Type 1 and type 2 cervical carcinomas: some cervical cancers are more difficult to prevent with screening.

Although the Papanicolaou (Pap) smear is medical history's most successful cancer screening test, some cervical cancers are more difficult to prevent with screening than others. Cervical cancers that are difficult to prevent are seen disproportionately among interval cancers arising in previously screened women and in Pap test litigation. These include (i) rapidly progressing cervical cancers; (ii) cervical cancers in younger women; (iii) glandular cervical cancers; and (iv) cervical cancers in elderly women. Screening protocols have generally been designed to optimize prevention of slower-growing cervical squamous carcinomas in middle-aged women. To focus further attention on the heterogeneous screening challenges posed by different cervical cancers, we designate the more screening preventable majority as type 1 cervical cancers and the more difficult to prevent minority as type 2 cervical cancers. We review available data on why some cervical cancers are more difficult to prevent with screening and newer methods that may improve prevention.

Cultured neonatal rat cardiomyocytes display differences in glucose uptake and sensitivity to dexamethasone related to maternal diet.

Feeding a low protein (LP) diet in rat pregnancy is associated with impaired cardiovascular health and function, possibly as a result of tissue remodelling. To assess whether cardiomyocytes retain differences induced by protein restriction, cells from neonatal rats exposed to control or LP diets in utero were cultured for a period of 10 days. At the end of this period, no differences in cell size, proliferation differentiation or metabolic function were noted. When treated with dexamethasone (0.1-10 µM) for 2 days, it was noted that insulin-stimulated glucose uptake was enhanced, but only in cells from LP rats. Increased glucocorticoid sensitivity of cardiomyocytes from LP rats could not be explained by differential expression of the glucocorticoid receptor or the glucose transporters, GLUT1 and GLUT4. The findings of the study suggest that sensitivity to endocrine signals may be permanently programmed by undernutrition through mechanisms that are preserved in vitro.

Cutaneous angiosarcoma in an irradiated breast after breast conservation therapy for cancer: association with chronic breast lymphedema.

The authors report a rare case of cutaneous angiosarcoma arising more than 5 years after excision of a 1.5 cm invasive ductal cancer of the breast. All lymph nodes were negative for metastatic breast cancer in this 68-year-old female. The patient had postoperative therapy consisting of 5040 cGy over a 5 week period using a 6 Megavolt linear accelerator. After radiation therapy to the breast and axillae, the patient developed chronic hard, taut edema of the irradiated right breast. Tamoxifen was administered for 5 years and then stopped. Three months after the cessation of tamoxifen, cutaneous angiosarcoma was found by skin biopsy. A complete mastectomy removed all tumor with clear margins. There are less than 60 cases of radiation associated breast angiosarcoma found in the literature. The presence of chronic lymphedema in the breast after radiation therapy possibly contributes to the development and is an early warning sign for later development of secondary angiosarcoma. The characteristic purple nodules and discoloration of the irradiated skin is the hallmark to suspect the diagnosis. The authors recommend long-term clinical surveillance for this tumor for all patients who have received breast conservative surgical therapy with concomitant radiation therapy for primary breast cancer.

Medicolegal affairs. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: Increasing litigation over alleged false negative cervical cytologic (CC) smears threatens the viability of this test for cervical cancer detection. The problem appears to be largely American but is beginning to appear in some other countries. In the vast majority of cases there is either a settlement or jury verdict for the plaintiff based largely on the testimony of expert witnesses. Cases are judged on an individual basis without significant consideration of the general performance of the CC smear in laboratories operating in compliance with a wide array of laboratory regulations and with documented and comprehensive quality control practices in place. It is acknowledged that there are problem laboratories and cytology practitioners. There is an emerging issue of automated preparation and screening devices and issues of informed patient consent. CONSENSUS POSITION: Cytology professionals have done an extraordinary and commendable job of educating the public about the benefits of the CC smear. We have been less successful and conscientious about explaining and defining the limitations of the CC test. There is a need for public and professional education as to the benefits and limitations of the CC smear for cervical cancer detection. The process suggested is to work with women's groups, public health agencies, government agencies, and state and national legislatures and to coordinate professional committees working on liability issues. Contextual information could be included with the CC smear report to indicate that a negative report confers a low probability of developing cervical cancer. It is suggested that appropriate language and a menu of statements be developed. Increased efforts should be directed to physician education with respect to informed consent concerning the benefits and limitations of CC smear testing and the application of new technology to improve smear accuracy. The process should include development of appropriate statements on the use of alternative technology. The profession should develop "process guidelines" for review of CC smears in the context of possible litigation, including standardized methods for blind slide review of smears that reduce or eliminate context and outcome bias. It is suggested that review panels be anonymous, that the process be standardized and that there be limitations on liability for participating organizations. Professional cytopathology and pathology societies should formulate acceptable guidelines for expert witnesses. The standards should be applicable to both defendant and plaintiff experts. All materials to the extent practical, including consultant opinions, should be available for peer review. Professional cytopathology and pathology societies should monitor expert testimony for objectivity and scientific accuracy. ONGOING ISSUES: For the near future, litigation will continue to focus on false negative CC smears on a case-by-case basis. Laboratories and individuals can reduce the risk of malpractice liability by directing their attention to proactive quality control and quality assurance methods. In the final analysis, consumer education about the benefits and limitations of the test is key to limiting malpractice claims. To stem the tide of continued medicolegal challenges to the integrity of cytology practice, the cytology community has now focused its efforts on developing and utilizing standards that convey to patients, attorneys and cytologists the contemporary status of and reasonable expectations for the practice of cytology. Guidelines such as those for uniform reporting terminology and clinical management of cervical abnormalities form the basis of cytology practice standards on which legal standards of practice can be based. Consensus conference reports, clinical management trials and scientifically valid studies of false negative rates that analyze the type, frequency and cause of missed cases represent sounder methods of establishing defensible

Increased detection of epithelial cell abnormalities by liquid-based gynecologic cytology preparations. A review of accumulated data.

OBJECTIVE: To review published and other available data comparing the effectiveness of liquid-based cytology preparations in detecting epithelial cell abnormalities in cervicovaginal (gynecologic) cytology as compared to the conventional Papanicolaou test. STUDY DESIGN: Available split-sample data comparing liquid-based gynecologic cytology preparations with the conventional cervical cytologic test were collated from published studies, unpublished studies reported on at professional meetings or in the press, and from Food and Drug Administration Premarket Clinical Trials on ThinPrep and AutoCyte PREP. Data were stratified with regard to use of newer preparatory instrument models, use of varying collection devices and different split-sample protocols. RESULTS: Available data from split-sample studies of liquid-based methods showed overall increased detection of epithelial cell abnormalities. Results have varied considerably from study to study and appear to be influenced by collection protocol methods and probably by collection devices' different delivery of cellular material in split-sample studies, first to the conventional smear and second to the liquid-based medium. Newer preparatory instrument models may also enhance detection. CONCLUSION: Liquid-based gynecologic cytology preparations increase detection of epithelial cell abnormalities, as compared to the conventional, single-slide cervical cytologic smear, based on available data from split-sample studies. The true potential impact of these methods in enhancing detection of epithelial cell abnormalities awaits accumulation of data from direct-to-vial studies, especially data on detection of biopsy-confirmed high grade squamous intraepithelial lesions from a wide variety-of clinical practice settings.

Results of blinded rescreening of Papanicolaou smears versus biased retrospective review.

Review of Papanicolaou smear cases that are the focus of litigation typically takes place in a biased setting with foreknowledge of an adverse patient outcome (outcome bias) or litigation and with more time allotted for slide review than is available in normal screening situations. Factors that normally mitigate against overly aggressive slide interpretation, such as concern about false-positive diagnoses and possible unnecessary surgical procedures and expense, are absent. This results in a tendency toward overly aggressive interpretation of questionable or uncertain cytologic abnormalities. These factors can be minimized by a variety of blinded slide review formats with the goal of simulating normal, on-the-job, prospective screening as in actual practice. Despite some limitations, blinded rescreening can provide valuable insight into the relative degree of difficulty involved in interpreting specific slides. The difficulty of a case in question is arguably the second most important factor, after assessment of overall laboratory performance, in determining whether a reasonable standard of practice has been followed.

Immunohistochemical staining for Ki-67 antigen, carcinoembryonic antigen, and p53 in the differential diagnosis of glandular lesions of the cervix.

Cytoplasmic carcinoembryonic antigen (CEA) positivity assists in the distinction of benign and malignant glandular lesions of the cervix, but some cases remain problematic. The accumulation of p53 protein and an increased proliferative index, as measured by the expression of Ki-67 antigen, have not been used as adjuncts to the diagnosis of these lesions. Immunohistochemical stains for CEA, p53 protein, and Ki-67 antigen were performed on 31 formalin-fixed, paraffin-embedded endocervical lesions including invasive adenocarcinoma, adenocarcinoma in situ, adenoma malignum, tunnel clusters, florid microglandular hyperplasia, mesonephric remnants, florid glandular hyperplasia, atypical glandular hyperplasia, and normal controls. Ki-67 antigen expression was quantitated as negligible, low, moderate, or high on the basis of the percentage (< 5%, 5-10%, 11-40%, > 40%, respectively) of glandular nuclei that were positive with MIB-1 antibody. Strong staining of more than 10% of the glandular epithelial nuclei was interpreted as positive for p53 protein overexpression. CEA positivity was determined by either diffuse or focal cytoplasmic staining of columnar epithelial cells equalling glycocalyceal staining in intensity. The combination of CEA positivity and a moderate-to-high proliferative index was limited to cases of invasive adenocarcinoma, adenoma malignum, and adenocarcinoma in situ, as compared with benign glandular lesions (P = 0.005). A high Ki-67 proliferative index and/or CEA positivity were features of malignant lesions rather than benign mimickers; there were no false positives or false negatives. Similarly, only malignant neoplasms shared a combination of p53 overexpression and CEA positivity (P = 0.043). The combination of cytoplasmic CEA positivity in glandular cells and a moderate-to-high Ki-67 proliferative index is diagnostic of malignancy in endocervical lesions. With the exception of florid microglandular hyperplasia, p53 expression is only seen in neoplastic lesions of the endocervix. An immunohistochemical battery consisting of MIB-1 (Ki-67), p53 protein, and CEA is useful in discriminating between benign and malignant endocervical lesions.

Chorionic villi or trophoblastic tissue in uterine samples of four women with ectopic pregnancies.

The diagnosis of early ectopic pregnancy remains challenging for the gynecologist. Although early detection of a suspected pregnancy has been facilitated by quantitative beta human chorionic gonadotropin studies and ultrasonography, a patient subgroup remains with an ambiguous presentation. In this group of patients, the clinician must rely on microscopic examination of products of conception in a uterine curettage specimen to rule out the presence of an extrauterine pregnancy. The presence of an implantation site, chorionic villi, or trophoblastic tissue in uterine curettage samples is conventionally held as definitive evidence of an intrauterine pregnancy. We present a series of four cases that challenge this convention. In these cases, chorionic villi or an implantation site were identified in uterine samples of pregnant women who each ultimately proved to have an ectopic pregnancy. If clinical suspicion is high, the finding of either chorionic villi or an implantation site should not preclude further workup of a possible ectopic pregnancy. In cases where only a few villi or a single chorionic villus are identified, other signs of intrauterine implantation such as intermediate trophoblastic cells, hyalinized vessels, and a fibrinoid matrix should be sought to establish firmly the diagnosis of an intrauterine pregnancy.

Transitional cell carcinoma of the endometrium.

Only one case of endometrial transitional cell carcinoma (TCC) has been previously reported in the literature. We report a second case. In both the previously reported case and in this case there was a separate focus of TCC in the adnexa. Both patients were treated with adjuvant whole pelvic radiation and are alive and without evidence of disease at 5 years and 15 months, respectively. Study of more cases of endometrial TCC is needed to determine whether this type of endometrial carcinoma has a more favorable response to radiation therapy than other types of endometrial carcinoma with extrauterine spread.