Origin and molecular pathogenesis of ovarian high-grade serous carcinoma.

A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial 'ovarian' cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated 'type I' and 'type II'. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs). As the serous tumors comprise ∼70% of all epithelial ovarian tumors and account for the majority of deaths, the serous tumors will be the subject of this review. There are marked differences between the low-grade and high-grade serous tumors. Briefly, the former are indolent, present in stage I (tumor confined to the ovary) and develop from well-established precursors, so-called 'atypical proliferative (borderline) tumors,' which are characterized by specific mutations, including KRAS, BRAF and ERBB2; they are relatively genetically stable. In contrast, HGSCs are aggressive, present in the advanced stage, and develop from intraepithelial carcinomas in the fallopian tube. They harbor TP53 mutations in over 95% of cases, but rarely harbor the mutations detected in the low-grade serous tumors. At the time of diagnosis they demonstrate marked chromosomal aberrations but over the course of the disease these changes remain relatively stable. Along with the recent advances in understanding the molecular pathogenesis of these tumors, studies have demonstrated that the long sought for precursor of ovarian HGSC appears to develop from an occult intraepithelial carcinoma in the fimbrial region of the fallopian tube designated 'serous tubal intraepithelial carcinoma (STIC)' and involves the ovary secondarily. Another possible mechanism for the development of ''ovarian'' HGSC is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs. We speculate that this tubal epithelium can result in the formation of a cortical inclusion cyst (CICs) that can then undergo malignant transformation. Thus, serous tumors may develop from inclusion cysts, as has been previously proposed, but by a process of implantation of tubal (müllerian-type) tissue rather than by a process of metaplasia from ovarian surface epithelium (OSE, mesothelial). The dualistic model serves as a framework for studying ovarian cancer and can assist investigators in organizing this complex group of neoplasms. In conjunction with the recognition that the majority of 'ovarian' carcinomas originate outside the ovary, this model also facilitates the development of new and novel approaches to prevention, screening and treatment of this devastating disease.

Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance.

The TP53 mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%, but a stringent analysis of TP53 using purified epithelial samples has not yet been performed to accurately assess the mutation frequency and to correlate it with the histologic grade. The purpose of this study was to assess the TP53 mutational profile in a relatively large series of high-grade (53 primary and 18 recurrent) and 13 low-grade ovarian serous tumors using DNA isolated from affinity-purified tumor cells and to correlate it with in vitro drug resistance. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4-9. In vitro drug resistance assays to carboplatin, cisplatin, paclitaxel, and taxotere were performed on the same tumor samples and correlated with the TP53 mutation status. TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13 low-grade serous tumors (an invasive low-grade serous carcinoma). The mutations were predominantly missense mutations (59.6%). TP53 mutations were associated with high-grade serous carcinomas and recurrent disease (P < 0.0001). There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage (P > 0.25). The frequency of TP53 mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported. Furthermore, we found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

Serous borderline tumours of the ovary.

Serous borderline tumours of the ovaryIn this Expert Opinion we have invited articles from two leading groups, to discuss serous borderline tumours (serous tumours of low malignant potential) of the ovary from their own perspectives. Controversy remains over heterogeneity within this group of tumours and their relationship to ovarian cancer. Our authors discuss the histopathological classification of these tumours in relation to morphological appearances, molecular and clinical data. The significance of a micropapillary pattern is discussed, and issues related to extra-ovarian implants.

Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement.

OBJECTIVES: A panel of 14 physicians practicing medicine in the United States with expertise in radiology, obstetrics and gynecology, gynecologic oncology, hysteroscopy, epidemiology, and pathology was convened by the Society of Radiologists in Ultrasound to discuss the role of sonography in women with postmenopausal bleeding. Broad objectives of this conference were (1) to advance understanding of the utility of different diagnostic techniques for evaluating the endometrium in women with postmenopausal bleeding; (2) to formulate useful and practical guidelines for evaluation of women with postmenopausal bleeding, specifically as it relates to the use of sonography; and (3) to offer suggestions for future research projects. SETTING: October 24 and 25, 2000, Washington, DC, preceding the annual Society of Radiologists in Ultrasound Advances in Sonography conference. PROCEDURE: Specific questions to the panel included the following: (1) What are the relative effectiveness and cost-effectiveness of using transvaginal sonography versus office (nondirected) endometrial biopsy as the initial examination for a woman with postmenopausal bleeding? (2) What are the sonographic standards for evaluating a woman with postmenopausal bleeding? (3) What are the abnormal sonographic findings in a woman with postmenopausal bleeding? (4) When should saline infusion sonohysterography or hysteroscopy be used in the evaluation of postmenopausal bleeding? (5) Should the diagnostic approach be modified for patients taking hormone replacement medications, tamoxifen, or other selective estrogen receptor modulators? CONCLUSIONS: Consensus recommendations were used to create an algorithm for evaluating women with postmenopausal bleeding. All panelists agreed that because postmenopausal bleeding is the most common presenting symptom of endometrial cancer, when postmenopausal bleeding occurs, clinical evaluation is indicated. The panelists also agreed that either transvaginal sonography or endometrial biopsy could be used safely and effectively as the first diagnostic step. Whether sonography or endometrial biopsy is used initially depends on the physician's assessment of patient risk, the nature of the physician's practice, the availability of high-quality sonography, and patient preference. Similar sensitivities for detecting endometrial carcinoma are reported for transvaginal sonography when an endometrial thickness of greater than 5 mm is considered abnormal and for endometrial biopsy when "sufficient" tissue is obtained. Currently, with respect to mortality, morbidity, and quality-of-life end points, there are insufficient data to comment as to which approach is more effective. The conference concluded by identifying several important unanswered questions and suggestions that could be addressed by future research projects.

Micronized progesterone regulation of the endometrial glandular cycling pool.

We sought to determine if micronized progesterone in estrogen-primed women has an effect on the available cycling pool of proliferating glandular cells by studying 107 postmenopausal women who participated in a double-blind cyclical HRT trial. Each received 0.625 mg/day of conjugated equine estrogen (Premarin) orally for 6 weeks (cycle 1), followed by a baseline endometrial biopsy. These women were randomized to one of four doses (100 through 400 mg/day) of progesterone taken the last 10 days of each cycle or to estrogen only. Cyclical HRT (25-day cycles) was continued for three more cycles. Endometrial biopsies were performed at the end of cycle 4 and 64 subjects demonstrated an adequate biopsy for immunohistochemical evaluation. The number of proliferating gland cells was determined by an immunohistochemical stain measuring positive MIB1 staining nuclei per thousand gland cells. The number of proliferating endometrial gland cells in the cycling pool of women receiving 300- and 400-mg daily doses of progesterone was low (mean 4.9 and 1.7, respectively) when compared with women receiving 100 mg progesterone (mean 27.0) or to unopposed estrogen (mean 30.3). Late secretory endometrium from 19 premenopausal women had a mean of 0.6. In the progesterone-treated subjects, biopsies showed that secretory maturation increased as the serum progesterone and doses of progesterone increased. We conclude that micronized progesterone given to estrogen-primed menopausal women results in a dose dependent decrease in endometrial gland proliferation. The use of an immunohistochemical stain and the diagnosis of histologic secretory maturation are complementary techniques in determining the inhibition of glandular proliferation.

Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by disseminated intraperitoneal mucinous tumors, often with mucinous ascites. The term PMP has been applied historically as a pathologic diagnostic term to both benign and malignant mucinous neoplasms that produce abundant extracellular mucin, resulting in a variable and poorly predictable prognosis. A recent study reported a pathologic classification that separated patients into prognostically distinct groups, but the follow-up was relatively short. METHODS: Long-term follow-up data were analyzed for a previously reported series of 109 patients with PMP to examine the prognostic utility of a pathologic classification system that divided patients into three groups: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis with intermediate or discordant features (PMCA-I/D). Patients whose tumors were classified 25 DPAM (n = 65 patients) had disease that was characterized by histologically bland to low-grade adenomatous mucinous epithelium associated with abundant extracellular mucin and fibrosis, often with an identifiable appendiceal mucinous adenoma that was the source of the peritoneal lesions. Patients whose tumors were classified 25 PMCA (n = 30 patients) had disease that was characterized by peritoneal lesions that displayed the cytologic and architectural features of mucinous carcinoma associated with extracellular mucin, often with an identifiable invasive mucinous adenocarcinoma of the gastrointestinal tract. Patients whose tumors were classified 25 PMCA-I (n = 11 patients) had peritoneal lesions that combined the features of DPAM and PMCA derived from well differentiated mucinous adenocarcinomas associated with adenomas. Patients whose tumors were classified 25 PMCA-D (n = 3 patients) had markedly atypical appendiceal adenomas associated with peritoneal lesions similar to PMCA. RESULTS: Patients with DPAM had 5-year and 10-year survival rates of 75% and 68%, respectively (mean follow-up, 96 months; median follow-up, 104 months). Patients with PMCA and PMCA-I/D had a significantly worse prognosis, with 5-year and 10-year survival rates, respectively, of 50% and 21% for PMCA-I/D (mean follow-up, 58 months; median follow-up, 51 months) and 14% and 3% for PMCA (mean follow-up, 27 months; median follow-up, 16 months; P = 0.0001). CONCLUSIONS: The term PMP should be used only as a clinical descriptor for patients who have the syndrome of mucinous ascites accompanied by a characteristic distribution of peritoneal mucinous tumors with the pathologic features of DPAM. DPAM should be used as a pathologic diagnostic term for patients with the bland peritoneal mucinous tumors associated with ruptured appendiceal mucinous adenomas and PMP. These patients should not be diagnosed with carcinoma, because they have disease that is distinct pathologically and prognostically from PMCA.

A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells.

Ovarian carcinomas are thought to arise from cells of the ovarian surface epithelium by mechanisms that are poorly understood. Molecules associated with neoplasia are potentially immunogenic, but few ovarian tumor antigens have been identified. Because ovarian carcinomas can elicit humoral responses in patients, we searched for novel tumor antigens by immunoscreening a cDNA expression library with ovarian cancer patient serum. Seven clones corresponding to the homeobox gene HOXB7 were isolated. ELISAs using purified recombinant HOXB7 protein revealed significant serologic reactivity to HOXB7 in 13 of 39 ovarian cancer patients and in only one of 29 healthy women (P < 0.0001). Ovarian carcinomas were found to express HOXB7 at markedly higher levels than normal ovarian surface epithelium, suggesting that immunogenicity of HOXB7 in patients could be associated with its elevated expression in ovarian carcinomas. Overexpression of HOXB7 in immortalized normal ovarian surface epithelial cells dramatically enhanced cellular proliferation. Furthermore, HOXB7 overexpression increased intracellular accumulation and secretion of basic fibroblast growth factor, a potent angiogenic and mitogenic factor. These results reveal HOXB7 as a tumor antigen whose up-regulated expression could play a significant role in promoting growth and development of ovarian carcinomas.

Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumors (borderline) and micropapillary serous carcinomas.

Characterization of invasive peritoneal implants from patients with noninvasive serous ovarian tumors has important prognostic and treatment implications, but the criteria for distinguishing invasive and noninvasive implants vary among investigators and can be difficult to apply. The authors studied 148 implants from 60 patients, 33 with primary atypical proliferative serous tumor, and 27 with primary noninvasive micropapillary serous carcinoma, with a mean follow-up of 62 months (median follow-up, 52 months). Previously reported and newly proposed histologic features for implant classification were evaluated and correlated with clinical outcome. Three criteria were applied for the diagnosis of "invasive" implants: invasion of underlying normal tissue, micropapillary architecture, and solid epithelial nests surrounded by clefts. Implants displaying any one of these three features were classified as "invasive," whereas those lacking all three features were classified as "noninvasive." Sixty-six implants were invasive and 82 were noninvasive. Of the 31 patients with invasive implants, six were dead of disease (DOD), 13 were alive with progressive disease (AWPD), and 12 were alive with no evidence of disease (NED). Of the 29 patients with noninvasive implants, two were DOD, one was dead of uncertain causes, one was AWPD, and 25 were alive with NED. Eighty-nine percent of invasive implants had a micropapillary architecture and 83% had solid epithelial nests surrounded by clefts. A minority of invasive implants (14% of those with underlying normal tissue) demonstrated invasion of normal underlying tissue. Nuclear atypia, mitoses, calcification, necrosis, and identification of individual cells "infiltrating" the stroma did not correlate with implant type. The proposed criteria permitted recognition of implants that correlated strongly with adverse outcome. Sixty-one percent of patients with implants displaying any one of the three features used to diagnose invasive implants were AWPD or DOD compared with 10% of patients whose implants lacked these features (p = 0.00001). Because implants associated with an adverse outcome can be identified before they invade underlying normal tissue, the term invasive implant to describe them is inaccurate and misleading. These implants resemble patterns of growth in micropapillary serous carcinoma of the ovary and the recurrent tumor that is obvious carcinoma. Accordingly, we propose that these extraovarian lesions be designated "well-differentiated serous carcinoma."

The pathology of intermediate trophoblastic tumors and tumor-like lesions.

An intermediate trophoblast is a distinctive trophoblastic cell population from which four trophoblastic lesions are thought to arise: exaggerated placental site (EPS), placental site nodule (PSN), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). EPSs and PSTTs are related to the differentiation of the intermediate trophoblast in the implantation site (implantation site intermediate trophoblast), whereas PSNs and ETTs are related to the intermediate trophoblast of the chorion laeve (chorionic-type intermediate trophoblast). EPSs and PSNs are nonneoplastic lesions, whereas PSTTs and ETTs are neoplasms with a potential for local invasion and metastasis. Microscopically, intermediate trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors, but an appreciation of the morphologic features and immunophenotype allows their diagnosis to be relatively straightforward in most instances. Correct diagnosis is important because each of these lesions may require different therapeutic approaches.

A prospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types.

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

Cervical HPV DNA detection as a predictor of a recurrent SIL diagnosis among untreated women.

OBJECTIVES: This study was conducted to test whether patient history of untreated cervical intraepithelial neoplasia (CIN) 1 or low-grade squamous intraepithelial lesions (LGSIL) modifies the interpretation of a positive HPV DNA result with regards to subsequent squamous intraepithelial lesions (SIL). METHODS: Seventy-three women with recurrent SIL were compared to 105 controls who remain cytologically normal during follow up. Cervical samples collected at enrollment were assayed for HPV DNA in the subject and control groups. RESULTS: Women with and without a history of LGSIL who tested positive for HPV DNA were at a similarly increased risk of having (recurrent) LGSIL as compared to controls. However, in women with a history of LGSIL, HPV DNA appeared to be less predictive for high-grade squamous intraepithelial lesions (HGSIL) than in women without a history of disease. CONCLUSIONS: Past history of untreated CIN1 or LGSIL does not modify the predictive value of a positive HPV DNA test for subsequent LGSIL. The observed difference of the predictive value of a positive HPV DNA test for the risk of recurrent HSIL compared to incident HSIL should be pursued.

A clinicopathologic analysis of atypical proliferative (borderline) tumors and well-differentiated endometrioid adenocarcinomas of the ovary.

Atypical proliferative (borderline) endometrioid tumors (APTs) and well-differentiated endometrioid carcinomas of the ovary constitute a spectrum of morphologically diverse proliferative tumors. There is currently no agreement on the criteria for distinguishing them. We report the clinicopathologic features of 56 proliferative endometrioid tumors focusing on the criteria for invasion, the clinical significance of microinvasion and cytologic atypia, and prognosis. Endometriomas, adenofibromas, adenosarcomas and moderately to poorly differentiated carcinomas were excluded, as were patients with concurrent endometrioid carcinoma of the endometrium. The tumors were classified as atypical proliferative tumor (APT) (33 tumors), APT with intraepithelial carcinoma (high-grade cytology in a tumor lacking stromal invasion) (three tumors), APT with microinvasion (invasion <5 mm) (five tumors), and invasive carcinoma (invasion > or = 5 mm) ( 15 tumors). All tumors were confined to the ovary (stage I). In 50 patients, the tumor involved one ovary, and in three patients, the tumors were bilateral. The predominant growth pattern was adenofibromatous in 29 tumors and glandular or papillary in 27 tumors. In 8 (24%) of 41 APTs, areas of benign adenofibroma were identified, and in 13 (87%) of 15 carcinomas, areas of associated APT were identified. Stromal invasion was manifested by confluent glandular growth in all 15 invasive carcinomas and all tumors with microinvasion. Destructive infiltrative growth was also present in 2 (13%) of 15 carcinomas. Confluent glandular growth was the most common manifestation of stromal invasion and therefore served as the best criterion for the diagnosis of carcinoma. Squamous differentiation was observed in 24 tumors, and mucinous differentiation was seen in 20 tumors and was most often seen in APTs. Endometriosis was present in 14 patients with APTs and one patient with carcinoma. Four patients had hyperplasia or atypical hyperplasia of the endometrium. One patient with an APT had a concurrent peritoneal serous neoplasm. Twenty-one patients had available clinical follow-up. Twenty (95%) of 21 patients, including six with invasive carcinoma, two with microinvasion, one with intraepithelial carcinoma, and 11 with APT were alive with no evidence of disease with a mean follow-up of 47 months. One patient with carcinoma had recurrent tumor after 46 months and was alive 40 months after resection of the recurrent tumor. In this large series of proliferative endometrioid tumors, all were stage I and only one patient had a recurrence. Most carcinomas contained evidence of a precursor APT, and in some APTs, an associated benign adenofibroma was identified. Microinvasion or intraepithelial carcinoma occurred in 19% of APTs. This finding likely reflects the various stages of endometrioid carcinogenesis in the ovary. For clinical management, we suggest that these tumors be divided into two categories-APTs and well-differentiated carcinoma-because based on the available data, cytologic atypia and microinvasion appear not to affect the prognosis.

Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity.

This exploratory study was designed to determine whether treatment with the Yuzpe regimen of emergency contraception altered endometrial integrin expression or other markers of uterine receptivity. Nineteen parous women were followed for two menstrual cycles. In the second cycle, each participant took 100 mg ethinyl oestradiol and 1 mg norgestrel on the day of the urinary luteinizing hormone (LH) surge and repeated the dose 12 h later. In both cycles, endometrial biopsy, phlebotomy and vaginal sonogram were performed 8-10 days after the urinary LH surge. No significant difference was found between untreated and treated cycles in most measures of endometrial histology or in endometrial expression of beta3 integrin subunit, leukaemia inhibitory factor, glycodelin, or progesterone receptors assessed by immunohistochemical techniques. Five statistically significant changes were noted in treated cycles: a reduction in endometrial MUC-1 expression, an increase in endometrial oestrogen receptor, lower luteal phase serum oestrogen concentration, reduced endometrial thickness, and greater proportion of glandular supranuclear vacuoles. The relationship of these findings to the contraceptive action of the Yuzpe regimen is unclear.

Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM).

Partial hydatidiform moles (PHM) have defined villous abnormalities and are usually triploid. Their diagnosis often can be made by morphology alone, without confirmation of ploidy, but considerable interobserver variability exists. Other genetic abnormalities such as trisomy can result in placentas with abnormal villous morphology (AVM) similar to that seen in PHMs, leading to diagnostic confusion. Twenty-three cases originally diagnosed as either PHM or AVM were independently reviewed by 3 pathologists. The consensus diagnosis was PHM in 14 cases and AVM in 9. Cases with AVM showed insufficient features for an unequivocal diagnosis of PHM. DNA content was determined on paraffin-embedded tissue by fluorescence in situ hybridization (fsSH) using a chromosome 1 centromeric probe and by image cytometry (IC). Thirteen of 14 cases (93%) classified as PHM were triploid by both FISH and IC. Seven cases of AVM were diploid by FISH and IC, and 1 was triploid by FISH and IC. One of the 9 cases of AVM was determined to be trisomy 18 by karyotyping. This good correlation of consensus diagnosis with ploidy data was much greater than that obtained based on original diagnoses. Comparative genomic hybridization performed on 6 cases of AVM showed gain of chromosome 21 in 1 case and loss of X in another. PHMs displayed at least 3 of the following histologic features: 2 discrete populations of villi, circumferential mild trophoblastic hyperplasia, trophoblastic inclusions, prominent scalloping of villi, cistern formation. Nontriploid AVMs displayed at most 2 of the diagnostic features of PHM. Placentas with genetic abnormalities other than triploidy can display morphologic changes suggestive of PHM and can be misinterpreted as such by routine light microscopy. Stringent application of morphologic criteria improves the correlation of the diagnosis of PHM with triploidy.

A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis.

The International Federation of Gynecology and Obstetrics (FIGO) grading of uterine endometrial endometrioid carcinoma requires evaluation of histologic features that can be difficult to assess, including recognition of small amounts of solid growth, distinction of squamous from nonsquamous solid growth, and assessment of degree of nuclear atypia. The authors describe a novel, binary architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. The authors analyzed its performance for predicting prognosis and with respect to intra- and interobserver reproducibility. A total of 141 endometrioid carcinomas from hysterectomy specimens were graded according to the FIGO system, nuclear grading, and the binary architectural system. A tumor was classified as high grade if at least two of the following three criteria were present: (1) more than 50% solid growth (without distinction of squamous from nonsquamous epithelium); (2) a diffusely infiltrative, rather than expansive, growth pattern; and (3) tumor cell necrosis. For tumors that were confined to the endometrium, only percent solid growth and necrosis were evaluated, and those with both solid growth of more than 50% and necrosis were considered high grade. All tumors were graded independently by three pathologists on two separate occasions. Both inter- and intraobserver agreement using the binary grading system (kappa = 0.65 and 0.79) were superior compared with FIGO (kappa = 0.55 and 0.67) and nuclear grading (kappa = 0.22 and 0.41). The binary grading system stratified patients into three distinct prognostic groups. Patients with stage I low-grade tumors with invasion confined to the inner half of the myometrium (stages IA and IB) had a 100% 5-year survival rate. Patients with low-grade tumors that invaded beyond the outer half of the myometrium (stage IC and stages II-IV) and those with high-grade tumors with invasion confined to the myometrium (stages IB and IC) had a 5-year survival rate of 67% to 76%. In striking contrast to patients with advance-stage low-grade tumors, patients with advance-stage high-grade tumors had a 26% 5-year survival rate. This binary grading system has advantages over FIGO and nuclear grading that permit greater interobserver and intraobserver reproducibility and should be tested in other studies of endometrial endometrioid carcinomas to validate its reproducibility and use for segregating patients into different prognostic groups.

Norethindrone acetate and estradiol-induced endometrial hyperplasia.

OBJECTIVE: To identify the lowest effective continuous dose of norethindrone acetate that significantly reduces 12-month incidence of endometrial hyperplasia associated with unopposed 17beta-estradiol (E2), 1 mg. METHODS: In a double-masked, randomized, multicenter study, 1176 healthy postmenopausal women 45 years of age or older without evidence of endometrial abnormalities were given 12 months of treatment with unopposed E2, 1 mg, or continuous-combined regimens of E2, 1 mg, and norethindrone acetate, 0.1 mg, 0.25 mg, or 0.5 mg. Endometrial histology was evaluated at the end of the treatment period. RESULTS: Continuous-combined E2-norethindrone acetate regimens significantly reduced 12-month incidence of endometrial hyperplasia compared with unopposed E2 1 mg (P <.001). Endometrial hyperplasia occurred in 14.6% of women treated with unopposed E2 1 mg, whereas in all continuous-combined groups, the rate decreased to less than 1%. Among patients who received E2-norethindrone acetate 0.1 mg, incidence was 0.8%; among those who received 0.25 mg and 0.5 mg, it was 0.4%. CONCLUSION: Continuous norethindrone acetate at doses as low as 0.1 mg combined with E2 1 mg effectively negated risk for endometrial hyperplasia associated with unopposed E2 1 mg, at least for the first year of therapy.

Detection of Chlamydia trachomatis DNA in archival paraffinized specimens from chronic salpingitis cases using the polymerase chain reaction.

OBJECTIVE: To identify Chlamydia trachomatis by the polymerase chain reaction (PCR) in fallopian tube tissues with chronic salpingitis. DESIGN: Retrospective case-control study. SETTING: Academic tertiary institution. PATIENT(S): Women with a pathological diagnosis of chronic salpingitis or normal fallopian tube hospitalized between September 1992 and November 1994. Initial identification of 248 specimens with final analysis of 154. INTERVENTION(S): Paraffin-embedded fallopian tube tissues were analyzed with use of PCR to detect C. trachomatis. MAIN OUTCOME MEASURE(S): Identification of C. trachomatis DNA; demographics of age, ethnicity, parity, history of sexually transmitted disease, and surgical procedure. RESULT(S): C. trachomatis DNA was detected in 9 of 77 chronic salpingitis cases. Seventy-seven controls were negative for C. trachomatis. No statistically significant difference in age or ethnicity between cases and controls was identified. Nulliparity was more frequent in cases (26 of 74) than controls (14 of 76). Sexually transmitted disease history was more prevalent in cases (24 of 74) than controls (6 of 76). Chlamydia infection was not associated with a particular surgical indication. CONCLUSION(S): Chronic salpingitis is highly associated with the presence of C. trachomatis infection as detected by PCR.

Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators.

BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category. METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential." RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%. CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."