Identification of a high-risk subgroup in cytology-positive stage IIIA endometrial cancer

OBJECTIVE: To identify a high-risk subgroup among patients with cytology-positive stage IIIA endometrial cancer. STUDY DESIGN: Fifty-four stage IIIA endometrial cancer patients who were positive only on peritoneal cytology were divided into two groups based on the cytologic pattern of their peritoneal smears. In group A, malignant cell clusters had well-defined edges, while the tumor cell clusters had scalloped edges in group B. The prognostic significance of these findings was investigated. RESULTS: The five-year disease-free survival rate was 97.5% in group A (n=40) versus 50% in group B (n = 14). Multivariate analysis confirmed that the cytologic pattern had an independent influence on survival. CONCLUSION: Positive peritoneal cytology composed of malignant cell clusters with well-defined edges has no impact on survival. Only endometrial cancer patients who show tumor cell clusters with scalloped edges in peritoneal smears are worth considering for upstaging.     

Comparison of cytohormonal status of postmenopausal women with cancer to age-matched controls

To determine whether the cytohormonal status of postmenopausal women with cancer involving the uterus and vagina differs from that of women free of cancer, 100 women 60 years of age or older with positive cervicovaginal smears were compared with an age-matched control group without malignant neoplasms. Epidermoid carcinoma was identified in 64 patients (average age: 67 years) and adenocarcinoma in 34 patients (average age: 69 years). One patient had leiomyosarcoma, and another had bladder carcinoma. The paucity of benign squamous cells in the smears precluded hormonal evaluation in 32% of the index cases; the smears from 10% of the controls were also indeterminate. Of the evaluable cases with epidermoid carcinoma of the cervix, a high maturation was noted in 46% as compared to 11% for the matched controls. In addition, high maturation was noted in 69% of those patients with endometrial adenocarcinoma as compared to 19% for the matched controls. None of the index cases were atrophic; 31% of the controls were. A history of exogenous estrogen usage was obtained in three patients with endometrial adenocarcinoma, all with high maturation, and in five controls, none with high maturation. These data appear to indicate a difference in the cytohormonal status of patients with cervical or endometrial carcinoma as compared to those without; consequently, cytologists should be especially attentive to smears showing high maturation from postmenopausal women.     

Histiocytes and the detection of endometrial adenocarcinoma

Histiocytes have long been recognized as part of the milieu of endometrial carcinoma in gynecologic smears. In an effort to determine whether a quantitative assessment of histiocytes, especially in the absence of endometrial cells, could increase the effectiveness of the cervicovaginal smear for diagnosis of endometrial carcinoma, smears obtained prior to a tissue diagnosis of endometrial adenocarcinoma were evaluated from 44 postmenopausal women. Smears from 97 age-matched patients in the same clinic were also evaluated and used as a control group for the endometrial carcinoma patients. All smears were evaluated for the presence of histiocytes and for the presence of benign or malignant endometrial cells, with the histiocytes quantitated as minimal (less than 5 per high-power field [HPF]), moderate (5 to 10/HPF) or heavy (greater than 10/HPF). Sensitivity and specificity were calculated to assess the role of histiocytes in the presence and in the absence of endometrial cells using cytologic findings. Our data indicate that the presence of moderate or heavy numbers of histiocytes on cervicovaginal smears of postmenopausal women increased the cytologic sensitivity from 61% to 82% when considered a marker of disease along with endometrial cells. These results suggest that attention to the presence of histiocytes on cervicovaginal smears may increase the utility of cytology for the diagnosis of endometrial lesions and may be a useful guideline for the cancer-related gynecologic examination.     

Sensitivity and insensitivity of breast cancer to tamoxifen

Tamoxifen is the endocrine treatment of choice for breast cancer. In several laboratory models in vivo tamoxifen is a tumoristatic agent. When MCF-7 breast cancer cells are inoculated into athymic mice, palpable tumors do not grow unless the animals are treated with estrogen, and tamoxifen inhibits estrogen-stimulated growth. If tamoxifen is stopped, tumors regrow. These results suggest that adjuvant tamoxifen therapy should involve long treatment periods (even lifetime) to prevent tumor recurrence. Unfortunately resistance to therapy and patient relapse inevitably occur, and such disease recurrence involving tamoxifen resistance is difficult to treat successfully. A laboratory model of endocrine therapy failure has been developed. When athymic mice with MCF-7 tumors are treated for 6–8 months with tamoxifen, several tumors grew and continued to grow in tamoxifen-treated mice. These estrogen receptor-positive tumors grow with either tamoxifen or estradiol. Tamoxifen-stimulated tumor growth has been observed in human endometrial tumors implanted into athymic animals. Growth of these tamoxifen-stimulated tumors can be inhibited with the pure antiestrogen ICI 164,384 upon withdrawal of tamoxifen. These data are discussed in terms of treatment strategies for tamoxifen-failed patients.     

Peritoneal washings in endometrial carcinoma. A study of 298 patients with histopathologic correlation

OBJECTIVE: To correlate findings of peritoneal washings in patients with endometrial carcinoma with histologic parameters. STUDY DESIGN: Between 1995 and 1998, 298 women with endometrial carcinoma were treated by hysterectomy with intraoperative peritoneal washings (PW) at Memorial Sloan-Kettering Cancer Center. All cytology and pathology slides were available for review. Pathologic parameters of hysterectomy specimens were evaluated and correlated with the findings of PW. RESULTS: Thirty-two patients (10.7%) had abnormal PW. Two hundred sixty-two had endometrioid adenocarcinoma; 26 of them had abnormal PW (10.0%). Thirty-six patients had other histologic subtypes (papillary serous carcinoma, clear cell carcinoma and adenosquamous carcinoma), and six of them had abnormal PW (16.7%). The incidence of abnormal PW in the two groups was not significantly different (P = .78). Among 26 patients with endometrioid adenocarcinoma and abnormal PW, there were 17 cases (9.9%) of International Federation of Gynecology and Obstetrics (FIGO) grade 1, 7 (12.7%) of grade 2 and 2 (5.7%) of grade 3 (P = .56). Ten cases (14.9%) had no myometrial invasion, 10 (7.0%) had myometrial invasion of < or = 50% of myometrial thickness, and 6 (11.5%) had invasion of > 50% of myometrial thickness (P = .18). Vascular invasion was present in 8 cases (14.8%) and absent from 17 (8.2%) (P = .14). Eighteen patients (7.6%) had stage I/II disease, and eight patients (30.8%) had stage III/IV disease (P = .001). Among 298 patients, cervicovaginal smears performed before surgery were available for review in 76. Five of the 7 patients (71.4%) with abnormal PW and 37 of the 69 patients (53.6%) with normal PW had abnormal Pap smears (P = .45). CONCLUSION: Abnormal PW did not correlate with histologic subtypes, FIGO grade, depth of myometrial invasion, vascular invasion or abnormal Pap smears. A significantly higher incidence of abnormal PW was associated with stage III/IV disease.     

Prevalence of psammoma bodies in Papanicolaou-stained cervicovaginal smears

Reports from sequential series of 234,318 cervicovaginal smears from a period of three years were reviewed to ascertain the prevalence and significance of psammoma bodies. Seven smears contained psammoma bodies. Three of the seven were associated with benign conditions and four were associated with a cancer (two serous papillary endometrial adenocarcinomas, one ovarian serous cystadenocarcinoma and one serous papillary carcinoma of the peritoneum). The prevalence of psammoma bodies in benign cases was much higher than reported in previous studies, in which most findings of psammoma bodies were associated with malignancy, particularly ovarian carcinoma. A consistent and useful feature in distinguishing psammoma bodies associated with benign or malignant disease was the presence of a few adherent small bland-appearing glandular cells in benign disorders and adherent malignant glandular cells in cases of carcinoma. A more conservative work-up may be merited in young women with clearly benign cells associated with psamoma bodies in a cervicovaginal smear and an otherwise negative physical examination and noncontributory endometrial sampling.     

The effect of tamoxifen on cervical squamous maturation in Papanicolaou stained cervical smears of post-menopausal women

Using cervical smears obtained as part of routine gynaecological examinations, a retrospective study of the effects of the drug tamoxifen on squamous epithelial maturation of the cervix of post-menopausal women being treated for advanced breast cancer was made. The degree of squamous epithelial maturation was quantitated by using the Maturation Index and the Maturation Value. Although tamoxifen is a synthetic, non-steroidal compound classified as anti-oestrogenic, the findings indicate that this drug commonly produces a level of squamous maturation indicative of oestrogenic stimulation in Papanicolaou stained cervical smears from post-menopausal patients receiving this drug. Knowledge of the oestrogenic effect of tamoxifen in the cervix can obviate clinical concern about endometrial carcinoma.     

Cytologic features of endometrial papillary serous carcinoma

Endometrial papillary serous carcinoma (EPSC) is an uncommon variant of endometrial carcinoma that histologically resembles ovarian serous carcinoma and has an aggressive clinical course. The cytomorphologic features of 17 patients with histologically confirmed EPSC of the endometrium were reviewed and compared with those of 20 patients with histologically typical endometrial adenocarcinoma (TEC). Preoperative cervicovaginal Papanicolaou smear results were available from 14 of the 17 patients with EPSC; 10 (71%) were positive, 1 (7%) was suspicious and 3 (21%) were negative for malignancy. Initial cervicovaginal smear results were available from all 20 patients with TEC; 7 (35%) were positive, 4 (20%) were atypical or suspicious and 9 (45%) were negative for malignancy. Twelve patients with EPSC had peritoneal washings or fluids examined; seven were positive and five negative. Twelve patients with TEC had peritoneal washings or fluids examined; two (17%) were positive and ten (83%) were negative. The cervicovaginal smears from patients with EPSC revealed numerous large tumor cells (with prominent nucleoli) frequently arranged in papillary clusters with background necrosis and, in two cases, amorphous material suggestive of psammoma bodies. In contrast, the smears of patients with TEC showed small to medium-sized cells with extensive phagocytosis and many background histiocytes. The diagnosis of EPSC should be considered when the cervicovaginal smear contains numerous papillary groups of large tumor cells with macronucleoli but without prominent phagocytosis, especially when structures suggestive of psammoma bodies are present. The peritoneal fluids in these patients are more often positive than in patients with TEC, a finding consistent with the propensity of EPSC to involve peritoneal surfaces.     

Effects of chemotherapy and tamoxifen on cervical and vaginal smears in bone marrow transplant recipients

OBJECTIVE: To clarify the importance of squamous and glandular atypia in the genital tracts of women undergoing high-dose chemotherapy and receiving tamoxifen. STUDY DESIGN: The pathology records of 769 female bone marrow transplant recipients from a five-year period at Duke University Medical Center were reviewed. One hundred fifteen cervicovaginal smears from 78 patients were available for evaluation; of these, 85 smears from 61 patients were selected. Only cases from patients with a complete medical history, including menopausal status and therapeutic regimen, were included in this study. Forty-five cases were from patients treated with chemotherapy alone, and 40 were from patients treated with a combination of chemotherapy and tamoxifen. RESULTS: A normal cellular pattern was the most common finding. Reactive cellular changes associated with therapy effect were identified in 21% of cases. In patients treated with chemotherapy alone, an atrophic smear pattern in a premenopausal woman was identified in 27% of cases. Squamous epithelial cell abnormalities were identified in approximately the same proportion of patients whether they received chemotherapy alone or with tamoxifen. Glandular changes were uncommon. CONCLUSION: The most common finding was a normal smear pattern. An atrophic smear was more commonly found in patients treated with chemotherapy alone than in those treated with both chemotherapy and tamoxifen. Squamous epithelial cell abnormalities are most probably independent of treatment effect. Glandular changes were rare in patients treated with chemotherapy, alone or in combination with tamoxifen.     

Clinical significance of atypical glandular cells of undetermined significance. A follow-up study from an academic medical center

OBJECTIVE: To determine the rate of atypical glandular cells of undetermined significance (AGUS) and the incidence of subsequent clinically significant lesions. STUDY DESIGN: A computer-based search of our cytology laboratory files was performed for cervicovaginal smears diagnosed as AGUS from January 1996 to December 1996. RESULTS: In 43,456 cervicovaginal smears examined during the 12-month period, AGUS was reported in 222 (0.5%) cases, with follow-up in 191 (86.0%) (133 [59.9%] biopsies and 58 [26.1%] repeat cervicovaginal smears). Among the patients with repeat cervicovaginal smears, 1 (1.7%) had a high grade squamous intraepithelial lesion, and 10 (17.2%) had persistent AGUS/atypical squamous cells of undetermined significance; the remainder were within normal limits. Thirty-three (24.8%) patients had preneoplastic or neoplastic, squamous or glandular lesions on biopsy (8 [6.0%] cervical intraepithelial neoplasia [CIN] 1, 18 [13.5%] CIN 2/3 and 7 [5.3%] endometrial adenocarcinomas). Half the patients with CIN 2/3 also had evidence of endocervical gland involvement. Squamous lesions were seen more commonly in premenopausal women, while glandular lesions were noted predominantly in postmenopausal women. Patients with a prior abnormal gynecologic history or a concomitant diagnosis of squamous intraepithelial lesion (SIL) had a higher incidence of significant lesions on subsequent biopsy. CONCLUSION: Our incidence of AGUS was 0.5%, similar to that in other published reports. AGUS is associated with a significant number of squamous or glandular, premalignant or malignant lesions. A majority of these lesions are high grade SIL, often with endocervical gland involvement. A small but significant number of patients had a glandular malignancy. Our results justify close and persistent follow-up for patients with a diagnosis of AGUS on cervicovaginal smears.     

Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women

OBJECTIVE: To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. STUDY DESIGN: From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. RESULTS: Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. CONCLUSION: Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.     

Cervicovaginal and endometrial cytology in ovarian cancer

The clinical significance of cytologic examination was studied in 114 patients with ovarian cancer who had received preoperative cytologic examinations. The overall positive rate of the cytologic examinations was 26.3% (30 of 114): 22 (19.3%) of the 114 cases had positive cervicovaginal smears while 13 of 31 endometrial aspiration smears (41.9%) were positive. The positive rate was not related to the volume of ascites but rather to its presence or absence. Thus, if ascites was observed, the positive rate was about 2.1 times higher than if it was absent. In two of four cases of ovarian cancer with no endometrial invasion but a positive cytologic examination of ascitic fluid, fallopian tube specimens contained cancer cells; this suggests that ovarian cancer cells may reach the cervix and/or vagina by passing through the fallopian tube, particularly if ascites is present. Since cytologic examination, especially of endometrial aspiration smears, shows a high positive rate if ovarian cancer cells are observed in the abdominal cavity, cytology should be used as an important ancillary method for the assessment of ovarian cancer.     

Ovarian carcinoma identified by psammoma bodies in the cervicovaginal and endometrial smears

A case of early bilateral serous papillary adenocarcinoma of the ovaries in an asymptomatic 58-year-old woman was diagnosed by the discovery of psammoma bodies in routine cervicovaginal and endometrial smears. Multiple small foci of carcinoma in-situ involving both fallopian tubes were also present. The significance of psammoma bodies in the cervicovaginal smear is discussed and the literature on the subject briefly reviewed.     

Impact of liquid-based gynecologic cytology on an HIV-positive population

OBJECTIVE: To examine the imprint of liquid-based technologies for cervicovaginal cytology on HIV-positive women, who are at high risk for cervical intraepithelial neoplasia. STUDY DESIGN: We performed a retrospective search of the cytopathology files of Johns Hopkins Hospital for the cervicovaginal cytology of HIV-positive women to examine the effect of liquid-based technology on this population. RESULTS: Significant intraepithelial lesions (SILs) (low grade SIL or greater) were identified in 24% of the conventional smears and 23% of the liquid-based cytology. Atypical squamous cells of undetermined significance (ASCUS)/atypical glandular cells of undetermined significance was diagnosed in 15% of the conventional smears and 9% of the liquid-based preparations (P = .02). In patients with ASCUS diagnoses and tissue follow-up within 7 months, significant SILs were identified in 29% with conventional smears and in 65% with liquid-based cytology. CONCLUSION: There was no statistically significant difference in the rate of SILs between conventional smears and liquid-based cervicovaginal preparations in HIV-positive women. The diagnosis of ASCUS on liquid-based cytology may have an increased likelihood of representing a significant SIL in comparison to conventional smears. For the high-risk, HIV-positive population, immediate colposcopy and biopsy may be warranted following ASCUS diagnoses on liquid-based cytology.     

Endocyte endometrial smears in the cytodiagnosis of endometrial carcinoma

The cytologic diagnosis of endometrial cancer using material obtained with the Endocyte endometrial sampler was assessed for 874 patients. The samples obtained were smeared directly on slides for fixation and staining; the smears were more difficult to assess than cervicovaginal smears, however, due to the presence of blood, the small size and density of the cells and the flattened three-dimensional architecture of the tissue fragments obtained. Only 8.2% of the samples were classified as inadequate; repeat sampling in some of those cases produced diagnostic material. All 12 cases of carcinoma (including one case in a woman less than 40 years of age) were diagnosed by cytology as malignant; however, the original cytologic sample in one of those cases was inadequate. For the diagnosis of benign versus malignant, cytology had a sensitivity of 92%, a specificity of 100% and predictive value of 100%. Cytology also diagnosed as suspicious the smears from 5 of 13 cases of endometrial hyperplasia and 2 of the 9 cases of endometrial polyps. The cytologic findings for benign and malignant samples are described and illustrated in detail. Relative to other endometrial sampling devices, the Endocyte is inexpensive and was easily used by the gynecologist and well tolerated by the patients, with no complications and minimal discomfort.     

The Prescription Pattern of Chinese Herbal Products That Contain Dang-Qui and Risk of Endometrial Cancer among Tamoxifen-Treated Female Breast Cancer Survivors in Taiwan: A Population-Based Study

Purpose

The increased practice of traditional Chinese medicine worldwide has raised concerns regarding herb-drug interactions. We analyzed the usage of Chinese herbal products containing dang-qui and investigated whether dang-qui therapy increases endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan.

Methods

All patients newly diagnosed with invasive breast cancer who received tamoxifen treatment from January 1, 1998, to December 31, 2008 were selected from the National Health Insurance Research Database. The usage, frequency of service and type of Chinese herbal products containing dang-qui prescribed across the 31,970 survivors were evaluated. Logistic regression method was employed to estimate the odds ratios for utilization of Chinese herbal products containing dang-qui. Cox proportional hazard regression was performed to calculate the hazard ratio of endometrial cancer associated with dang-qui use within the cohort.

Results

Almost one in two study subjects had used dang-qui. Among 31,938 tamoxifen-treated breast cancer survivors, 157 cases of subsequent endometrial cancer were identified. The hazard ratio for development of endometrial cancer among breast cancer survivors aged 20–79 years who had taken dang-qui after tamoxifen treatment was decreased compared to survivors who had never used dang-qui (HR: 0.61, 95%CI: 0.44–0.84). To minimise potential confounding factors, women with breast cancer in the reproductive age were excluded from further analysis, and the negative relationship between dang-qui consumption and subsequent endometrial cancer among breast cancer survivors aged 55–79 years was still observed, although not significantly (HR: 0.74, 95%CI: 0.46–1.17).

Conclusions

Dang-qui consumption is common among breast cancer survivors aged 20–79 years and seems decrease the risk of subsequent endometrial cancer after less than a cumulative dose of 7,500 mg of tamoxifen treatment.     

Effects of low-dose tamoxifen on breast cancer biomarkers Ki-67, estrogen and progesterone receptors

Breast carcinoma is the most common malignancy among women and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with a standard dose of the drug, and there has been a reduction in healthcare costs and side effects.The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days.A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group-without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions. Patients underwent incisional biopsy before treatment and 14 days later a tumor tissue sample was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and α was set at 5%.Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p = 0.627), estrogen receptor (1D5) (p = 0.296) and progesterone receptor positivity (PgR 636) (p = 0.381).In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki-67 (MIB-1) was 24.69% before and 10.43% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.53% before and 25.99% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.34 before and 29.59% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p < 0.001).Tamoxifen significantly reduced monoclonal antibody Ki-67 (MIB-1), estrogen receptor (1D5) and progesterone receptor positivity (PgR 636) in the breast epithelium of carcinoma patients treated with a 10 mg dose of tamoxifen for 14 days.     

Pap smears in women with endometrial carcinoma

OBJECTIVE: To correlate Pap smear findings with the histology of endometrial carcinoma and stage of the disease. STUDY DESIGN: Between 1995 and 1998, 76 women with endometrial carcinoma, having had Pap smears done within two to three months of hysterectomy at Memorial Sloan-Kettering Cancer Center, formed the basis for this study. All Pap smears and histologic sections were reviewed. RESULTS: Thirty-four patients had normal Pap smears (45%), and 42 had abnormal ones (55%). The mean age of the two groups was 65.1 and 65.2 years, respectively. Histologic subtypes included 44 International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid adenocarcinoma (low grade) and 32 high grade carcinomas, including 19 FIGO grade 2 or 3 endometrioid adenocarcinomas, 5 papillary serous carcinomas (PSC), 2 clear cell carcinomas (CC), 1 adenosquamous carcinoma, 3 endometrioid adenocarcinomas mixed with PSC and 2 endometrioid adenocarcinomas mixed with CC. The proportions of patients with low and high grade tumors with abnormal Pap smears were 43% (19/44) and 72% (23/32), respectively (P=.01). The proportions of patients with abnormal Pap smears and no myometrial invasion, invasion of <50% and >50% myometrial thickness were 40% (8/20), 62% (26/42) and 57% (8/14), respectively (P =.27). Vascular invasion was identified in 56% (9/16) of patients with abnormal Pap smears and in 55% (33/60) of patients with normal ones (P = .93). The proportions of patients having abnormal Pap smears with stage I and stages II, III or IV disease were 48% (30/62) and 86% (12/14), respectively (P =.01). CONCLUSION: Although the Pap smear is not a sensitive screening test for endometrial cancer and a negative Pap smear does not rule it out, this study revealed that abnormal Pap smears are significantly associated with high grade of tumor and stage II-IV endometrial carcinoma. However, they are not associated with patient age, depth of myometrial invasion or vascular invasion.     

Tamoxifen inhibits lipoprotein activity: in vivo and in vitro studies

Tamoxifen, a nonsteroidal antiestrogenic antitumor agent, has weak estrogen-like effects on lipid metabolism, however, the mechanism remains unknown. We previously reported that tamoxifen decreases the activity of lipoprotein lipase (LPL), a key enzyme in triglyceride metabolism, in patients with breast cancer. This study evaluated the effect of tamoxifen on LPL activity in vitro and in vivo. In experiment 1, total cholesterol, triglyceride, adipose tissue weight, and LPL activity of post-heparin plasma were measured in ovariectomized female rats with and without tamoxifen treatment. In experiment 2, purified very-low-density lipoprotein (VLDL) and purified LPL were incubated with and without tamoxifen or estrogen, and the triglycerides in VLDL were measured using an enzymatic method. In experiment 1, total cholesterol and adipose tissue weight decreased significantly in tamoxifen-treated rats (p < 0.001 and p < 0.01, respectively). Triglyceride measurements were not significantly different between the two groups, however, the LPL activity was lower in tamoxifen-treated rats (p < 0.005). In experiment 2, triglycerides in VLDL were significantly higher after VLDL and LPL were incubated with tamoxifen and estrogen (p < 0.005). We concluded that tamoxifen inhibits the hydrolytic activity of LPL in vivo and in vitro. This mechanism may explain the elevated serum triglyceride levels in some patients treated with tamoxifen.     

Atypical squamous cells of undetermined significance in women over 55. Comparison with the general population and implications for management.

OBJECTIVE: To determine the significance of atypical squamous cells of undetermined significance (ASCUS) in patients 55 years or older. STUDY DESIGN: From January 1994, to January 1997, 8,175 cervicovaginal smears were obtained from patients 55 years or older (mean age, 64.8; range, 56-84) at University Hospitals of Cleveland. Ninety-six of these patients were diagnosed with ASCUS only or ASCUS with a qualifying statement on the smear. Patient records, follow-up cervicovaginal smears and biopsies were reviewed for a period of one to four years following the diagnosis of ASCUS. RESULTS: The incidence of ASCUS only or ASCUS with a qualifying statement for patients 55 years or older was 1.8%. The ASCUS:SIL ratio was 2.6:1. An estrogen stimulation test was recommended in two cases. Women older than 55 with ASCUS were three times more likely to be receiving hormonal replacement therapy than similar-aged women with normal cervicovaginal smears. Follow-up cervicovaginal smears or biopsies were obtained on 93 (80 cervicovaginal smears, 13 biopsies). The results were the following: LSIL (13), squamous carcinoma in situ (1) and ASCUS (53); the remainder of the cases were normal. In the patients who received a second diagnosis of ASCUS, follow-up cervi covaginal smears or biopsies revealed low grade dysplasia in six. CONCLUSION: Although the incidence of ASCUS and the frequency of underlying dysplasia is lower in postmenopausal women than the general population, there is still a real risk that a postmenopausal woman with ASCUS has underlying intraepithelial neoplasia. Therefore, these patients should be managed as is the general population.