Gelatinase A expression in endothelial cells is regulated by at least two cis-acting promoter elements.

Increased expression of gelatinase A is associated with both angiogenesis and alterations in blood vessel structure. Heart-derived endothelial cells derived from spontaneously hypertensive rats (SHR) were found to express significantly more gelatinase A in culture, both at the protein and mRNA level, than endothelial cells from normotensive Wistar-Kyoto (WKY) rats. Other matrix metalloproteinases, as well as their tissue inhibitors, were not differentially regulated. A 1683 bp gelatinase A promoter fragment linked to a luciferase reporter demonstrated up to 40-fold more activity when transfected into SHR-derived cells versus WKY-derived cells. The promoter region between -1324 and -1272, previously termed RE1, contributed up to a five-fold increase in basal promoter activity in both cells, but contributed only 12% of the promoter activity in SHR-derived cells compared to 85% in WKY-derived cells. In SHR-derived cells, but not in WKY-derived cells, a second region between -1435 and -1375, termed RE2, contributed 60% of the total activity of the 1683 bp promoter fragment. Both electrophoretic mobility shift assays and Southwestern blots demonstrated differences in RE2-specific binding factors in nuclear extracts derived from the two cell types. SHR-derived endothelial cells thus represent a new model system to study the regulation of gelatinase A expression, which itself may contribute to the abnormal vascular structure seen in the SHR.

Kaposi's sarcoma involving the lung in patients with the acquired immunodeficiency syndrome.

To determine the distinguishing features of pulmonary Kaposi's sarcoma (KS) in patients with the acquired immunodeficiency syndrome (AIDS), we compared three groups of patients, 16 with endobronchial KS, 15 with endobronchial KS and an opportunistic lung infection, and 40 with Pneumocystis carinii pneumonia (PCP) without concomitant pulmonary KS. The majority of pulmonary KS patients had extensive cutaneous disease at the time of pulmonary diagnosis, and the diagnosis of pulmonary KS was easily established by the characteristic appearance of the endobronchial lesions. Dyspnea, fever, and cough were common presenting symptoms, but occurred more commonly in association with accompanying opportunistic infection. Diffuse interstitial infiltrates were observed in most patients in both groups, but the findings of nodular parenchymal densities or pleural effusion were more commonly observed in patients with pulmonary KS than in those with PCP alone. Pulmonary uptake of gallium-67 citrate or a diffusing capacity less than 80% were unusual in patients with pulmonary KS alone, but common in those with accompanying opportunistic infection or with PCP alone. Median survival in patients with pulmonary KS was only 2 months, and most patients had complicating opportunistic infections at the time of death. Pulmonary KS is generally a late and often preterminal manifestation of AIDS. Chest radiographs, gallium lung scans, and pulmonary function testing may provide diagnostic information that is helpful in distinguishing pulmonary KS from opportunistic lung infections.

Autopsy: moribund art or vital science?

The autopsy rate in the United States has fallen dramatically in the past 40 years. Factors contributing to its decline include diagnostic over-confidence among clinicians, competing demands upon pathologists, difficulties obtaining consent from families, and its costs. The benefits of autopsy are clear: confirmation, clarification, and correction of antemortem diagnoses; discovery and definition of new diseases; evaluation of new diagnostic tests, new surgical techniques, and new drugs; investigation of environmental and occupational diseases; reassurance of family members; and contributions to medical and epidemiologic research. Proposals to revive the autopsy are reviewed, including altering the method of obtaining consent, altering autopsy procedures, structuring teaching around the autopsy, training autopsy pathologists in anatomic subspecialties, reinstating minimal autopsy requirements for hospital accreditation, providing financial support, and educating the public and the medical profession about its values. Accomplishing these changes quickly will prevent loss of its many benefits to the clinician, family, hospital, and society.

Fine needle aspiration biopsy. Has its time come?

Fine needle aspiration biopsy has been undergoing a revival in the United States, but a recent survey showed that many clinicians were uncertain how to utilize this test. The scope of fine needle aspiration biopsy as practiced at the University of California, San Francisco, and the San Francisco General Hospital is described. The relevant accuracy data available in the world literature on this procedure are also reviewed.

To redeem them from death. Reactions of family members to autopsy.

Attitudes towards autopsy were examined in family members of 102 subjects who died in a university teaching hospital. The majority of responding families (88 percent) considered autopsy beneficial. Families permitting autopsy identified advancement of medical knowledge, comfort in knowing the cause of death, and reassurance that all appropriate care was given as the most important benefits. Fifty-five percent of the families of 40 subjects not undergoing autopsy declined permission and 45 percent had not been asked for such permission. The most frequent reasons given for not wanting autopsy were disfigurement of the body, stress of permitting autopsy, lack of information about autopsy, and family members' objections. Twenty-seven percent of 62 families permitting autopsy did not learn its results. Family members receiving results complained about long delays in receiving and complex terminology of autopsy reports. These findings suggest need for improvement in obtaining consent for autopsy, reporting autopsy results, and educating and counseling families of dying patients.

Enzyme histochemical characterization of chordomas.

The differential diagnosis of chordoma includes chondrosarcoma and ependymoma. We describe four cases of chordoma characterized by enzyme histochemistry in plastic-embedded sections. All the chordomas exhibited strong 5'-nucleotidase positivity localized on the plasma membrane. None of the fetal notochord remnants, chondrosarcomas, ependymomas, or chondroid chordomas tested showed such a reaction. The lack of similarity in enzyme staining between fetal notochord and chordomas is unexpected since notochord has been traditionally regarded as the source of chordomas. This staining pattern provides a marker that can be useful in differentiating chordoma from other neoplasms which have a similar appearance by light microscopy.

Cytologic diagnosis of metastatic epithelioid sarcoma. A cytologic mimic of squamous cell carcinoma.

A case of epithelioid sarcoma in a 39-year-old woman who had metastatic lesions in her lung from a primary arm tumor is presented. A review of the literature and analysis of this case did not identify any specific light microscopic or immunohistochemical way to separate definitively the lung cytologic smear in this case from squamous cell carcinoma. The authors believe cytologic smears from epithelioid sarcoma can closely mimic smears from squamous cell carcinoma. Pathologists should be alert to these similarities.

Diagnosis of Kaposi's sarcoma by fine-needle aspiration biopsy.

Fifteen cases of Kaposi's sarcoma diagnosed by fine-needle aspiration biopsy were reviewed. The diagnosis was confirmed by tissue biopsy in eight of the cases. All of the patients were homosexual males, and 13 had a previous diagnosis of AIDS. The aspirates were obtained from enlarged lymph nodes (five cases), soft-tissue masses (two cases), oral cavity lesions (seven cases), and an abdominal mass. The most characteristic cytologic features were intact tissue fragments composed of overlapping spindle cells with nuclear distortion and ill-defined cytoplasmic borders. Smaller groups of loosely cohesive spindle-shaped cells and individual spindle cells with cytoplasm were also helpful features. In the appropriate clinical setting, these cytologic features on FNAB are felt to be diagnostic of Kaposi's sarcoma.

Cytologic criteria for fibroadenoma. A step-wise logistic regression analysis.

The authors reviewed the fine-needle aspiration biopsy smears from 62 subjects with proven fibroadenoma, 60 subjects with proven ductal carcinoma, and 42 subjects with proven fibrocystic disease. All smears were coded as to the presence or absence of the following variables: epithelial cells, stroma, honeycomb sheets, antler horn clusters, naked nuclei, nucleoli, marked cellularity, foam cells, apocrine cells, anisokaryosis, atypical nuclear hyperchromasia, single cells with cytoplasm, mitotic figures, and nuclei greater than two red blood cell diameters. Step-wise logistic regression analyses were performed to determine the variables predictive of fibroadenoma. The statistical analyses selected stroma, antler horn clusters, and marked cellularity as the key cytologic criteria to differentiate fibroadenomas from fibrocystic disease. The statistical analyses selected stroma, antler horn clusters, and honeycomb sheets as the key cytologic criteria to differentiate fibroadenoma from ductal carcinoma.

Cytologic criteria to distinguish hepatocellular carcinoma from nonneoplastic liver.

The authors reviewed a series of fine-needle aspiration biopsy (FNAB) specimens of the liver to identify useful cytologic criteria to distinguish hepatocellular carcinoma (HCC) from nonneoplastic liver. Ten cytologic features were examined in this study: high cellularity, acinar pattern, trabecular pattern, hyperchromasia, pleomorphism, irregularly granular chromatin, uniformly prominent nucleoli, multiple nucleoli, increased nuclear/cytoplasmic ratio, and atypical naked hepatocytic nuclei. These features were examined in a series of 82 FNAB specimens from 52 patients with HCC and 30 patients with nonneoplastic lesions. With the use of a step-wise logistic regression analysis, three features were identified as predictive of HCC: increased nuclear/cytoplasmic ratio (P = 0.001), trabecular pattern (P = 0.002), and atypical naked hepatocytic nuclei (P = 0.03). When these three criteria were used, the sensitivity of diagnosing HCC by FNAB was 100%, and the specificity was 87%.

Pathology and probability. Likelihood ratios and receiver operating characteristic curves in the interpretation of bronchial brush specimens.

Diagnoses in pathology often are qualitative, such as atypical or suspicious, and consequently are thought to have limited clinical value. To investigate the utility of a qualitative diagnostic system, seven pathologists retrospectively evaluated 100 bronchial brush specimens using the following categories: definitely benign, probably benign, possibly malignant, probably malignant, and definitely malignant. The likelihood ratio (LR) and receiver operating characteristic (ROC) curve, two statistical probabilistic measurements, were used to calculate diagnostic accuracy among individuals and groups. The results show: (1) the LR for individual diagnostic categories varied among observers, resulting in different clinically malignant probabilities; (2) observer experience did not appear to play a role in overall diagnostic accuracy, except in the diagnosis of small cell carcinoma; (3) observers operate at higher levels of diagnostic accuracy with, rather than without, clinical history. The authors conclude that qualitative diagnoses contain important information and can be interpreted effectively with LR and ROC.

Diagnosis of breast masses in pregnant and lactating women by aspiration cytology.

Five pregnant women with dominant breast masses underwent fine-needle aspiration cytology. Fine-needle aspiration cytology findings of the three patients with benign pregnancy adenomas and the two patients with ductal carcinoma are described. More extensive use of fine-needle aspiration cytology in the evaluation of breast masses in pregnant patients may decrease delays in diagnosis of breast cancer in pregnant women.

Malignant fibrous histiocytoma of the vulva.

Primary sarcomas of the vulva are rare neoplasms; malignant fibrous histiocytoma is a sarcoma that usually occurs in the extremities of elderly patients, but it also has been seen in a number of other sites. Presented is the second case report of malignant fibrous histiocytoma arising in the vulva. The diagnosis and management of vulvar sarcomas are reviewed.

Problems encountered with the Bethesda System: the University of Iowa experience.

This paper provides a descriptive summary of 1 year's experience with the Bethesda Cytologic Classification System at the University of Iowa Hospitals and Clinics. Cytotechnologists and pathologists criticized the failure of the new classification system to provide microscopic criteria for the following categories: adequacy of the smear (satisfactory, less than optimal, unsatisfactory), atypical squamous cells of undetermined significance, atypical glandular cells of undetermined significance, and inflammation-associated changes. Clinicians criticized the "less than optimal" category and the reporting of koilocytosis, moderate dysplasia, and endometrial cells. Suggestions for modifying the Bethesda System include: eliminating the less than optimal response, defining what constitutes an unsatisfactory smear, eliminating the terms low-grade and high-grade squamous intraepithelial lesion, and changing the reporting of endometrial cells.

Intraoperative autologous blood collection and autotransfusion in the surgical management of early cancers of the uterine cervix.

OBJECTIVES: To evaluate intraoperative autologous blood collection with autotransfusion (Cell Saver) with respect to patient acceptance, risk of tumor cell co-transfusion, and risk of recurrence in patients undergoing radical hysterectomy for cervical cancer. METHODS: All patients explored for radical hysterectomy between August 1991 and July 1994 were offered the use of intraoperative autotransfusion. Clinical-pathologic and transfusion-related characteristics were compared for a group of historic controls surgically treated for similar disease. The risk of tumor cell co-transfusion was assessed intraoperatively with peritoneal cytology before blood collection, and postoperatively with Cell Saver blood cytology. RESULTS: Ninety-eight patients were offered enrollment; four declined Cell Saver use, and 71 were acceptable for analysis. Thirty-one women (mean estimated blood loss 1338 mL) were reinfused with their own blood collected in the Cell Saver, whereas 40 patients (mean estimated blood loss 631 mL) were not autotransfused. There was no significant difference in preoperative hemoglobin concentration between groups. Cell Saver use significantly reduced the need for homologous transfusions, intraoperatively (P < .001) and postoperatively (P = .02). Historic controls (mean operative blood loss 1743 mL) were nearly four times more likely to have been transfused and three times more likely to have been transfused postoperatively than was the auto-transfused Cell Saver group. The mean hemoglobin concentration at discharge was lower in the autotransfused group, 9.3 g/dL, than in the historic controls, 10.8 g/dL. Nontransfused Cell Saver blood and all peritoneal cytologies were negative for tumor cells. Three pelvic recurrences, but no disseminated disease, have been noted over a mean follow-up of 24 months: one in the autotransfused group and two in the group in which the collected blood was discarded. CONCLUSION: Cell Saver use is well accepted by patients, decreases the need for homologous transfusions, and does not appear to co-transfuse tumor cells.

Merkel cell carcinoma of the vulva.

The authors describe the clinical and histologic findings in a case of Merkel cell carcinoma of the vulva, which was associated with squamous cell carcinoma in situ and lichen sclerosus. Electron microscopy of the tumor revealed membrane-bound granules. At postmortem examination, metastases from this primary skin tumor were found in the pelvic lymph nodes, in paraortic lymph nodes, in the liver, and in vertebral bodies. The case is unusual because Merkel cell tumors are usually found on the face or the extremities and seldom metastasize widely.

Dexamethasone enhances agonist induction of tissue factor in monocytes but not in endothelial cells.

Stimulation of monocytic cells by inflammatory agents such as bacterial lipopolysaccharide or tumour necrosis factor-alpha leads to the rapid and transient expression of tissue factor, the major cellular initiator of the extrinsic coagulation cascade in both haemostasis and tissue inflammation. In this study we investigated whether the synthetic anti-inflammatory glucocorticoid, dexamethasone, would inhibit agonist induction of tissue factor expression in both monocytes and endothelial cells. Surprisingly, dexamethasone significantly enhanced the induction of tissue factor expression by peripheral blood mononuclear cells and an established monocytic cell line, THP-1, in response to lipopolysaccharide or tumour necrosis factor-alpha. However, unlike monocytic cells, dexamethasone did not enhance agonist induction of tissue factor in endothelial cells. Synergistic enhancement of tissue factor expression by dexamethasone was also reflected in tissue factor mRNA levels in THP-1 cells, but was not the result of improved TF mRNA stability. Synergism between bacterial lipopolysaccharide and glucocorticoid in the induction of monocyte effector function is extremely unusual and may help to explain the variable outcome of glucocorticoid treatment of septic shock.

Serum concentrations of estradiol, progesterone, and levonorgestrel are not determinants of endometrial histology or abnormal bleeding in long-term Norplant implant users.

The objective of this study was to determine the relevance of serum estradiol, progesterone and levonorgestrel concentrations to endometrial histology and uterine bleeding associated with long-term Norplant implants use. Eighteen five-year users of Norplant implants had endometrial biopsies and determinations of serum estradiol, progesterone and levonorgestrel concentrations. Correlations among these factors and uterine bleeding were calculated. Proliferative endometrium (but not sex steroid levels) was associated with abnormal bleeding. Neither ovarian steroid nor levonorgestrel concentrations was a predictor of abnormal bleeding. Hyperplastic changes were not seen even with high estradiol and low levonorgestrel levels.

PIP: At the gynecologic clinic of San Francisco General Hospital in California, 18 women aged 27-44 who had used Norplant contraceptive implants for the full 5 years of effectiveness and who had at least 1 year of recurrent episodes of vaginal bleeding agreed to have an endometrial biopsy and a venipuncture for determination of serum estradiol, progesterone, and levonorgestrel levels. Investigators wanted to learn whether hormonal factors contributed to abnormal bleeding patterns in women who had used levonorgestrel-releasing contraceptive implants for 5 years. At the time of biopsy and venipuncture, 13 (72%) women had normal bleeding patterns. Two women had no apparent follicular activity. Six other women (44%) had a low estradiol level (i.e., 100 pg/ml). 14 women (77%) had no signs of luteal development (i.e., progesterone level 3 ng/ml). None of the women had hyperplastic endometrium. The endometrial index was used to describe endometrial histology and ranged from secretory to proliferated characteristics of the endometrium. It differed significantly between Norplant users with normal bleeding and those with abnormal bleeding (0.32 [a mixture of secretory and proliferative characteristics, but especially secretory characteristics] vs. 0.9 [close to full proliferation of the endometrium]; p 0.01). Serum estradiol, progesterone, and levonorgestrel levels were not significantly different between the two groups. These findings suggest that a proliferative endometrium, rather than sex steroid levels, was linked to abnormal bleeding. Thus, abnormal bleeding among long-term Norplant users is probably not a risk factor for developing endometrial cancer.

Clinical determinants for the management of thyroid nodules by fine-needle aspiration cytology.

To evaluate the utility of clinical features for the selection of patients with thyroid lesions suitable for diagnosis by fine-needle aspiration cytologic study, we reviewed 149 cases with complete clinical histories, laboratory evaluations, fine-needle aspirates, and histologic study of the index lesion. Review of these data demonstrated that only the presence of lymphadenopathy was of statistical value in the distinction of benign from malignant nodules. Moreover, once an aspiration diagnosis of "follicular neoplasm" had been made, no clinical, radiologic, or laboratory test aided in the distinction of follicular adenoma from follicular carcinoma.

Technology assessment in anatomic pathology. An illustration of test evaluation using fine-needle aspiration biopsy.

Although anatomic pathology diagnoses are the standard on which treatments often are based, many facets of anatomic pathology have not been rigorously examined. These areas include the evaluation of a procedure's technical and diagnostic characteristics, clinical utility, and cost. Technology assessment is the disciplined scientific and systematic evaluation of a test or procedure, and it can be used to evaluate these areas in anatomic pathology. To illustrate and promote the use of technology assessment in anatomic pathology, we show examples in fine-needle aspiration biopsy, which is a subspecialty of cytopathology. We discuss some of the more commonly encountered problems and misconceptions of test evaluation and also the need for further fine-needle aspiration biopsy evaluation. We conclude that technology assessment is a powerful but underutilized tool for test evaluation in fine-needle aspiration biopsy and in anatomic pathology.