Unusual presentation of benign cystic brenner tumor with exuberant psammomatous calcifications

Transitional cell tumors of the ovary comprise about 1% to 2% of all ovarian neoplasms. Most of these tumors are benign Brenner tumors and account for about 5% of benign surface epithelial-stromal tumors. Spicules of calcifications are found in the stroma of about 50% of benign Brenner tumors. Although diagnostic challenges might occur more frequently with either of the borderline or malignant Brenner tumors, this problem is not that common when diagnosing a benign Brenner tumor. This study reports a case of benign Brenner tumor with exuberant dystrophic calcifications that obscured most of the epithelium and posed a diagnostic challenge in differentiating it from the more common malignant counterparts such as serous carcinoma and specifically psammocarcinoma.     

WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma

AIMS: It has been suggested that WT-1 is helpful in distinguishing a primary ovarian serous carcinoma (OSC) from a primary uterine serous carcinoma (USC). Since both neoplasms are often disseminated at diagnosis and since USC often spreads to the ovary and vice versa, it may be difficult to ascertain the primary site. This is important, since adjuvant therapies for OSC and USC may differ. WT-1 staining patterns also differ between OSC and ovarian endometrioid carcinoma and so it is possible that WT-1 may assist in the distinction of these two neoplasms, which is sometimes problematic, especially with poorly differentiated tumours. This study aims to document the value of WT-1 in these settings. Cases of ovarian borderline serous tumour, primary peritoneal serous carcinoma (PPSC) and uterine endometrioid carcinoma were also studied. METHODS AND RESULTS: Cases of OSC (n = 38), USC (n = 25) (in five of these cases there was also a component of endometrioid adenocarcinoma), ovarian endometrioid carcinoma (n = 13), uterine endometrioid carcinoma (n = 7), ovarian borderline serous tumour (n = 16) and PPSC (n = 6) were stained with WT-1. Cases were scored on a scale of 0-3, depending on the percentage of positive cells. The intensity of staining was scored as weak, moderate or strong. There was positive nuclear staining of 36 of 38 (94.7%) OSC with WT-1. In most OSC (68.4%), >50% of cells stained positively and staining was usually strong. Five of 25 (20%) USC were positive with only two cases exhibiting staining of >50% of cells. All primary ovarian and uterine endometrioid carcinomas were negative. All PPSC were positive, usually with diffuse strong immunoreactivity. Fourteen of 16 borderline serous tumours exhibited positivity with WT-1. CONCLUSIONS: WT-1 is useful in distinguishing OSC (characteristically diffuse strong nuclear positivity) from USC (characteristically negative). However, rarely OSC is negative and occasional cases of USC are positive. WT-1 may also be helpful in differentiating poorly differentiated OSC from poorly differentiated ovarian endometrioid carcinoma.     

High-grade ovarian serous carcinoma exhibits significantly higher p16 expression than low-grade serous carcinoma and serous borderline tumour

AIMS: A dualistic pathway of ovarian serous carcinogenesis is now well established whereby high-grade serous carcinoma and low-grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis. The aim of this study was to compare expression of p16 INK4A (p16) in these two tumour types. We also included cases of serous borderline tumour, since these are considered to represent a precursor lesion of low-grade serous carcinoma. METHODS AND RESULTS: Cases of serous borderline tumour (n = 18), low-grade ovarian serous carcinoma (n = 22) and high-grade ovarian serous carcinoma (n = 24) were stained with a monoclonal antibody against p16. Cases were scored both with respect to intensity of immunoreactivity (weak, 1+; moderate, 2+; or strong, 3+) and distribution (0, negative or occasional positive cells; 1+, < 10% cells positive; 2+, 10-25% cells positive; 3+, 26-50% cells positive; 4+, 51-75% cells positive; or 5+, 76-100% cells positive). An immunohistochemical composite score was also calculated (0-15) by multiplying the intensity and distribution scores. There was a statistically significant difference in p16 immunoreactivity with respect to intensity, distribution and composite score between high-grade serous carcinoma and each of the other two groups, with the high-grade neoplasms exhibiting stronger and more diffuse positivity. Most high-grade serous carcinomas exhibited positivity of close to 100% of tumour cells. There was no significant difference in p16 expression between the borderline tumours and low-grade serous carcinomas. CONCLUSIONS: The increased expression of p16 in high-grade serous carcinoma compared with low-grade serous carcinoma and serous borderline tumour is in keeping with a different underlying pathogenesis. p16 may be implicated in the development of high-grade serous neoplasia within the ovary and elsewhere within the female genital tract.     

基质金属蛋白酶-7在卵巢浆液性肿瘤中的表达

目的：探讨MMP－7在卵巢浆液性肿瘤中的表达情况。方法：采用免疫组化SP法对6例正常卵巢、12例卵巢浆液性囊腺瘤、6例交界性囊腺瘤及22例卵巢浆液性囊腺癌MMP－7的表达进行了研究。结果：正常卵巢不表达MMP－7。大部分卵巢浆液性肿瘤的胞浆及间质中都有MMP－7的阳性表达。MMP－7的卵巢良性，恶性及交界性浆液性肿瘤胞浆中的表达无明显差异；而在肿瘤间质中，恶性及交界性卵巢浆液性肿瘤中的表达远高于良性肿瘤（P＜0．05）。在交界性及恶性浆液性卵巢肿瘤中，部分肿瘤细胞的细胞核中也有MMP－7的表达，为国内外首次报道。结论：MMP－7可能在卵巢浆液性肿瘤的进展中发挥重要作用。     

Ovarian serous cystadenofibromas associated with a low-grade serous carcinoma of the peritoneum

Ovarian serous cystadenofibromas are benign neoplasms that sometimes have focal areas of borderline serous tumor and rarely have been associated with epithelial proliferations in the peritoneum, resembling implants. We are reporting 2 cases of ovarian serous cystadenofibromas with serous peritoneal lesions of higher grade than the ovarian tumor: 1 case had a serous carcinoma and another 1 a serous borderline tumor.     

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high‐grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end – serous tubal intra‐epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high‐grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high‐grade serous carcinoma with rapid tumour growth. For invasive low‐grade serous carcinoma, it is well‐established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non‐invasive micropapillary (low‐grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low‐grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low‐grade pathway, including serous borderline tumours, non‐invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high‐grade serous carcinomas originates in the fallopian tube, and that for low‐grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.     

Primary papillary serous neoplasia of the peritoneum: a clinicopathologic and ultrastructural study of eight cases

The well-documented but rare primary papillary serous peritoneal tumors are difficult problems for the pathologist and the clinician. Because of their unusual location, these tumors are often classified as mesothelioma or advanced ovarian carcinoma. In this study, we report the clinicopathologic features of eight primary peritoneal serous papillary tumors and compare their histologic and ultrastructural features to 12 serous ovarian tumors and 16 epithelial mesotheliomas (two peritoneal and 14 pleural). The eight peritoneal serous papillary tumors occurred in women aged 19 to 75 years; two were serous tumors of low malignant potential (borderline) and six were serous carcinomas. The tumors were located in the mesosalpinx, left pelvis, omentum, and/or surface of the ovary. The two patients with borderline neoplasms had long disease-free survival (11 years and 20 years), while three of the four patients with carcinoma with more than 1 year of follow-up died of disease. The peritoneal serous papillary tumors were morphologically identical to serous ovarian tumors of equivalent grade. Well-differentiated papillary structures with distinct fibrovascular cores and one or several layers of columnar, crowded cells, dense overlapping nuclei with a long axis perpendicular to the surface of the papillary cores, and numerous psammoma bodies were features of the peritoneal and ovarian serous tumors. In contrast, the tubulo-alveolar, solid, or poorly defined papillary structures lined by well-spaced polygonal to cuboidal cells with abundant cytoplasm, absence of nuclear polarity, and infrequent psammoma bodies characterized the mesotheliomas. Epithelial mucin and carcinoembryonic antigen (CEA) immunoreactivity, when present, supported a diagnosis of serous tumor in these generally mucin-poor and CEA-negative neoplasms. Ultrastructurally, the cells of serous tumors had slender, straight microvilli of variable length interspersed with or without cilia, while the nonciliated cells of mesothelioma had long, exuberant, wavy microvilli. The morphologic and clinical features of the peritoneal papillary serous tumors are distinctive enough to warrant their separation from mesotheliomas.     

Uncommon ovarian epithelial tumours

Epithelial ovarian tumours represent the most common type of ovarian tumour. Most of malignant cases represent high-grade serous, clear cell and endometrioid carcinomas; borderline serous and mucinous tumours of intestinal type are less common. This review focuses on the uncommon or rare epithelial tumours of the ovary which include borderline and malignant Brenner tumours, the recently-described mesonephric-like carcinoma of the ovary, and primary ovarian neuroendocrine tumours, with emphasis on helpful and diagnostic features.     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

上皮性卵巢癌组织脆性组氨酸三联基因甲基化和3p14的等位基因丢失

目的 探讨肿瘤抑制基因脆性组氨酸三联(FHIT)基因在上皮性卵巢癌(简称卵巢癌)组织中的甲基化状态以及该基因定位的3p14位点的等位基因丢失及其在卵巢癌的发生发展中的作用。方法采用甲基化特异性聚合酶链反应(MSP)方法检测61例卵巢癌组织及10例交界性上皮性卵巢肿瘤(简称交界性卵巢肿瘤)组织FHIT基因启动子CpG岛的甲基化频率,并采用微卫星多态性标志D3S1287检测45例卵巢癌组织3p14位点杂合子丢失(LOH)和纯合子丢失(HD)状态。结果卵巢癌组织中FHIT基因甲基化频率为39．3％(24／61),其中浆液性囊腺癌为45．2％(19／42),黏液性囊腺癌为14．3％(1／7),子宫内膜样癌为33．3％(4／12);交界性卵巢肿瘤组织中FHIT基因甲基化为6／10,其中交界性浆液性囊腺瘤1／3,交界性黏液性囊腺瘤5／7。卵巢癌组织甲基化频率与临床分期、细胞分化程度相关性无统计学意义。交界性卵巢肿瘤与卵巢癌之甲基化频率差异无统计学意义。43．5％(10／23)卵巢癌显示LOH;有信息的浆液性囊腺癌中33．3％(6／18)检测到HD。FHIT基因甲基化与基因丢失之间无明显相关性。结论首次证实卵巢癌FHIT基因启动子有较高的甲基化频率,这可能是FHIT基因沉默的重要原因,在卵巢癌的发生与发展过程中起着重要的作用;同时3p14位点等位基因的丢失可使基因完全失去功能,促进肿瘤的发生。     

Paratesticular cystadenomas with ovarian stroma,metaplastic serous müllerian epithelium,and male adnexal tumor of probable wolffian origin: A series of 5 hitherto poorly recognized testicular tumors

We present 5 paratesticular tumors, which manifested ovarian-type stroma and various serous müllerian epithelial structures including serous fallopian-like epithelium and proliferations closely mimicking cystic serous borderline tumors of the ovary. In addition, 3 of the tumors in our series revealed a solid epithelial component, which was morphologically and immunohistochemically similar to so called “female adnexal tumor of probable wolffian origin,” which is a rare neoplasm described so far only in the female genital tract, retroperitoneum, and the pelvic cavity. In analogy with mixed epithelial and stromal tumors of the kidney, which are renal neoplasms producing ovarian-type stroma, we suggest to designate the above paratesticular tumors containing ovarian-type stroma as “mixed epithelial and stromal tumors of the paratestis with features of cystic serous borderline tumor” (cases 1 and 2) and “mixed epithelial and stromal tumors of the paratestis with male adnexal tumor of probable wolffian origin” (cases 3-5).     

Diverse tumorigenic pathways in ovarian serous carcinoma

This study was undertaken to analyze genetic alterations in 108 sporadic serous ovarian neoplasms to elucidate ovarian serous carcinogenesis. Our results demonstrate that K-ras mutations occur in approximately 50% of serous borderline tumors (SBTs), non-invasive micropapillary serous carcinomas (MPSCs), and invasive micropapillary serous carcinomas, which represent a morphological continuum of tumor progression. Moreover, progressive increase in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was observed comparing serous borderline tumors to noninvasive and invasive micropapillary serous carcinomas. In contrast, high-grade (conventional serous carcinoma) tumors contained wild-type K-ras in all 23 cases studied and a high frequency of allelic imbalance even in small (early) primary tumors similar to that found in advanced stage tumors. Based on these findings, we propose a dualistic model for ovarian serous carcinogenesis. One pathway involves a stepwise progression from SBT to noninvasive and then invasive MPSC. The other pathway is characterized by rapid progression from the ovarian surface epithelium or inclusion cysts to a conventional (high-grade) serous carcinoma.     

Calcifications in prostate and ejaculatory system: a study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens

Although calcifications in the prostate are a common manifestation, the relationship between calcifications and prostate cancer is not clearly documented as in breast cancer. In addition, anatomical distribution of calcifications by zones of the prostate and ejaculatory system has not been systematically studied. To study the frequency and patterns of calcifications within the prostate and ejaculatory system, we reviewed the whole mount sections of 298 consecutive prostatectomy or cystoprostatectomy specimens. Calcifications were evaluated in the prostate (central, peripheral and transition zones, and verumontanum), ejaculatory ducts, and seminal vesicles. We graded the degree of calcifications as mild, moderate, or severe. Calcifications in the prostate and ejaculatory system were common, and their frequency in our series is as follows: 88.6% (264/298) of prostates, 58.1% (173/298) of seminal vesicles, and 17.1% (51/298) of ejaculatory ducts. The prostatic calcifications occurred mostly in benign glands and/or stroma of all zones and the verumontanum. Calcifications were more common in the transition zone than other zones. There were 4 cases of prostatic calcifications in the areas of prostatic adenocarcinoma: 3 cases with calcifications in the tumor glands and 1 case with calcifications in tumor stroma but not in the accompanying tumor glands. In conclusion, calcifications are a very common finding in prostatectomy specimens and seem mostly to be associated with benign prostatic hyperplasia. However, calcifications can occur in direct association with prostatic adenocarcinoma, although the incidence of this association is not as high as in breast carcinoma. Also, ejaculatory system calcifications are not an infrequent finding.     

Different proportions of aneusomic cells in ovarian inclusion cysts associated with serous borderline tumours and serous high-grade carcinomas support different pathogenetic pathways

Ovarian serous tumours may arise from the ovarian surface epithelium or from ovarian cortical epithelial inclusion cysts. However, little is known about the pathogenetic mechanisms involved in the progression from ovarian surface epithelium or inclusion cysts to neoplastic disease. In the present study, chromosomal aberrations typical of ovarian serous tumours were studied in ovarian surface epithelium and inclusion cysts. Ten ovaries with inclusion cysts obtained from patients without a gynaecological tumour, as well as 15 serous borderline tumours and 16 invasive high-grade serous carcinomas with inclusion cysts either in the ipsi- or in the contralateral ovary, were investigated by fluorescence in situ hybridization (FISH) using centromere enumeration probes directed against chromosomes 1, 6, 7, and X. The proportions of aneusomic cells were assessed. Trisomies 1 and 7 and monosomies 6 and X were present in the surface epithelium, inclusion cysts, and tumours, providing evidence for a link between the surface epithelium, and inclusion cysts, and serous neoplasia. Inclusion cysts generally harboured more aneusomic cells than the associated surface epithelium, suggesting an influence of the ovarian stroma on the development of chromosomal instability. Moreover, inclusion cysts associated with borderline tumours displayed a higher proportion of aneusomic cells than inclusion cysts associated with invasive high-grade carcinoma and than inclusion cysts in ovaries without neoplastic disease. These results suggest a genetic field defect of the inclusion cyst epithelium in serous borderline tumours. Invasive high-grade serous carcinomas, by contrast, may arise from single cell clones subject to a different set of genetic events.     

Evolution of the concept and termiology of borderline ovarian tumours

The borderline category of ovarian tumours was established in the early 1970s because of the observation that a group of proliferative epithelial ovarian tumours lacking invasion that generally behaved in a benign fashion occasionally pursued an indolent malignant course. Over the last 25 years, a large database on these tumours has been accrued. Recent studies suggest that the borderline group can now be subclassified into benign and malignant neoplasms. The survival for patients with serous borderline tumours confined to the ovaries is virtually 100%. Patients with ovarian serous borderline tumours with invasive peritoneal implants have a 34% mortality rate; therefore, these cases are classified as low grade carcinomas. Micropapillary serous carcinoma, a distinctive neoplasm that fails to display unequivocal evidence of invasion and therefore has been included in the borderline category, is strongly associated with invasive implants and recurs as invasive carcinoma. After these neoplasms with invasive implants are excluded from the group of tumours classified as borderline, the remaining advanced stage serous borderline tumours (those with non-invasive implants) have a disease-specific survival rate of nearly 100% and should be considered benign. In a similar fashion, the vast majority of mucinous borderline tumours reported to display aggressive behaviour have been associated with the clinical syndrome of pseudomyxoma peritonei. It is now clear that pseudomyxoma peritonei is a condition of appendiceal origin in virtually all cases. In addition, there is a small group of mucinous carcinomas typically from the pancreas and biliary system that present with relatively bland-appearing metastases to the ovaries that closely simulate mucinous borderline tumours. Once these metastatic carcinomas and mucinous tumours associated with pseudomyxoma peritonei are removed from the borderline category, the remaining mucinous borderline tumours are always confined to the ovaries and have a benign behaviour. Finally, review of the literature indicates the other epithelial types of borderline tumours (endometrioid, clear cell and transitional cell) behave in a benign fashion. Since borderline tumours can now be classified into benign and malignant types, the borderline category has no further utility and can be abandoned. This will be of great benefit to patients and clinicians, and will also help in more clearly focusing research efforts on ovarian cancer.     

WT1 expression in the female genital tract

The Wilms tumor gene 1 (WT1) has been reported in normal tissues and many neoplasms of the female genital tract. This review discusses WT1 expression in the female genital tract and its potential utility in the differential diagnosis of neoplasms that occur at this location. WT1 is of value in the differential diagnosis of synchronous serous carcinomas arising in the ovary/fallopian tube/peritoneum and endometrium, as strong WT1 positivity in both tumors points toward an extrauterine origin. In addition, WT1 can be used to distinguish sex cord stromal tumors (WT1 positive) from endometrioid carcinomas (OECs). WT1 expression is not helpful in the differential diagnosis of ovarian serous carcinomas (OSCs) and transitional carcinomas, as both are typically positive and has limited value in the distinction of serous tumors arising in the ovary/fallopian tube/peritoneum from mesotheliomas. WT1 is also not helpful to differentiate small cell carcinoma of hypercalcemic type from juvenile granulosa cell tumor, a common diagnostic problem. Intra-abdominal desmoplastic round cell tumor reacts to WT1 (C-terminal) in contrast to all other tumors discussed which helps to separate this rare tumor from most other small round cell tumors that may involve, primarily or secondarily, the ovary with the exception of small cell carcinoma of hypercalcemic type that typically reacts with the N-terminal of WT1.     

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.     

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.