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.

Leydig cell hypoplasia causing male pseudohermaphroditism: diagnosis 13 years after prepubertal castration.

An 11-yr-old patient with male pseudohermaphroditism who was castrated at nine days of age and raised thereafter as a female was evaluated to determine the cause of abnormal sexual differentiation. Stimulation with ACTH for 8 h revealed no abnormality in the biosynthesis of cortisol or adrenal androgens. The administration of fluoxymesterone (10 mg, orally, daily) for 5 weeks at age 13 yr led to significant decrements in serum levels of sex steroid-binding globulin and T4-binding globulin to a degree similar to that found in 2 normal men, but no change in the basally elevated levels of FSH and LH. LH bioactivity was normal in the rat Leydig cell bioassay. Skin fibroblasts cultured from a labial skin biopsy revealed normal 5 alpha-reductase activity and normal androgen receptors. Reexamination of the original testis specimens by light microscopy failed to reveal Leydig cells. Furthermore, when immunoperoxidase staining for testosterone was performed on the tissue sections, only 30-35 positive cells/10 high power fields were seen. In contrast, examination of testis sections from 4 male infants who died of other causes revealed 94-836 cells/10 high power fields that stained positively for testosterone. Although hCG stimulation testing to confirm Leydig cell hypoplasia could not be done in this patient because of previous castration, this patient demonstrates that the diagnosis can be made without it by the use of immunohistochemical stains and in vivo and in vitro tests to exclude other disorders of androgen biosynthesis or androgen action.

Fibromatosis of the breast. A clinical and pathological study of 28 cases.

The clinical and pathologic findings of 28 examples of fibromatosis of the breast not involving the deep fascia or chest wall are reported. Five of the 20 lesions treated by local excision recurred. Recurrences developed within a 4 to 8 month period following surgery in four of the five instances, and 6 years after surgery in one instance. One lesion recurred five times over a period of 3 years. None of the patients died from their disease, and none developed a metastasis. Those lesions that recurred had been inadequately excised initially, since surgical margins showed fibromatosis. Specific histological features, such as size, cellularity, atypia, and mitotic figures, were not helpful in predicting recurrence. Although local excision appears to have been adequate in the majority (75%) of the patients, the infiltrative nature of fibromatosis necessitates documentation of tissue margins in order to avoid the possibility of recurrence. The differential diagnosis includes benign reactive processes (such as keloid and nodular fasciitis), fibrous histiocytoma, low-grade spindle-cell (metaplastic) carcinoma, and fibrosarcoma.

Liposarcoma of the breast: a clinicopathologic study of 20 cases.

The clinical and pathologic features of 13 patients with pure liposarcomas of the breast and seven patients with liposarcomas that had arisen in cystosarcomas are reviewed. Metastases occurred in three of the 13 patients with pure mammary liposarcomas, and two women died of tumor. One of the patients with a liposarcoma that had arisen in a cystosarcoma had a local recurrence one year after diagnosis but was subsequently lost to follow-up study. Fourteen of the 20 patients for whom follow-up information was available for as long as 14 years had no evidence of recurrence. Features associated with the development of recurrence, based on the cases studied here and previous reports, included the pleomorphic liposarcoma pattern and an infiltrative margin. Features associated with tumor-free survival included the well-differentiated liposarcoma pattern, male gender (two patients), and a circumscribed microscopic tumor margin. There were no axillary lymph node metastases. Follow-up data indicate that complete surgical excision of tumor with tumor-free margins is necessary, but total mastectomy and removal of the axillary tail are not required unless these procedures are needed for complete excision.

Infiltrating (intramuscular) lipomas and angiolipomas. A clinicopathologic study of six cases.

Infiltrating (intramuscular) lipomas and angiolipomas are benign mesenchymal tumors that usually appear as a deep, nontender mass within soft tissue, particularly in the extremities. The average tumor size in six cases studied was 11.2 cm (range, 2.0 to 22.0 cm). On gross examination, these tumors are circumscribed but unencapsulated, with infiltration of adjacent skeletal muscle. The correct preoperative diagnosis is seldom made, and the characteristic infiltrating pattern seen microscopically can lead to a mistaken diagnosis of sarcoma. Soft-tissue roentgenograms can be helpful in diagnosis and localization. The recommended mode of therapy is complete local excision with tumor-free soft-tissue margins. None of the six patients described here have experienced recurrence of tumor an average of two years after surgical resection. Prolonged follow-up is recommended, however, since inadequate resection can result in late tumor recurrence.

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.

Fine-needle aspiration cytology of an endometrioid-like variant of yolk sac tumor.

A 36-year-old male with a history of immature teratoma and embryonal carcinoma of the testis was admitted to the hospital for abdominal pain and fever. A CT scan revealed a large right abdominal mass. The patient's serum alpha-fetoprotein (AFP) was 46.8 ng/ml (reference < 25 ng/ml). Fine-needle aspiration (FNA) of the mass revealed malignant glandular cells. Chemotherapy was instituted, followed by resection of the large abdominal mass. The tumor was grossly encapsulated, consisting of large areas of necrotic, hemorrhagic tissue surrounded by smaller, multiloculated cysts. Microscopically, the tumor had a villoglandular pattern and variably stratified tall columnar cells. A prominent feature of the columnar cells was supranuclear and subnuclear vacuolization. Intracytoplasmic PAS-positive, diastase-resistant hyaline globules were occasionally present. AFP by immunoperoxidase was prominent within the tumor. This recurrence of the previously diagnosed testicular teratoma with embryonal carcinoma represents a yolk sac tumor with components strongly resembling endometrioid carcinoma, a variant only recently described in eight cases of ovarian origin (Clement et al.: Am J Surg Pathol 1987; 11(10):767-778). We believe this is the first reported case of an endometrioid-like variant of testicular yolk sac tumor and also the first report of the FNA cytology findings in this variant.

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.

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

Liquid preservation of baboon red blood cells in acid-citrate-dextrose or citrate-phosphate-dextrose anticoagulant: effects of washing liquid-stored red blood cells.

Autologous baboon RBC stored at 4 C in acid-citrate-dextrose (ACD) or in citrate-phosphate-dextrose (CPD) for 3 weeks after collection had 24-hour 51Cr posttransfusion survival values of about 77%. When 20-day-old ACD and CPD baboon RBC were washed and then stored at 4 C for 24 hours before autotransfusion, the 24-hour 51Cr posttransfusion survival values were about 81%. These values were similar to those seen in studies of human RBC preserved in an identical manner. Our results indicated that the baboon can be used to evaluate RBC preservation techniques before human volunteers are studied.

Measurement of red blood cell volume, plasma volume, and total blood volume in baboons.

Red blood cell volume was measured directly in baboons by infusion of 51Cr-labeled autologous RBC, and was indirectly estimated from the plasma volume measured with 125I-labeled albumin and the total body hematocrit. The total body hematocrit was calculated from the peripheral venous hematocrit multiplied by a correction factor; for nonanemic baboons the correction factor was 0.87, and for anemic baboons, 0.75. Within 2 weeks after the phlebotomy (150 ml of blood), the baboon's RBC volume was restored to normal. Posttransfusion survival of baboon RBC can be measured accurately in nonanemic baboons; the preserved RBC can be labeled with 51Cr and the RBC volume of the baboon can be measured indirectly from the plasma volume measured with 125I-labeled albumin and the total body hematocrit.

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.