Robert V. Higgins

Transvaginal sonography as a screening method for ovarian cancer a report of the first 1000 cases screened

From November 1987 to April 1989, 1000 women 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center (Lexington, KY). Patients included in this investigation were all asymptomatic and had no known pelvic abnormalities. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in postmenopausal women. In patients with normal scans, mean ovarian volumes decreased from 6.8 cm3 to 3.0 cm3 with menopause. Thirtyone patients (3.1%) had abnormal vaginal sonograms and 24 underwent exploratory laparotomy. All patients undergoing surgery had ovarian or fallopian tube tumors with dimensions identical to those predicted by ultrasound. Histologic diagnoses of these tumors included the following: adenocarcinoma, one; serous cystadenoma, eight; endometrioma, six; and cystic teratomas, two. Vaginal sonography was performed easily and without complications, and was well accepted by patients. All patients with normal sonograms have been rescreened annually and none have subsequently developed ovarian cancer. Further clinical trials to determine the efficacy of vaginal sonography as a screening method for ovarian cancer are indicated.

Small cell carcinoma of the uterine cervix

From 1962 to 1985, 2201 patients with invasive cervical cancer were staged, evaluated, and treated at the University of Kentucky Medical Center. After a thorough evaluation, 25 cases (1.1%) fulfilled the histologic criteria for small cell cancer defined by Reagan and coworkers. These patients were computermatched for age, disease stage, and lesion size to 25 patients with large cell nonkeratinizing cancer and 25 patients with keratinizing squamous cell cancer. Morphometric analyses of nuclear size and maximum nuclear diameter were performed on all cases without knowledge of cell type. Small cell cancers were characterized by a nuclear area of 160 μ2 or less and a maximum nuclear diameter of 16.2 μ, which was significantly lower than that for large cell tumors. Thirty‐three percent of the small cell carcinomas stained positively for the neuroendocrine markers (neuron‐specific enolase [NSE] and chromogranin [CGR]), whereas the remainder contained only epithelial markers such as cytokeratin (CYK) and epithelial membrane antigen (EMA). Small cell cancers were associated with a high frequency of lymph‐vascular space invasion and a diminished lymphoplasmacytic response. Patients with small cell cancer had a significantly higher recurrence rate, particularly to extrapelvic sites, than the matched patients with large cell cancers, and their survival was lower. Clinical trials to determine the efficacy of adjuvant chemotherapy in the treatment of small cell cervical cancer are needed.

Predictive factors from cold knife conization for residual cervical intraepithelial neoplasia in subsequent hysterectomy

OBJECTIVE The optimal management of cervical intraepithelial neoplasia after cold knife conization remains controversial. Reliable predictors of residual dysplasia in the cervix after cold knife conization have not been consistently identified. This study was initiated to examine the accuracy of the traditional factors used to predict residual dysplasia in hysterectomy specimens after cold knife conization. STUDY DESIGN A retrospective 10-year chart review identified a cohort of 1272 patients who underwent cold knife conization, of whom 311 had a subsequent hysterectomy within 1 year of conization. Residual disease was defined as cervical intraepithelial neoplasia or cancer in the hysterectomy specimen. All cone specimens were completely submitted for pathologic examination, and the following factors were analyzed for their predictive value: degree of dysplasia, margin involvement, endocervical gland involvement, and status of the endocervical curettage. The predictive value of age, race, gravidity, parity, socioeconomic status, cigarette smoking, and marital status were also examined. The chi 2 test, t test, and logistic regression were used for statistical analysis. RESULTS Dysplasia or cancer were identified in 1066 (84%) of the 1272 patients who underwent cold knife conization. Of the 311 patients having a subsequent hysterectomy, 106 (34%) had residual disease in their hysterectomy specimen. By multivariate analysis only increasing age and degree of dysplasia were predictive of residual disease. The odds ratio of residual disease in the hysterectomy specimen for a 25-year-old woman was 2.7 (95% confidence interval 1.6 to 4.4) compared with a 40-year-old woman whose odds ratio was 4.9 (95% confidence interval 2.2 to 10.8). The presence of dysplasia in the cold knife conization specimen conferred an odds ratio of 12.1 (95% confidence interval 2.7 to 54.5) of identifying residual disease. Dysplasia involving the ectocervical margin, endocervical margin, and endocervical glands was not predictive of disease in the hysterectomy specimens. Endocervical curettage was not performed in 44% of the patients, preventing reliable statistical evaluation. Further analysis indicated that residual disease was found in 32% of the hysterectomy specimens with negative margins, in 31% with no endocervical gland involvement, and in 23% with a negative endocervical curettage sample. CONCLUSIONS The presence or absence of dysplasia in the cold knife conization ectocervical margin, endocervical margin, and endocervical glands was not predictive of residual dysplasia in post-cold knife conization hysterectomy specimens. Increasing age and severity of disease in the cone specimen were the only factors that accurately predicted residual dysplasia. The traditional factors used to justify hysterectomy after cold knife conization may not be valid on the basis of these results.

Stage I serous papillary carcinoma of the endometrium.

From 1973 to 1987, 16 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I serous papillary endometrial carcinoma were evaluated and treated at the University of Kentucky Medical Center (Lexington, KY). All patients were 60 years of age or older, and all were postmenopausal. Patients were treated with total abdominal hysterectomy, bilateral salpingo‐oophorectomy, and paraaortic lymph node sampling, and 38% were noted to have more extensive disease than appreciated clinically. Nine patients were given adjuvant postoperative radiation. Seven patients (44%) developed recurrent cancer with liver, lung, and upper abdomen being the most common sites of spread. Prognosis was most directly related to the presence of lymph vascular space invasion and the depth of myometrial penetration. No patient with serous papillary carcinoma confined to the endometriunt developed recurrent cancer. In contrast, the recurrence rate of patients having myometrial invasion was 70% (P < 0.03). Hormonal therapy was of limited value in the treatment of recurrent disease. This data suggests the need for adjuvant systemic therapy in the treatment of patients with Stage I serous papillary carcinoma of the endometrium who have myometrial invasion.

Interobserver variation in ovarian measurements using transvaginal sonography

Ultrasound examination of ovarian size and morphology has been proposed as a screening method for ovarian carcinoma. A screening test must give consistent results when performed by different examiners to reliably determine the sensitivity and specificity of the test. This study was designed to evaluate interobserver variation in ovarian size measurements using transvaginal sonography. Two examiners independently measured 86 ovaries in three planes and ovarian volumes were calculated using the prolate ellipsoid formula. The correlation coefficient between the ovarian volume measurements made by each examiner was 0.960. These results indicate that interobserver variation in ovarian volume measurements is extremely low as determined by transvaginal sonography.

The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer.

Abstract To identify potential prognostic indicators of ovarian cancer and identify targets for therapeutic strategies, mRNA differential display was used to analyze gene expression differences in normal, benign, and cancerous ovarian tissue. One cDNA isolated by this technique, Op18/stathmin, is a highly conserved gene that is reported to have many different functions within a cell, including signal transduction, control of the cell cycle, and the regulation of microtubules. Quantitative Northern blot analysis of 12 malignant ovarian samples, 8 benign ovarian tumors, and 10 normal ovarian tissue samples demonstrated overexpresaion of Op18/stathmin mRNA in the malignant cancers. Immunohistochemistry showed an apparent overex-pression of Op18/stathmin protein level and an association with proliferating cells

Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation☆

OBJECTIVE The goal of this study was to determine the clinical implications of a progressively rising serum CA-125 level in the normal (< 35 U/ml) range in ovarian cancer patients with complete response to therapy. METHODS A multi-institutional investigation was undertaken to identify patients with CA-125-producing epithelial ovarian cancers who experienced progressively rising antigen levels in the normal (<35 U/ml) range after completion of therapy. All patients had (1) histologic documentation of epithelial ovarian cancer and (2) complete clinical remission (CR) as defined by negative imaging studies, normal clinical examination, and a normal (<35 U/ml) serum CA-125 value. All patients had serum CA-125 determinations at 1- to 3-month intervals after treatment. A rising serum CA-125 level was defined as a progressive increase in at least three CA-125 values above the coefficient of variation (CV) for the assay. No patient had a known episode of pelvic or gastrointestinal inflammatory disease during the period when the progressive rise in serum CA-125 took place. RESULTS Eleven patients with rising serum CA-125 levels in the normal range were identified. Original stage of disease was as follows: stage IIA, 1; stage IIIC, 10. Cell type was as follows: endometrioid adenocarcinoma, 4; serous adenocarcinoma, 6; clear cell carcinoma, 1. Of the 11 patients identified, all developed recurrent ovarian cancer. Tumor recurrence was documented either by new lesions appearing on imaging studies (6/11) or by histologic confirmation (5/11). The mean time from CR to recurrence was 21 months (median = 22, range = 12-33). The mean time from the third early rising serum CA 125 value to clinical or radiographic confirmation of recurrence was 189 days (range = 84-518). All recurrences were intraabdominal with the exception of one axillary recurrence. CONCLUSION In patients with a history of ovarian cancer, three progressively rising serum CA-125 values in the normal range (< 35 U/ml) at 1- to 3-month intervals are associated with a high likelihood of tumor recurrence. Patients with such a pattern should undergo immediate investigation to rule out and/or identify recurrent cancer.

Comparison of fine-needle aspiration cytologic findings of ovarian cysts with ovarian histologic findings

OBJECTIVE The purpose of this study was to compare cytologic findings of fluid from ovarian cysts with ovarian histologic findings. STUDY DESIGN Ovaries submitted for pathologic examination were grossly examined for ovarian cysts. Fluid was removed by needle aspiration from intact ovarian cysts and prepared for cytologic examination. The cytologic findings were categorized as benign, malignant, indeterminate, and nondiagnostic. Histologic classification was assigned using the guidelines established by the World Health Organization. A single pathologist evaluated each cytologic specimen and was blinded to the gross appearance and histologic findings of each ovary. Cytologic diagnoses were compared with the histologic diagnoses. RESULTS The study material consisted of 105 ovaries from 98 women. A comparison of the ovarian histologic findings with the cytologic diagnosis was performed in 89 of 105 cases. Histologic examination of the ovaries revealed 89 benign ovarian tumors and 13 ovarian carcinomas. The sensitivity of ovarian cyst cytologic evaluation was 25%, and the specificity was 90%. The false-positive rate for ovarian cytologic evaluation was 73%, and the false-negative rate was 12%. CONCLUSIONS Cytologic examination of aspirated ovarian cyst fluid does not accurately predict ovarian histologic findings.

Management of low-grade squamous intraepithelial lesions during pregnancy.

OBJECTIVE Our purpose was to determine whether prenatal colposcopy is beneficial in pregnant women with squamous atypia, atypical squamous cells of undetermined significance, or low-grade squamous intraepithelial lesions on an initial screening Papanicolaou smear. STUDY DESIGN A retrospective chart review identified a cohort of pregnant patients referred to the colposcopy clinic at Carolinas Medical Center between October 1991 and December 1994 with squamous atypia, atypical squamous cells of undetermined significance, or low-grade squamous intraepithelial lesions. Results of the colposcopic examination, cervical biopsy specimens, postpartum evaluation, and postpartum treatment were recorded. Descriptive statistics were used to tabulate numbers and percentages for all variables with 95% confidence intervals to determine disease progression. RESULTS Prenatal colposcopy was performed on 253 women during the study period. The colposcopic impression was normal or consistent with low-grade squamous intraepithelial lesions in 235 (93%) of the women. Of the 67 women who had a cervical biopsy, 6 had a histologic diagnosis of high-grade squamous intraepithelial lesions. Postpartum Papanicolaou smears were obtained in 224 patients; 71 (32%) were normal, 145 (65%) were unchanged, and 8 (3%) showed high-grade squamous intraepithelial lesions. Of the 69 patients who had a postpartum cervical biopsy, 4 were found to have high-grade squamous intraepithelial lesions. Eight of the 10 women with biopsy-proved high-grade squamous intraepithelial lesions were compliant with treatment after delivery. Histologic examination of the cervix with tissue obtained by either loop conization or cold knife conization showed no evidence of invasive carcinoma. CONCLUSION Squamous atypia, atypical squamous, cells of undetermined significance, or low-grade squamous intraepithelial lesions on a Papanicolaou smear in a pregnant patient does not require colposcopic evaluation during pregnancy. Progression of low-grade dysplasia to carcinoma during pregnancy is unusual, and no patient in this study was found to have invasive cancer.

Prognostic factors in early vulvar, cancer

Prognostic parameters were evaluated in 22 patients with small (less than or equal to 2 cm) superficially invasive (less than 5 mm) squamous cell carcinoma of the vulva. Primary surgery included radical vulvectomy with bilateral superficial and deep inguinal lymph node dissection in 11 patients, and wide local excision with ipsilateral superficial inguinal lymph node dissection in 11 patients. Of the 22 patients studied, only 2 (9%) had lymph node metastases. Both patients had a single positive ipsilateral superficial inguinal node. Perineural invasion was strongly associated with lymph node metastases (P less than 0.01). In this group of patients, grade, depth of invasion, lymph-vascular space invasion, and lymphoplasmacytic infiltration were not predictive of lymph node metastases (P greater than 0.05). Two patients initially treated with wide local excision and ipsilateral superficial inguinal lymph node dissection developed recurrent vulvar neoplasia on the contralateral vulva, and both were successfully retreated by wide local excision. All patients are presently alive and well with no evidence of disease. None of the histomorphologic parameters studied were predictive of tumor recurrence. These data suggest that wide local excision with ipsilateral superficial inguinal lymphadenectomy is effective in the treatment of patients with small, superficially invasive carcinomas of the vulva.