John R. van Nagell

The staging of cervical cancer: Inevitable discrepancies between clinical staging and pathologic findings

Abstract Three hundred seventy previously untreated patients with invasive cervical carcinoma were evaluated, staged, and treated at the University of Kentucky Medical Center from January 1964, to July 1970. Of these, 125 patients were operated upon within 4 weeks of staging. The initial stage was found to be correct in 66 per cent of the cases, with staging accuracy decreasing from Stage I (78 per cent) to Stage III (25 per cent). The most common error was failure to accurately define the extent of parametrial disease. The most effective method of staging was the conventional system which consists of dividing cervical carcinoma into four stages as originally presented by the League of Nations in 1929 and modified by the Cancer Committee of the International Federation of Gynecology and Obstetrics. The TNM staging system did not alter staging accuracy. It is suggested that in certain selected patients diagnostic laparotomy may be indicated.

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.

Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors

OBJECTIVE: To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. METHODS: The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. RESULTS: The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty-three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late-stage cancers. CONCLUSION: The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies. LEVEL OF EVIDENCE: III

The impact of obesity on the incidence and treatment of gynecologic cancers: a review.

Sixty-five percent of the adult population in the United States is overweight and 30% of the population is obese. There is mounting evidence that obesity is a risk factor for gynecologic cancers and may also adversely impact survival. The objectives of this review were to systematically evaluate and discuss the impact of overweight and obesity on endometrial, ovarian, and cervical cancer incidence and to review the data on the impact of obesity on treatment of these same gynecologic cancers. A PUBMED literature search was performed to identify articles in the English language that focused on the impact of obesity on cancer incidence and treatment. References of identified articles were also used to find additional related articles. Obesity profoundly increases the incidence of endometrial cancer, predominantly through the effects of unopposed estrogen. Although the data are less compelling in ovarian and cervical cancer, obesity may modestly increase the incidence of premenopausal ovarian cancer and might potentially increase cervical cancer incidence, perhaps as a result of the impact on glandular cancers or decreased screening compliance. Obese women with cancer have decreased survival; this may be disease-specific, the result of comorbid illnesses, or response to treatment. Obese women have increased surgical complications, may also have increased radiation complications, and there is no current consensus regarding appropriate chemotherapy dosing in the obese patient. Obesity is a serious health problem with significant effects on the incidence and treatment of the gynecologic malignancies. Target Audience: Obstetricians & Gynecologists, Family Physicians. Learning Objectives: After completion of this article, the reader should be able to summarize the clear evidence that obesity is a risk factor for many cancers, including gynecologic malignancies; describe the role of unopposed estrogen in gynecologic cancers; and explain that obese women overall have a poorer survival rate when afflicted with cancer.

The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer.

Surgical specimens from 111 patients with Stage I endometrial cancer were reviewed for the presence of lymph‐vascular space invasion by tumor cells. Lymph‐vascular space invasion was noted in 16 cases, and occurred most frequently in poorly differentiated tumors with deep myometrial penetration. Tumor recurrence developed in 44% of patients whose tumors demonstrated lymph‐vascular space invasion as opposed to only 2% of patients without this finding (p < 0.001). Of seven patients with lymph‐vascular space invasion who experienced tumor recurrence, five developed extra‐pelvic metastases. Discriminant function analysis of these data revealed a statistically significant correlation between lymph‐vascular space invasion and tumor recurrence, independent of histologic differentiation of myometrial penetration. These findings suggest that lymph‐vascular space invasion by tumor cells is an important prognostic variable in Stage I endometrial cancer which should be considered in treatment planning.

Ten-year relative survival for epithelial ovarian cancer.

OBJECTIVE: Most patients with epithelial ovarian cancer who are alive at 5 years have active disease. Thus, 10-year survival rather than 5-year survival may be a more appropriate endpoint. Relative survival adjusts for the general survival of the United States population for that race, sex, age, and date at which the diagnosis was coded. Our objective was to estimate relative survival in epithelial ovarian cancer over the course of 10 years. METHODS: Using the Surveillance, Epidemiology and End Results 1995–2007 database, epithelial ovarian cancer cases were identified. Using the actuarial life table method, relative survival over the course of 10 years was calculated, stratified by stage, classification of residence, surgery as the first course of treatment, race, and age. RESULTS: There were 40,692 patients who met inclusion criteria. The overall relative survival was 65%, 44%, and 36% at 2, 5, and 10 years, respectively. The slope of decline in relative survival was reduced for years 5–10 as compared with years 1–5 after diagnosis. Relative survival at 5 years was 89%, 70%, 36%, and 17%, and at 10 years relative survival was 84%, 59%, 23%, and 8% for stages I, II III, and IV, respectively. At all stages, patients with nonsurgical primary treatment and those with advanced age had reduced relative survival. CONCLUSIONS: The 10-year relative survival for stage III is higher than expected. This information provides the physician and the patient with more accurate prognostic information. LEVEL OF EVIDENCE: III

Uterine sarcomas express KIT protein but lack mutation(s) in exon 11 or 17 of c-KIT.

OBJECTIVE Several tumors express the protein product of the protooncogene c-KIT. Some of these respond to imatinib mesylate, a tyrosine kinase inhibitor. The tumors that respond frequently have mutation(s) in exon 11 of c-KIT that encodes for the regulatory juxtamembrane helix. Some tumors that express KIT protein have mutation(s) in exon 17 of c-KIT; however, these do not respond to imatinib mesylate. This investigation was performed to determine the expression of KIT protein and mutational status of exons 11 and 17 of c-KIT in uterine sarcomas. METHODS Twenty-five uterine sarcomas treated from 1990 to 2002 were evaluated. These included 14 malignant mullerian mixed tumors (MMMT), 7 leiomyosarcomas (LMS), 2 endometrial stromal sarcomas (ESS), and 2 high-grade heterologous sarcomas (HGHS). Formalin-fixed, paraffin-embedded tissue sections were immunostained with anti-KIT antibody (Santa Cruz Biotechnology, Santa Cruz, CA) with a semiquantitative assessment. Normal myometrium when present in the section was used as an internal negative control. Areas of tumor were microdissected followed by DNA extraction, polymerase chain reaction (PCR) amplification of exons 11 and 17, single-strand conformational polymorphism (SSCP), and DNA sequencing to detect the presence of mutation(s). RESULTS All 25 tumors expressed KIT protein at varying levels as assessed by immunohistochemistry. The staining was diffuse and of moderate to strong intensity in 22 tumors. In three tumors (one of each type except MMMT) the staining intensity was weak. In MMMT the epithelial and sarcomatous foci stained similarly. No mutation(s) in exons 11 or 17 of c-KIT were identified in 24/25 tumors. One LMS had deletion of both exons 11 and 17. CONCLUSIONS Although uterine sarcomas express KIT protein, they lack KIT-activating mutation(s) in exon 11 or 17 of c-KIT. Therefore, these tumors are unlikely to respond to imatinib mesylate.

Transvaginal sonography as a screening method for ovarian cancer

From November 1, 1987, to July 1, 1988, 506 asymptomatic patients 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center. Eligibility requirements included no known pelvic symptoms or clinical abnormalities, no history of pelvic radiation, and no history of ovarian cancer. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. Ovarian morphology was classified as uniformly hypoechogenic, cystic, solid, or complex. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in post-menopausal women. With respect to these criteria, 12 patients (2.4%) were noted to have abnormal sonograms, and 10 agreed to surgery. All 10 patients had ovarian tumors with dimensions equal to those predicted by ultrasound. These tumors included four serous cystadenomas, three endometriomas, two cystic teratomas, and one adenocarcinoma. Vaginal sonography is a relatively simple test that can detect subtle changes in ovarian size and morphology. Further evaluation of this test as a screening method for ovarian cancer should be performed in the setting of controlled clinical trials that emphasize cost control and strict patient follow-up.

Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel‐shaped cervical cancer

Seventy‐five patients with bulky barrel‐shaped Stage IB cervical cancers, treated at the University of Kentucky from 1965 to 1981, were the subjects of this investigation. Thirty‐two of these patients were treated with radiation therapy alone and 43 were treated with radiation followed by extrafascial hysterectomy. There were no significant differences in age, gravidity, or tumor cell type between the two treatment groups. Patients were seen at regular intervals from 2 to 11 years after treatment and none were lost to follow‐up. Recurrent cancer was noted in 47% of patients treated by radiation alone as compared to 16% of those treated with combined therapy (P < 0.01). The incidence of pelvic recurrence was reduced from 19% to 2% and extrapelvic recurrence from 16% to 7% in patients treated by combination therapy. No rectal or urinary tract fistulae were noted after extrafascial hysterectomy. The findings of this study suggest that the use of extrafascial hysterectomy following radiation therapy in patients with bulky Stage IB cervical cancer causes a significant reduction in tumor recurrence without producing an increase in treatment‐related complications.

Neurologic complications of cervical cancer. A review of 2261 cases

The authors reviewed the records of 2261 patients with histologically proven cervical cancer. Among the 1042 patients with carcinoma in situ, four neurologic complications occurred (0.4%), including three strokes and one seizure. None of the neurologic complications were related to cervical cancer. Among the 1219 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I or greater disease, 99 neurologic complications occurred (8%). Metastatic neurologic complications were twice as common as nonmetastatic neurologic complications and included lumbosacral plexopathy (50 patients), peripheral nerve compressions (eight patients), spinal cord compressions (two patients), and brain metastases (six patients). Nonmetastatic neurologic complications were less frequent and included stroke (11 patients), encephalopathies (three patients), infectious complications (two patients), effects of therapy (six patients), and seizures (11 patients). In conclusion, neurologic complications are rare in cervical cancer and virtually nonexistant in Stage 0 disease. Metastatic neurologic complications were more common than nonmetastatic complications and lumbosacral plexopathy caused by retroperitoneal lymph node metastases was the most common neurologic complication.