C. Robert Stanhope

Aggressive surgical effort and improved survival in advanced-stage ovarian cancer

OBJECTIVE: Residual disease after initial surgery for ovarian cancer is the strongest prognostic factor for survival. However, the extent of surgical resection required to achieve optimal cytoreduction is controversial. Our goal was to estimate the effect of aggressive surgical resection on ovarian cancer patient survival. METHODS: A retrospective cohort study of consecutive patients with International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer undergoing primary surgery was conducted between January 1, 1994, and December 31, 1998. The main outcome measures were residual disease after cytoreduction, frequency of radical surgical resection, and 5-year disease-specific survival. RESULTS: The study comprised 194 patients, including 144 with carcinomatosis. The mean patient age and follow-up time were 64.4 and 3.5 years, respectively. After surgery, 131 (67.5%) of the 194 patients had less than 1 cm of residual disease (definition of optimal cytoreduction). Considering all patients, residual disease was the only independent predictor of survival; the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. For the subgroup of patients with carcinomatosis, residual disease and the performance of radical surgical procedures were the only independent predictors. Disease-specific survival was markedly improved for patients with carcinomatosis operated on by surgeons who most frequently used radical procedures compared with those least likely to use radical procedures (44% versus 17%, P < .001). CONCLUSION: Overall, residual disease was the only independent predictor of survival. Minimizing residual disease through aggressive surgical resection was beneficial, especially in patients with carcinomatosis. LEVEL OF EVIDENCE: II-2

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.

Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses. Discrimination of benign from malignant disease

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.

Gynecologic Cancer in Patients With Subacute Cerebellar Degeneration Predicted by Anti-Purkinje Cell Antibodies and Limited in Metastatic Volume

Between 1982 and 1989, 19 patients with gynecologic carcinoma, paraneoplastic cerebellar degeneration, and seropositivity for anti-Purkinje cell cytoplasmic antibodies were identified at our institution. Seven of the patients had no clinical, computed tomographic, or magnetic resonance imaging evidence of cancer but had undergone laparotomy solely because anti-Purkinje cell antibodies were found in their serum; all had high-grade adenocarcinoma. Cerebellar symptoms preceded or coincided with the initial cancer diagnosis in 15 patients and preceded the diagnosis of recurrent cancer in 4 patients. The cancers were 14 ovarian, 2 fallopian tube, 2 surface papillary, and 1 poorly differentiated metastatic adenocarcinoma in a periaortic lymph node. Two remarkable surgical observations in patients with high-grade ovarian and tubal cancers were the conspicuous lack of peritoneal implants and the small metastatic volume. A comparison of the 8 patients who had primary stage III cancer with 24 matched control patients without paraneoplastic cerebellar degeneration revealed no difference in primary tumor volume but a significantly smaller volume of metastatic tumor in the seropositive group (P = 0.05). Anti-Purkinje cell antibodies were not detected in 111 neurologically normal patients with advanced ovarian cancer. The small metastatic volume in the face of high-grade and advanced stage malignancy in seropositive patients with paraneoplastic cerebellar degeneration suggests that an immune response to the tumor (presumably cross-reactive with cerebellar cells) may impair the metastatic process. Earlier diagnosis and treatment of cancer, based on prompt serologic testing, may offer an improved neurologic and oncologic prognosis.

Genital warts and cervical cancer: IV. A colposcopic index for differentiating subclinical papillomaviral infection from cervical intraepithelial neoplasia☆

Five colposcopic signs (thickness, color, contour, vascular atypia, and iodine staining) were graded into three objective categories representing (1) subclinical papillomaviral infection, (2) lower-grade dysplasia, and (3) grade 3 cervical intraepithelial neoplasia. Seventy-two colposcopically different biopsy specimens (25 of subclinical papillomaviral infection and 18 of grade 1, 18 of grade 2, and 11 of grade 3 cervical intraepithelial neoplasia) were collected from 52 women and interpreted by validated, quantitative histologic analysis. Attempts to grade lesions by the prominence of the acetowhitening reaction or the mere presence of aberrant surface capillaries were unsuccessful. In contrast, each of five new colposcopic criteria were significantly correlated with histologic severity. Differences in color, vascular atypia, and iodine staining were more predictive than those of thickness and contour. Combined into a weighted index, these colposcopic features were 96% correct in forecasting approximate histologic findings. Because this method relies upon critical analysis rather than pattern recall, the use of this colposcopic index greatly simplifies the learning of colposcopy.

Recurrent disease after negative second-look laparotomy in stages III and IV ovarian carcinoma

Between 1977 and 1984, second-look laparotomy to evaluate disease status after adjuvant chemotherapy was performed in 134 patients originally presenting with advanced epithelial ovarian carcinoma. Surgical and histologic assessment did not detect persistent disease in 50 patients (37%). Recurrent carcinoma was subsequently documented in 15 patients (30%), all failures occurring within the abdominal cavity or the retroperitoneal space. Several patient subgroups at high risk for recurrence after negative second-look laparotomy are identified that might benefit from additional adjunctive therapy. Because of different treatment-associated morbidities, the corresponding sensitivities and specificities of the high-risk groups may assist subsequent treatment selection.

Genital warts and cervical cancer. III. Subclinical papillomaviral infection and cervical neoplasia are linked by a spectrum of continuous morphologic and biologic change

Human papillomaviral (HPV) infection is now widely advanced as an important etiologic factor in cervical cancer. This study was undertaken to clarify morphologic relationships within the biologic spectrum linking subclinical papillomaviral infection (SPI) to cervical intraepithelial (CIN). Two pathologists analyzed 72 colposcopic biopsies, using a semi‐objective rating scheme that scored 24 different histologic criteria. Each individual criterion was checked for reproducibility, and validated against an objective measure of papillomaviral infection (immunoperoxidase staining) or premalignant change (microspec‐trophotometry). The individual criteria were then combined into histologic indices of benign warty change, presumed viral atypia, abnormal cell phenotype, and disturbed tissue maturation. Histologic expression of papillomaviral infection decreased with increasing degrees of premalignant change. Plotting the index of abnormal cell phenotype against that of disturbed tissue maturation produced a linear plot in which cases clustered into four diagnostic groups. The histologic indices of papillomaviral infection displayed significant curvilinear correlations with genotypic distortion, benign warty change being maximal in the CIN 1 range and presumed viral atypia in the CIN 2 range. Disturbance of nuclear DNA content also increased with worsening diagnosis; diploidy being most common in SPI (67%), polyploidy in CIN 1 (59%), and aneuploidy in CIN 2 (65%) and CIN 3 (82%). Conversely, capsid antigen production decreased from 36% in SPI to 9% in CIN 3. Three aneuploid epithelia were immunoperoxidase positive. These inverse relationships between late viral expression and nuclear distortion fit experimental models of viral oncogenesis. The gradual transition and morphologic overlap between diagnostic groups support the postulate that SPI and CIN are a single disease spectrum, in which differences are those of degree rather than of kind.

Invasive vaginal carcinoma: analysis of early-stage disease.

From 1960 through 1987, 89 patients with stage I (44 patients) or II (45 patients) vaginal carcinoma (excluding melanomas) were treated primarily at the Mayo Clinic. Treatment consisted of surgery alone in 52 patients, surgery plus radiation in 14, and radiation alone in 23. The median duration of follow-up was 4.4 years. The 5-year survival (Kaplan-Meier method) was 82% for patients with stage I disease and 53% for those with stage II disease (p = 0.009). Analysis of survival according to treatment did not show statistically significant differences. This report is consistent with previous studies showing that stage is an important prognostic factor and that treatment can be individualized, including surgical treatment for primary early-stage vaginal cancer.

Evaluation of treatment and survival after positive second-look laparotomy☆

During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, 116 (46%) were found to have clinically occult ovarian carcinoma. Salvage therapy consisted of external irradiation in 37, intraperitoneal 32P in 12, chemotherapy in 63, and no therapy in 3 or other therapy in 1. Eligible follow-up time ranged from 1 to 9 years. The Kaplan-Meier projected median time-to-progression and survival were 15 and 22.5 months, respectively, with 4-year progression-free and overall survival rates being 21 and 27%, respectively. Survival was independent of the original stage of disease but was significantly influenced by histologic grade and microscopic (55%) versus macroscopic (19%) residual tumor after the laparotomy. Projected 4-year salvage rates in patients with microscopic or residual disease less than or equal to 5 mm was 72, 39, and 19% for intraperitoneal 32P, external irradiation (33/37, whole abdominopelvic), and chemotherapy, respectively. However, multivariable analysis demonstrated that histologic grade and isotope therapy retained independent influence on survival, but no therapeutic advantage for external irradiation over chemotherapy was demonstrable. Furthermore, use of regimens that were identical to, partially altered from, or different from the first-trial agents did not affect chemotherapy salvage rates.

CA 125 in gynecologic practice

Serum CA 125 levels were determined in 64 women with benign ovarian lesions, 92 women with uterine fundal lesions, and six patients who had negative second-look laparotomy for epithelial ovarian carcinoma. Of those with benign lesions, 13 of 31 patients with endometriosis had levels greater than 35 U/ml. Six of 34 patients with endometrial carcinoma had elevated levels before the primary operation, and six of 15 patients with recurrent endometrial carcinoma had elevated levels. The six ovarian cancer patients had had negative findings at second look 7 to 40 months before recurrence. Where close serial levels were available, the level became elevated 2 to 5 months before clinically apparent recurrent disease was noted.