OBJECTIVE: This study reviews experience at Indiana University with recurrent squamous carcinoma of the vulva over an 18-year period from 1971 to 1989. The pattern of recurrence, time interval to recurrence, and efficacy of salvage therapy are evaluated in the context of the primary tumor. STUDY DESIGN: This is a retrospective study of 40 patients, 21 of whom underwent primary therapy for invasive squamous carcinoma of the vulva at Indiana University. RESULTS: Vulvar recurrences were observed in 17 patients (43%), the groin was involved in 12 (30%), whereas pelvic and distant recurrences were observed in 2 (5%) and 9 (22.5%) patients, respectively. Salvage surgery and/or radiotherapy were successful in 25 patients (62.5%) alive from 1 to 144 months (median 8 months) from secondary therapy. Survival after retreatment varied significantly by site of recurrence (p = 0.002), tumor grade (p = 0.009), and interval to recurrence (p<0.001). Best outcomes were in patients with initial stage I or II disease (International Federation of Gynecology and Obstetrics), grade 1 tumors, local failure, and interval to relapse of >16 months' duration. Two of 12 patients with groin recurrences were salvaged with surgery and radiotherapy. CONCLUSION: Long-term follow-up of patients with vulvar cancer and careful restaging at the time of recurrence are mandatory. Although local and nodal recurrences may be controlled with surgery and/or radiotherapy, regional recurrences are usually fatal.

OBJECTIVE: Our purpose was to determine if postoperative transfusion increases the risk of recurrence in patients who have undergone operation for squamous carcinoma of the vulva.STUDY DESIGN: Data from 154 patients with squamous carcinoma of the vulva treated at Indiana University Medical Center from 1974 through 1988 were retrospectively analyzed to determine the influence of postoperative transfusion on recurrence risk. Patients were evaluated for International Federation of Gynecology and Obstetrics stage, lesion size, lesion depth, grade, patient age, number of transfusions, and recurrence with chi2 analysis, Fisher's exact test. and the Student t test where appropriate.RESULTS: Transfusions were given to 57 patients (37%) with a mean of 2.2 units delivered (range 1 to 5 units). Transfused patients differed significantly from those not transfused in that they had more advanced stage (p = 0.002), more positive nodes (p = 0.03), and higher grade lesions (p = 0.03), and they were older (p = 0.005). Recurrences developed in 25 patients (16.2%). Recurrences were more common in those with positive nodes (10-39, 25.6%) than in those with negative nodes (8/99, 8%), (p = 0.01). Only nodal status was predictive of recurrence in this series. Transfused patients had a 14% (8/57) rate of recurrence, whereas the recurrence risk was 17.5% (17/97) in those not transfused (p = 0.65).CONCLUSIONS: We have been unable to confirm that postoperative transfusions increase the risk of recurrence in patients with squamous carcinoma of the vulva.

Cancer cells have an increased ability to synthesize GTP (guanosine triphosphate) because of increased activity of IMP DH (inosine 5'-phosphate dehydrogenase, EC 1.1.1.205). Because IMP DH activity is rate limiting for de novo biosynthesis of GTP, this enzyme was suggested as a sensitive target for chemotherapy. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted in the cells into the active metabolite, TAD, (thiazole-4-carboxamide adenine dinucleotide) which potently inhibits IMP DH activity. By adding TAD to tissue extracts one can determine the extent of inhibition of IMP DH. We applied the IMP DH assay method to extracts of normal ovaries (N = 11) and epithelial ovarian carcinomas (N = 10). The IMP DH activity (mean +/- SE) in ovarian carcinoma was 21.1 +/- 5.8 which was markedly higher than that observed in normal ovaries (2.9 +/- 0.7 nmol/hr/mg protein) (P < 0.05%). The inhibition by TAD of IMP DH activity in ovarian carcinomas (N = 4) was 81%. The results indicate that IMP DH activity is elevated sevenfold in ovarian carcinomas as compared to normal ovary and can be inhibited by exposure to tiazofurin (TAD). Similar high IMP DH activity and inhibition of the activity by TAD was observed in patients with chronic granulocytic leukemia in blast crisis among whom 70 to 80% remissions were reported. Since there is increased IMP DH activity in human ovarian carcinomas and in OVCAR-5 cells and tiazofurin and TAD inhibit IMP DH activity of these cells and the proliferation of human ovarian carcinoma xenografts in the mouse, tiazofurin may merit serious consideration for a Phase II trial for patients with recurrent/refractory epithelial ovarian carcinoma.

From January 1974 to March 1988, 150 patients with primary invasive squamous cell carcinoma of the vulva underwent surgery at Indiana University. There has been a trend toward more conservative surgical management of this disease. To determine the impact of this trend on clinical outcome, cases were divided into three groups according to date of operation: group I, 1974 to 1978; group II, 1979 to 1983; and group III, 1984 to 1988. Overall, 80 patients had en bloc radical vulvectomy and groin dissection, 20 had modified radical vulvectomy and bilateral groin dissection through three separate incisions, and 36 had modified radical vulvectomy and unilateral superficial groin dissection. Fourteen patients had other operations. Forty-two patients (27.3%) had radiotherapy in addition to surgery. Among the three groups, there were no differences when mean age, International Federation of Gynecology and Obstetrics stage distribution (1988 system), mean lesion size, mean depth of invasion, or grade distribution were compared. A significant trend toward more conservative surgical therapy was observed. En bloc radical vulvectomy was performed in 77.4% of group I patients, 71.1% of group II patients, and 35.8% of group III patients (p less than 0.001). Mean days of hospitalization were also reduced significantly. Group I had a mean stay of 30 days, group II had a mean stay of 23 days, and group III had a mean stay of 11 days (p less than 0.001). Mean operative blood loss (group I, 754.8 ml; group II, 620.0 ml; group III, 393.6 ml; p = 0.03), mean units of blood transfused (group I, 1.4 units; group II, 1.3 units; group III, 0.4 units; p less than 0.01), and mean hours of operating time (group I, 3.7 hours; group II, 3.7 hours; group III, 3.2 hours; p = 0.02) were also reduced.

Age, clinical stage, histologic grade, depth of myometrial penetration, adnexal status, peritoneal cytology, and progesterone and estrogen receptor status were available for 139 patients with clinical stage IA, IB, or II endometrial adenocarcinoma who had therapy at Indiana University Hospital or St. Vincent Hospital in Indianapolis. These features were analyzed for their association with survival and disease-free survival. Patients treated at Indiana University Hospital were similar to those from St. Vincent Hospital when comparisons were made by chi 2 test for age, clinical stage, grade, adnexal metastases, peritoneal cytologic results, progesterone receptor status, or estrogen receptor status. However, patients treated at Indiana University Hospital had lesions that were deeper (p = 0.03) than those treated at St. Vincent Hospital. Survival differences were observed for patients with progesterone receptor-rich versus progesterone receptor-poor tumors (p = 0.004), grades 1 and 2 versus grade 3 lesions (p = 0.013), and malignant versus benign peritoneal cytologic results (p = 0.01). Differences in disease-free survival were observed for those patients with adnexal metastases versus those with no adnexal disease (p = 0.002), those with estrogen receptor-rich versus estrogen receptor-poor tumors, outer third myometrial invasion (p = 0.002), and patients with clinical stage I versus clinical stage II disease (p = 0.03). A stepwise Cox proportional hazards model was constructed to determine correlates of disease-free survival. In the final model, grade (p = 0.0002), peritoneal cytologic results (p = 0.0002), progesterone receptor status (p = 0.004), and age as a continuous variable (p = 0.008) were most closely associated with disease-free survival.

Fifty-six patients were randomly assigned to receive either one-day cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy (PAC-I) or five-day PAC (PAC-V) for advanced epithelial ovarian carcinoma. Follow-up has been 120+ months or to death. Ninety-one percent had either suboptimal stage III or stage IV disease and 55% had grade 2 or 3 lesions. Two patients died of toxicity and were free of disease at autopsy. A third patient died of congestive heart failure with no disease at 103 months. Additionally, eight patients had a negative second-look laparotomy, and three (37.5%) are alive with no evidence of disease (NED) 133 to 144 months after diagnosis. Five patients (62.5%) died of disease 2 to 123 months after negative second-look. Patients with optimal stage III disease had a longer median progression-free interval (PFI) and survival (33.3 and 44.5 months, respectively) than those with suboptimal or stage IV disease (16.4 and 22.5 months, respectively), and the difference in median PFI is significant (P less than .02). Patients with ascites at diagnosis had a shorter median PFI and survival (14.7 and 18 months) than those without ascites (30.0 and 33.0 months). Both differences were significant (PFI, P less than .04; survival, P = .005). PAC produces response rates that are superior to those obtained historically with single-agent alkylating therapy. Late recurrences after negative second-look laparotomy suggest that 5-year survival data may be inadequate in ovarian carcinoma.

When a 32-year-old woman was first seen, physical findings suggested she had a large levator hernia, but at the time of surgical resection an aggressive angiomyxoma was found.

Hydatidiform mole will progress to malignant gestational trophoblastic neoplasia (GTN) in some cases. Aneuploidy and high proliferative activity are associated with malignant tumors. Molar pregnancy tissue was considered a precursor to malignant GTN, and was studied retrospectively using paraffin-embedded tissue to determine whether aneuploidy or proliferative rates measured on molar tissue could predict a malignant course. Tissues from 51 complete hydatidiform moles were analyzed for nuclear DNA content by flow cytometric techniques. A chart review identified the clinical course after evacuation of the mole. A satisfactory DNA histogram was generated in 40 cases. Of the 40 patients, 22 (55%) had spontaneous resolution, and 18 patients (45%) required treatment for persistent GTN. The molar tissue was found to be euploid in 27 cases and aneuploid in 13 cases. Eight of the twenty-seven euploid cases (30%) required treatment after evacuation, whereas 10 of the 13 aneuploid cases (77%) required treatment after molar evacuation. Proliferative index (PI) was compared with treatment requirements. Average PI was 0.11 ±0.10 for the treatment group and 0.08 ± 0.06 for the spontaneous resolution group. The correlation of clinical course with ploidy was significant (P < 0.01). The association with proliferative index was not (P > 0.05). Aneuploidy, therefore, identifies a high-risk group of molar pregnancies, and may represent those that have undergone one stage of malignant transformation.

Eaton-Lambert or myasthenic syndrome was diagnosed in a young woman with recurrent small-cell carcinoma of the cervix. Therapy with vincristine, doxorubicin, and cyclophosphamide resulted in a partial response of the tumor and marked improvement in neurologic symptoms. Diagnosis and treatment of this paraneoplastic syndrome are discussed.

Prior to undergoing second-look laparotomy, 57 patients with ovarian cancer were evaluated with computed axial tomography (CT). All patients were clinically free of disease following chemotherapy. At laparotomy, 25 patients had visible evidence of disease, 9 had microscopic disease only, and 23 were free of cancer. Tumor was correctly identified on CT in 9 of the 25 patients (36%) with macroscopic disease. Tumors smaller than 2 cm in size were not detected by CT. CT suggested disease in 8 of the 32 patients (25%) who were free of macroscopic disease. CT provides useful information when it is abnormal. Fine needle aspiration of suspicious areas can spare some patients laparotomy. However, CT has a significant false-negative rate due to its inability to detect small volume disease. Patients with negative CT will continue to require reexploration and tissue confirmation to assess the need for further therapy.

From 1971-1986, peritoneal washings were obtained for cytologic examination at the time of primary exploratory laparotomy in 340 patients with endometrial adenocarcinoma. Seventy-two samples (21.2%) contained malignant cells. The finding of malignant cytology increased with stage of disease: stage I, 17%; stage II, 19.5%; stage III, 68.7%; and stage IV, 85.7% (P less than .001). In 248 patients with clinical stage I disease for whom uterine evaluation was complete, there was an increasing incidence of malignant cytology with increasing grade (P = .002), depth of myometrial invasion (P = .003), and adnexal spread (P less than .001). Twelve of 41 patients (29.3%) with clinical stage I and positive cytology developed recurrent disease, compared with six of 207 (2.9%) with negative cytology (P less than .001). Survival for all stages together was poorer in patients with positive washings than in those with negative washings (P less than .001). This difference in survival was also observed in patients with clinical stage I disease (P less than .001). Among patients with surgical stage I disease, disease-free survival was also superior in the group with negative cytology. In both clinical and surgical stage I, intra-abdominal recurrences were more common among patients with malignant peritoneal cytology.

Progesterone receptor content was measured in tissue samples from 175 patients with endometrial adenocarcinoma by use of the dextran-charcoal method. The estradiol receptor content was determined in 138 of these samples. Ninety-two tumors (52.6%) tested positive for progesterone receptors (greater than 50 fmol/mg cytosol protein) and 111 (80.4%) tested positive for estradiol receptors (greater than 6 fmol/mg). Median follow-up was 27.3 months (range 1 to 152 months). Progesterone receptor status correlated significantly with grade, histology, adnexal spread, age, and recurrence rate in stage I cancer. There was no correlation between progesterone receptor status and clinical stage, myometrial invasion, peritoneal cytology, retroperitoneal lymph node involvement, or spread to the cervix. Estradiol receptor status correlated with adnexal spread and recurrence rate. Recurrence in patients with stage I disease was significantly more common if tumors were negative for progesterone receptor (16 of 43, 37.2%) than if they were positive (four of 57, 7%; p less than 0.001). Recurrence was also more common if tumors were negative for estradiol receptor (seven of 17, 41.2%) than if they were positive (eight of 63, 12.7%; p = 0.02). In recurrent or advanced disease, response to progestin was independent of estradiol receptor content, but tumors positive for progesterone receptors responded significantly more often than those lacking progesterone receptors. Overall survival was superior for patients with progesterone receptor-positive tumors (p = 0.001). Although survival in clinical stages I and II was also superior in patients with lesions positive for progesterone receptors (p = 0.13), there was no statistical difference in survival between patients with progesterone receptor-positive or -negative cancers and surgical stages I and II disease (p = 0.12). Estradiol receptor status had no apparent correlation with survival.

The records of 23 patients with confirmed carcinoma of the fallopian tube, treated between 1966 and 1983, were reviewed. Patients ranged in age from 41 to 88 years. A pelvic mass was the most common preoperative finding (61%), followed by abnormal bleeding (43%), and pain (39%). Fifteen patients had stage I or II disease, 8 had Stage III or IV disease. In patients with metastatic disease, involvement of the peritoneal surfaces, bowel, and omentum were noted most often. Lymph nodes were the most common site(s) of recurrent disease. Twelve evaluable patients with measurable disease were treated with cisplatin and cyclophosphamide (PC) ± doxorubicin (PAC). There were 9 complete and 2 partial responses, a 92% response rate. Incorporation of cisplatin therapy appears to have resulted in improved short-term survival.

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue specimens from 51 patients with genital condyloma acuminata or invasive cervical or vulvar carcinomas were analyzed for the presence of human papillomavirus deoxyribonucleic acid (DNA) using the dot blot technique. Of ten condylomas, 80% contained DNA related to human papillomavirus 6 or 11. Sixty percent had evidence of DNA related to human papillomavirus 16, and 30% contained DNA related to human papillomavirus 18. Of 24 squamous cervical carcinomas, 58% had human papillomavirus type 16-related DNA, 33% had type 6- or 11-related DNA, and 4% had type 18-related DNA. Nine primary or recurrent vulvar carcinomas were analyzed. Seventy-eight percent contained human papillomavirus type 6- or 11-related DNA, 33% type 16-related DNA, and 22% type 18-related DNA. Whereas invasive cervical carcinomas predominantly contained DNA related to human papillomavirus 16 or 18, invasive vulvar carcinomas predominantly contained DNA related to types 6 or 11. Thus, human papillomavirus type alone cannot distinguish benign from malignant epithelial disease in the female genital tract.

In a review of 440 patients treated for endometrial adenocarcinoma at this center since 1974, 21 patients with tumors of papillary histology were identified. Eleven (2.5%) lesions contained histologic changes characteristic of uterine papillary serous carcinoma: complex papillary architecture, high nuclear/cytoplasmic ratio, and irregular epithelial tufting. Ten lesions (2.3%) containing areas of papillary morphology but lacking the criteria for the diagnosis of papillary serous tumors were termed papillary endometrioid adenocarcinoma. Patient age, stage, and the presence of obesity, hypertension, and diabetes were similar in both groups and reflected those characteristics well established for endometrial adenocarcinoma in general. Fewer papillary serous tumors (16.7%) and papillary endometrioid tumors (33.3%) contained progesterone receptors than did other adenocarcinomas (52.3%). In clinical stage I, surgical findings indicating a more advanced stage were present in 40% of patients with papillary serous tumors compared to 10% in papillary endometrioid tumors and 12.5% in nonpapillary adenocarcinomas (P = 0.03, Fisher's exact test). Recurrences were observed in 50% of patients with papillary serous lesions compared to 42.9% in papillary endometrioid lesions and 24.3% in other adenocarcinomas. Survival for clinical stage I papillary serous tumors was worse than that for nonpapillary grade 3 controls (P = 0.042) and survival for papillary endometrioid lesions was not different from that of the same controls. These findings support those of J. L. Chen, D. C. Trost, and E. J. Wilkinson (Int. J. Gynecol. Pathol.4, 279–288 (1985)) that papillary serous and papillary endometrioid adenocarcinomas represent two distinct subtypes of papillary endometrial neoplasia.

A randomized clinical trial was conducted in women with bulky (suboptimal) Stage III and Stage IV ovarian carcinoma, using doxorubicin (Adriamycin) and cyclophosphamide with or without cisplatin. There were 440 evaluable cases, of which 227 had measurable disease. One hundred twenty of these latter patients were treated with cyclophosphamide and doxorubicin (CA), while 107 received cyclophosphamide, doxorubicin and cisplatin (CAP). The clinical complete response (CR) rate for CA was 26% (31/120) compared with 51% (55/107) for CAP (P = less than 0.0001). Of 23 CRs receiving CA who had a second-look laparotomy, only four were negative; of 39 CRs receiving CAP and a second-look, 13 were negative (not statistically significant). The response duration for patients with measurable disease (median 14.6 versus 8.8 months), progression-free interval for all patients (13.1 versus 7.7 months), and survival for patients with measurable disease (19.7 versus 15.7 months) showed a statistically significant advantage for CAP; however, there was no difference in survival of patients with nonmeasurable disease. Toxicity was more severe with CAP but was tolerable. Thus, the addition of cisplatin improves the chemotherapy of advanced ovarian carcinoma.

TEN PATIENTS WITH OVARIAN CARCINOMA WHOSE TUMORS HAD PROGRESSED on first-trial chemotherapy were treated with cisplatin, vinblastine, and bleomycin (PVB) to determine the efficacy, dose range, and toxicity of this combination. Two dose levels of vinblastine were used. Objective responses occurred in 5/10 patients (3 CR, 2 PR), with a median response duration of 17.0 weeks. Toxicity was appreciable. One patient expired of bleomycin-induced pulmonary fibrosis. With the higher dose of vinblastine, four patients had grade III and three patients had grade IV hematologic toxicity At the lower dose, two patients had grade II and one patient had grade III hematologic toxicity. PVB has activity in second-trial therapy of ovarian carcinoma at the dose and schedule tested, but the role of this regimen in the future treatment of this disease remains to be determined.

After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.

A 66-year-old patient was treated with external radiation therapy for an advanced carcinoma of the vulva. Seven years later, a lymphangiosarcoma developed in her edematous lower extremity. Lymphangiosarcomas have been reported to occur in postmastectomy patients; however, this is only the third case in a patient with a gynecologic primary malignancy. In anticipation of possible increased use of radiation therapy in vulvar carcinoma, gynecologists should be aware of this rare, highly aggressive neoplasm.