Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study.

BACKGROUND: High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells. METHODS: Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen. RESULTS: Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH). CONCLUSION: The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.

Sampling, sampling errors and specimen preparation.

To obtain an adequate cervical smear for making a correct cytologic diagnosis, smear taking, laboratory handling and interpretation must be optimal. Many people are involved, and only by a combined effort of all links can this target be seriously approached: the smear takers will have to be open minded about technical improvements and read the morphologic descriptions cautiously; in the laboratory, cytotechnicians and physicians will have to challenge themselves and each other. It is mandatory to discard specimens that do not meet general standards of adequacy. At present a host of new techniques are being implemented. It is not feasible for all laboratories to be engaged in testing these new methods, but we are all requested to follow the development the best we can and switch to new ways when justified. Our working conditions are very different; therefore, it is our professional responsibility and plight to respond at the right time. So far the conclusion is that the conventional Pap smear is the international standard of care for the diagnosis of cervical cancer precursers in cancer screening programs. Certainly, this may change within a very short time. Liquid-based techniques, and in particular HPV technologies, are just around the corner.

The AutoPap 300 QC System multicenter clinical trials for use in quality control rescreening of cervical smears: I. A prospective intended use study.

BACKGROUND: The AutoPap 300 QC System is an automated device for the analysis of conventionally prepared cervical cytology slides. The AutoPap System selects an enriched population of cases for human quality control (QC) review. The device assigns a score based on the likelihood that a slide is abnormal. Cases are selected for QC rescreening that have scores exceeding a preset threshold corresponding to approximately the top 10% (or greater) of scores. METHODS: AutoPap false-negative detection, compared with a 10% random QC process, was tested in a 6-center clinical evaluation study. At each site, a block of up to 150 consecutive negative slides (including detected false-negative cases) were selected randomly daily. All slides were run on the AutoPap System and rescreened by cytotechnologists for truth determination. The false-negative cases included in the top 10% group selected by AutoPap System then were compared with false-negative detection by the random selection process. RESULTS: Fourteen thousand nine hundred fourteen cases were analyzed. The AutoPap-enriched 10% quality control group contained false-negative cases at rates 3 to 5 times that of the random selection method (P < 0.01). The sensitivity for all false-negative cases was 35% and was 52% for false-negative cases at the level of low grade squamous intraepithelial lesion and higher. CONCLUSIONS: The AutoPap 300 QC System provides the potential for a marked increase in the number of false-negative cervical cytology cases that can be detected on QC rescreening. A significant reduction in laboratory false-negative rates can be expected if this device is utilized in routine practice.

The AutoPap 300 QC System multicenter clinical trials for use in quality control rescreening of cervical smears: II. Prospective and archival sensitivity studies.

BACKGROUND: The AutoPap 300 QC System is an automated device for the analysis of conventional cervical cytology slides. The AutoPap selects an enriched population of cases for quality control review. These studies evaluated the overall sensitivity of AutoPap device to a wider variety of cytologic abnormalities than could be analyzed in the prospective portion of the clinical trials. METHODS: At five clinical trial sites, positive cases were selected from: 1) archives (historic sensitivity study) or 2) current positive cases (current archive sensitivity study). Cases were analyzed by the AutoPap System along with matched negative cases and stratified into detection deciles by instrument score for each diagnostic category. RESULTS: For the historic sensitivity study, the percentages of cases present within the top 10% instrument scores were as follows: atypical glandular cells of undetermined significance (AGUS): 33.7% (n = 243); low grade squamous intraepithelial lesion (LSIL): 57% (n = 412); high grade squamous intraepithelial lesion (HSIL): 81.6% (n = 385); and carcinoma: 77.7% (n = 139). For the current archive sensitivity study, the percentage of cases within the top 10% of instrument scores were as follows: atypical squamous cells of undetermined significance (ASCUS): 37.6% (n = 205); AGUS: 27.3% (n = 22); LSIL: 53.7% (n = 410); HSIL: 80.7% (n = 202); and carcinoma: 62.5% (n = 8). Sensitivities at higher percentiles proportionately were greater. CONCLUSIONS: The AutoPap 300 QC System is detection sensitive, particularly at the level of LSIL and greater. When coupled with the data from the prospective intended use study, these results provided confirmation of the instrument's ability to enhance the false-negative detection rate significantly when compared with a 10% random case selection process. In addition, high sensitivities to all categories of abnormality suggest the possibility of using such instrumentation as a primary screening device for cervical cytology.

The effects of endocervical canal topography, tubal metaplasia, and high canal sampling on the cytologic presentation of nonneoplastic endocervical cells.

Use of new endocervical cytologic sampling devices has correlated with increased numbers of cases showing endocervical "atypia." To ascertain the potential causes, a cytologic and histologic correlative study of the normal endocervical canal was undertaken. Hysterectomy specimens from 25 patients with no history of cervical disease were used. The anterior and posterior endocervical canals were divided into three equal sections. Each of the sections of the anterior canal were sampled cytologically, with the corresponding posterior canal processed for histology. Endocervical gland number, depth, and cellular crowding were most pronounced in the middle third of the canal. Tubal metaplasia (present in 100% of cases) was most prominent in the upper third. The most cellular cytologic samples were obtained from the middle third. "Atypical" endocervical groups were most commonly identified in the upper third. The normal topography of the endocervical canal, with sampling of the upper regions by newly utilized devices, may account for the increase in samples showing cytologic patterns that mimic endocervical neoplasia.

Sensitivity of the AutoPap 300 QC System for cervical cytologic abnormalities. Biopsy data confirmation.

OBJECTIVE: To assess the AutoPap 300 QC System's sensitivity to cases of high grade squamous intraepithelial cervical lesion and invasive cervical cancer, a comparison of outcome was made in cases that had surgical biopsy confirmation. STUDY DESIGN: The sensitivity of the device to biopsy-confirmed diagnostic categories at the level of high grade squamous intraepithelial lesion (HSIL) and greater was calculated. At two of six clinical trial sites, biopsy data were available and were compared to device scores indicating whether a case would or would not be selected for 10% or 20% quality control rescreening. RESULTS: In 86 biopsy-positive cases that had a cytologic diagnosis of HSIL or greater, the device indicated inclusion in the 10% or 20% review fraction for 66 slides (77%) and 74 (86%), respectively. This figure indicated an approximately eightfold improvement in the ability of the device to include such cases for quality control rescreening when compared to a 10% random case selection process. CONCLUSION: These data showed that the sensitivity of the AutoPap in identifying cases of HSIL and greater was similar to that previously calculated for these diagnostic categories in clinical trials, when calculated on the basis of an alternate or "higher" standard of tissue confirmation.

Particulate titanium and cobalt-chrome metallic debris in failed total knee arthroplasty. A quantitative histologic analysis.

Histologic examination of synovial tissue from the revisions of six cobalt-chrome and six titanium alloy total knee arthroplasties was made. Aseptic polyethylene wear-through had resulted in metal-on-metal contact of bearing surfaces and was the primary indication for revision surgery in all knees. The cobalt-chrome alloy prostheses failed at the femorotibial articulation at a mean of 92 months, while the titanium prostheses experienced patellofemoral failure at a mean of 39 months after implantation. Neither alloy was associated with any meaningful inflammatory infiltrate, and cement debris was comparable in both groups. Titanium alloy knees generated significantly more metallic debris than the cobalt-chrome alloy knees (P < .001). Cobalt-chrome alloy knees had more polyethylene debris (P < .01) and a greater number of histiocytes (P < .005). Titanium and polyethylene debris were associated with a prominent giant cell reaction. Titanium exhibited greater abrasive wear and elicited a different cellular response than cobalt-chrome under conditions of polyethylene failure allowing metal-on-metal contact. The variability of this foreign body reaction may be due to important differences in particle size and number, as well as in the material properties of the two alloys.

ThinPrep Processor. Clinical trials demonstrate an increased detection rate of abnormal cervical cytologic specimens.

The authors compared the accuracy of conventionally prepared smears and smears prepared by an automated, fluid-based, thin-layer processing device in the detection of cytologic abnormalities. A total of 3218 patients from five centers took part in this study, in which a single cervical sample was split into a matched pair. The conventional smear was made in the routine fashion; the remainder of the cells on the sampling device were rinsed into a transport-fixation fluid. A slide was then prepared from the solution using the thin-layer processor. Diagnostic findings identified on the two preparations were compared in a blinded fashion, and a discrepancy resolution procedure was used to eliminate screening differences. Overall, there was a high correlation in the diagnoses of the two methods. For low-grade or more severe disease, the thin-layer method resulted in a 13% increase in the rate of detection, as compared with the conventional Papanicolaou smear technique.

Computed tomography of leiomyomatosis peritonealis disseminata with malignant transformation.

Malignant transformation of leiomyomatosis peritonealis disseminata is a very rare occurrence, reported twice previously. We report the third case and present the computed tomography findings associated with the development of this unusual pathologic condition.

Quality assurance in cytopathology. Recommendations and ongoing quality assurance activities of the American Society of Clinical Pathologists.

The recommendations and activities of the American Society of Clinical Pathologists (ASCP) pertaining to quality assurance in cytopathology are reviewed. To assure the early detection of cervical cancer, the ASCP recommends that all women who are, or have been, sexually active should have an annual Papanicolaou smear examination, the reasons for which are discussed. To assure the optimal quality in the evaluation of these smears, the ASCP recommends that the screening should be performed (1) in an accredited laboratory by certified cytotechnologists, (2) for whom realistic workloads have been established, (3) under the supervision of a pathologist adequately trained in cytology, (4) who will maintain an ongoing quality assurance program. In addition, (5) Papanicolaou smear evaluations should be available to all patients at a reasonable cost and (6) the financial incentives for the performance of low-quality screening should be eliminated. The society's quality assurance activities discussed include the Check Sample program, self-assessment examinations, meetings and publications; planned additions to this arena include a challenge exam and proficiency survey mechanisms.

The pathology and biologic behavior of ovarian cancer. An autopsy review.

1. Widespread visceral and intestinal wall metastases are present in women dying with ovarian cancer. Intestinal wall invasion is commonly found at autopsy and is associated with bowel obstruction. Liver parenchymal replacement by metastases in more extensive than that in the lung, where most metastases have a subpleural location. Multifocality characterizes metastases in both of these organs. 2. Neoplastic lymphatic invasion is common. Lymphatic and blood vascular invasion are associated with an increased incidence of metastases in lymph nodes, small bowel wall, pancreas, lungs, ureter, and liver. 3. The mean survival time from diagnosis to death is less than 2 years. Both increasing neoplastic histological grade and clinical stage at diagnosis are associated with decreased survival time. 4. The most common causes of death are carcinomatosis, infection, or a combination of these processes. Sepsis, pneumonia, or both of these account for most of the fatal infections. 5. Bowel and ureteral obstruction constitute the most common forms of tumor-induced morbidity. The former process tends to be multifocal, involving the small and large intestines, and it is found during the disease course as well as at autopsy. Ureteral involvement is usually associated with hydronephrosis and is bilateral in approximately one fourth of the cases.

Survival time, causes of death, and tumor/treatment-related morbidity in 100 women with ovarian cancer.

One hundred cases of ovarian cancer were studied at autopsy to determine the effect of morphologic and clinical factors on survival time, the primary cause of death, and tumor/treatment-related morbidity. The mean survival time was 19 months (0 to 174 months). Increasing neoplastic histologic grade and increasing clinical stage at diagnosis were each associated with decreased survival time. In grade I tumors, the mean survival time was 84 months; in grade II tumors, it was 18 months; and in grade III tumors, it was 12 months (P = .0008). Patients who presented in stage I or II had a better survival time (28 months) than those who presented in stage III or IV (15 months) (P = .02). The most common causes of death were disseminated carcinomatosis (48%), infection (17%), pulmonary embolus (8%), and combinations of infection and carcinomatosis (11%). In patients dying of infection, 43% had sepsis, 21% had pneumonia, and 25% had a combination of sepsis and pneumonia. Escherichia coli and Klebsiella were the most common pathogens identified postmortem. Intestinal obstruction (51%) and ureteral obstruction (28%) were the most common forms of tumor-induced morbidity. Bone marrow depression and resultant pancytopenia was the most common form of treatment-induced morbidity.

Epithelioid haemangioma-like vascular proliferation in AIDS: manifestation of cat scratch disease bacillus infection?

Papular and nodular skin lesions that clinically resembled Kaposi sarcoma, but histologically showed a distinct epithelioid haemangioma-like appearance, were noted in seven patients with the acquired immunodeficiency syndrome. Clusters of bacteria that had the structure of gram-negative rods were identified within each of the vascular proliferations by electron microscopy. The bacteria did not stain with the Brown-Brenn, acid-fast, or other histochemical stains for infectious organisms, but did stain with Warthin-Starry--ie, the staining profile was that described for the cat scratch disease (CSD) bacillus. Immunoperoxidase staining, using antisera raised in rabbits against cultured CSD bacillus, showed a positive reaction with the bacterium in all five cases tested. The two surviving patients have both given histories of having been scratched by a cat. In several patients, the vascular lesions regressed after therapy with antibiotics appropriate for CSD bacillus infection.

Continuity of human papillomavirus (HPV) type between neoplastic precursors and invasive cervical carcinoma. An in situ hybridization study.

Infection by the human papillomaviruses (HPV) represents an important risk factor in squamous lesions of various sites. More recently, data suggest that the glandular components of some tumors may also contain human papillomaviruses. This association may implicate HPVs in the genesis of these lesions as well. We present a longitudinal in situ hybridization study of HPV expression within a single patient, showing viral mRNA in squamous dysplasia, squamous and adenocarcinoma in situ, and in invasive adenosquamous carcinoma. There was continuity of the viral type (HPV 16) in the preinvasive and invasive portions of the lesions, and HPV mRNA was clearly demonstrable in the glandular components. The case illustrates the utility of in situ hybridization for the microscopic localization of viral gene expression, in addition to providing information about the viral type and perhaps the biologic potential of the lesion.

Variable ploidy of ovarian clear cell carcinomas. Implications for adequacy of tissue sampling.

Ten cases of clear cell (mesonephroid) adenocarcinoma of the ovary were examined for (1) variations of morphology within each tumor and its metastases, (2) ploidy of each morphologic region and (3) clinical behavior. Correlations were sought among these factors. Analysis of the ploidy in up to six morphologic regions per tumor showed variations in the ploidy in seven of the ten cases, with all seven having both diploid and nondiploid regions. The presence or absence of abnormal ploidy was not predictable based on the histomorphologic appearance of a given section. These results suggest that (1) the evaluation of a single random tissue sample may not discover aneuploidy that is present and (2) future ploidy studies on malignant tumors may require extensive tumor sampling in order to definitively exclude the presence of aneuploid populations.

Distribution of disease at autopsy in 100 women with ovarian cancer.

Clinical and morphologic factors that affected the distribution of disease are described in 100 cases of ovarian cancer at autopsy. In addition to the expected pattern of pelvic and abdominal peritoneal spread, extensive visceral parenchymal metastases were seen: liver parenchyma (45%), lung parenchyma (39%), small and large intestinal wall (52% and 55%), lymph nodes (70%), pancreas (21%), ureter (24%), bone (11%), and brain (6%). Liver parenchymal metastases replaced more than one third of the liver in 25% of cases, whereas lung metastases always involved less than one third of the lungs. When intestinal wall invasion was seen, bowel obstruction was present more often (71%) than when only intestinal serosa was involved (30%). Lymphatic invasion was predictive of lymph node, small intestinal wall, pancreatic, and liver as well as lung parenchymal metastases. Blood vessel invasion was predictive of pancreatic and ureteral metastases. Clinical stage I at diagnosis was associated with high incidences of liver parenchymal (56%), lymph node (56%), lung parenchymal (44%), large intestinal wall (33%), and bone (33%) metastases. Thus, ovarian cancer has parenchymal metastases similar to other carcinomas in addition to its peritoneal spread. Lymphatic and blood vessel invasion is predictive of such involvement. Intestinal wall invasion predicts bowel obstruction.