural findings.