Immunohistochemical evaluation is not prognostic for recurrence in fully staged high-risk endometrial cancer.

The objective of this study was to determine the prognostic significance of common immunohistochemical pathologic risk factors in fully staged high-risk endometrial cancers. Sixty-two of 265 consecutive endometrioid adenocarcinomas were considered high risk for recurrence because of deep myometrial invasion and poor differentiation (stage IC, G3), cervical metastasis (stage II), ovarian metastasis (stage IIIA) or lymph node metastasis (stage IIIC). All patients underwent complete surgical staging with bilateral pelvic and aortic lymphadenectomy. Expression of estrogen receptors, progesterone receptors, p53, HER-2/neu, c-myc, bcl-2, FVIII, and Ki-67 were analyzed by immunohistochemistry using commercially available monoclonal antibodies. A general linear model multiple regression analysis was used to determine if any of the immunostains, along with grade or stage, were predictors of recurrence. Mean age was 68 years and mean weight 188 pounds. Sixty-eight percent of patients had associated medical illness. The majority of tumors were poorly differentiated (44%) and were stage IIIC (29%). Mean follow-up was 4.3 years. Fourteen patients (22%) developed tumor recurrence. Using multiple regression analysis, none of the immunostains were predictive for recurrence (P = 0.19-.96). Only stage and grade were predictive of tumor recurrence (P = 0.04,.02). We conclude that in completely staged high risk endometrial cancer, commonly used immunohistochemical risk factors are not predictive for recurrence.

Cisplatin-paclitaxel-cyclophosphamide with G-CSF in primary advanced epithelial ovarian cancer.

INTRODUCTION: In an attempt to increase survival, we performed a prospective trial of high-dose cisplatin-paclitaxel-cyclophosphamide with granulocyte colony-stimulating factor (G-CSF) for three cycles followed by carboplatin-paclitaxel for three cycles after cytoreduction of primary advanced epithelial ovarian cancer. MATERIALS AND METHODS: Thirty consecutive women with Stage 3 or 4 invasive primary epithelial ovarian cancer were treated with cytoreductive surgery. Postoperatively patients received 100 mg/m(2) of cisplatin, 200 mg/m(2) of paclitaxel, and 500 mg/m(2) of cyclophosphamide IV q 21 days x 3 cycles with 300 microg of G-CSF daily x5 beginning the first day following chemotherapy. This was followed by carboplatin AUC-5 and 135 mg/m(2) of paclitaxel IV q 21 days x3. All administration was outpatient and paclitaxel was administered over 3 h. RESULTS: Eighty percent of tumors were Stage 3C, 77% were serous, and 60% were Grade 3. Maximum cytoreduction to <2 cm was performed in 96%. Median follow-up is 30 months. Sixty-three percent of patients developed recurrence. Currently 50% of patients are alive with no evidence of disease. Estimated mean survival is 61 months and estimated mean progression-free survival is 29 months. No patient developed thrombocytopenia, neutropenic sepsis, significant neuropathy, or renal toxicity. CONCLUSION: This treatment regimen resulted in minimal toxicity and, following aggressive cytoreduction, produced good progression-free and overall survival.

Prognostic characteristics of surgical stage I endometrial adenocarcinoma.

PURPOSE: To evaluate and correlate the expression of pathologic characteristics, flow cytometric DNA content analysis, and estrogen and progesterone receptor levels with survival in patients with surgical Stage I endometrial carcinoma. METHODS AND MATERIALS: Hospital tumor registry records were surveyed, and this identified 232 patients diagnosed with endometrial adenocarcinoma between July 1, 1989, and December 30, 1993. DNA content analysis was performed on either paraffin-embedded or fresh tissue samples. Survival was calculated from the date of diagnosis by the Kaplan-Meier method. Postoperative irradiation (whole pelvis external beam therapy and low dose rate vaginal cuff brachytherapy) was delivered to patients felt to be at high risk for failure. RESULTS: One hundred seventy-one patients had Stage I tumors and were available for analysis. Patients with Stage 1C tumors had a statistically significant lower survival rate compared to patients with Stages IA or IB (p = 0.03 and p < 0.01, respectively). Patients with DNA content diploid tumors had a slightly increased (but nonsignificantly so) survival compared to patients with non-DNA content diploid tumors (p = 0.12). Logistic regression analysis failed to identify an independent prognostic factor that could predict for disease specific survival in patients with Stage I cancers. CONCLUSION: Logistic regression analysis did not identify a single independent prognostic factor in patients with Stage I tumors. Pathologic characteristics reported to predict survival advantage correlated with pathologic stage. Additional translational research is needed to identify molecular characteristics of tumors that may indicate more aggressive treatment for patients at high risk for recurrence.

Clinicopathologic correlation of DNA flow cytometric content analysis (DFCA), surgical staging, and estrogen/progesterone receptor status in endometrial adenocarcinoma.

DNA flow cytometric content analysis (DFCA) and estrogen (ER) and progesterone (PR) receptor levels are reported to be prognostic with regard to the malignant potential of endometrial adenocarcinoma. We retrospectively reviewed the records of 50 patients presenting with endometrial adenocarcinoma between July 1990 and December 1992, to determine the extent of any pathologic features reported at the time of hysterectomy. Patients whose tumors were nondiploid (aneuploid) by flow cytometry generally presented with a higher pathologic stage, higher grade, and more frequent lymph node involvement. In addition, the majority of clear cell and uterine papillary serous (UPS) adenocarcinoma were also nondiploid. Fourteen of 21 ER-positive tumors aneuploid, as were 18 of 37 PR-positive tumors. We also found DNA-A (DNA content aneuploid) patterns frequently associated with tumor characteristics implicated by other authors as related to aggressiveness. Further studies comparing the molecular biology of tumors to their clinicopathologic features and behavior are needed to fully understand the ultimate malignant potential.

Flow cytometric DNA content analysis of paraffin-embedded tissue derived from cervical carcinoma.

PURPOSE: Flow cytometric deoxyribonucleic acid (DNA) content analysis has been shown to be of prognostic importance in some cancers. There have been recent reports of a prognostic importance for DNA content analysis in cervical carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the hospital and radiation oncology records of cervical carcinoma patients who presented between 1984-1990. RESULTS: A total of 101 archival paraffin-embedded blocks were processed, of which 77 were of technical quality for analysis. Thirty-five percent were found to be DNA content aneuploid (DNA-A) and 65% DNA content diploid (DNA-D). No statistical difference was found between the two groups in age at diagnosis, % S-phase, coefficient of variation (CV), or proliferative index (PI). A statistical difference was noted in the G2M phase between the two groups (p = 0.004). The median % S-phase was 8.4% in the DNA-D group. A statistical difference (p = 0.017) in survival was noted between the low and high % S-phase DNA-D groups. In patients who received radiation alone, high-PI patients had improved survival compared to low-PI patients. No statistical difference in survival was noted in the high % S-phase DNA-D group and DNA-A group (p = 0.28). Proportional Hazard (Cox) Regression found clinical stage the only independent prognostic indicator for survival. CONCLUSION: Flow cytometric DNA content analysis is being used more frequently in the management of different malignant tumors. Our study shows that DNA content analysis is useful in determining the prognosis and survival outcomes in cervical carcinomas and may aid in predicting outcome to certain types of treatment regimens.

The use of intraoperative electron beam radiation therapy in the treatment of para-aortic metastases from gynecologic tumors: a pilot study.

The abdomens of 16 patients with para-aortic nodal metastases were explored in the Clement O. Miniger Radiation Oncology Center's (COMROC) intraoperative radiation therapy suite. At the time of initial diagnosis 8 patients were found to have para-aortic metastases, and 8 developed para-aortic disease after completion of primary treatment. The median age of patients in the "initial group" was 37.5 years: 7 of these 8 patients had radiation only, and 1 patient had radiation and chemotherapy as initial treatment. Bulk disease in the para-aortic region was noted in 2 patients, microscopic disease in 5 patients, and prophylactic radiation was given to the para-aortic area in 1 patient. Ten para-aortic fields in 8 patients were treated with a median dose of 20 (range 10-25) Gy with 6-18 MeV electrons. Median survival from time of diagnosis was 31 (range 9-59) months and 27 (range 8-56) months from the date of IOEBRT. The median time to recurrence after IOEBRT was 8 (range 4-32) months. One patient is alive without disease 59 months and 1 is alive with disease 44 months from IOEBRT, with neither patient failing in the treated area. Eight patients were treated for recurrent disease in the para-aortic area: 5 cervical primaries, 2 endometrial adenocarcinoma primaries, and 1 uterine sarcoma. The median age was 60.5 (range 45-70) years. Median time to recurrence from initial diagnosis was 20 (range 7-37) months. In seven fields 6 of 8 patients received IOEBRT, median dose 20 (range 10-25) Gy. After IOEBRT, 4 of 6 patients received 45 Gy external beam irradiation. Median survival from IOEBRT was 9 (range 3-23) months, 37.5 (range 11-56) months from diagnosis. One patient is alive without disease at 11 months and one is alive with disease 19 months after IOEBRT. Toxicity of the IOEBRT is discussed.

Flow cytometric DNA content analysis of paraffin block embedded endometrial carcinomas.

Flow cytometry is being used as an aid in planning the treatment of patients with various malignancies. We report our experience with DNA content analysis on paraffin-embedded carcinomas. Hospital, radiation therapy, clinic, and pathology records were reviewed in 139 cases of endometrial carcinoma diagnosed between December 1980 and December 1986. Patients having Stage IV tumors, endometrial sarcomas, dual primary tumors, or incomplete records were eliminated from the analysis, which left 98 evaluable patients. This report outlines our experience with the first 20 patients. Five of 20 (25%) specimens demonstrated DNA content consistent with aneuploidy, median coefficient of variance of 5.3%. The median survival time of these five patients is 55 months, with three dying of cancer and one patient dying of other causes but with metastatic disease. The median %S phase was 3.7% in the 15 patients comprising the DNA content diploid population, median coefficient of variance 5.4%. No patient whose tumor showed S-phase cells below 3.7% died of endometrial cancer. Four of 7 patients developed recurrent cancer with 3 of the 4 patients dying of disease in the high %S phase group. The median patients survival time in the DNA content diploid population was 73 (range: 17-98) months. Patients with 3.7% or below S-phase cells had a median survival time of 75 (range: 40-98) months whereas the median survival time was 48 (range: 17-89) months for patients having a %S phase fraction above 3.7%. Although the number of patients studied is small, it appears that DNA content aneuploid tumors are frequently "upstaged" at surgery. These patients may not benefit from preoperative irradiation. Accurate determination of the %S phase fraction in DNA content diploid tumors may possibly identify patients with a poorer prognosis who may benefit from adjuvant therapy.

A pilot study investigating intraoperative electron beam irradiation in the treatment of ovarian malignancies.

Intraoperative electron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies was investigated at the Clement O. Miniger Radiation Oncology Center (COMROC). Nine patients were operated in the COMROC IOEBRT operating amphitheater and five were found to have disease sufficiently limited to allow for IOEBRT. The patients' ages ranged from 13 to 80 (median 53) years. Five patients had serous cystadenocarcinoma, one papillary adenocarcinoma, one mixed germ cell tumor, one squamous cell carcinoma, and one granular cell tumor of the ovary. The median survival of the non-IOEBRT group was 13 (range 12-29) months, while the IOEBRT group's median survival was 14 (range 18-46) months. All of the patients tolerated IOEBRT well without addition to the surgical morbidity.

Sexually transmitted papillomaviral infections. I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types.

Multiple colposcopic biopsy specimens were collected from 160 women, with sampling of principal cervical and vulvar lesions as well as secondary areas of either minor acetowhitening or normal epithelium. Papillomaviral deoxyribonucleic acid was detected by Southern blot hybridization in 197 (90%) of the 218 principal biopsy specimens and 93 (46%) of 198 secondary biopsy specimens. Although different papillomaviruses were found at different sites in 31 women, only six of 416 specimens contained multiple types within the same sample. Specific viral types were associated with specific disease patterns. Only one of 80 type 6 or 11 infections had a diagnosis greater than cervical intraepithelial neoplasia, grade 2. In contrast, 42 of 48 (90%) biopsy specimens of cervical intraepithelial neoplasia, grade 3, or invasive cancer contained type 16, 18, or 31. Nonetheless, 12 of 124 (10%) cases of condyloma and cervical intraepithelial neoplasia, grade 1, were associated with types 16, 18, and 31 infections. Of 58 women with multicentric disease, 46 had positive hybridizations for both cervical and vulvar lesions (32 showing the same type in both samples and 14 showing different viruses). Differing patterns of papillomavirus-induced disease arise partly from the predilection of specific viral types for certain anatomic sites and partly through variations in host response. Detection of viral deoxyribonucleic acid in 46% of the secondary biopsy specimens suggests that disease expression may represent focal breakdown of host surveillance within a field of latent papillomaviral infection.

Analysis of sites of persistent cancer at "second-look" laparotomy in patients with ovarian cancer.

Forty-two patients with ovarian cancer underwent "second-look" laparotomy to determine disease status. Seventeen patients were free of disease; 15 demonstrated tumor regression, but microscopic (3) or macroscopic (12) cancer persisted; and 10 had progressive disease. A significantly increased correlation between positive biopsy sites at second look and sites of known initial residual cancer was noted (76.7% versus 42.3% total positive), particularly in patients with minute disease, at second look. This correlation increased (85.3% versus 64.8%) when both the initial tumor reduction and documentation of residual disease and the second-look procedure were performed by the same surgeon. No such difference was noted in patients with progressive disease. In no instance was disease found at new sites when sites of previous residual cancer were disease free. These results underscore the need for accurate documentation of residual tumor after initial tumor reduction in order to direct the biopsy pattern more accurately, particularly in patients with minute or microscopic disease at second look.

Carbon dioxide laser surgery.

Lower genital tract intraepithelial neoplasia was the predominant indication for CO2 laser surgery in 203 patients treated at Wayne State University. One hundred nineteen patients had cervical intraepithelial neoplasia (CIN) III and, in the 99 patients who were adequately followed, the failure rate following the first treatment was 9%. Secondary treatment with laser surgery, cryosurgery or, in one instance, hysterectomy, was effective in treating all persistent CIN. Success in treating vaginal intraepithelial neoplasia with laser surgery was most favorable in patients who had not had prior pelvic irradiation. Small (less than 1.5 cm) vulvar intraepithelial neoplasia III was successfully treated in seven patients. Recalcitrant condyloma acuminata responded well to laser surgery in 31 patients.

Genital warts and cervical cancer. I. Evidence of an association between subclinical papillomavirus infection and cervical malignancy.

A blind comparative survey was undertaken to study the prevalence of subclinical papillomavirus infection (SPI) in a representative sample of women treated surgically for invasive or preinvasive cervical neoplasia. According to a semiobjective rating system, 73 of 80 women (91%) with cervical neoplasia and ten of 80 matched controls (12.5%) showed histologic evidence of human papillomavirus (HPV) infection. Sixty of the controls (75%), but none of the study group, had normal cervicovaginal epithelium. A highly significant statistical relationship exists between subclinical papillomavirus infection of the lower genital tract and the occurrence of cervical neoplasia (F = 378; P less than 0.001; X2 = 109, P less than 0.001). The prevalence of SPI was seven times greater in the study group than in comparable controls of equivalent disease status. Because both are covariables of promiscuity, statistical association exist between cervical neoplasia and all sexually transmitted diseases. However, the strength, specificity and consistency of this relationship suggest that SPI may be a precursor or cervical malignancy. This contention is given biologic plausibility by a broad fabric of supporting epidemiology, virologic and clinicopathologic evidence.