Bone metastasis from gynecologic carcinomas: a clinicopathologic study.

Between 1948 and 1984, autopsies were performed on 305 patients with primary carcinomas of the cervix, endometrium, ovaries, fallopian tubes, vulva, and vagina. Skeletal metastases were detected premortem and at autopsy in 49 cases (16.1%): cervix, 20 (40.8%); endometrium, 17 (34.7%); ovary, 7 (14.3%); vulva, 4 (8.2%); fallopian tube, 1 (2%). There were no cases of osseous metastasis from vaginal carcinoma. The incidence and sites of metastasis from these gynecologic carcinomas were correlated with their clinical and histopathologic classifications. This clinicopathologic study, based on autopsy data, demonstrates that osseous metastases are not uncommon, are significantly greater than clinically appreciated, and correlate with advanced anatomic stage and histopathologic type and grade.

Induction of cervical neoplasia in the mouse by an extract of cells infected by varicella-zoster virus.

Since several human herpesviruses, including varicella-zoster virus (VZV), have been demonstrated to transform mammalian cells in vitro, VZV was tested in a mouse model of virus-induced cervical neoplasia to determine whether it is oncogenic in vivo. Herpes simplex viruses types 1 and 2 and cytomegalovirus have been previously shown to induce cervical neoplasia in this mouse model. VZV was propagated in WI-38 cell cultures and inactivated by ultraviolet irradiation. Control material was prepared in an identical manner from uninfected cell cultures. Cotton tampons, saturated with inactivated virus or control material, were inserted into the vaginas of C57BL mice three times a week for 60 weeks. Cervical dysplasia was detected in 40% and invasive carcinoma in 34% of virus-exposed mice by histological examination. No lesions were detected in control animals. These observations indicate that VZV, or some product of virus-infected cells, is oncogenic in vivo for the mouse cervix.

Induction of cervical neoplasia in the mouse by herpes simplex virus type 2 DNA.

Induction of cervical neoplasia in the mouse cervix by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) has been reported. The present study was done to determine if transfection with DNA of HSV-2 can induce carcinogenesis in this animal model. Genomic HSV-2 DNA was isolated from infected HEp-2 cells and separated from host cell DNA by cesium chloride density gradient centrifugation. The DNA was applied to mouse cervix for periods of 80-100 weeks. Experimental controls were treated with uninfected genomic HEp-2 cell DNA or with calf thymus DNA. Vaginal cytological preparations from all animals were examined monthly to detect epithelial abnormalities. Animals were sacrificed and histopathology studies were done when cellular changes indicative of premalignant or malignant lesions were seen on vaginal smears. Cytologic and histologic materials were coded and evaluated without knowledge of whether they were from animals treated with virus or control DNA. Premalignant and malignant cervical lesions similar to those that occur in women were detected in 61% of the histologic specimens obtained from animals exposed to HSV-2 DNA. The yield of invasive cancers was 21% in animals treated with HSV-2 DNA. No cancers were detected in mice treated with either HEp-2 or calf thymus DNA. Dysplasia was detected in only one of these control animals.

Roles of cytomegalovirus and Chlamydia trachomatis in the induction of cervical neoplasia in the mouse.

Cytomegalovirus and Chlamydia trachomatis are prevalent sexually transmissible pathogens. They produce persistent infections of the cervix and have been associated with cervical neoplasia. Cytomegalovirus has also been shown to induce transformation of cells in culture. Because of the high prevalence of genital infections with these pathogens and evidence that they may have oncogenic effects on the cervix, cytomegalovirus (strain AD-169) and C. trachomatis (serovar LGV-2) were tested for oncogenicity in a mouse model in which induction of cervical neoplasia by repeated exposure to inactivated herpes simplex viruses has been demonstrated previously. Cotton tampons, saturated with UV-inactivated cytomegalovirus, C. trachomatis, or corresponding control fluids, were inserted into the vaginas of virgin C57 mice 3 times a week. Smears of vaginal aspirates for cytological examination were obtained every 5 weeks. After 75-90 weeks of exposure, the mice were sacrificed and serial sections of their reproductive tracts were examined. Cervical dysplasia was detected by histological examination in 51% and cervical carcinoma in 10% of mice exposed to cytomegalovirus. In control mice, in contrast, dysplasia developed in 3% and carcinoma in none. The progression from normal cervical epithelium to dysplasia to carcinoma observed with cytomegalovirus exposure was similar to that observed previously in this model after exposure of mice to herpes simplex virus types 1 and 2. The frequencies of cervical abnormalities in mice exposed to C. trachomatis or corresponding control fluid were low, and differences between the two groups were not statistically significant. These data indicate that strain AD-169 of cytomegalovirus is oncogenic for the mouse cervix and suggest that the LGV-2 serovar of C. trachomatis is not.

Malignant placental site trophoblastic tumor.

Placental site trophoblastic tumor is a rare variant of trophoblastic disease. The malignant form of this disease with metastasis and death is even more infrequent, as is evident from only five cases in the literature. A 30-year-old black woman who died from this disease is presented. Patients with metastases are at extremely high risk with no reported survivors and must be treated aggressively with chemotherapy and cytoreductive surgery. This type of trophoblastic tumor apparently exhibits a different biologic behavior as compared with choriocarcinoma.

Progestin therapy in lesions of the endometrium.

This paper details several studies of the effect of a single progestin, megestrol acetate, in patients with persistent endometrial hyperplasia and recurrent or persistent endometrial adenocarcinoma. Results of these studies indicate that megestrol acetate inhibits recurrence of adenomatous and atypical hyperplasia as well as adenocarcinoma in situ. These diseases when left untreated often progress to invasive adenocarcinoma. Additional studies presented here show that megestrol acetate is effective in the treatment of endometrial adenocarcinoma in inoperable patients and increases survival in patients with recurrent endometrial cancer.

Effect of prior immunization on induction of cervial cancer in mice by herpes simplex virus type 2.

Previous studies at this laboratory showed that repeated application of inactivated herpes simplex virus type 2 to the mouse cevix produced premalignant and malignant lesions. In the present study mice were inoculated with inactivated herpes simplex virus type 2 or control solution and Freund's adjuvant by intraperitoneal and subcuaneous routes before exposure of the cervix to inactivated virus. It appears that immunization with inactivated virus conferred a protection against the induction of cervical carcinoma.

Morphometric study of intraepithelial neoplasia of the uterine cervix.

Treatment failure for intraepithelial neoplasia of the uterine cervix following electrocautery, cryosurgery, or carbon dioxide laser therapy is related primarily to incomplete eradication of the lesion. This may be due to the depth of crypt involvement, the linear extent, or the location of the abnormal epithelium. In view of this, the extent (depth and linear extent) and the location of cervical intraepithelial neoplasia (CIN) in 319 cervical cone specimens were analyzed. There is a significant correlation between the severity and the extent of the change. The mean depths of CIN I, II, and III were 0.42 +/- 0.28, 0.93 +/- 0.71, and 1.35 +/- 1.15 mm, respectively. The mean linear extents for CIN I, II, and III were 4.10 +/- 2.84, 5.84 +/- 4.13, and 7.60 +/- 4.32 mm, respectively. To eradicate 99.7% of CIN III lesions, it is necessary to destroy the tissue up to 4.80 mm in depth and of sufficient linear extent. While most lesions (87.2%) involved the transformation zone, 9.7% were higher in the cervical canal and 3.1% were located in the ectocervix. Appropriate cytologic samples, endocervical curettage, and colposcopic examination should be employed in evaluating the CIN, and strict criteria should be followed in selecting the patients for conservative management.

Adenocarcinoma and mixed carcinoma of the uterine cervix. I. A. clinicopathologic study.

Ninety-two primary glandular neoplasms of the uterine cervix, including 51 endocervical adenocarcinomas, four endometrioid carcinomas, and 37 mixed carcinomas, were reviewed to define the biologic significance of pathologic features. Pure adenocarcinomas were found to have a better prognosis from mixed carcinomas of comparable stage (overall five-year survival rate, 49 vs. 36%). Endocervical adenocarcinomas with glandular and papillary patterns had a better prognosis than mucinous adenocarcinomas. When mixed carcinomas were separated into mature, signet-ring, and glassy-cell types, patients with the glassy-cell type had a better five-year survival rate than patients with the other types. However, the long-term prognosis was equally poor. The degree of differentiation as determined by the nuclear features was useful in predicting the outcome in patients with adenocarcinomas. Although the number of cases was small, combined surgery and radiotherapy achieved the best long-term survival for patients with pure adenocarcinomas. This was less apparent for mixed carcinomas.

Induction of uterine cancer with inactivated herpes simplex virus, types 1 and 2.

A series of studies were performed to evaluate the oncogenic potential of inactivated herpes simplex viruses types 1 (HSV-1) and 2 (HSV-2) in the mouse cervix. HSV-1 or HSV-2 prepared in HEp-2 cell cultures and inactivated by exposure to formalin or ultraviolet light was applied to the mouse cervix for periods ranging from 20 to 90 weeks. Control mice were exposed for the same period to control fluids. Vaginal cytologic preparations from all animals were examined weekly to detect epithelial abnormalities. Animals were sacrificed and histopathological studies were carried out when cellular changes seen on vaginal smears resembled those indicative of premalignant or malignant changes as previously established in a similar model system using coal tar hydrocarbons. Other animals were exposed for periods up to 90 weeks, or until there was cellular evidence of invasive cancer. Cytologic and histologic materials were coded and evaluated without knowledge of whether they were from virus-exposed or control animals. Premalignant and malignant cervical lesions similar to those that occur in women were encountered in 78 to 90% of the virus-exposed animals. All controls were normal. Invasive cancer was detected in 24 to 60% of the animals and dysplasia was found in 18 to 66%. The yield of invasive cancer was twice as great after exposure to ultraviolet-inactivated HSV-2 as compared with formalin-inactivated virus. Various histologic grades of carcinoma of the cervix and endometrium were found. No primary lesions were found in the vagina or ovaries.

Nuclear DNA study of vulvar intraepithelial and invasive squamous neoplasms.

In this study, 59 vulvar intraepithelial squamous neoplasms (8 atypia and 51 carcinoma in situ) and 33 invasive squamous carcinomas were analyzed for their nuclear DNA content using Feulgen microspectrophotometry. Four cases of atypia had a polyploid DNA distribution. The remaining 4 cases of atypia and all cases of carcinoma in situ had an aneuploid pattern, and nearly two thirds of these had high ploidy stem cells (greater than 3N). This is in contrast to the low ploidy stem cells (less than 3N) seen in 70% of the invasive carcinomas and in 82% of the intraepithelial neoplasms in the vicinity of invasive carcinomas. This observation suggests that not all vulvar intraepithelial neoplasms have the same propensity to become invasive. Invasive carcinomas of comparable size and depth of invasion with low ploidy stem cells had a higher frequency of lymph node metastasis than those having high ploidy stem cells. The significance of nuclear DNA findings related to gynecologic neoplasms is discussed.

Primary adenosquamous carcinoma of the fallopian tube.

The first reported case of primary adenosquamous carcinoma of the fallopian tube is presented. Primary carcinoma of the fallopian tube and adenosquamous lesions of the endometrium and ovary are discussed. The aggressive potential and increasing frequency of adenosquamous carcinoma in the female genital tract are emphasized.

Significance of squamous components in endometrioid carcinoma of the ovary.

Forty-nine cases of ovarian endometrioid carcinoma with squamous foci were reviewed. Of particular interest was the biologic behavior of the neoplasms in relation to the appearance of the epithelium. As previously noted for the analogous uterine endometrial tumors, the ovarian adenosquamous lesions occurred later in life, were more advanced, were associated with less differentiated adenocarcinomatous components, and had a poorer prognosis. The five-year survival rate for patients with adenosquamous endometrioid ovarian carcinoma was 21% in comparison with the 90% survival found in patients with ovarian endometrioid adenocanthoma.

Cellular detection of vaginal adenosis.

Cellular samples obtained by vaginal scrapings from 204 women exposed to diethylstilbestrol (DES) in utero were evaluated and compared with samples collected from a like number of controls. Several different sampling methods were evaluated. Vaginal scrapings contained columnar cells existing alone or in combination with squamous metaplastic cells and less frequently were characterized only by metaplastic cells. None of the control samples contained columnar cells and only 1 of 200 control samples contained metaplastic cells. The cellular findings in the offspring of women exposed to DES in utero varied in relation to age. Cellular abnormalities were demonstrated in 90.4% of women having scrapings of visible lesions and in 88.1% of women studied by 4-quadrant vaginal scrapings in the absence of clinical disease. Of 58 women with histopathologically proven adenosis, 57 (98.3%) had similar cellular abnormalities. Abnormalities were demonstrated in squamous epithelial cells of the vagina in 8 (3.9%) of the women exposed to DES in utero, and in 5 of these women there were similar changes in the uterine cervix. Only 2 (0.9%) of the women had cellular changes suggesting dysplasia of the vagina.

Cervical carcinogenesis with herpes simplex virus, type 2.

In the past few years there have been a number of reports correlating a high frequency of herpes simplex virus type 2(HSV-2) infection with lesions of the uterine cervix. These studies have used a clinical history of herpetic infection or the demonstration of herpetic antibodies in the cancer patients. The present study was performed to evaluate any possible carcinogenic activity of the formalin-inoculated herpes simplex virus type 2 in the reproductive tract of the female mouse. This approach to the study was selected because of previous experience with a model system of carcinogenesis of the cervix uteri using coal tar hydrocarbons. Cytologic and histologic preparations from experimental animals and controls are presented to demonstrate the mucosal alterations and tumors observed in the animals. Noninvasive lesions of the cervix were identified in 76.8% and invasive adenocarcinoma detected in 30.2% of the mice.