Basic fibroblast growth factor and receptor expression in human ovarian cancer.

Basic fibroblast growth factor (bFGF) and other members of the FGF family share several biological properties that have the potential to mediate neoplastic cell growth. To test the hypothesis that bFGF may play a role in human ovarian cancer cell growth, three ovarian cancer cell lines, A90, A121(P), and A121(A), were investigated for their ability to respond to bFGF as a mitogen, to express endogenous bFGF protein or message for FGF proteins, and to exhibit FGF receptor or its message. Addition of bFGF to cultures of all three cell lines maintained in chemically defined media resulted in a statistically significant increase in cell number. Cell extracts from A90, A121(P), and A121(A) contained an immunoreactive protein that comigrated with hr-bFGF by Western blot analysis. Several bands of higher molecular weight were also noted. Immunohistochemical staining for bFGF demonstrated a cytoplasmic distribution of bFGF in the three cell lines. Both high- and low-affinity binding sites for human recombinant bFGF (hr-bFGF) were expressed by all three lines. High-affinity sites varied from 2700 sites per cell (Kd = 29 pM) to 13,500 sites per cell (Kd = 71 pM). All three cell lines were screened for mRNA expression for seven FGF proteins and four FGF receptors. In all three lines, mRNA for FGF2 (bFGF) was detected by PCR analysis, and in two lines, mRNA for FGF1 (aFGF) and FGF5 were also found. The FGFR1 receptor subtype (flg) was common to all of the cell lines. Finally, suramin inhibited proliferation of A90 and A121 (P and A) with IC50's of 60 and 210 micrograms/ml, respectively. This is consistent with the A90 cell line having higher levels of endogenous bFGF and flg and therefore being more responsive to suramin inhibition than the A121 cell line. The results indicate that these ovarian cancer cell lines can produce bFGF as well as other members of the FGF family of genes and have the ability to respond to bFGF.

Three related near-haploid clones in a primary endometrioid carcinoma of the ovary.

We report the cytogenetic findings in a primary endometrioid carcinoma of the ovary from a 29-year-old woman. Three clones with counts of 30, 29, and 27 chromosomes were observed. The predominant clone had 29 chromosomes and the following karyotype: 29, X, -X, -3, -3, +der(3)ins(3;?) (q21;?), -4, -5, -6, -8, -9, -11, -13, -14, -15, -16, -17, -18, -19, -21, -22, +mar. The clone with 30 chromosomes had an additional marker in the form of a minute chromosome, and the clone with 27 chromosomes was monosomic for chromosomes 12 and 20 also. Interestingly, there was no nullisomy of any of the chromosomes.

Characterization of human ovarian and endometrial carcinoma cell lines established on extracellular matrix.

Six cell lines were established from four patients with advanced carcinoma of the ovary and from one patient with carcinoma of the endometrium. These lines were established from fresh tumor material maintained initially on culture dishes coated with an extracellular matrix (ECM) produced by bovine corneal endothelial cells. Two of the six lines continue to require ECM as a substrate for optimal growth while the remaining four lines will proliferate on ECM or plastic substrate. Four cell lines transplanted into athymic nude mice were tumorigenic and maintained histologic and karyotypic similarities between the patient's original tumor, the cell line, and the transplantable tumor. Furthermore, in vitro degradation of ECM was grossly apparent by those cell lines which formed nude mice xenografts. Tumor cells were characterized by cytology, transmission electron microscopy, karyology, substrate requirements, steroid binding protein analysis, and morphological appearance in culture.

Borderline epithelial tumors of the ovary: ovarian intraepithelial neoplasia.

Although the concept of low malignant potential and/or borderline malignancy of some epithelial ovarian tumors was endorsed by the World Health Organization in 1973, uncertainty exists regarding the biologic behavior aspects of these lesions and this may account for the discrepancy in the 5-year survival figures reported for patients afflicted with these malignancies (76-95 per cent). We have reviewed the clinicopathologic aspects of 26 cases of borderline epithelial ovarian tumors and searched the literature. Based on our analysis, we have concluded that: 1) rupture of the cyst at surgery did not affect the patient's outcome but positive peritoneal fluid cytology did. 2) The term borderline should be replaced by ovarian intraepithelial neoplasia or preinvasive carcinoma and should solely be used in patients with stage I disease. 3) There is no justification for adjuvant therapy in adequately staged and surgically treated stage Ia and Ib disease. 4) Patients with stage II or more disease and those with positive peritoneal fluid cytology should be treated as aggressively as all other invasive, well-differentiated, epithelial ovarian tumors. 5) Our observation in cases of epithelial ovarian tumor cells grown on an extracellular matrix tends to indicate that parameters other than morphology may aid in assessing the invasive potential of these malignancies.

Primary fallopian tube carcinoma: treatment and spread pattern.

The clinicopathologic aspects of seven cases of Fallopian tube adenocarcinoma are analyzed. Potential early spread of this malignancy to the retroperitoneal lymph nodes and right subdiaphragmatic area is documented. Multimodality treatment of tubal cancer to include surgery, radiation, and drug therapy (alkylating agents, progestins, with or without 5-fluorouracil and adriamycin) appears feasible and promising.

Effective multimodality treatment of epithelial ovarian tumors.

Forty patients with epithelial ovarian tumors underwent cyto-reductive surgery followed by a five drug (Adriamycin, D.D.P., 5FU, M.T.X. and C.T.X.) combination chemo and progestin therapy. They all had an initial complete clinical response and 58% were complete histologic responders. One patient developed reactivated disease six months after a negative second look laparotomy. Two of four fatal outcomes were due to development of mixed mesodermal tumors in patients who originally had serous cystadenocarcinomas. We conclude that this regimen is highly effective, independent of residual tumor size, histologic grade of tumor and prior therapy. Its attendant toxicity is acceptably low.

Borderline malignant serous tumors of the ovary maintained on extracellular matrix: evidence for clonal evolution and invasive potential.

Four cases of advanced stage (II or III) and one case of early stage (IC) borderline malignant serous cystadenocarcinomas of the ovary were maintained on culture dishes coated with an extracellular matrix (ECM) produced by bovine corneal endothelial cells. Cells harvested for chromosomal analysis after 2-3 days showed diploid or near-diploid modalities in all cases. Banded chromosome studies in two cases revealed nonrandom clonal abnormalities with trisomy 2, 7, and 12 in seven of 13 metaphases. No structural abnormalities were noted. These cytogenetic findings differ from those found in malignant serous tumors of the ovary. In addition, borderline tumor cells digested the ECM in all cases and formed a cribiform pattern within a few days of primary culture. This study suggests clonal progression from early to advanced stages of borderline malignant serous tumors; readily distinguishable from overtly malignant serous tumors of the ovary. Ability of tumor cells derived from both primary tumors and metastatic implants to digest the ECM implies the possibility that borderline serous tumors have invasive potential.

Extracellular matrix-coated culture dishes: an in vitro model for primary human gynecologic tumors.

Culture dishes coated with an extracellular matrix (ECM) produced by bovine corneal endothelial cells were utilized to investigate human gynecologic carcinomas of epithelial origin. A high culture success rate was achieved for both solid tumor (83%) and ascitic fluid (75%) derived from specimens from 59 patients. Because of the high percentage of tumor cells attaching to the ECM and actively proliferating, a variety of in vitro studies (karyotypic analysis, morphologic appearance on ECM, and ability to digest the ECM) could be done. A preliminary in vitro profile of the various tumor cell types could be made on the basis of these studies. In addition, five long-term cultures were established utilizing the ECM model system.

Association of actinomyces and intrauterine contraceptive devices.

We analyzed the clinicopathologic aspects of 19 cases of actinomycosis associated with intrauterine devices (IUDs) seen and treated at hospitals affiliated with the State University of New York at Buffalo between 1972 and 1982. Clinical manifestations included the following: (1) asymptomatic IUD-associated Actinomyces colonization, (2) endocervicitis, (3) endometritis, (4) endometritis with salpingitis and/or tuboovarian abscesses and (5) abdominopelvic abscesses. No consistent relationship was found between the total peripheral lymphocyte count and/or degree of histologic lymphocytic reaction and the clinical picture. Abnormal uterine bleeding and/or discharge, pain, fever and abdominopelvic masses were among the symptoms and signs encountered. Patients with endocervicitis and/or endometritis responded to removal of the IUD, dilatation and curettage and antibiotic therapy for two to four weeks. Those who developed abscesses were treated successfully with surgical drainage and added antibiotic treatment.

Clear cell ovarian adenocarcinoma.

A retrospective analysis of the clinico-pathologic aspects of 22 cases of clear cell ovarian carcinoma with a literature survey is the subject of this report. The rarity of these neoplasms below the age of 40 is reaffirmed. Tumor-related hypercalcemia was observed in two patients and postoperative thromboembolic complications were encountered in three others. Electron microscopic examination revealed abundant cytoplasmic glycogen content in two cases. Ten patients in this group and 26% in reported series had coexistent endometriosis. Association with endometrial carcinoma was observed in two patients and was reported in 14% of the cases. No patient of ours with Stage III or IV disease survived 5 years or longer and only 8% have reportedly survived in collective series. There was suggestive evidence of radiation tumor response in two patients with Stage IIC disease who had received 5,000 rads pelvic radiotherapy. Objective partial responses were also observed with adriamycin-, cytoxan-, and cis-platinum-containing combinations. A management plan is outlined.

Treatment of advanced invasive cervical cancer: changing times and trends.

A retrospective analysis of the treatment results and complications in 140 patients with advanced (Stage IIB or more) invasive cervical cancer treated at the Albert Einstein College of Medicine (AECOM) from 1962-1970 and the State University of New York at Buffalo (SUNYAB) from 1974-1982 is the subject of this report. All patients were clinically staged and received external pelvic radiotherapy followed by one to two intracavitary radium insertions, and those with histologically proven positive para-aortic nodes received on additional 4,500 to 5,000 rads to the para-aortic areas. Forty-four patients had pretherapy surgical staging (26 transperitoneal, 18 extraperitoneal). In the clinical staging group, a survival time of 5 years or longer was attained in 22 of 39 patients (56%); with Stage IIB, 11 of 30 patients (37%) with Stage IIIA, two of 13 patients with Stage IIIB and two of 12 patients with Stage IVA disease. Of 26 patients staged via transperitoneal approach, two survived more than 5 years and three others were alive at last contact (after more than 3 years follow-up). The last 18 patients have been subjected to laparoscopy and retroperitoneal pelvic and para-aortic node biopsies followed by tailored radiotherapy with [12] or without [6] chemotherapy. Chemotherapy consisted of alternating weekly courses of vincristine and bleomycin and hydroxyurea. Mitomycin-C was added to this regimen at the conclusion of the course of radiotherapy. Only one patient developed a vesicovaginal fistula. At last contact, seven patients in the combined therapy group were alive and free of disease. Combined therapy following extraperitoneal surgical staging appears to be feasible and justifiable. It deserves further trials in larger series.

Microinvasive squamous carcinoma of the vulva.

The clinico-pathologic aspects of 15 cases of microinvasive squamous cell carcinoma of the vulva are analyzed and the literature on this subject is reviewed. Three patients in this group and 12.5% of the 279 reported cases, all with 5 mm or less depth of invasion, have had lymph node metastases and/or recurrences or have ultimately died of their disease. The prognostic value of lymphatic/vascular permeation, the degree of cellular anaplasia, the pattern as well as the depth of invasion, all have been alluded to, and the latter is popularized. It is noted, however, that the arbitrarily chosen 3 or 5 mm depth of invasion alone does not allow for consistent identification of individuals with a negligible risk for groin lymph node metastasis. There is indeed documentation of nodal metastases in 20 of 178 (11%) of the reported cases with 1-3.5 mm invasion. It is suggested that the level of invasion, as determined by Clark's classification, which provides a histologic reference point, may correlate better with the incidence of groin nodal metastasis, and its use may allow for individualized therapy and eventually aid in identifying cases of microinvasive carcinoma of the vulva that could safely be treated without lymphadenectomy.

Human ovarian carcinoma cells maintained on extracellular matrix versus plastic.

The ability of culture dishes coated with an extracellular matrix (ECM) to act as a suitable substrate for human ovarian carcinoma cells in vitro has been examined. The plating efficiency on ECM was 30 to 80% (dispersed tumor cells from solid tumor tissue and effusions) with active proliferation of tumor cells being observed. Within a few min, ovarian carcinoma cells seeded on an ECM were noted to attach firmly and assume a flattened morphology. In addition, ovarian carcinoma cells maintained on ECM-coated dishes could be released easily via trypsinization or with a cell scraper. This is in marked contradistinction to tumor cells seeded onto plastic dishes without an ECM. Invasion through the ECM by tumor cells from solid tumor tissue was occasionally noted. Nonmalignant cells were removed from dispersed tumor cell preparations by preplating on plastic culture dishes without an ECM. The malignant origin of the tumor cells was confirmed by morphological, histochemical, and cytogenetic criteria. This culture system represents a significant improvement over current methods for routinely culturing human ovarian carcinoma cells. Such a model may be utilized for screening anticancer drugs for their ability to inhibit proliferation of human ovarian carcinoma cells from individual patients. This system also may be useful for elucidating mechanisms of ovarian tumor cell attachment and invasion in the process of metastasis.

Self-retaining ureteral stent catheters in the management of urologic complications of gynecologic malignancies.

Fifteen patients with ureteral obstruction secondary to advanced and/or recurrent gynecologic malignancies underwent endoscopic (3) or surgical transvesical (12) insertion of Gibbons (12) or Double "J" (3) stent catheters. Renal function improvement was noted in all but one patient who had renal parenchymal disease. No complication attributable to the insertion procedure was recorded. This approach to the treatment of ureteral occlusion in patients with gynecologic cancer is discussed and recommended.

Cervical intra-epithelial neoplasia in pregnancy.

A retrospective analysis of 110 cases of suspected cervical intra-epithelial neoplasia (CIN) associated with pregnancy seen at the State University of New York at Buffalo (SUNYAB) affiliated hospitals is the subject of this report. One hundred anf five patients had abnormal cytology and five had negative pap smears. The majority of patients (60%) were in their twenties, and 24% were primigravidas. Colposcopic examination with or without directed biopsy eliminated the need for conization in 104 of 107 patients. Only two patients had to have cone biopsy and one had a modified conization after colposcopically directed biopsies. Varying degrees of cervical intra-epithelial neoplasia (Grades I-III) were diagnosed in 55 cases. One patient had therapeutic conization and two with a poor follow-up history had cesarean section hysterectomies. Post pregnancy regression of CIN was documented in 20 cases and persistence in 19 cases. The literature is surveyed and the management of CIN in pregnancy is discussed.

Benign glandular elements and decidual reaction in retroperitoneal lymph nodes.

Among 70 patients with gynecologic malignancies who underwent surgical staging and pelvic and periaortic lymphadenectomy, five were found to have benign glandular and/or stromal elements in the retroperitoneal lymph nodes. In three instances, these were originally diagnosed as metastatic cancer. The literature on this subject is reviewed and its significance is discussed.

DES story: review and report.

PIP: The clinicopathologic findings in 217 patients believed to have been exposed in utero to diethylstilbestrol (DES) were examined. Patient histories and physical findings, reports of gross and colposcopic examinations, and cytologic and pathologic diagnoses were recorded. The pathology slides were reviewed by a gynecologist and a pathologist, and an attempt was make to determine the incidence of cervicovaginal intraepithelial neoplasia. Of 182 patients with a history of in utero drug exposure, DES was believed to have been the agent in 180 cases. Maternal drug intake was suspected but not documented in 35 instances. The majority of the patients were between the ages of 20 and 29. No gross abnormality was noted in 27 cases, and the only abnormal finding in an additional 64 patients was cervical erythroplakia (clinical erosion). Class 1 Papanicolaou smear findings were reported in 172 patients, class 2 in 42 patients, and class 3 in 3 patients. The presence of vaginal adenosis with or without squamous metaplasia was histologically confirmed in 30 cases (14%). 7 patients had hysterosalpingograms, and 3 were reported as having a hypoplastic (infantile) uterus. In sum, the analysis reaffirms the contention that typical and atypical squamous metaplasia in DES-exposed daughters could be mistaken for dysplasia.^ieng

Gastrointestinal tract complications following radiotherapy of uterine cervical cancer: past and present.

A retrospective analysis of the gastrointestinal tract complications in 298 patients with cervical cancer treated with radiotherapy at the State University of New York at Buffalo and Albert Einstein College of Medicine affiliated hospitals was carried out. Fifty-two patients had pretreatment surgical staging (39 transperitoneal and 13 extraperitoneal). Twenty-four percent had varying degrees of radiation sickness. They all responded to conservative therapy. Seven percent developed Stage I radiation proctitis. In the clinical staging group late complications consisted of: Three small bowel injuries, 4% persistent Stage I, 3% Stage III, and one patient with Stage II radiation proctitis. Among 39 patients who had transperitoneal surgical staging, two small bowel injuries, one case of gastric ulcer, and three cases of radiation proctitis were encountered. Only one of 13 patients who had extraperitoneal surgical staging developed intestino-vesico-vaginal fistula. A literature search was conducted, and prophylactic and therapeutic measures are discussed. The importance of careful selection of patients for radiotherapy and recognition of high risk clinical factors is reemphasized.

Cytologic screening for cancer of the uterine cervix. "The debate of 1980s".

A review of 2971 cytology specimens taken during 4725 college student clinic visits yielded only 14 abnormal Pap smears suggestive of mild to moderate dysplasia. Eight of these patients had colposcopic evaluation and seven had biopsy-proven dysplasia. These findings in a low-risk population along with the recent American Cancer Society's guidelines are discussed.