Sexual, reproductive, and other risk factors for adenocarcinoma of the cervix: results from a population-based case-control study (California, United States)

The incidence of adenocarcinoma of the cervix increased steadily in young women in the United States between the early 1970s and the mid-1980s. Despite this increase, little is known about the etiology of this cancer, although a role for risk factors for both squamous cell carcinoma of the cervix and endometrial adenocarcinoma has been suggested. Incident cases of adenocarcinoma of the cervix diagnosed in women born after 1935 (ages 42 to 56 at diagnosis) were identified from the Los Angeles (California) County Cancer Surveillance Program (LACCSP). Data from personal interviews with 195 cases and 386 controls (matched on age, race, and neighborhood) were analyzed. Compared with women in the highest categories of education and income, women in the lowest categories had a 2.5 and 3.1-fold elevated risk of adenocarcinoma of the cervix. Number of sexual partners, especially before age 20, was strongly predictive of risk (odds ratio = 5.6, 95 percent confidence interval = 1.4-22.0 for 10 or more compared with no partners before age 20). Smoking was not associated significantly with risk. Weight gain and long-term use of oral contraceptives increased risk, while long-term diaphragm use was protective. This study suggests that both sexual and hormonal factors are important etiologic factors for adenocarcinoma of the cervix.

Oral contraceptive use and adenocarcinoma of cervix.

The incidence of adenocarcinoma of the cervix in the USA more than doubled between the early 1970s and the mid 1980s among women under 35 years of age. It was suggested that this increase was due to the introduction of oral contraceptives in the early 1960s. Adenocarcinoma of the cervix diagnosed in women born after 1935 was identified between 1977 and 1991 from the Los Angeles County Cancer Surveillance Program. Data from personal interviews of 195 cases and 386 controls (matched on age, race, and neighbourhood) were analysed. Information on medical, sexual, contraceptive, and reproductive history, previous cervical smears, and sexually transmitted diseases was collected. Compared with never use, ever use of oral contraceptives was associated with twice as great a risk of adenocarcinoma of the cervix (adjusted odds ratio 2.1, 95% CI 1.1-3.8). The highest risk was observed for oral contraceptive use for more than 12 years (4.4, 1.8-10.8). No additional increased risk was found for early age at start of oral contraceptive use, use before age 20 or before first pregnancy, time since first use, time since last use, or particular formulations, once total duration of use had been accounted for.

Peripheral primitive neuroectodermal tumor of the vulva.

A 10-year-old Hispanic female presented with a 3-month history of a vulvar mass. The histologic diagnosis was a peripheral primitive neuroectodermal tumor (PNET). To our knowledge, this is the second reported case of vulvar peripheral PNET and the first such case reported in the English language.

Loss of heterozygosity on chromosome 13 is common only in the biologically more aggressive subtypes of ovarian epithelial tumors and is associated with normal retinoblastoma gene expression.

We examined the frequencies of loss of heterozygosity on chromosome 13 in 77 primary ovarian epithelial tumors subdivided into cystadenomas, tumors of low malignant potential, low grade carcinomas, and high grade carcinomas. Such losses were found in approximately 50% of high grade carcinomas but were not detected in any of the other tumor subtypes (P < 0.0001), suggesting a strong association between these abnormalities and the high grade carcinoma phenotype. The tumors were also examined for abnormalities in expression of the retinoblastoma susceptibility gene (RB). This was assessed by immunohistochemical staining of archival tumor sections with a polyclonal antibody directed against both the phosphorylated and the underphosphorylated forms of the RB protein. Most of the tumors, including those with allelic deletions on chromosome 13, showed normal RB nuclear protein staining patterns. We conclude that loss of RB expression is not a frequent event in primary ovarian carcinomas and that this gene is probably not the target of the frequent allelic deletions on chromosome 13 found in high grade ovarian carcinomas.

Malignant germ cell tumors of the ovary: 20-year report of LAC-USC Women's Hospital.

Thirty-six patients with malignant germ cell tumors (GCT) of the ovary were treated during the period from 1971 to 1990. Twenty-five of these patients underwent initial surgery at this institution; 11 were referred after initial surgery. Endodermal sinus tumor (EST) was the most common subtype (N = 13), followed by immature teratoma (IMT) N = 11), dysgerminoma (N = 9), and mixed germ cell tumor (N = 3). Eight of nine patients with dysgerminoma and 14 of 27 patients with non-dysgerminomatous germ cell tumors had stage I disease. Surgical staging resulted in a change of stage in 10 of 31 patients; seven were upstaged, and three were downstaged. Thirty-five of 36 patients are alive with no evidence of disease at a median follow-up of 47 months (range 12-210 months). Two of nine patients with dysgerminoma received postoperative radiotherapy; two additional patients required radiotherapy for recurrence. Twenty-five of 27 patients with non-dysgerminomatous tumors were treated with combination chemotherapy. Second-look laparotomy was done in 18 patients, four of whom had positive results. Three of the four patients with positive second-look laparotomy results remain free of disease after salvage chemotherapy; the fourth patient died of progressive grade 3 IMT. Nineteen of 27 patients undergoing fertility-preserving surgery have resumed normal menses, and four of these have delivered normal infants. The other eight patients remain on oral contraceptives. We conclude that surgical staging provided important information in this study of 36 patients with ovarian germ cell malignancies. As noted by many previous reports, combination chemotherapy (developed during the past 20 years) has dramatically improved prognosis for this group of patients. Second-look laparotomy (SLL), especially for patients with advanced disease, was able to identify patients requiring additional therapy. Most patients with this disease can retain their normal, uninvolved ovary with preservation of normal menstrual and reproductive function.

Cervical cancer in pregnancy: reporting on planned delay in therapy.

OBJECTIVE: To report our experience with invasive carcinoma of the cervix during pregnancy, assessing maternal morbidity due to treatment delay and reporting maternal and fetal outcome. METHODS: Twenty-seven patients with invasive cervical cancer, who were pregnant at the time of diagnosis or treatment, were identified from review of morbidity and mortality statistics between January 1, 1980 and December 31, 1991. All medical records were examined retrospectively. RESULTS: The incidence of cervical carcinoma in our population was 1.2 cases per 10,000 pregnancies. Most patients had stage I lesions. The predominant histologic cell type was squamous cell carcinoma, followed by adenosquamous carcinoma and adenocarcinoma. Eight patients with stage Ia or Ib cervical cancer postponed therapy to optimize fetal outcome, with a mean diagnosis-to-treatment interval of 144 days (range 53-212). Nineteen patients elected immediate treatment, with a mean diagnosis-to-treatment interval of 17 days (range 2-42). Fetal outcome was uniformly good for the delayed-treatment group. Nine fetal deaths and two neonatal deaths occurred in the immediate-treatment group. All patients who delayed therapy are free of disease after a median follow-up of 23 months. CONCLUSION: Deliberate delay of therapy to achieve fetal maturity appears to be a reasonable option for patients with stage I cervical cancer complicating pregnancy.

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Preservation of ovarian tissue in adnexal torsion with fluorescein.

OBJECTIVE: Our purpose was to assess the ability of fluorescein to intraoperatively detect viable fallopian and ovarian tissues involved in adnexal torsion. STUDY DESIGN: This prospective study was performed at Los Angeles County+University of Southern California Women's Hospital. Participants were female patients 18 to 45 years old with adnexal torsion confirmed at exploratory celiotomy. Five milliliters of 10% fluorescein were injected intravenously, and the involved untwisted adnexa was observed under ultraviolet light. Nonfluorescent tissue was resected and histologically evaluated. RESULTS: Eleven patients were entered into the study. Mean age was 25 years (range 15 to 42). Eight patients (72%) had preservation of involved ovarian tissue. No complications were associated with this procedure. Only three patients (28%) underwent oophorectomy. CONCLUSION: The use of intravenous fluorescein appears to be a valuable adjunct in the management of adnexal torsion. Application of this technique in reproductive-aged patients resulted in a three-quarter reduction in oophorectomy procedures.

Myxoid leiomyosarcoma of the uterus.

BACKGROUND: A case of myxoid leiomyosarcoma of the uterus is presented. In contrast to 10 of the 11 previously published cases, our patient has a tumor with a high mitotic rate. CASE: The patient presented with a 2-month history of vaginal bleeding and a 20-week-size uterine mass. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. At the time of surgery, the tumor appeared well circumscribed. Microscopically, an infiltrative growth pattern, bizarre nuclei, and 30 abnormal mitotic figures per 10 high power fields were noted. The patient was treated with ifosfamide and mesna. After the fifth course of chemotherapy, a pelvic mass was palpated. Exploratory laparotomy demonstrated a large sidewall recurrence and upper abdominal metastases which were completely resected. The patient is currently being treated with combination chemotherapy consisting of vincristine, Adriamycin, and cyclophosphamide. CONCLUSION: Ten of the 11 previously reported cases of myxoid leiomyosarcoma had a low mitotic count. However, our patient has a high mitotic count in combination with an infiltrative growth pattern. Ifosfamide was ineffective as adjuvant chemotherapy and there was aggressive tumor growth while the patient was on this regimen.

A randomized clinical trial comparing the Cytobrush and cotton swab for Papanicolaou smears.

OBJECTIVE: We sought to determine whether use of the Cytobrush/spatula or the cotton swab/spatula is better in obtaining satisfactory Papanicolaou smears as defined by the Bethesda System. METHODS: This 1-year randomized trial was performed at the Los Angeles County + University of Southern California Women's Hospital colposcopy clinic. Participants were all nonpregnant patients referred to the colposcopy clinic for abnormal Papanicolaou smears. The main outcome measurement was the effectiveness in obtaining satisfactory Papanicolaou smears as defined by the Bethesda System. Data were analyzed using the Pearson chi 2 test. RESULTS: The sampling methods had similar abilities to obtain a satisfactory smear (Cytobrush/spatula 63%, cotton swab/spatula 57%; P = .23). Less-than-optimal smears accounted for 28% of the Cytobrush group and 38% of the cotton-swab group. The Cytobrush was superior in its ability to obtain endocervical cells (Cytobrush 80%, cotton swab 60%; P less than .01). Both sampling methods had similar rates of correlation with histologic diagnosis. No complications were associated with either technique. CONCLUSIONS: The Cytobrush/spatula is superior to the cotton swab/spatula in obtaining endocervical cells. There appears to be no difference in each method's ability to obtain satisfactory smears. Application of the Bethesda System results in a significant number of less-than-optimal smears using either technique.

Secretion of prorenin by a virilizing ovarian tumor.

A 53-year-old normotensive, normokalemic female presented with a 6-month history of virilization. Estradiol, LH, FSH, urinary-free cortisol, and DHEA-S levels were normal. Pelvic ultrasound and computerized tomography were also within normal limits. Her serum testosterone (551 ng/dl; nl, 20-70) and plasma prorenin (124 ng AI/ml/hr; nl, less than 50) levels were elevated. At surgery, a lipoid/steroid cell tumor of the right ovary was removed. Postoperative testosterone and prorenin levels were normal. Ovarian tumor cells, in culture, produced large amounts of prorenin. Immunohistochemistry localized prorenin and/or renin to tumor cells. Determining plasma prorenin levels may be a useful adjunct in diagnosing or following patients with nonepithelial ovarian tumors. A larger clinical study of prorenin levels in patients with such tumors is needed.

A clinical-pathology review of cervical intraepithelial neoplasia following cryotherapy failure.

Cervical intraepithelial neoplasia (CIN) after cryotherapy can pose both diagnostic and therapeutic problems. To clarify these issues, 27 consecutive patients who underwent cone biopsy for CIN after cryotherapy over a 10-year period at Women's Hospital LAC + USC Medical Center were reviewed. Although the initial features of the cervical intraepithelial neoplasia allowed for outpatient cryotherapy, the features of these failures did not (unsatisfactory colposcopy or CIN in the endocervical curettings). Eleven percent of these patients had stromal invasion on cone biopsy that was not suspected clinically. Patients presenting with cervical intraepithelial neoplasia following cryotherapy may, in fact, have progressive disease (i.e., stromal invasion) that is inapparent clinically. Hence, surgical excision should be considered in these circumstances.

Gastrointestinal signet ring carcinoma metastatic to the cervix during pregnancy. A case report.

Extragenital carcinoma metastatic to the cervix is uncommon. In such a case a complication not previously described occurred in association with pregnancy: gastrointestinal signet ring carcinoma metastatic to the cervix. The entity was initially detected on a histologic examination of cervical biopsy specimens and was confirmed with gastric endoscopic biopsies, thereby preventing an exploratory laparotomy. The patient declined palliative chemotherapy.

Mifepristone (RU 486) failure in an ovarian heterotopic pregnancy.

A patient treated with mifepristone (RU 486), which successfully induced abortion of an intrauterine pregnancy, was discovered to have a heterotopic ovarian pregnancy resistant to this antiprogesterone. The ovarian pregnancy was removed with operative laparoscopy. This case demonstrates for the first time that an ovarian pregnancy may be resistant to treatment with RU 486 at a dose adequate to abort an intrauterine pregnancy.

Relative frequency of malignant parovarian tumors: should parovarian tumors be aspirated?

There is a paucity of information concerning the frequency of malignant parovarian tumors and how to diagnose them preoperatively. Our retrospective 10-year analysis showed that among 168 women with parovarian tumors, three had malignancy (2%). Our data and a literature review suggest that most malignancies occur in reproductive-age women with cysts over 5 cm containing internal papillary excrescences. It remains to be determined what the roles of ultrasound and cytology are in diagnosing malignancy.

Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas.

The incidence of leiomyosarcoma in uterine leiomyomas is estimated to be between 0.13 to 0.29%. However, the exact incidence of leiomyosarcoma in uteri removed with a preoperative diagnosis of benign uterine leiomyomas has not been previously reported. Between 1983 and 1988, a total of 1432 patients in Women's Hospital, a self-referred indigent population, had a hysterectomy planned because of abnormal uterine bleeding or abdominal pain associated with the presence of uterine leiomyomas, or because of a pelvic mass thought to be uterine leiomyoma of sufficient size or character to warrant surgical exploration. The ages of these women ranged from 36 to 62 years and the presence of leiomyosarcoma in the hysterectomy specimens increased steadily from the fourth to seventh decades of age (0.2%, 0.9%, 1.4%, and 1.7%, respectively). Preoperative histologic examination of the endometrium was performed in eight patients. Three of the eight patients had a preoperative tissue diagnosis of leiomyosarcoma that was clinically confined to the uterus. After the hysterectomy in the 1429 patients with presumed benign disease, histologic diagnosis of leiomyosarcoma was made in seven (0.49%). There was no evidence of malignancy in the endometrial sampling of any of these seven patients and the diagnosis was suspected intraoperatively in only three. Preoperative uterine size ranged from 8 to 20 weeks' gestational size and postoperative uterine weight ranged from 120 to 1100 gm. Seven of the 10 patients had symptoms of abnormal uterine bleeding. Between the ages of 40 and 60 years, 1% (8 of 817) of women with presumed uterine leiomyomas producing symptoms that necessitated hysterectomy in this series had leiomyosarcoma diagnosis postoperatively. Such treatments as gonadotropin-releasing hormone agonists, endometrial ablation, myomectomy by hysteroscopy or laparotomy instead of hysterectomy in such women could delay the diagnosis and definitive treatment of leiomyosarcoma.

Decreased in vitro production of 6-keto-prostaglandin F1 alpha by uterine arteries from postmenopausal women.

Cessation of ovarian function is associated with a marked increased in morbidity and mortality secondary to ischemic heart disease. Estrogen replacement has been shown to impart protection against ischemic heart disease. We hypothesized that estrogen may influence vascular production of vasodilators such as prostacyclin. To investigate this relationship we have measured the production of 6-keto-prostaglandin F1 alpha, and thromboxane B2 by superfused uterine arteries from pre- and postmenopausal women. Arterial specimens from healthy normotensive premenopausal (n = 5) and postmenopausal women (n = 5) were superfused for 5 hours. Production of 6-keto-prostaglandin F1 alpha reached steady state levels by 120 minutes and remained linear for the length of the experiment. Indomethacin (4 x 10(-5) mol/L) added at 120 minutes significantly decreased prostanoid production. In subsequent experiments, 17 beta-estradiol in concentrations of 10, 100, 1000 ng/ml was added to the superfusion media at 120 minutes. Total production of 6-keto-prostaglandin F1 alpha by premenopausal arteries superfused with neat media during the steady state interval (3 hours) was significantly greater than that of postmenopausal specimens (1.25 versus 0.27 ng/mg dry tissue, p less than 0.05). Thromboxane B2 levels were undetectable in spent media. However, the addition of 17 beta-estradiol did not alter production of 6-keto-prostaglandin F1 alpha. These data suggest that arterial production of prostacyclin is significantly decreased in uterine arteries from postmenopausal women, but in this in vitro model system estrogens did not affect vascular prostanoid production.

Extrarenal renin-secreting tumors: insights into hypertension and ovarian renin production.

Although renin-secreting tumors are rare, they must be considered in the differential diagnosis of hypertension associated with hypokalemia, which occurs commonly in the hypertensive population. The finding of an ovarian renin-secreting tumor emphasizes the potential importance of the ovary as an extrarenal source of renin; the local ovarian renin-angiotensin system may play a key role in reproductive function by regulating vascular reactivity, local blood flow, steroidogenesis and other physiologic effects. In the illustrative case presented, a renin-secreting ovarian leiomyosarcoma was obtained from a women who presented with hypertension and hypokalemia. Plasma prorenin levels were markedly elevated. Tumor excision was quickly followed by a fall in prorenin levels and tumor recurrence was accompanied by an increase in prorenin levels. Active renin concentration in the tumor homogenates was similar to that found in kidney homogenates while the tissue prorenin concentration was approximately 20 times that found in kidney tissue. When cultured for up to 4 weeks, ovarian tumor cells secreted greater than 95% prorenin. Immunoblot analysis demonstrated that tumor renin had a molecular weight of 47,000, similar to that of human recombinant prorenin. Immunohistochemical staining of tumor tissue with antibodies against human renal renin at the electron microscopic level demonstrated the presence of renin primarily in membrane-bound vesicles and rarely in dense-core secretory granules. These findings suggest that prorenin in this ovarian tumor was secreted by the constitutive pathway, which is mediated by these amorphous vesicles.

The diagnosis of immature teratoma by maternal serum alpha-fetoprotein screening.

We report a case in which maternal serum alpha-fetoprotein (MSAFP) screening of a low-risk patient led to the antepartum detection of an asymptomatic and previously undetected stage Ia immature teratoma of the ovary. It is widely accepted that MSAFP screening is valuable in the antepartum diagnosis of neural tube defects, ventral wall defects, and aneuploid fetuses. Similarly, such screening may lead to the diagnosis of AFP-producing neoplasms not appreciated on physical or ultrasonic examinations. This benefit, though extremely rare, is significant when a potentially aggressive malignancy is detected in the earliest stages, prior to extraovarian spread.

Correlation of endometrial maturation with four methods of estimating day of ovulation.

Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)