The histogenesis of mixed cervical carcinomas. The concept of endocervical columnar-cell dysplasia.

In a case of cervical adenocarcinoma in situ, accompanied by relatively minor squamous-cell dysplasia, the neoplastic glandular cells were associated with "abnormal" but not clearly cancerous surface cells of the endocervix. Measurements of the nuclear DNA of these cells revealed an aneuploid pattern similar to that of epidermoid dysplasias. It is suggested that endocervical dysplasia is a valid entity and represents a step in the evolution of cervical adenocarcinoma from reserve cells comparable to the position of epidermoid dysplasia in the genesis of epidermoid carcinoma.

Endosalpingiosis.

Endosalpingiosis is defined as ectopic tubal epithelium and is considered homologous with endometriosis. In its usual form, the lesion is asymptomatic and has no serious prognostic associations. Recognition of endosalpingiosis, however, is important in avoiding overdiagnosis of disseminated lesions. The possibility of carcinoma--usually serous--arising primarily in a focus of endosalpingiosis is discussed.

p53 as a significant prognostic marker in endometrial carcinoma.

Although several studies have reported that p53 overexpression is associated with poor survival from endometrial cancer, this relationship might be confounded by a number of possible factors. The objective of this study was to examine the prognostic role of p53 overexpression in endometrial cancer when a panel of well-selected potential confounding factors were controlled. One hundred and twenty-five endometrial cancers were examined for p53 overexpression by immunohistochemistry (IHC). Demographic and clinical data, including age at diagnosis, race, residence, tumor grade, surgical stage, and other possible confounding factors for endometrial cancer such as diabetes, family history of cancer, hypertension, hormone replacement therapy (HRT), and obesity were collected from medical charts and pathologic reports. Survival status was determined at the end of follow-up. The Kaplan-Meier method was used to derive the survival curve, while the log-rank test was used to compare curves for two or more groups of patients. The proportional hazards regression model was used to obtain maximum likelihood estimates of relative risks (RR) and their 95% confidence intervals. Compared to the p53 nonaltered group, the presence of p53 overexpression in endometrial carcinoma was related to significantly decreased patient survival. High nuclear grade and high FIGO stage were associated with poor survival. No obvious association was found between survival and study site, race, age, and other potential risk factors of endometrial cancer. Only two variables (p53 and stage) were significantly associated with poor survival in the multivariate proportional hazards analysis. Overexpression of p53 was found to be the most significant predictor of specific survival. The relative risk for p53 overexpression was 7.46 (95% CI: 4.26-13.1) and for late stage was 4.35 (95% CI: 1.91-9.92). We conclude that p53 overexpression is the most important predictor for patient survival when a panel of well-selected potential confounding factors are taken into account. Patients with endometrial cancers who have p53 overexpression have a seven-fold higher risk of dying from disease compared to those without p53 overexpression. Whether detection of p53 alteration may serve as an indicator of high-risk patients for whom more aggressive adjuvant chemotherapy may be considered needs to be explored in the future.

Tubal (serous) carcinoma of the endometrium.

The logic of cancer histopathology demands that the presence of tubal epithelium in the endometrium be followed in some cases by the corresponding carcinoma. With tubal epithelium, this carcinoma is the homologue of the serous carcinomas of the ovary or the usually encountered carcinoma of the oviduct. A series of eight of these cases was studied. Many of the features were similar to those of ordinary endometrial carcinoma, but the prognosis was strikingly worse; many of the patients died of widespread metastases, with no or only minimal myometrial invasion.

Psammoma bodies in cervico-vaginal smears. Case report and review of the literature.

A case is reported in which psammoma bodies were present in a cervico-vaginal smear. No malignancy was found upon hysterectomy. Both this case and a review of the literature emphasize the non-specificity of psammoma bodies in the diagnosis of malignancies.

Cervicovaginal cytology in patients 16 years of age and younger.

A four-year survey of cervicovaginal cytology in 1,664 patients 16 years of age and younger showed 13 cases of dysplasia (0.78%). All were mild or moderate in degree. No cases of severe dysplasia, carcinoma in situ or invasive carcinoma were detected. Small numbers of cases of herpesvirus infection and of condyloma were also detected. The occurrence rate of trichomoniasis, however, was twice that normally seen in an adult population. The cytologic diagnosis of a low but significant number of cases of cervical dysplasia indicates a population whose continued surveillance by cytologic or other means is warranted. In this young population the detection of other sources of morbidity, such as trichomoniasis, offers an opportunity for beneficial medical intervention.

Non-invasive ovarian carcinoma.

The subset of ovarian epithelial tumors that is morphologically carcinoma, but has not yet shown any stromal invasion, is discussed. It is emphasized that metastasis is a function of invasive tumors, and that the spread of a noninvasive lesion cannot be explained by the usual concepts of metastasis. The multicentricity of peritoneal origin of ovarian epithelial tumors is a far more likely reason for morbidity and mortality, and is inescapable when the ovaries contain no lesion, when they contain a lesion that is noninvasive, or when the ovaries have been surgically removed.

The secondary müllerian system revisited.

The peritoneum is the matrix where benign and malignant proliferation of secondary müllerian epithelium occur. Endometriosis, endosalpingiosis, and endocervicosis are benign peritoneal neoplasms corresponding to endometrioid, serous, and mucinous carcinomas. These latter are concentrated predominantly, although not exclusively in the ovary, and reasons for this localization are discussed. Exposure to talc, or perhaps to the asbestos that often contaminates it, occurs in the process of powdering during infancy and may be the major initiating factor in benign and malignant disorders of the secondary müllerian system. It can be anticipated that the incidence both of endometriosis and of ovarian tumors will be reduced in those women powdered with starch instead of talc during infancy, as well as by the continued use of ovulation-suppressing agents such as contraceptive steroids.

Metaplasias and neoplasias of Müllerian epithelium.

The three primary epithelia of the Müllerian system are correlated with the three anatomic divisions of that system. Exceptions to normally expected associations and complicating factors including squamous epithelia and clear cells are discussed. A rationale for anticipating these anomalies is offered, and a plea is made for a diagnostic system which will accommodate both the cell type of Müllerian tumours and their anatomic location.

Benign and malignant serous and endometrioid epithelium in the omentum.

OBJECTIVES: Benign and malignant serous and endometrioid epithelial proliferations are found in the omentum, where their presence may be interpreted either as metastases from Müllerian tumors elsewhere or as primary peritoneal tumors. The present study was undertaken in an attempt to gather data that might help resolve the issue. METHODS: The ratios of serous epithelium to endometrioid epithelium in the omentum, in both the benign and malignant states, were determined for cases from January 1985 to July 1997 and January 1991 to December 1997, respectively. RESULTS: In ovarian carcinoma, the ratio of malignant serous epithelium to endometrioid epithelium involving the omentum is 15:1. This is comparable to the ratio of benign serous epithelium to endometrioid epithelium in the omentum, which is 10:1. The ratio of primary peritoneal serous carcinoma to endometrioid carcinoma is 10.5:1. CONCLUSION: It seems not reasonable that endometrioid carcinoma of the ovary is 15 times less likely to metastasize to the omentum than its serous counterpart. The ratio, however, is not unreasonable if endometrioid and serous carcinomas arise from preexisting endometrioid or serous epithelium. We conclude that serous and endometrioid carcinomas may arise primarily in the omentum and, in at least some cases, may derive from their benign counterparts.

p53 immunoreactivity in endometrial metaplasia with dysfunctional uterine bleeding.

AIM: Overexpression of p53 has been reported in endometrial carcinomas, especially in uterine papillary serous carcinoma (UPSC), to correlate with worse prognosis. Endometrial metaplasia is commonly encountered in patients with dysfunctional uterine bleeding (DUB) and may on occasion be difficult to distinguish from atypical endometrial hyperplasia or carcinoma on biopsies. The present study was initiated in the belief that metaplastic tissue might not show overexpression of p53 and would thus help to distinguish it from carcinomas of non-endometrioid histology. METHODS AND RESULTS: Paraffin-embedded tissue of endometrial biopsies with papillary metaplasia (22 cases), tubal metaplasia (five cases) and eosinophilic meta-plasia (seven cases) from patients with DUB were immunostained for p53 immunoreactivity. No evidence of hyperplasia was noted in any of the cases selected for the study. Twenty-eight cases of UPSC were included for comparison. Our study showed p53 overexpression in 25 of 28 (89%) UPSC. Weak and heterogeneous p53 immunoreactivity was present in 10 of 22 (45%) papillary metaplasias, four of five (80%) tubal metaplasias and four of seven (57%) eosinophilic metaplasias. Follow-up of 16-45 (median 32) months was unremarkable except for one patient with eosinophilic metaplasia who had simple endometrial hyperplasia in subsequent biopsy. CONCLUSIONS: The presence of weak and heterogeneous p53 immunoreactivity in metaplastic endometrium is unexpected and might be a consequence of DNA damage. Intense, diffuse and homogeneous p53 staining favours carcinoma.

Atypical squamous metaplastic cells: reproducibility, outcome, and diagnostic features on ThinPrep Pap test.

BACKGROUND: Atypical squamous metaplastic (ASM) cells are associated with high-grade squamous intraepithelial lesions (HGSIL) in many cases. The reproducibility of the diagnosis and biopsy follow-up results of cases designated as ASM were studied at Women and Infants' Hospital of Rhode Island. METHODS: Of 180 patients with ASM who the authors examined from January 1, 1998 to September 30, 1998, 147 (81.7%) had subsequent biopsies. Results of the biopsies were tallied. Twenty cases were rescreened in a blinded fashion to determine intra- and interobserver agreement and to identify diagnostic features. RESULTS: Sixty-five (44.2%) cases of ASM had HGSIL on biopsy, 26 (17.7%) had low-grade squamous intraepithelial lesion, and 56 cases (38.1%) were benign. Overall individual consistency is 8 of 16 (50%), and overall agreement is 13 of 64 (20%). CONCLUSIONS: Sixty-two percent of cases designated as ASM cytologically were associated with SIL, primarily HGSIL, at biopsies. The findings underscore the importance of this subcategory of atypical squamous cells. However, poor reproducibility suggests the need for refined criteria and/or continuing education, and obtaining second opinion. Cancer (Cancer Cytopathol)

Decreased luteinizing hormone receptor mRNA expression in human ovarian epithelial cancer.

OBJECTIVES: The objective of this study was to examine the distribution and cellular localization of luteinizing hormone receptor (LHR) in ovarian epithelial tumors (OETs) and their presumed precursor lesions-ovarian epithelial inclusions (OEIs). The clinicopathologic correlation of the receptor expression in OET was also examined. METHODS: Fifteen microdissected samples of ovarian surface epithelium (OSE), 20 OEIs from benign ovaries, and 141 OETs, including 48 cystadenomas, 33 borderline tumors, 60 carcinomas, and 5 metastatic cancers, were examined for LHR expression by using reverse transcription polymerase chain reaction and in situ hybridization. LHR expression in tumor epithelium and tumor stroma was analyzed separately. The clinicopathologic correlation data were analyzed by standard analysis of variance and contingency table methods. RESULTS: LHR expression was identified in the majority of OSE and OEI samples. In OETs, LHR positivity was found in the epithelial cells in 27% of cases and in the stromal compartment in 37% of cases. LHR-positive stromal cells were mainly luteinized cells. Within the tumor epithelium, LHR expression was detected in 42% of benign, 24% of borderline, and 17% of malignant OETs. LHR expression in tumor stroma showed a similar trend of reduction from benign to malignant OETs. Within the 17 carcinomas, LHR was expressed in the epithelium in 47% of grade 1, 12% of grade 2, and only 5% of grade 3 cancers. The mean age of the LHR-positive group was younger than that of the receptor-negative patients. Compared with mucinous and other types of OETs, serous OETs showed higher LHR expression in the epithelium. Compared with the OETs removed in the different menstrual phases, OETs in the secretory phase showed higher LHR in the tumor stroma than in the proliferative phase. No receptor mRNA was detected in the epithelium of five carcinomas metastatic to the ovary. LHR transcription splicing variants from a single previous report were confirmed in this study. CONCLUSIONS: Malignant OETs have significant reduction of LHR expression compared with precursor lesions and benign and borderline OETs. LHR expression shows a steady decline from low-grade to high-grade ovarian cancer. The presence of LHR receptor in tumor epithelium suggests that luteinizing hormone in serum may have direct influence on tumor growth, whereas the receptor in tumor stroma may be indicative of a paracrine function of LH in the development of OETs.

Alpha and beta subunits of inhibin/activin as sex cord-stromal differentiation markers.

Inhibins (alpha and beta heterodimers) and activins (beta homodimers) are related peptides with opposing biologic action on gonadotropin regulation. They serve as components of the pituitary-gonadal feedback system. Although sex-cord stromal tumors can usually be distinguished from ovarian epithelial tumors or their metastases by morphology or by using antibodies against intermediate filaments, the diagnosis remains difficult in rare situations in such cases as sarcomatoid granulosa-theca cell tumors, ovarian small cell carcinomas, or soft-tissue sarcomas. A total of 28 sex cord-stromal tumors of the ovary and 43 non-sex cord-stromal tumors were immunohistochemically evaluated for the presence of alpha and beta subunits of inhibin and activin. For comparison, 10 normal adult gonads including seven ovaries with hilar regions and three testes also were examined. Immunoreactivity for both alpha and beta subunits of inhibin/activin was identified in both non-neoplastic and neoplastic granulosa, Sertoli, Leydig, hilar and luteinized theca cells, with the strongest immunoreactivity in Leydig and hilar cells. One of three Sertoli-Leydig cell tumors that showed a sarcomatoid growth pattern and one sex-cord tumor with annular tubules also were immunoreactive for both subunits. For non-sex cord stromal-derived ovarian tumors, alpha subunit immunoreactivity was negative in all but two of five ovarian mucinous tumors. Weak immunoreactivity for beta subunit was found in most ovarian surface epithelial carcinomas, two of four colonic, and one of three pancreatic carcinomas. No immunostaining was found in nonspecialized gonadal stromal or interstitial cells, thecal cells, germ cells, ovarian small cell carcinomas, carcinoid tumors, dysgerminomas, or leiomyosarcomas. Immunostaining of alpha subunit (inhibin alpha), but not of beta subunit could serve as a sex cord-stromal differentiation marker because alpha subunit alone is largely confined to sex cord-stromal lesions with the exception of some ovarian mucinous tumors. Further studies are needed to define the usefulness of this sex cord-stromal differentiation marker in the practice of surgical pathology. Coexpression of alpha and beta subunits in sex cord-stromal elements suggests that dimeric inhibin is expressed in these cells.

Early occurrence and prognostic significance of p53 alteration in primary carcinoma of the fallopian tube.

The pathogenesis of primary carcinoma of the fallopian tube (PCFT) is poorly understood. Tumor suppressor p53 gene alterations are common in human malignancies, but their role in the tumorigenesis and survival of PCFT is undefined. The objectives of this study were to define the occurrence and prognostic role of p53 alteration in PCFT and to examine the efficiency of immunohistochemistry (IHC) in detecting p53 alteration in PCFT. Fifty-two PCFT and 10 normal fallopian tubes were examined for p53 alteration by IHC and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). The Kaplan-Meier method was used to derive the survival function, while the log-rank test was used to compare curves for two or more groups. Other patients' characteristics were analyzed by two-tailed Fisher's exact tests. IHC correlated well with PCR-SSCP with 100% sensitivity and 83.3% specificity for detecting p53 alteration in this study. Thirty-one of 52 (57%) PCFT showed p53 alteration. Alteration of p53 occurred in all stages of PCFT with a similar incidence in carcinoma in situ and late-stage disease. Alteration of p53 was related to tumor histologic type. Significant survival difference was noted between advanced and early clinical stages but no such difference was identified among different tumor grades. Compared to the p53-nonaltered group, the presence of p53 alteration in PCFT was related to significantly decreased patient survival (RR = 6.8, 95% CI = 2.9-16.2) in multivariate analysis. In the subgroup of patients with residual tumor after surgery, those with p53-altered tumors had a significantly decreased survival compared to those with p53-nonaltered group (RR = 7.4, 95% CI = 1.9-28.2). Alteration of p53 is common and IHC is an efficient method to detect p53 alteration in PCFT. Shorter survival is associated with p53 alteration which is an independent marker for the disease in this study. Alteration of p53 may be an early event in tubal tumorigenesis and may play an important role in the development of PCFT. Whether detection of p53 alteration may serve as an indicator of high-risk patients for whom more aggressive adjuvant chemotherapy may be considered needs to be explored in the future.

Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone.

OBJECTIVES: The role of gonadotropins in ovarian epithelial cancer development is still controversial. Follicle-stimulating hormone receptor (FSHR) status in ovarian epithelial tumors (OETs) and their presumed precursor lesions has never been studied in detail. The objective of this study was to examine whether FSHR is expressed in OETs and to investigate the possible different roles of the gonadotropins in ovarian cancer development. METHODS: Twenty ovarian epithelial inclusions (entrapments or invaginations of ovarian surface epithelium) from benign ovaries and 60 OETs including 12 cystadenomas, 18 borderline tumors, and 30 carcinomas were examined for FSHR expression by using reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization (ISH), and immunohistochemistry (IHC). We also studied the mitogenic activity of FSH on two FSH and luteinizing hormone (LH) receptor-positive ovarian epithelial carcinoma cell lines (AO and 3AO) and on the modifying effect of LH on this activity. Growth-stimulating effects of the gonadotropins were tested in vitro with measurement of cell numbers, S-phase by flow cytometry, and changes in the cellular proliferative marker Ki-67. RESULTS: Positive FSHR mRNA expression by RT-PCR (the most sensitive method) was found in 100% of epithelial inclusions, 100% of cystadenomas, 94% of borderline tumors, and 60% of carcinomas. There was a nonstatistically significant trend of decreasing positivity with increasing carcinoma grade. ISH and IHC gave similar, but somewhat less sensitive, results. A dose-response effect was seen with FSH, with a 1.6-fold increase in cell numbers with a maximally stimulating FSH concentration of 40 IU/L for a period of 48 h. These proliferative cellular effects were not observed when the cells were stimulated by LH in the range 1 to 100 IU/L. Most significantly, the growth stimulating effects of FSH could be blocked by the simultaneous administration of LH. CONCLUSIONS: FSHR is present in the majority of ovarian epithelial inclusions and OETs. The steady decline of FSHR expression from benign cystadenoma to borderline tumor to carcinoma suggests that FSH may be needed in early ovarian cancer development. Gonadotropins, FSH and LH, may have different roles in ovarian cancer cell proliferation. FSH, not LH, may be an important ovarian epithelial cell growth-promoting factor. The "opposing" effect of LH on FSH stimulation may explain why high FSH levels at postmenopausal ages are not associated with great increases in ovarian cancer risk.

Imbalanced expression of inhibin and activin subunits in primary epithelial ovarian cancer.

OBJECTIVES: Inhibins and activins are related gonadal peptides with opposing biologic actions on gonadotropin regulation, cell differentiation, and proliferation. The previous study of activin in ovarian cancer cell lines suggests that activin may promote growth of ovarian cancer. Elevated serum inhibin levels were also found in ovarian cancer patients; however, the source of elevated inhibin is unknown. This study is designed to examine the expression of inhibin and activin subunits as well as activin receptor in primary ovarian epithelial tumors to explore their role in the process of ovarian epithelial tumorigenesis. METHODS: The protein and mRNA expression of alpha and betaA subunits of inhibin/activin as well as of activin receptor mRNA were examined with immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) in 112 ovarian carcinomas. Cases included 59 serous, 23 endometrioid, 16 mucinous, 9 clear cell, and 5 undifferentiated carcinomas. We also tested normal ovary and benign and borderline ovarian tumors for comparison. These included 17 ovarian surface epithelial samples, 6 serous and 5 mucinous cystadenomas, and 9 serous and 7 mucinous tumors of low malignant potential. A total of 139 ovarian tumors were analyzed by IHC and a total of 63 ovarian tumor samples were tested by RT-PCR. RESULTS: Inhibin alpha subunit expression was found in 47% of ovarian surface epithelia and focal alpha immunoreactivity was seen in tumor stroma, but was not found in the epithelial component of ovarian cystadenomas, tumors of low malignant potential (LMP), or carcinomas. Activin betaA subunit was expressed in 93% of surface epithelia, in the epithelial component of all cystadenomas, in 81% of LMP tumors, and in 72% of carcinomas, but not in tumor stroma. Activin expression did not correlate with histologic grades, tumor types, and surgical stages. Activin receptor type I and II mRNA-amplified products were found in virtually all the surface epithelial samples and ovarian tumors. CONCLUSIONS: The data suggest that imbalanced expression of inhibin and activin subunits in ovarian surface epithelium may represent an early event which leads to epithelial proliferation. Unopposed betaA and activin receptor expression in epithelial compartment of ovarian tumors suggest that activin may be available as autocrine and/or paracrine factors in ovarian epithelial tumors. But exact roles of inhibin and activin in ovarian epithelial tumors remain to be defined.