Role of DNA ploidy analysis in endometrial adenocarcinoma.

Endometrial adenocarcinoma is the leading cause of malignancy of the female genital tract. Prognosis of this tumor, which has implications on patient management, is determined by evaluation of the stage of disease, architectural grade, nuclear grade, myometrial invasion, and peritoneal cytology. These parameters have inherent subjectivity and, therefore, the search for an objective reliable parameter to determine prognosis is required. DNA ploidy is under investigation as an objective and reproducible prognostic parameter. This study will evaluate the role of DNA ploidy and its relationship to the traditional parameters as predictors of prognosis in patients with endometrial carcinoma. Fifty-eight patients were evaluated by two observers for architectural grade according to the International Federation of Gynecology and Obstetrics classification, nuclear grade, and depth of myometrial invasion. DNA ploidy was evaluated using flow cytometer (FACscan, Becton Dickinson, San Jose, CA). Histologic parameters were than compared with DNA ploidy. Survival data were obtained from the tumor registry. Results of patient survival were compared with histologic parameters and DNA ploidy. Higher nuclear grade and aneuploidy correlated with poor survival rate (P <.05). Higher nuclear grade correlated with aneuploidy. The survival of patients with architectural grade 2 (moderately differentiated) endometrial adenocarcinoma is poorer if the tumor is aneuploid as compared with diploid as determined by flow cytometry. In conclusion, aneuploidy and nuclear grade correlates with poor patient survival. The poorer survival rates with aneuploid architectural grade 2 endometrial adenocarcinoma may have an impact on clinical management.

Measuring contributions to the clinical mission of medical schools and teaching hospitals.

This is the final report of a panel convened as part of the Association of American Medical College's (AAMC's) Mission-based Management Program to examine the use of metrics (i.e., measures) in assessing faculty and departmental contributions to the clinical mission. The authors begin by focusing on methods employed to estimate clinical effort and calculate a "clinical full-time equivalent," a prerequisite to comparing productivity among faculty members and departments. They then identify commonly used metrics, including relative-value units, total patient-care gross charges, total net patient fee-for-service revenue, total volume per CPT (current procedural terminologies) code by service category and number of patients per physician, discussing their advantages and disadvantages. These measures reflect the "twin pillars" of measurement criteria, those based on financial or revenue information, and those based on measured activity. In addition, the authors urge that the assessment of quality of care become more highly developed and integrated into an institution's measurement criteria. The authors acknowledge the various ways users of clinical metrics can develop standards against which to benchmark performance. They identify organizations that are sources of information about external national standards, acknowledge various factors that confound the interpretation of productivity data, and urge schools to identify and measure secondary service indicators to assist with interpretation and provide a fuller picture of performance. Finally, they discuss other, non-patient-care, activities that contribute to the clinical mission, information about which should be incorporated into the overall assessment. In summary, the authors encourage the use of clinical productivity metrics as an integral part of a comprehensive evaluation process based upon clearly articulated and agreed-upon goals and objectives. When carefully designed, these measurement systems can provide critical information that will enable institutional leaders to recognize and reward faculty and departmental performance in fulfillment of the clinical mission.

Redesigning the surgery clerkship at MCP Hahnemann School of Medicine to address the educational needs of generalists.

This article describes how the surgery clerkship at MCP Hahnemann School of Medicine was redesigned to provide all students a well-rounded general professional education and to address the specific educational needs of generalists. During the 12-week clerkship, students spend eight weeks on two different general surgery rotations, which include significant experiences in outpatient settings. The evaluation and management of common general surgical problems, as well as the holistic approach to patient care, are emphasized. A nurse educator, recruited through funding obtained from The Robert Wood Johnson Foundation's Generalist Physician Initiative, provides formal instruction in holistic care and teaches bedside procedures. Two weeks are devoted to focused surgical subspecialty experiences addressing common conditions and are conducted primarily in outpatient settings. The remaining two weeks include an integrated musculoskeletal disease rotation, including orthopaedic surgery, rheumatology, physiatry, and radiology. Didactic teaching includes criteria for referral of patients from generalists to specialists. The new clerkship model has been well received by the students. Review of student logs for the first six months indicates the breadth of surgical experience has been maintained and appropriate balance achieved between simple and complex surgical cases. Further evaluation of the model will continue through longitudinal follow-up.

Cervical cytologic smear false negative fraction. Reduction in a small community hospital.

OBJECTIVE: To determine the false negative fraction (FNF) at a small community hospital and its relation to the discovery of a significant error. STUDY DESIGN: All cervical cytologic smears (6,889) initially interpreted over a one-year period (1992) as "normal" or "near normal" were retrospectively rescreened and interpreted by outside institutions, without knowledge of the initial interpretation, to calculate yearly and quarterly FNFs. RESULTS: The overall FNF for 1992 was 12.3% and was 19.1%, 22.2%, 3.8% and 6.1% per successive quarters in 1992. A significant error was discovered at the start of the third quarter that subsequently received both local and national media attention. CONCLUSION: This study gives further proof that the FNF can be reduced to < 5% by motivated cytotechnologist/ pathologist teams, although it may not be possible to maintain this low an FNF.

Order of endocervical and ectocervical cytologic sampling and the quality of the Papanicolaou smear.

OBJECTIVE: To determine whether the order of cell collection, endocervical or ectocervical cells first, has an effect on the quality of the Papanicolaou smear. METHODS: One thousand smears were obtained using an Ayre spatula and an endocervical brush. In 500 cases the endocervical brush was used first, and in 500 cases the spatula was used first. All Papanicolaou smears were collected by resident physicians in our university hospital gynecologic clinics. A smear was considered limited for interpretation for the following reasons: 1) lack of endocervical component, 2) obscured by blood, 3) obscured by inflammation, 4) drying artifact, and 5) too thick. RESULTS: The brush-first group had 405 (81%) adequate smears compared with 410 (82%) adequate smears in the spatula-first group. More smears were obscured by blood when the brush was used first (22 or 4.4% compared with three or 0.6%, P < .001). No endocervical component (ie, metaplastic cells, endocervical cells, or mucus) was found in 29 (5.8%) smears from the brush-first group compared with 45 (9.0%) of the spatula-first group, an insignificant difference. More squamous intraepithelial lesions were found when the spatula was used first (55 or 11% compared with 35 or 7.0%, P < .05). CONCLUSION: The quality of the Papanicolaou smear can be improved by using the Ayre spatula first followed by the endocervical brush. Fewer smears will be obscured by blood, which could result in more squamous intraepithelial lesions being detected.

Clinical Significance of a cervical cytologic diagnosis of atypical squamous cells of undetermined significance. Favoring a reactive process or low grade squamous intraepithelial lesion.

OBJECTIVE: To define the clinical significance of qualifying the cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS) as favoring either a reactive process or a low grade squamous intraepithelial lesion (LSIL) in an effort to provide management guidelines. STUDY DESIGN: A total of 118 consecutive nonpregnant women with a cytological diagnosis of ASCUS favoring either a reactive process or LSIL were evaluated in our colposcopy clinic by repeat cervical cytologic smear, colposcopy and colposcopically directed biopsies and/or endocervical curettage, as indicated. RESULTS: Of the 58 patients evaluated for a smear of ASCUS, favoring a reactive process, 5 (8.6%) had cervical intraepithelial neoplasia (CIN) CIN 1 documented by biopsy. None had a high grade lesion. Twenty-six (45%) of the 58 patients who had a cytologic diagnosis of ASCUS favoring a reactive process had a repeat smear that was normal. None was found to have CIN. Of the 60 patients who had a cervical diagnosis of ASCUS favoring LSIL, 9 (15%) had CIN 1 or CIN 2. Nineteen (32%) of the 60 patients who had a cytologic diagnosis of ASCUS favoring LSIL had a repeat smear that was normal. One of these patients had CIN 1 on biopsy. The sensitivity of a repeat smear, in this limited series, after an initial smear of ASCUS favoring a reactive process is 100%, while it was 66% after an initial smear of ASCUS favoring LSIL. CONCLUSION: This study showed that in our laboratory a cytologic diagnosis of ASCUS favoring either a reactive process or LSIL is associated with a very low risk that the patient is haboring CIN. In the patient whose initial smear shows ASCUS favoring a reactive process, a repeat smear that is normal is reassuring. The patient whose smear shows ASCUS favoring LSIL probably requires further evaluation even in the presence of a normal repeat smear.

The effects of short-term lansoprazole therapy on Helicobacter pylori infection and antral gastritis in duodenal ulcer patients.

BACKGROUND/AIMS: Lansoprazole is a new potent proton pump inhibitor that exhibits activity against Helicobacter pylori in vitro. This study endeavored to determine the effects of 4 wk of lansoprazole therapy upon H. pylori infection and antral gastritis in duodenal ulcer patients and to determine the relationship of the gastritis with Helicobacter infection and with ulcer activity. METHODS: Satisfactory antral biopsies were obtained from 119 duodenal ulcer patients before and after 4 wk of therapy with lansoprazole, ranitidine, or placebo. Sections were scored blindly for degree of active and chronic inflammation and extent of H. pylori infection. RESULTS: Four weeks of lansoprazole (30 mg daily) or ranitidine (300 mg daily) therapy produced a significant decrease in H. pylori infection. The reduction of H. pylori infection, but not ulcer healing per se, correlated with the decrease in active and chronic antral inflammation. Reduction of H. pylori infection, however, did not improve the good ulcer-healing rates already achieved at 4 wk by potent acid inhibition. CONCLUSIONS: Lansoprazole exhibits activity against H. pylori in vivo. Short-term improvement in antral gastritis is affected by reduction of H. pylori infection but not by ulcer healing.

Interobserver variability of cervical smears with squamous-cell abnormalities: a Philadelphia study.

The reproducibility of reporting squamous lesions by the Bethesda System (TBS) was evaluated by distributing 20 slides to be classified among 5 panelists considered experts in the field of cytopathology. Four cases were chosen for their classic morphology and the remainder were foreseen to produce possible discrepancies within one diagnostic category. For 7/20 (35%) cases there was unanimous agreement. Participants disagreed within one category of magnitude for seven (35%) cases. In six (30%) cases there was a range of more than one category disagreement. However, additional written comments modifying TBS diagnoses often diminished the clinical significance of these discrepancies. We conclude that despite the important role of TBS in standardization of Pap smear reports, a great degree of subjectivity exists in classifying squamous abnormalities without "classic" morphology. The lack of reproducibility should be taken into account in cytology proficiency testing.

Unusual immunocytochemical and ultrastructural features of synovial fluid cells in multicentric reticulohistiocytosis. A case report.

We present the first report in which cells in synovial fluid from a patient with multicentric reticulohistiocytosis (MRH) were studied by immunocytochemistry for correlation with routine light and electron microscopy. MRH cells stained predominantly for lymphocyte-related surface antigens and not for the monocyte marker LEU M3 (CD14). These findings suggest a lymphocytic origin of MRH cells and not a histiocytic origin, as previously suggested. In addition, large numbers of membrane-bound, electron-dense, secretory-type granules were found ultrastructurally in the cytoplasm of these cells.

Fine-needle aspiration cytology of idiopathic pancreatic islet cell adenosis.

A 68-yr-old woman was hospitalized because of abdominal pain, an enlarged pancreatic head by CT, and a questionable 4-cm mass in the liver. Fine-needle aspiration (FNA) of the pancreatic head disclosed a highly cellular specimen consisting of clusters of cytologically bland, monotonous, small nuclei and variable but generally sparse cytoplasm. Because of the differentiated monomorphic character of the cell clusters, the postaspiration differential cytopathologic diagnosis included islet cell tumor, acinic cell tumor, carcinoid, lymphoma, and well differentiated ductal adenocarcinoma. Pancreaticoduodenectomy and hepatic biopsy yielded a grossly normal pancreas and a cirrhotic liver. Histologic examination of the pancreas revealed a spotty but extensive spectrum of islet changes ranging from normal to bland hyperplasia, nesidioblastosis, microadenosis, and neuroendocrine microadenomas, all appearing in a light and electron microscopic context of an otherwise normal pancreas. This case highlights the differential diagnostic ambiguities presented by a continuum of pancreatic islet cell proliferations, especially among patients in whom there are no known predisposing factors for such diffuse preneoplastic or neoplastic changes.

Ovarian carcinoma heterogeneity as demonstrated by DNA ploidy.

BACKGROUND: In ovarian carcinoma, DNA ploidy measured by flow cytometric (FCM) analysis is an independent prognostic factor. However, limited sampling may underestimate the extent of ploidy variation (i.e., heterogeneity). Uncovering these hidden populations may explain poor outcomes in patients with ostensibly favorable ploidy patterns. The authors examined ploidy in a mean of 6.4 tumor samples per patient to better assess the occurrence of heterogeneity. METHODS: FCM analysis was performed on multiple samples from 19 cases of advanced, serous ovarian carcinoma. Tumors were considered as heterogeneous by two definitions: (1) the presence of more than one ploidy pattern (e.g., diploidy and tetraploidy); and (2) the existence of DNA indices of sufficient variation so as to characterize two distinct populations of neoplastic cells. RESULTS: With the first definition, 47% (9 of 19) of the tumors were heterogeneous, 37% (7 of 19) homogeneous-aneuploid, and 16% (3 of 19) homogeneous-diploid. These three groups showed no significant differences in histologic type, grade, patient age, stage, or survival. With the second definition, 27% (4 of 15) of the non-diploid cases were heterogeneous and 73% (11 of 15) were homogeneous. When these two groups were compared as to type, grade, patient age, and stage, no significant differences were demonstrated. However, the median survival of the patients with heterogeneous tumors was significantly longer (P < 0.05) than the survival of patients with homogeneous tumors. CONCLUSIONS: Ovarian carcinoma heterogeneity is high when multiple sites are assayed. This suggests conservative interpretation of ploidy when only a single sample is analyzed and examination of multiple samples when practicable.

Invasive cervical thymoma masquerading as a solitary thyroid nodule. Report of a case studied by fine needle aspiration.

A 49-year-old woman underwent fine needle aspiration (FNA) biopsy of a presumed thyroid nodule. The initial cytopathologic interpretation suggested a chronic lymphocytic thyroiditis or a malignant lymphoma. The examination of frozen sections during surgery also suggested the presence of a lymphoma. However, histopathologic examination of permanent sections showed the lesion to be an invasive ectopic lymphocyte-predominant thymoma adjacent to the thyroid. Immunoperoxidase staining of FNA cell block sections and permanent sections showed positivity for keratin, proving the epithelial nature of the elongated and spindle-shaped tumor cells. This case high-lights the need to be aware of unusual lesions that may occur in the area of the thyroid; recognizing the potential diversity of "thyroid" masses that ultimately prove to be of nonthyroid origin should aid in making the correct cytologic differential diagnosis and interpretation of FNA samples obtained from such masses.

Monoclonal antibody-dependent, cell-mediated cytotoxicity against human malignant gliomas.

Two monoclonal antibodies (MAbs), IgG2a MAb ASHG4 and IgG2b MAb ASHE2, were produced in mice immunized with cultured human malignant glioma cells. Both MAbs bound strongly to the surfaces of long-term cultured glioma cells, and MAb ASHE2 also bound strongly to short-term cultured glioma cells. Sections of frozen glioma tissues bound both MAbs strongly, whereas normal brain tissues showed weaker reactivities, and tissues derived from carcinomas of various histological types were completely unreactive. Furthermore, the MAbs did not bind to peripheral blood cells or bone marrow cells. Although both MAbs bound to the same Mr 27,000-29,000 protein, they may detect different or overlapping epitopes on this antigen. Because MAbs ASHE2 and ASHG4 lysed cultured glioma cells with human peripheral blood lymphocytes as effector cells, they are promising reagents for approaches to immunotherapy of human malignant gliomas.

Monoclonal antibodies with cytotoxic reactivities against human gliomas.

Monoclonal antibodies (MAb's) reactive with human malignant glioma cells were derived from mice inoculated with cells from fresh glioma tissue. Seven MAb's were selected for study based on their high-level binding in immunoperoxidase and immunofluorescence assay to most of the glioma tissues derived from various patients and based on the absence of binding to normal bone marrow cells. Four of the seven MAb's did not bind to any of the four normal brain tissues tested, whereas three MAb's bound to one or two of these tissues. Two MAb's bound to the surfaces of cultured glioma cells in radioimmunoassay. One of these MAb's (AS-AY1, immunoglobulin (Ig)(G1) lysed cultured glioma cells with human lymphocytes or murine macrophages as effector cells; the other MAb (AS-AY2, IgM) was reactive in complement-dependent cytotoxicity assay. These two MAb's therefore seem especially promising reagents in approaches to immunotherapy of human malignant glioma.

Diagnosis of Pneumocystis carinii pneumonia by cytologic evaluation of Papanicolaou-stained bronchial specimens.

To evaluate the sensitivity and specificity of diagnosing Pneumocystis carinii pneumonia (PCP) by Papanicolaou-stained bronchial brushing and wash/lavage specimens obtained by fiberoptic bronchoscopy, the cytologic preparations and clinical records from 58 immunocompromised patients were reviewed. Bronchial brushings and wash/lavage specimens were examined using methenamine silver (Grocott) and Papanicolaou stains. Pneumocystis carinii pneumonia was recognized with Papanicolaou stain by identifying distinctive alveolar casts, which frequently contained collections of encysted sporozoites. Thirty cases of PCP were identified, and Grocott-stained bronchial wash/lavage specimens were positive in 29 instances (97%). Grocott staining of the transbronchial biopsy was positive for PCP in 18 of 22 specimens (82%). Bronchial brushings were insensitive, yielding a positive specimen in only 30% of cases of PCP. Alveolar casts of PCP were identified by Papanicolaou-stained slides of wash/lavage specimens in 83% of cases of Pneumocystis pneumonia. These proteinaceous alveolar casts were not seen in other pulmonary disorders. Encysted sporozoites were found in 56% of cases in which Papanicolaou-stained alveolar casts were identified. We conclude that the diagnosis of PCP can be made rapidly and reliably on the Papanicolaou-stained bronchial wash/lavage or bronchial brush specimens by detecting the characteristic alveolar casts, which contain P. carinii-encysted sporozoites. The presence of encysted sporozoites within alveolar casts is pathognomonic for PCP, and methenamine silver stains can be eliminated in those cases in which encysted sporozoites are identified.

The fibrolamellar variant of hepatocellular carcinoma. Its association with focal nodular hyperplasia.

A case of fibrolamellar hepatocellular carcinoma (FL-HCC) associated with adjacent focal nodular hyperplasia (FNH) is described. These two regions were adjacent but distinct, both on gross and microscopic examination. Currently, it is unclear whether FL-HCC rarely arises in preexisting FNH, or whether FNH is a typical response to this vascular variant of hepatocellular carcinoma (HCC). The FNH region, which is peripheral, may be biopsied to exclude the underlying carcinoma, and thus lead to inadequate therapy. Previous reports of this association are reviewed.

Psammoma bodies in fine needle aspirate of the thyroid in lymphocytic thyroiditis.

Psammoma bodies are concentric, laminated microcalcifications that are regarded as nearly specific markers in the thyroid gland for the presence of papillary carcinoma. While psammoma bodies have been seen rarely in some benign thyroid diseases, there appear to be no reports of psammoma body formation in lymphocytic or Hashimoto's thyroiditis. We report a case of Hashimoto's thyroiditis in which psammoma bodies were identified in a fine needle aspiration specimen of the thyroid and in histologic sections of the right thyroid lobectomy; papillary carcinoma was not found in either specimen. We conclude that psammoma bodies may be seen in any benign process, such as nodular goiter or lymphocytic thyroiditis, that produces reactive papillary hyperplasia of thyroid epithelium, as well as in papillary carcinoma. However, the finding of psammoma bodies in a fine needle aspirate without corroborating cytologic evidence of papillary cancer is still an indication for surgical removal of the thyroid nodule since these structures are reliable markers for occult papillary carcinoma of the thyroid, despite the rarity of their formation in benign diseases.

Purification and amino terminal sequencing of human melanoma nerve growth factor receptor.

The nerve growth factor (NGF) receptor, solubilized with Triton X-100 detergent, has been purified from human melanoma cell line A875. Purification to near-homogeneity was achieved by chromatography on wheat germ agglutinin-agarose, followed by immunoaffinity chromatography on Sepharose columns coupled with anti-NGF receptor monoclonal antibody (MAb). The purified receptor, a 75,000-dalton protein, retains the capacity to bind NGF as well as anti-receptor MAbs. Final purification was achieved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The sequence of amino acid residues at the amino terminus has been determined. Possible sequence homology between the NGF receptor and several other proteins is discussed. Using the purified receptor as immunogen, new MAbs to the NGF receptor have been produced. The NGF receptor was visualized by immunoperoxidase staining in tissue sections of dorsal root ganglia from monkeys.