9p21 Deletion in the Diagnosis of Malignant Mesothelioma in Serous Effusions Additional to Immunocytochemistry, DNA-ICM, and AgNOR Analysis
|
|
- Ambrose Lyons
- 8 years ago
- Views:
Transcription
1 204 9p21 Deletion in the Diagnosis of Malignant Mesothelioma in Serous Effusions Additional to Immunocytochemistry, DNA-ICM, and AgNOR Analysis Fabiana Botelho de Miranda Onofre, MSc 1 Alexandre Sherlley Casimiro Onofre, MSc 1 Natalia Pomjanski, MD, MIAC 1 Birgit Buckstegge 1 Hans Juergen Grote, MD, MIAC 1,2 Alfred Böcking, MD, FIAC 1 1 Institute of Cytopathology. Heinrich-Heine University, Dusseldorf, Germany. 2 Target Research, Merck KGaA, Darmstadt, Germany. BACKGROUND. The diagnosis of malignant mesothelioma (MM) in serous effusions is difficult but may be achieved by the application of adjuvant methods. METHODS. The authors cytologically diagnosed 33 effusions as suspicious or positive for MM cells by using DNA-image cytometry (DNA-ICM), immunocytochemistry and AgNOR analysis. The authors further detected 9p21 deletions by chromosomal fluorescence in situ hybridization (FISH). In addition, 31 cases of metastatic carcinomas and 39 of tumor cell-negative effusions were investigated. All diagnoses were confirmed by histologic and/or clinical follow-up. RESULTS. DNA aneuploidy was found in 71% of MMs, 100% of metastatic carcinomas, and in none of the negative effusions. Calretinin was positive in 100% of MMs, in none of the metastatic carcinomas, and in 94.9% of negative effusions. BerEP4 showed positivity in 15.6% of MMs, 87.1% of metastatic carcinomas, and in none of the negative effusions. With AgNOR analysis, 89.3% of MMs and 96.7% of metastatic carcinomas showed 2.5 AgNOR dots as satellites and 4.5 as total AgNOR counts. 9p21 deletions were demonstrated in 90.9% of MM cases, 45.2% of metastatic carcinomas, and in none of the negative effusions. By cytology alone, 81.8% of MMs were identified unequivocally. Addition of DNA-ICM improved the prevalence of tumor cell detection to 87.9% and of AgNOR analysis to 97%. The introduction of 9p21 deletions by FISH improved this prevalence to 100%. CONCLUSIONS. Because of these results, the authors propose the sequential application of immunocytochemistry, DNA-ICM, and AgNOR analysis to establish a cytological diagnosis of malignant mesothelioma in serous effusions. In persistent doubtful diagnoses, the authors recommend fluorescence in situ hybridization to analyze the 9p21 deletion. Cancer (Cancer Cytopathol) 2008;114: Ó 2008 American Cancer Society. Coordenaç~ao de Aperfeiçoamento de Pessoal de N ivel Superior grant (F.B.M. Onofre and A.S.C. Onofre). Address for reprints: Alfred Böcking, MD, FIAC, Institute of Cytopathology, Heinrich-Heine University D usseldorf, Moorenstrasse 5, D D usseldorf, Germany; Fax: ; Boecking@uni-duesseldorf.de Received October 23, 2007; revision received December 21, 2007; accepted January 25, KEYWORDS: 9p21, CDKN2A, fluorescence in situ hybridization, DNA-ICM, AgNOR analysis, immunocytochemistry, mesothelioma, effusion. Malignant mesothelioma (MM) is a primary aggressive tumor that affects the mesothelial lining of serosal membranes, such as those of the pleural, peritoneal, and pericardial cavities. 1 Exposure to asbestos is considered to contribute to the development of this tumor in the majority of MM patients. 2 5 Studies predict an increasing incidence of this tumor in the next decade. 6 9 The diagnosis of MM is initially based on cytologic examination of serous effusions because of its high accuracy, time effectiveness, and cost effectiveness. However, the diagnosis of MM in serous effusion is difficult and represents one of the classic diagnostic challenges of Ó2008 American Cancer Society DOI /cncr Published online 27 February 2008 in Wiley InterScience (
2 9p21 Deletion and Adjuvant Methods in MM/Onofre et al. 205 cytopathology. 10 The morphological features are not always reliable for differentiation between neoplastic and non-neoplastic mesothelial cells or between mesothelioma cells and those from metastatic adenocarcinomas. 11 Recent advances in therapy for patients with MM can result in an improved outcome if they are applied to stage I disease. 12 Furthermore, from a legal viewpoint, compensation claims of workers who have been occupationally exposed to asbestos demand an accurate and early diagnosis of MM, and unnecessary invasive diagnostic procedures should be avoided. To improve diagnostic sensitivity, various additional approaches have been proposed including DNA-image cytometry (DNA-ICM), immunocytochemistry, and silver staining of nucleolar organizer region-associated proteins (AgNORs). DNA-ICM is a quantitative adjuvant method that identifies DNA stemlines outside the euploid (diploid, tetraploid, or octaploid) regions as abnormal, named DNA aneuploidy, which is used as a sensitive marker for the identification of neoplastic cells. 13,14 A specific immunocytochemical marker for mesotheliomas has not yet been recognized; therefore, panels of markers have been composed of both negative and positive mesothelioma markers. 15 Nucleolar organizer regions (NORs) are large rdna loops that are responsible for the transcription of rrna. 16 AgNOR can be considered as a marker of cell proliferation and could also help distinguish benign from malignant lesions. 16,17 The use of fluorescent in situ hybridization (FISH) for diagnostic purposes has increased significantly in the last few years, primarily because it provides in situ information about genetic or chromosomal changes and because it is applicable to archival and fresh material. 12 Cytogenetic and molecular studies have identified several frequent genetic alterations in mesothelioma, 18 of which one of the most common is homozygous deletion of the 9p21 locus within a cluster of genes (CDKN2B, CDKN2A, and MTAP). 12,19 23 CDKN2A encodes 2 important cell-cycle regulatory proteins, the p16 protein and, in an alternative reading frame, the p14arf protein. p16, a cyclin-dependent kinase inhibitor, acts through CDK4/CDK6 and blocks the phosphorylation of the RB protein, and p14arf binds MDM2, thus preventing the latter from binding p53 and targeting it for degradation. 19,24 The detection of homozygous CDKN2A deletion by FISH would be helpful in confirming a diagnosis of MM instead of reactive mesothelial cells. 12 The aim of this study was to find the prevalence of heterozygous and homozygous deletions at chromosome region 9p21 in abnormal mesothelial cells in effusions of the body cavities by using FISH to differentiate MM from reactive mesothelial cells and these from those of metastatic carcinomas. We, furthermore, wanted to analyze the diagnostic usefulness of cytomorphology, DNA-ICM, immunocytochemistry, AgNOR analysis, and chromosomal FISH for the diagnosis of malignant mesothelioma in serous effusions. MATERIALS AND METHODS Patient Selection Between March 2005 and May 2007, 48 body-cavity effusion specimens from 47 patients were positive or suspicious for MM after routine investigation by conventional cytology, DNA-ICM, immunocytochemistry and AgNOR analysis at the Institute of Cytopathology of the Heinrich-Heine University. The patients were from the University Hospital of Dusseldorf and from hospitals in the surrounding area. A total of 33 effusions (30 pleural and 3 peritoneal) taken from the routine files were analyzed in the current study (28 men and 5 women; mean age, 70 years; range, 47 years to 88 years), in which 6 were cytologically suspicious and 27 positive for mesothelioma. When FISH could not be performed because of a small number of atypical cells, because of the presence of atypical cells in clusters only, or because of unsuitable hybridization, 15 cases were excluded. In addition to MM cases, effusions from 31 metastatic carcinomas (20 pleural and 11 peritoneal; 7 men and 24 women; mean age, 66 years; age range, 43 years to 87 years) and 40 effusions with reactive mesothelial cells (36 pleural and 4 peritoneal; 24 men and 16 women; mean age 67 years; age range, 21 years to 91 years) were opportunistically obtained for subsequent applications of adjuvant methods such as DNA-ICM, immunocytochemistry, AgNOR analysis, and FISH. Cytological Procedure Routinely, 8 slides per native effusion were processed. Three of them were air dried and stained according to May-Grunwald-Giemsa (MGG). Five further slides were immediately fixed in Delaunay fixative and stained according to Papanicolaou (PAP). Two MGG slides were used for Feulgen and silver staining, and PAP slides were used for immunocytochemistry. Slides were evaluated according to generally accepted diagnostic criteria 10,25 by 2 experienced cytopathologists (authors N.P. and A.B.). DNA Image Cytometry After morphologic investigation, the MGG slides were uncovered in xylene and restained according to the
3 206 CANCER (CANCER CYTOPATHOLOGY) June 25, 2008 / Volume 114 / Number 3 method described by Feulgen. 26 Measurements of nuclear DNA contents were performed as previously described. 14 We used a computer-based image analysis system consisting of a Zeiss Axioplan 2 microscope (Zeiss, Jena, Germany) with a 403 objective (numeric aperture, 0.75; Kohler illumination) and a charge-coupled device black-and-white video camera with 572 lines of resolution (VariCam CCIR; PCO Computer Optics, Kehlheim, Germany). The software package used in the current study was the AutoCyte QUIC-DNA-Workstation (AutoCyte, Burlington, NC), which provides shading and glare correction. The latter was performed at a rate of 2.2%. In each case, at least 30 lymphocytes were measured as internal reference cells. The coefficient of variation of reference cells was always below 5%. 27 A minimum of 300 chosen nuclei of interest (reactive or atypical mesothelial or carcinoma cells) were randomly measured per specimen. All technical instruments and all software used met the standard requirements of the consensus reports of the European Society for Analytical Cellular Pathology (ESACP). 13,27,28,29 Several parameters were assessed for diagnostic interpretation. 13,27,28,29 DNA stemline ploidy was defined as the modal value of a DNA stemline in c units (c 5 DNA content). DNA stemline aneuploidy was assumed if the modal value of a stemline was \1.80c or [2.20c and \3.60c or [4.40c. Single-cell aneuploidy was diagnosed when at least 1 cell per slide had DNA content [9c (9cEE [1). 27 Cells between 5c and 8c occur in 6.5% of mesothelial cells in tumor cell-negative effusions. 30 This is the reason why the threshold for the detection of rare aneuploid cells had to be set at 9c and not at 5c. 31,32 We used 2 algorithms for the identification of DNA aneuploidy: abnormal position of any DNA stemline and occurrence of cells [9c. Immunocytochemistry After morphologic investigation, cells of interest were marked on PAP slides by felt-tip pen. Then, coverslips were removed in xylene at room temperature (RT). The coverslips fell off within 24 hours. All steps were performed according to our previous study. 31 Apart from the finding that all of our antibodies were originally tested with tumor-positive and tumor-negative effusions, we, because of scarcity of smears, did not routinely apply positive and negative controls on separate slides. Normal macrophages, lymphocytes, and granulocytes were usually used for internal negative control. Incubations were performed with commercially available monoclonal primary antibodies (Table 1) followed by a biotinylated link antibody and the avidin-biotin complex method of Elite TABLE 1 Antibodies, Clones, Dilutions, Pretreatments and Providers Antibody Clone Dilution Pretreatment Provider BerEP4 BerEP4(1) 1:200 None Dako Calretinin DAK-Calret 1 1:200 None Dako EMA E-29 1:1600 None Dako Mesothelin NCL Meso 1:200 None Novocastra WT-1 6F-H2 1:200 None Dako BerEP4 indicates surface and cytoplasmic glycoprotein; EMA, epithelial membrane antigen; WT-1, Wilms tumor protein 1. Standard (Vector, Burlingame, Calif) for the observation of immunologic reactions. We applied BerEP4 and calretinin in all effusions from MM, metastatic carcinoma, and reactive mesothelial cells. When there were enough slides from morphologically suspicious cases of MM, we also applied epithelial membrane antigen (28 cases), mesothelin (11 cases) and WT-1 (Wilms Tumor protein 1) (15 cases). Antibody reactions were evaluated per case, without knowledge of patient s follow-up in order to avoid any bias. To exclude false-positive results, artificial or unspecific staining cases that stained 10% of cells or showed diffuse weak staining were considered negative. Results were obtained as percentage per slide. AgNOR Analysis Silver staining was performed according to the 1-step method of Ploton et al., 33 Crocker et al., 34 and Rüschoff 35 with some modifications. Routine MGG-slides from effusions were uncovered in xylene. All steps were performed according to our previous study. 36 AgNOR counting was performed on 100 cells for each cytologic slide. These were examined at a magnification under oil immersion. Unequivocal benign cells were not counted in malignant effusions, and only reactive mesothelial cells were counted in benign effusion samples. To standardize the counting, we followed the Crocker method 34 with minor modifications as follows: first, silver-stained dot aggregations or partly disaggregated nucleoli (clusters) treated as 1 structure were counted. Second, individual dots (satellites) outside the clusters of silver-stained structures were counted. Third, clusters and satellites were counted together to obtain the total AgNORs counts. The mean number per nucleus of AgNORs as clusters, as satellites, and as total AgNOR counts (clusters plus satellites) was calculated in each case. For a correct tumor cell identification and to avoid overlap between reactive and malignant cells in effusions, we applied the threshold
4 9p21 Deletion and Adjuvant Methods in MM/Onofre et al. 207 of 2.5 AgNOR dots as satellites and 4.5 as total AgNOR counts as published in our previous study. 36 Values greater than or equal to this threshold were considered to be AgNOR positive. Fluorescence in situ Hybridization For FISH analysis, additional cytospin slides were made from each specimen and stained according to PAP to verify the presence of mesothelial or atypical cells. In each slide, the LSI p16/cep 9 dual-color probe was performed according to the recommendations of the manufacturer (Abbot/Vysis, Downers Grove, Ill) with minor modifications. Briefly, slides were uncovered in xylene, rehydrated through 2 series of 100%, 95%, and 80% ethanol, placed under running tap water for 5 minutes, then put in 0.5% HCl in 70% ethanol for 15 minutes at room temperature. After immersion in 2X saline sodium citrate (SSC) for 5 minutes at 738C, slides were digested by using 0.2mg/mL pepsin in 0.01 mol/l HCl for 15 minutes at 378C in a humidified chamber. The slides were washed in phosphate-buffered saline (PBS) for 5 minutes at room temperature, fixed in 1% neutralbuffered formalin/pbs for 5 minutes, washed in PBS again for 5 minutes, and air dried at room temperature. The FISH probe mix (7 ll LSI/WCP hybridization buffer, 2 ll purified water, and 1 ll 9p21/CEP 9 dual-color probe) was applied, cover slipped, and sealed with rubber cement (Q Biogene, Montreal, Canada). After denaturation at 738C for 10 minutes, slides were incubated at 378C overnight in a humidified chamber. After hybridization, the samples were washed in 0.4X SSC/0.1% NP-40 at 738C and in 0.4X SSC/0.1% NP-40 at room temperature for 2 minutes each. Then, 4.6-diamidine-2-2phenylindole dihydrochloride (DAPI) (Abbot/Vysis, Downers Grove, Ill) was used for counterstaining. The slides were scored on a cell-by-cell basis by using a Zeiss Axio Imager M1 fluorescence microscope (Zeiss, Gottingen, Germany) with a singleband pass filter for DAPI, SpectrumGreen (chromosome 9), and SpectrumOrange (9p21 locus). It contains a charge-coupled device black-and-white video camera with 1.4 Megapixel (AxioCam MRm, München-Hallbergmoos, Germany), and it is equipped with the Axio Vision QuantiFISH software (Zeiss, Hallbergmoos, Germany). Signal counting was performed by an experienced observer with FISH analysis (author F.O.). A minimum of 100 cells per case was counted manually under a 1003 planar objective. Inflammatory cells and macrophages were not counted. Two staining colors, orange for 9p21 locus and green for CEP 9, were simultaneously counted in a given nucleus. In each specimen, polymorphonuclear cells and lymphocytes served as internal controls, and hybridization efficiency was evaluated in these cells. Homozygous deletion was defined as the absence of both 9p21 signals in the presence of at least 1 chromosome 9 centromere signal. Heterozygous deletion was defined as the presence of only 1 9p21 signal or when the number of 9p21 signals was lower than the number of chromosome 9 centromere signals. Follow-up According to patient s histological and/or clinical follow-up, the investigated effusions were classified as either containing malignant cells or not and by what kind of tumor was present when the patient presented with a malignancy. Clinical evidence was considered valid, applying such diagnostic techniques as radiology and/or computed tomography. RESULTS From 33 cases cytologically diagnosed as suspicious or positive for MM, 2 cases were re-evaluated after routine application of immunocytochemistry, DNA- ICM, and AgNOR analysis (Fig. 1). One case, primarily reported as suspicious for MM, was revised as negative for tumor cells after routine application of those adjuvant methods, but histologic and clinical follow-up confirmed MM. The other case was rediagnosed as metastatic nonsmall cell carcinoma after application of those methods, but it was finally confirmed as MM by histologic follow-up. Another case diagnosed as suspicious for MM continued to be suspicious even after the application of adjuvant methods, which was confirmed as MM after histologic follow-up. One case cytologically reported as negative for tumor cells was not corroborated by histologic follow-up, which revealed a pleural involvement of a non-hodgkin lymphoma. In consequence, the additional effusions were resumed as 31 cases with metastatic carcinomas and 39 with reactive mesothelial cells. The most often found etiologies of negative effusions were pulmonary emphysema, pneumonia, congestive heart failure, coronary disease, renal insufficiency, cirrhosis of the liver, rheumatic fever, chronic inflammation, and foreign substances like talc. The primary tumors metastasized to the pleura were localized in the breasts (12 cases), the lungs (3 cases), the ovaries (3 cases), the stomach (1 case), and the endometrium (1 case). In peritoneal carcinosis, the primary tumors came from metastatic carcinomas of the ovary (6 cases), the stomach (2 cases),
5 208 CANCER (CANCER CYTOPATHOLOGY) June 25, 2008 / Volume 114 / Number 3 FIGURE 1. Flow chart illustrating the diagnostic results. MM: malignant mesothelioma; CA: carcinoma. TABLE 2 Prevalence of DNA Aneuploidy in Tumor-Cell Positive and Negative Effusions DNA ploidy status Without tumor cells n 5 39 (%) Follow-up diagnosis Total with tumor cells n 5 62 (%) Carcinoma n 5 31 (%) Mesothelioma n 5 31 (%) Euploidy 39 (100.0) 9 (14.5) 0 (0.0) 9 (29.0) Aneuploidy 0 (0.0) 53 (85.5) 31 (100.0) 22 (71.0) the pancreas (1 case), the endometrium (1 case), and the breast (1 case). DNA Image Cytometry None of the DNA histograms obtained from tumor cell-negative effusions revealed any of the mentioned parameters of DNA aneuploidy. This corresponds to a prevalence of 100% of the DNA euploidy in reactive mesothelial cells (Table 2). The prevalence of DNA aneuploidy was 100% for metastatic carcinomas and 71% for MMs (Table 2). In 2 cases of MM, DNA-ICM was not performed because of scarcity of cells. The prevalence of DNA aneuploidy in effusions depended on the algorithm applied (see table 3). Whereas 61.3% (19 of 31) of MMs showed their greatest DNA stemline within the range of 1.8c and 2.2c and/or 3.6c and 4.4c, only 19.4% (6 of 31) of metastatic carcinomas showed their greatest stemline in this region. Immunocytochemistry The immunocytochemical results are summarized in Table 4. All 32 cases of MM demonstrated positivity with calretinin (Fig. 2a). From 2 effusions from the same patient, immunocytochemistry was performed in only 1 case. BerEp4 was negative in 84.4% cases of MM (Fig. 2b). Only 2 cases demonstrated strong reaction ([80%) with BerEP4, in which calretinin demonstrated strong reaction in tumor cells also. Epithelial membrane antigen and mesothelin showed positivity in the majority of cases of MM and WT-1 in 66.7%. Calretinin was negative in all cases of effusions that contained metastatic carcinomas. In 87.1% of those cases, BerEP4 showed positivity. In 2 cases of metastatic carcinoma of the breast, 1 of the ovary, and 1 of the stomach, calretinin and BerEP4 were negative. The majority of negative cases with reactive mesothelial cells demonstrated positivity with calretinin. BerEP4 was completely negative in all of them. AgNOR Analysis AgNORs were strictly located only within nuclei and were clearly visible as distinct black or brown dots. We could not perform AgNOR counting in 10 cases (4 negatives, 1 metastatic carcinoma, and 5 MMs) because of the small number of cells, overlap of cells, or technical staining problems as hyperstaining or hypostaining with silver nitrate. By using receiver-operator characteristic (ROC) curves (Figs. 3 and 4), we confirmed the statement of our previous study 36 by applying the threshold of 2.5 AgNOR dots as satellites and 4.5 as total AgNOR counts. The AgNOR dots were discrete and smaller in benign effusion cases (Fig. 5a) compared with their coarse and aggregated appearance in malignant effusions (Fig. 5b). The AgNOR analysis results are summarized in Table 5. AgNOR analysis was positive in 89.3% of MM cases. In 1 case, the AgNOR analysis showed 2.16 and 3.16 (satellites/total AgNOR counts); this case was initially reported as suspicious for MM, and, after application of adjuvant methods, it was reevaluated as negative, but histologic and clinical follow-up confirmed MM. Two doubtful cases were found with 2.30 and 4.92 and 3.04 and 4.48 (satellites/total AgNOR counts). In MM cases, the mean
6 9p21 Deletion and Adjuvant Methods in MM/Onofre et al. 209 TABLE 3 Prevalence of DNA Aneuploidy in Effusions According to the Application of Different Algorithms DNA Aneuploidy Cytology No. of cases Single-cell aneuploidy (%) STL Aneuploidy (%) Single-cell and STL aneuploidy (%) Malignant mesothelioma (86.4) 12 (54.5) 9 (40.9) Metastatic carcinomas (83.9) 25 (80.6) 20 (64.5) Total with tumor cell (84.9) 37 (69.8) 29 (54.7) DNA-ICM indicates DNA-image cytometry; STL, stemline; single-cell aneuploidy, at least 1 cell with DNA content [9c. TABLE 4 Immunocytochemical Findings in Malignant Mesotheliomas, Metastatic Carcinomas and Reactive Effusions Grading of positive reactivity Markers No. of cases Negative (%) Positive (%) 11% 39% 40% 79% 80% 100% Malignant mesothelioma BerEP (84.4) 5 (15.6) Calretinin 32 0 (0.0) 32 (100.0) EMA 28 2 (7.1) 26 (92.9) Mesothelin 11 1 (9.1) 10 (90.9) WT (33.3) 10 (66.7) Metastatic carcinoma BerEP (12.9) 27 (87.1) Calretinin (100.0) 0 (0.0) Reactive effusion BerEP (100.0) 0 (0.0) Calretinin 39 2 (5.1) 37 (94.9) BerEP4 indicates surface and cytoplasmic glycoprotein; EMA, epithelial membrane antigen; WT-1, Wilms tumor protein 1. number of satellites was 4.91 (range, ), and the total AgNOR count was 7.04 (range, ). In 96.7% of metastatic carcinoma cases, AgNOR analysis was positive. In only 1 case of metastatic carcinoma of the breast, the AgNOR analysis was doubtful (2.44 satellites/5.16 total AgNOR counts). In metastatic carcinoma cases, the mean number of satellites was 5.31 (range, ), and the total AgNOR count was 7.04 (range, ). Only 1 case of negative effusion demonstrated an increased number of AgNOR dots (2.5 satellites/5.13 total AgNOR counts). This patient was clinically diagnosed as having lung embolism and pneumonia without indication of malignant cells in effusions. Of negative cases, 97.1% were AgNOR-analysis negative. The mean number of satellites was 1.07 (range, ), and the total AgNOR count was 2.94 (range, ) in reactive mesothelial cells. Fluorescence in situ Hybridization We focused on both homozygous and heterozygous deletion of 9p21 as criteria for positivity because of the relatively low frequency of these events in the normal cell population. To avoid overinterpretation of incomplete hybridization, we considered as positive all specimens containing 5 nuclei showing homozygous deletion of 9p21 or containing 15 nuclei showing heterozygous deletion of 9p21. Prevalence of 9p21 deletion in cases of reactive mesothelial cells, MM, and metastatic carcinoma is summarized in Table 6. FISH was positive in 90.9% of MM cases, in which 48.5% showed homozygous deletion (Fig. 6a), 36.4% heterozygous deletion (Fig. 6b), and 6.0% both. From 31 metastatic carcinomas cases, FISH was positive in 45.2%. Cases with homozygous deletion were carcinoma of the breast, the ovary, the pancreas, and the endometrium. The heterozygous deletion cases were carcinoma of the endometrium (1 case), the lungs (1 case), the stomach (2 cases), the breast (2 cases), and the ovary (2 cases). Two cases of carcinoma of the ovary showed homozygous and heterozygous deletion. No 9p21 deletion was detected in any negative effusion. One case cytologically diagnosed as tumor cell-negative effusion demonstrated positivity of 9p21 homozygous deletion, and the histologic follow-up reported a non-hodgkin lymphoma. Another case was first diagnosed cytologically as suspicious for MM and rediagnosed as negative after DNA-ICM, immunocytochemistry, and AgNOR analysis, but histologic and
7 210 CANCER (CANCER CYTOPATHOLOGY) June 25, 2008 / Volume 114 / Number 3 clinical follow-up confirmed MM. In this case, FISH demonstrated 9p21 heterozygous deletion. Application of Adjuvant Methods In the current study, when cytology was used alone for the diagnosis of MM, 81.8% of cases were reported as tumor cell-positive with certainty. The addition of DNA-ICM improved the prevalence to 87.9% and of AgNORs to 97% (Table 7). Application of FISH improved the prevalence of correct MM diagnosis to 100%, especially when 9p21 homozygous and heterozygous deletion were used as parameters. The combination of calretinin positive and BerEP4 negative was found in 84.4% of MM cases and calretinin negative and BerEP4 positive in 87.1% of metastatic carcinoma. FIGURE 2. Malignant mesothelioma cells are a) stained with calretinin (original magnification, 3400) and b) faintly stained with BerEP4 (original magnification, 3400). DISCUSSION Malignant mesothelioma (MM) is an aggressive neoplasm of the serosal membranes with a poor prognosis. Predictive studies have reported an increased incidence of MM for the next decade. 6 8 An early and precise diagnosis of MM in effusions is crucial for patient management and may avoid unnecessary invasive diagnostic procedures. Cytological diagnosis of MM is difficult but may be achieved by the application of adjuvant methods. DNA-ICM is a standardized, quantitative, adjuvant method that measures nuclear DNA content by the cytometric equivalent of nuclear Integrated Optical Density (IOD). 13 None of the DNA histograms measured from negative effusions revealed any of the mentioned parameters of DNA aneuploidy in the FIGURE 3. Receiver-operator characteristic (ROC) curve shows the sensitivity and specificity of AgNOR analysis for tumor cell detection based on the number of total AgNOR counts.
8 9p21 Deletion and Adjuvant Methods in MM/Onofre et al. 211 FIGURE 4. Receiver-operator characteristic (ROC) curve shows the sensitivity and specificity of AgNOR analysis for tumor cell detection based on the number of AgNOR satellites. FIGURE 5. a) Benign reactive mesothelial cells have small and discrete AgNOR dots (clusters) and a low number of satellites (oil immersion; original magnification, 31000), and b) malignant mesothelioma cells show an increased AgNOR number (oil immersion; original magnification, 31000). TABLE 5 Prevalence of AgNOR-Analysis in Tumor Cell-Positive and Negative Effusions Follow-up diagnosis AgNOR-analysis (Satellites/Total AgNOR counts) Without tumor cells n 5 35 (%) Total with tumor cells n 5 58 (%) Carcinoma n 5 30 (%) Mesothelioma n 5 28 (%) Negative (\2.5/\4.5) 34 (97.1) 1 (1.7) 0 (0.0) 1 (3.6) Positive (2.5/4.5) 1 (2.9) 54 (93.1) 29 (96.7) 25 (89.3) Doubtful* 0 (0.0) 3 (5.2) 1 (3.3) 2 (7.1) AgNOR: silver staining of nucleolar organizer regions-associated proteins. * Doubtful represents the cases that satellites or the total AgNOR counts is contradictory (\2.5/[4.5 or [2.5/\4.5). current study. This result is in concordance with the majority of the studies that have analyzed DNA-ICM in effusions. 31,36 39 In contrast, Palaoro et al. 40 found aneuploidy in 3 of 23 (13%) cases of negative effusions, but they did not follow the standard requirements reported by the European Society for Analytical Cellular Pathology (ESACP), which possibly contributed to these false-positive results. 13,14,27,28 In our study, all cases of metastatic carcinomas were found to be DNA aneuploid. The prevalence of
9 212 CANCER (CANCER CYTOPATHOLOGY) June 25, 2008 / Volume 114 / Number 3 TABLE 6 Prevalence of 9p21 Deletion in Cases of Reactive Mesothelial Cells, Malignant Mesothelioma and Metastatic Carcinoma 9p21 Deletion (%) Type of FISH positivity (%) Cytology No. of cases FISH Negative FISH Positive Homo deletion Hetero deletion Homo & Hetero deletion Reactive mesothelial cell (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Malignant mesothelioma 33 3 (9.1) 30 (90.9) 16 (48.5) 12 (36.4) 2 (6.0) Metastatic carcinomas (54.8) 14 (45.2) 4 (12.9) 8 (25.8) 2 (6.5) FISH indicates fluorescence in situ hybridization; Homo, positive homozygous deletion of 9p21 5 nuclei; Hetero, positive heterozygous deletion 15 nuclei. FIGURE 6. Fluorescence in situ hybridization in malignant mesothelioma nuclei shows a) (left) 2 signals for chromosome 9 centromeric probe (CEP-9; Spectrum Green) and no signals for the 9p21 locus probe (LSI p16; Spectrum Orange); b) (right) 2 signals for chromosome 9 centromeric probe and only 1 signal for the 9p21 locus. TABLE 7 Prevalence of Cytology Correlated With Adjuvant Methods in Effusions With Malignant Mesothelioma Cells Cytology1FISH Cytology1DNA-ICM1AgNOR1FISH No. of cases Cytology Cytology1DNA-ICM Cytology1AgNOR Homo Homo & Hetero Homo Homo & Hetero Prevalence, % (81.8) 29 (87.9) 32 (97.0) 30 (90.9) 33 (100.0) 32 (97.0) 33 (100.0) DNA-ICM indicates DNA-image cytometry, DNA-aneuploidy; AgNOR, silver staining of nucleolar organizer regions-associated proteins. 2.5/4.5 (satellites/total AgNOR counts); FISH, fluorescence in situ hybridization; Homo, positive homozygous deletion of 9p21 5 nuclei; Hetero, positive heterozygous deletion 15 nuclei. aneuploidy in cells from metastatic carcinomas in effusions varies between 88.5% and 100%. 31,36 39 DNA aneuploidy was found in 71% of MM cases in the current study. This is in agreement with some reports DNA aneuploidy seems to represent a consistent marker of malignancy; however, euploidy cannot exclude it. Our data confirm the higher proportion of euploidy in MMs compared with metastatic carcinomas, which showed no euploid cases. In MMs, 61.3% showed their greatest stemline within the range of 1.8c and 2.2c and/or 3.6c and 4.4c. This parameter is able to contribute to the differential diagnosis between MM and metastatic carcinoma, which showed only 19.4% in that region. Similar findings have been published. 31,36 In recent years, immunocytochemistry has contributed to the differentiation of mesotheliomas from adenocarcinomas As a specific marker for mesotheliomas has not yet been recognized, panels of markers that frequently are expressed in mesotheliomas combined with those that are commonly expressed in adenocarcinomas are used. 15 Calretinin
10 9p21 Deletion and Adjuvant Methods in MM/Onofre et al. 213 and BerEP4 have been used in panels, using calretinin as marker for mesothelial cells and BerEP4 for carcinoma cells. 36,41,42,44,45 In the current study, calretinin revealed positivity in 100% and BerEP4 in 15.6% of MM cases. These results are in concordance with other authors who have found similar results. 36,42,44 Li et al. 41 and Politi et al. 45 reported calretinin positivity and BerEP4 negativity in all of their cases of MM. Our metastatic carcinoma cases showed BerEP4 positivity in 87.1% and calretinin in none of them. Some studies found calretinin positivity in metastatic carcinomas. 36,42,44 It is suggested that a positive background of benign mesothelial cells could be a potential pitfall in the interpretation of calretinin staining patterns. 41 Epithelial membrane antigen revealed positivity in 92.9% of MM cases. Similar results have been found by other studies. 36,44 Only 1 of our MMs was negative for mesothelin, and WT-1 was positive in 66.7%. Ordonez found positivity of WT-1 between 72% and 93% of MMs. 43,46 AgNOR is a proliferation marker useful in the differential diagnosis of benign and malignant cells. Unfortunately, a definitive standard for AgNOR staining and quantification has not yet been achieved. By using a digital-image analysis system, Wolanski et al. 47 reported a significant overlap in nuclei in AgNOR counting. In the current study, we generated ROC curves that confirmed those thresholds suggested by Pomjanski et al. 36 In concordance with previous studies, 40,48 our study showed that malignant cells mostly exhibit a greater AgNOR protein content compared with corresponding benign cells. AgNOR analysis was positive in 89.3% of MM and 96.7% of metastatic carcinomas. Only 1 case of MM showed AgNOR negativity. AgNOR analysis was negative in 97.1% of negative effusions. Only 1 case of negative effusion demonstrated an increased number of AgNOR dots (2.5 as satellites and 5.13 as total AgNOR counts). The AgNOR analysis appears to be a sensitive method to distinguish between benign and malignant cells in effusions. The occurrence of multiple cytogenetic deletions in MM suggests that the loss and/or the inactivation of tumor-suppressor genes may be critical to the development and progression of this tumor. 19,49 The most common cytogenetic abnormality in MM is deletion at the 9p21 locus, 12,19 23 which can be used as a marker for malignancy in serous effusions. 12 In the current study, 90.9% of MM cases demonstrated 9p21 deletion, of which 54.5% were homozygous and 42.4% heterozygous. This occurrence of deletions was reduced in metastatic carcinomas, which were revealed to be homozygous in 19.4% and heterozygous in 32.3%. No 9p21 deletion was detected in any tumor cell-negative effusion. Previous studies have indicated that the 9p21 homozygous deletion is present in approximately 72% to 75% of MM patients 19,22,50 and up to 100% in mesothelioma cell lines. 23,50 Illei et al. 12 confirmed a diagnosis of MM in 12 of 13 patients with positive or suspicious cytology. In concordance with the current study, they also reported that all 19 cytologically negative specimens were negative for 9p21 deletion. 12 Cheng et al. 23 reported homozygous deletion of 9p21-p22 in 43% and homozygous and/or heterozygous deletion in 83% of MM cell lines. To our knowledge, no study has so far reported the 9p21 deletion in metastatic carcinomas by FISH, as well as 9p21 heterozygous deletions as criteria for FISH-positive in serous effusions. The 9p21 heterozygous deletion is a criterion used for FISH positivity also in other tumor sites, such as bladder cancer in bladder-washing samples. 51 Because of the dependence of the type of preparation and staining, volume examined, investigator experience, and number of sufficient specimens investigated, the reported sensitivity of conventional cytology to serous effusions varies between 50% and 84%. 37,52 The sequential use of different adjuvant methods can contribute to establish a diagnosis in cytologically doubtful and suspicious cases. In the current study, 81.8% of MMs were identified unequivocally by cytology alone, as confirmed by follow-up. The addition of DNA-ICM improved the prevalence of tumor-cell detection to 87.9% and to 97% with the addition of AgNOR analysis. Our results confirm the impact of DNA-ICM and AgNOR to diagnose MM. 31,36 The introduction of FISH could improve the prevalence of tumor-cell detection to 100% if 9p21 homozygous and heterozygous deletions were used as diagnostic parameters. To differentiate metastatic carcinoma from MM or reactive mesothelial cells, the application of calretinin and BerEP4 plays an important role. It is generally agreed that no single antibody is sufficiently sensitive or specific. In our study, the combination of calretinin positivity and BerEP4 negativity was found in 84.4% of MM cases and calretinin negativity and BerEP4 positivity in 87.1% of metastatic carcinomas. The documented low sensitivity of conventional cytology to identify MM cells in effusions indicates the necessity of applying adjuvant diagnostic methods to improve diagnostic accuracy. Following our results, we state that immunocytochemistry (calretinin and BerEP4) should be applied to differentiate
11 214 CANCER (CANCER CYTOPATHOLOGY) June 25, 2008 / Volume 114 / Number 3 epithelial cells from mesothelial cells. If BerEP4 is positive and calretinin negative, the diagnosis should be focused on metastatic carcinoma, applying other immunocytochemical panels if the primary tumor is unknown. 53 If BerEP4 is negative and calretinin is positive, then the diagnosis should be focused on differentiating reactive mesothelial cells from MM. The application of DNA-ICM and AgNOR analysis is recommended to establish the detection of tumor cells. If the results of those methods remain doubtful, then the application of FISH (9p21 deletion) is indicated. In conclusion, to establish a cytological diagnosis of malignant mesothelioma in serous effusions, we propose the sequential application of immunocytochemistry, DNA-ICM, and AgNOR analysis. In persistent doubtful diagnoses, we recommend fluorescence in situ hybridization to analyze the 9p21 deletion. Further studies on larger series of patients are needed to evaluate the validity and efficiency of this approach for improving the diagnostic accuracy of effusion cytology. REFERENCES 1. Churg A, Cagle PT, Roggli VL.Tumors of the serosal membranes. In: Atlas of Tumor Pathology. 4th series, fascicle 10. Washington, DC: Armed Forces Institute of Pathology; Yarborough CM. The risk of mesothelioma from exposure to chrysotile asbestos. Curr Opin Pulm Med. 2007;13: Carbone M, Bedrossian CW. The pathogenesis of mesothelioma. Semin Diagn Pathol. 2006;23: Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366: Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med. 1960;17: Hodgson JT, McElvenny DM, Darnton AJ, Price MJ, Peto J. The expected burden of mesothelioma mortality in Great Britain from 2002 to Br J Cancer. 2005;92: Price B, Ware A. Mesothelioma trends in the United States: An update based on Surveillance, Epidemiology, and End Results Program data for 1973 through Am J Epidemiol. 2004;159: Leigh J, Davidson P, Hendrie L, Berry D. Malignant mesothelioma in Australia, Am J Ind Med. 2002; 41: Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer. 1999;79: Gray W, Mckee GT. Diagnostic Cytopathology. 2nd ed. Edinburgh: Churchill Livingstone; Bedrossian CW. Diagnostic problems in serous effusions. Diagn Cytopathol. 1998;19: Illei PB, Ladanyi M, Rusch VW, Zakowski M. The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer (Cancer Cytopathol). 2003;99: Haroske G, Baak JP, Danielsen H, et al. Fourth updated ESACP consensus report on diagnostic DNA image cytometry. Anal Cell Pathol. 2001;23: Böcking A.DNA measurements. When and why? In: Wied GL,Keebler CM, Rosenthal DL, Schenk U, Somrak TM, Vooijs GP, eds. Compendium on Quality Assurance, Proficiency Testing, and Workload Limitations. Chicago: Tutorials of Cytology; 1995: Ordonez NG. What are the current best immunohistochemical markers for the diagnosis of the epithelioid mesothelioma? A review and update. Hum Pathol. 2007;38: Derenzini M. The AgNORs. Micron. 2000;31: Sirri V; Roussel P; Hernandez-Verdun D. The AgNOR proteins: qualitative and quantitative changes during the cell cycle. Micron. 2000;31: Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Mesothelioma. Cancer Genet Cytogenet. 2001;127: Illei PB; Rusch VW, Zakowski MF, Ladanyi M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin Cancer Res. 2003;9: Hirao T, Bueno R, Chen CJ, Gordon GJ, Heilig E, Kelsey KT. Alterations of the p16 INK4 locus in human malignant mesothelial tumors. Carcinogenesis. 2002;23: Bjorkqvist AM, Tammilehto L, Anttila S, Mattson K, Knuutila S. Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. Br J Cancer. 1997;75: Xiao S, Li D, Vijg J, Sugarbaker DJ, Corson JM, Fletcher JA. Codeletion of p15 and p16 in primary malignant mesothelioma. Oncogene. 1995;11: Cheng JQ, Jhanwar SC, Klein WM, et al. p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res. 1994;54: Stahel RA. Malignant pleural mesothelioma: a new standard of care. Lung Cancer. 2006;545:S9 S Koss LG, Melamed MR.Koss diagnostic cytology and its histopathologic bases. Volumes I and II. 5th ed. Philadelphia: Lippincott Williams & Wilkins; Chatelain R, Willms A, Biesterfeld S, Auffermann W, Bocking A. Automated Feulgen staining with a temperature controlled staining machine. Anal Quant Cytol Histol. 1989;11: Haroske G, Giroud F, Reith A, Böcking A ESACP consensus report on diagnostic DNA image cytometry. Part I: basic considerations and recommendations for preparation, measurement and interpretation. European Society for Analytical Cellular Pathology. Anal Cell Pathol. 1998;17: Giroud F, Haroske G, Reith A, Böcking A ESACP consensus report on diagnostic DNA image cytometry. Part II: Specific recommendations for quality assurance. European Society for Analytical Cellular Pathology. Anal Cell Pathol. 1998;17: Böcking A, Giroud F, Reith A. Consensus report of the ESACP task force on standardization of diagnostic DNA image cytometry. European Society for Analytical Cellular Pathology. Anal Cell Pathol. 1995;8: Biesterfeld S, Gerres K, Fischer-Wein G, Böcking A. Polyploidy in non-neoplastic tissues. J Clin Pathol. 1994;47:38 42.
12 9p21 Deletion and Adjuvant Methods in MM/Onofre et al Motherby H, Kube M, Friedrichs N, et al. Immunocytochemistry and DNA-image cytometry in diagnostic effusion cytology. I. Prevalence of markers in tumor cell positive and negative smears. Anal Cell Pathol. 1999;19: Motherby H, Marcy T, Hecker M, et al. Static DNA cytometry as a diagnostic aid in effusion cytology. I. DNA aneuploidy for identification and differentiation of primary and secondary tumor of the serous membranes. Analyt Quant Cytol Histol. 1998;20: Ploton D, Menager M, Jeannesson P, Himber G, Pigeon F, Adnet JJ. Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region at the optical level. Histochem J. 1986;18: Crocker J, Boldy DA, Egan MJ. How should we count AgNORs? Proposals for a standardized approach. J Pathol. 1989;158: Rüschoff J. Nukleolus Organisierende Regionen (NORs) in der Pathomorphologischen Tumordiagnostik. Stuttgart: Gustav Fischer Verlag; Pomjanski N, Motherby H, Buckstegge B, Knops K, Rohn BL, Böcking A. Early diagnosis of mesothelioma in serous effusions using AgNOR analysis. Analyt Quant Cytol Histol. 2001;23: Osterheld MC, Liette C, Anca M. Image Cytometry: an aid for cytological diagnosis of pleural effusions. Diagn Cytopathol. 2005;32: Motherby H, Pomjanski N, Kube M, et al. Diagnostic DNAflow vs. image-cytometry in effusion cytology. Anal Cell Pathol. 2002;24: Kayser K, Blum S, Beyer M, Haroske G, Kunze KD, Meyer W. Routine DNA cytometry of benign and malignant pleural effusions by means of the remote quantification server Euroquant: a prospective study. J Clin Pathol. 2000;53: Palaoro LA, Blanco AM, Gamboni M, Rocher AE, Rotenberg RG. Usefulness of ploidy, AgNOR and immunocytochemistry for differentiating benign and malignant cells in serous effusions. Cytopathology. 2007;18: Li Q, Bavikatty N, Michael CW. The role of immunohistochemistry in distinguishing squamous cell carcinoma from mesothelioma and adenocarcinoma in pleural effusion. Semin Diagn Pathol. 2006;23: Ordonez NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study. Mod Pathol. 2006;19: Ordonez NG. The immunohistochemical diagnosis of mesothelioma. A comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27: Comin AE, Novelli L, Boddi V, Paglierani M, Dini S. Calretinin, Thrombomodulin, CEA, and CD15: a useful combination of immunohistochemical markers for differentiating pleural epithelial mesothelioma from peripheral pulmonary adenocarcinoma. Hum Pathol. 2001;32: Politi E, Kandaraki C, Apostolopoulou C, Kyritsi T, Koutselini H. Immunocytochemical panel for distinguishing between carcinoma and reactive mesothelial cells in body cavity fluids. Diagnostic Cytopathol. 2005;32: Ordonez NG. Value of thyroid transcription factor-1, E- Cadherin, BG8, WT1, and CD44s immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma. Am J Surg Pathol. 2000;24: Wolanski KD, Whitaker D, Shilkin KB, Henderson DW. The use of epithelial membrane antigen and silver-stained nucleolar organizer regions testing in the differential diagnosis of mesothelioma from benign reactive mesothelioses. Cancer. 1998;82: Mohanty SK, Dey P, Rana P. Manual and automated AgNOR count in differentiating reactive mesothelial from metastatic malignant cells in serous effusions. Anal Quant Cytol Histol. 2003;25: Musti M, Kettunen E, Dragonieri S, et al. Cytogenetic and molecular genetic changes in malignant mesothelioma. Cancer Genet Cytogenet. 2006;170: Prins JB, Williamson KA, Kamp MM, et al. The gene for the cyclin-dependent-kinase-4 inhibitor, CDKN2A, is preferentially deleted in malignant mesothelioma Int J Cancer. 1998;75: Zellweger T, Benz G, Cathomas G, et al. Multi-target fluorescence in situ hybridization in bladder washings for prediction of recurrent bladder cancer. Int J Cancer. 2006;119: Metzgeroth G, Kuhn C, Schultheis B, Hehlmann R, Hastka J. Diagnostic accuracy of cytology and immunocytology in carcinomatous effusions. Cytopathology. 2007;DOI: / j x. In press. 53. Pomjanski N, Grote HJ, Doganay P, Schmiemann V, Buckstegge B, Böcking A. Immunocytochemical identification of carcinomas of unknown primary in serous effusions. Diagn Cytopathol. 2005;33:
Practical Effusion Cytology
Practical Effusion Cytology A Community Pathologist s Approach to Immunocytochemistry in Body Fluid Cytology Emily E. Volk, MD William Beaumont Hospital Troy, MI College of American Pathologists 2004.
More informationCytopathology Case Presentation #8
Cytopathology Case Presentation #8 Emily E. Volk, MD William Beaumont Hospital, Troy, MI Jonathan H. Hughes, MD Laboratory Medicine Consultants, Las Vegas, Nevada Clinical History 44 year old woman presents
More information20 Diagnostic Cytopathology, Vol 36, No 1 ' 2007 WILEY-LISS, INC.
Utility of WT-1, p63, MOC31, Mesothelin, and Cytokeratin (K903 and CK5/6) Immunostains in Differentiating Adenocarcinoma, Squamous Cell Carcinoma, and Malignant Mesothelioma in Effusions Robert T. Pu,
More informationCytology : first alert of mesothelioma? Professor B. Weynand, UCL Yvoir, Belgium
Cytology : first alert of mesothelioma? Professor B. Weynand, UCL Yvoir, Belgium Introduction 3 cavities with the same embryologic origin the mesoderme Pleura Exudates Pleura Peritoneum Pericardium 22%
More informationDiagnostic Challenge. Department of Pathology,
Cytology of Pleural Fluid as a Diagnostic Challenge Paavo Pääkkö,, MD, PhD Chief Physician and Head of the Department Department of Pathology, Oulu University Hospital,, Finland Oulu University Hospital
More informationDiagnosis of Mesothelioma Pitfalls and Practical Information
Diagnosis of Mesothelioma Pitfalls and Practical Information Mary Beth Beasley, M.D. Mt Sinai Medical Ctr Dept of Pathology One Gustave L Levy Place New York, NY 10029 (212) 241-5307 mbbeasleymd@yahoo.com
More informationMALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY
MALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY Sisko Anttila, MD, PhD Jorvi Hospital Laboratory of Pathology Helsinki University Hospital Espoo, Finland 2nd Nordic Conference on Applied
More informationMALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY
MALIGNANT MESOTHELIOMA CLASSIFICATION MALIGNANT MESOTHELIOMA UPDATE ON PATHOLOGY AND IMMUNOHISTOCHEMISTRY Sisko Anttila, MD, PhD Jorvi Hospital Laboratory of Pathology Helsinki University Hospital Espoo,
More informationUpdate on Mesothelioma
November 8, 2012 Update on Mesothelioma Intro incidence and nomenclature Update on Classification Diagnostic specimens Morphologic features Epithelioid Histology Biphasic Histology Immunohistochemical
More informationCase of the. Month October, 2012
Case of the Month October, 2012 Case The patient is a 47-year-old male with a 3-week history of abdominal pain. A CT scan of the abdomen revealed a suggestion of wall thickening at the tip of the appendix
More informationThe Value of Thyroid Transcription Factor-1 in Cytologic Preparations as a Marker for Metastatic Adenocarcinoma of Lung Origin
Anatomic Pathology / TTF-1 IN CYTOLOGY OF BODY FLUIDS The Value of Thyroid Transcription Factor-1 in Cytologic Preparations as a Marker for Metastatic Adenocarcinoma of Lung Origin Jonathan L. Hecht, MD,
More informationOutline. Workup for metastatic breast cancer. Metastatic breast cancer
Metastatic breast cancer Immunostain Update: Diagnosis of metastatic breast carcinoma, emphasizing distinction from GYN primary 1/3 of breast cancer patients will show metastasis 1 st presentation or 20-30
More informationHow To Diagnose And Treat A Tumour In An Effusion
Effusions of the Serous Cavities Annika Dejmek Professor/Consultant in Cytopathology Clinical Pathology; Department of Laboratory Medicine, Malmö, Lund University 5th EFCS Tutorial Trondheim 2012 Pleura
More informationImmunohistochemistry on cytology specimens from pleural and peritoneal fluid
Immunohistochemistry on cytology specimens from pleural and peritoneal fluid Dr Naveena Singh Consultant Pathologist Bart health NHS Trust London United Kingdom Disclosures and Acknowledgements I have
More informationDisclosures. Learning Objectives. Effusion = Confusion. Diagnosis Of Serous Cavity Effusions - Beware The Mesothelial Cell!
Disclosures Diagnosis Of Serous Cavity Effusions - Beware The Mesothelial Cell! No Relevant Financial Relationships with Commercial Interests Syed Z. Ali, M.D. Syed Z. Ali, M.D. Associate Professor of
More informationSeattle. Case Presentations. Case 1. 76 year old female with a history of breast cancer 12 years ago. Now presents with a pleural effusion.
Seattle Montreal IAP September 2006 Case Presentations Allen M. Gown, M.D. Medical Director and Chief Pathologist PhenoPath Laboratories Clinical Professor of Pathology University of British Columbia Case
More informationNotice of Faculty Disclosure
The Diagnosis of Malignant Mesothelioma Andrew Churg, MD Department of Pathology University of British Columbia Vancouver, BC, Canada achurg@mail.ubc.ca Notice of Faculty Disclosure In accordance with
More informationHow To Test For Cancer
Diagnosis Of Serous Cavity Effusions - Beware The Mesothelial Cell! Effusion = Confusion Syed Z. Ali, M.D. Professor of Pathology and Radiology The Johns Hopkins Hospital Baltimore, Maryland Diagnostic
More informationA 70-year old Man with Pleural Effusion
Mesothelioma Diagnosis: Pitfalls and Latest Updates S Klebe and DW Henderson Recommendations Indisputable malignant cells on cytomorphological criteria which demonstrate a mesothelial phenotype, which
More informationThe Use of Immunohistochemistry to Distinguish Reactive Mesothelial Cells From Malignant Mesothelioma in Cytologic Effusions
The Use of Immunohistochemistry to Distinguish Reactive Mesothelial Cells From Malignant Mesothelioma in Cytologic Effusions Farnaz Hasteh, MD 1 ; Grace Y. Lin, MD, PhD 1 ; Noel Weidner, MD 1 ; and Claire
More informationDistinguishing benign from malignant mesothelial
ORIGINAL ARTICLE IMP3 and GLUT-1 Immunohistochemistry for Distinguishing Benign From Malignant Mesothelial Proliferations Anna F. Lee, MDCM, PhD,*w Allen M. Gown, MD,wz and Andrew Churg, MD*w Abstract:
More informationEffusions: Mesothelioma and Metastatic Cancers
Effusions: Mesothelioma and Metastatic Cancers Malignant Mesothelioma Incidence: 2,500 cases/year ~60-80% pts with pleural MM relationship with asbestos exposure Other risk factors: radiation, other carcinogens,
More informationThe develpemental origin of mesothelium
Mesothelioma Tallinn 14.12.06 Henrik Wolff Finnish Institute of Occupational Health The develpemental origin of mesothelium Mesodermal cavities (pleura, peritoneum and pericardium ) are lined with mesenchymal
More informationPleural and Pericardial fluids a one year analysis
Pleural and Pericardial fluids a one year analysis Dr Olafsdottir Dr J Williams Department of Cytology, Llandough Hospital Contents Background Standards Aims/Questions Investigation group Results Conclusions
More informationPATHOLOGY OF THE PLEURA: Mesothelioma and mimickers Necessity of Immunohistochemistry. M. Praet
PATHOLOGY OF THE PLEURA: Mesothelioma and mimickers Necessity of Immunohistochemistry M. Praet Pathology of the Pleura Normal serosa: visceral and parietal layers Inflammation Neoplasia: Primary: mesothelioma
More informationMaterials and Methods Specimens
The Expression Pattern of b-catenin in Mesothelial Proliferative Lesions and Its Diagnostic Utilities Yiran Dai, M.D., 1 * Carlos W.M. Bedrossian, M.D., FIAC, 2 and Claire W. Michael, M.D. 1 b-catenin
More informationTowards a single cell cancer diagnosis. Multimodal and Monocellular Measurements of Markers and Morphology (5M)
Letter to the editor of J Cellular Oncology Towards a single cell cancer diagnosis. Multimodal and Monocellular Measurements of Markers and Morphology (5M) A. Böcking 1, J. Stockhausen 2, D. Meyer-Ebrecht
More informationNo Difference Between Mesothelioma and Pulmonary and Nonpulmonary Adenocarcinoma DO NOT DUPLICATE. Malignancy is a common cause of effusions of the
NONGYNECOLOGIC CYTOPTHOLOGY CK5/6 in Effusions No Difference etween Mesothelioma and Pulmonary and Nonpulmonary denocarcinoma nnika Dejmek, M.D., Ph.D. Objective To test the performance of CK5/6 for the
More informationAcadémie internationale de Pathologie - Division arabe XX ème congrès 24-26 novembre 2008 Alger. Immunohistochemistry in malignant mesotheliomas
Académie internationale de Pathologie - Division arabe XX ème congrès 24-26 novembre 2008 Alger Immunohistochemistry in malignant mesotheliomas Françoise Thivolet-Béjui Groupement Hospitalier Est Lyon-Bron
More informationThe Diagnostic Utility of p16 FISH and GLUT-1 Immunohistochemical Analysis in Mesothelial Proliferations
Anatomic Pathology / P16 and GLUT-1 in Mesothelial Proliferations The Diagnostic Utility of p16 FISH and GLUT-1 Immunohistochemical Analysis in Mesothelial Proliferations Sara E. Monaco, MD, 1 Yongli Shuai,
More informationPRIMARY SEROUS CARCINOMA OF PERITONEUM: A CASE REPORT
PRIMARY SEROUS CARCINOMA OF PERITONEUM: A CASE REPORT Dott. Francesco Pontieri (*) U.O. di Anatomia Patologica P.O. di Rossano (CS) Dott. Gian Franco Zannoni Anatomia Patologica Facoltà di Medicina e Chirurgia
More informationThe diagnostic usefulness of tumour markers CEA and CA-125 in pleural effusion
Malaysian J Path01 2002; 24(1) : 53-58 The diagnostic usefulness of tumour markers CEA and CA-125 in pleural effusion Pavai STHANESHWAR MD, Sook-Fan YAP FRCPath, FRCPA and Gita JAYARAM MDPath, MRCPath
More informationLYMPHOMA. BACHIR ALOBEID, M.D. HEMATOPATHOLOGY DIVISION PATHOLOGY DEPARTMENT Columbia University/ College of Physicians & Surgeons
LYMPHOMA BACHIR ALOBEID, M.D. HEMATOPATHOLOGY DIVISION PATHOLOGY DEPARTMENT Columbia University/ College of Physicians & Surgeons Normal development of lymphocytes Lymphocyte proliferation and differentiation:
More informationMarch 19, 2014. Dear Dr. Duvall, Dr. Hambrick, and Ms. Smith,
Dr. Daniel Duvall, Medical Officer Center for Medicare, Hospital and Ambulatory Policy Group Centers for Medicare and Medicaid Services 7500 Security Boulevard Baltimore, Maryland 21244 Dr. Edith Hambrick,
More informationPROTOCOL OF THE RITA DATA QUALITY STUDY
PROTOCOL OF THE RITA DATA QUALITY STUDY INTRODUCTION The RITA project is aimed at estimating the burden of rare malignant tumours in Italy using the population based cancer registries (CRs) data. One of
More informationORIGINAL ARTICLES. Materials and Methods
ORIGINAL ARTICLES Cytomorphologic Features of Metastatic Urothelial Carcinoma in Serous Effusions Cheng Cheng Huang, M.D., PH.D., 1 Anoja Attele, M.D., 1 and Claire W. Michael, M.D. 2 * Metastatic urothelial
More informationHow To Use Calretinin
Product Code: MP-092-CR01 (0.1ml concentrate) MP-092-CR05 (0.5ml concentrate) MP-092-CR1 (1ml concentrate) MP-092-PR6 (6ml RTU) Product Description: Calretinin Concentrated and Prediluted Polyclonal Antibody
More information264 Diagnostic Cytopathology, Vol 38, No 4 ' 2010 WILEY-LISS, INC.
Podoplanin Is a Useful Marker for Identifying Mesothelioma in Malignant Effusions Atef Hanna, M.D., Ph.D., 1 Yijun Pang, M.D., Ph.D., 1 Carlos W. M. Bedrossian, M.D., 2 Annika Dejmek, M.D., Ph.D., 3 and
More informationHKCPath Anatomical Pathology Peer Review and Scores : PDF version for download
AP2003R1 http://hkcpath.org. Correspondence: pkhui@ha.org.hk 1of 10 07/08/2003 HKCPath Anatomical Pathology Peer Review and Scores : PDF version for download AP141 Bone Marrow: Metastatic Carcinoma from
More informationThe Role of Genetic Testing in the Evaluation of Thyroid Nodules. Thyroid Cancer and FNA. Thyroid Cancer. Pure Follicular Cancers.
Where does Molecular Analysis of FNA Specimens fit into the evaluation of thyroid nodules? The Role of Genetic Testing in the Evaluation of Thyroid Nodules Ultrasound TSH Risk factors Jill E. Langer, MD
More informationSEROUS EFFUSION CYTOLOGY- A PRACTICAL APPROACH
Video Microsc copy Tutorial #20 Ashish Chandr ra, MD Disclosur re information The speaker has no relationship that representss a possible conflict of interest with respect to the content of this presentation.
More informationMale. Female. Death rates from lung cancer in USA
Male Female Death rates from lung cancer in USA Smoking represents an interesting combination of an entrenched industry and a clearly drug-induced cancer Tobacco Use in the US, 1900-2000 5000 100 Per Capita
More informationToday s Topics. Tumors of the Peritoneum in Women
Today s Topics Tumors of the Peritoneum in Women Charles Zaloudek, M.D. Department of Pathology 505 Parnassus Ave., M563 University of California, San Francisco San Francisco, CA USA charles.zaloudek@ucsf.edu
More informationHER2 Testing in Breast Cancer
HER2 Testing in Breast Cancer GAIL H. VANCE, M.D. AGT MEETING JUNE 13, 2014 LOUISVILLE, KENTUCKY No Conflict of Interest to Report Human Epidermal Growth Factor Receptor 2-HER2 Human epidermal growth factor
More informationTumour Markers. What are Tumour Markers? How Are Tumour Markers Used?
Dr. Anthony C.H. YING What are? Tumour markers are substances that can be found in the body when cancer is present. They are usually found in the blood or urine. They can be products of cancer cells or
More informationHER2 FISH pharmdx. Assay Kit
PATHOLOGY HER2 FISH pharmdx Assay Kit HER2 FISH pharmdx Clarity You Can Count On Reliable Results at a Glance The robust HER2 FISH pharmdx assay offers bright and distinct signals for easy and fast reading
More information3-F. Pathology of Mesothelioma
3-F. Pathology of Mesothelioma Kouki Inai Professor of Department of Pathology, Graduate School of Biomedical Science, Hiroshima University Introduction Mesothelioma is a peculiar type of malignancy, which
More informationVideo Microscopy Tutorial 5
Video Microscopy Tutorial 5 Lool Alikes in Effusion Cytology:Review of Diagnostic Challenges Claire Michael, MD There are no disclosures necessary. Look-Alikes in Effusion Cytology: Review of Diagnostic
More informationCase presentation. Awatif Al-Nafussi
Case presentation Awatif Al-Nafussi Case History 49 year old DVT & small PE June 08, Pelvic mass Ca125 33 Laparotomy-TAHBSO, drainage of ascites Ovarian carcinoma Clinical diagnosis Multiple specimens
More informationWhat is Cancer? Cancer is a genetic disease: Cancer typically involves a change in gene expression/function:
Cancer is a genetic disease: Inherited cancer Sporadic cancer What is Cancer? Cancer typically involves a change in gene expression/function: Qualitative change Quantitative change Any cancer causing genetic
More informationInteresting Case Review. Renuka Agrawal, MD Dept. of Pathology City of Hope National Medical Center Duarte, CA
Interesting Case Review Renuka Agrawal, MD Dept. of Pathology City of Hope National Medical Center Duarte, CA History 63 y/o male with h/o CLL for 10 years Presents with worsening renal function and hypercalcemia
More informationProduct Datasheet and Instructions for Use
Product Code: MP-378-CMK01 (0.1ml conc) MP-378-CMK05 (0.5ml conc) MP-378-PM6 (6ml RTU) Product Description: CD141 (Thrombomodulin) Concentrated and Prediluted Monoclonal Antibody Control Number: 901-378-071709
More informationRecommendations for the Reporting of Pleural Mesothelioma
Recommendations for the Reporting of Pleural Mesothelioma Association of Directors of Anatomic and Surgical Pathology * DOI: 10.1309/6A30YQHBMTHEJTEM It has been evident for decades that pathology reports
More informationBRIEF REPORTS. Introduction
BRIEF REPORTS WT1, Monoclonal CEA, TTF1, and CA125 Antibodies in the Differential Diagnosis of Lung, Breast, and Ovarian Adenocarcinomas in Serous Effusions Weijian Zhu, M.D., Ph.D. and Claire W. Michael,
More informationDiseases. Inflammations Non-inflammatory pleural effusions Pneumothorax Tumours
Pleura Visceral pleura covers lungs and extends into fissures Parietal pleura limits mediastinum and covers dome of diaphragm and inner aspect of chest wall. Two layers between them (pleural cavity) contains
More informationImmunocytochemistry of CD146 is useful to discriminate between malignant pleural mesothelioma and reactive mesothelium
& 2010 USCAP, Inc. All rights reserved 0893-3952/10 $32.00 1 Immunocytochemistry of CD146 is useful to discriminate between malignant pleural mesothelioma and reactive mesothelium Ayuko Sato 1, Ikuko Torii
More informationUses and Abuses of Pathology in Asbestos-exposed Populations
Uses and Abuses of Pathology in Asbestos-exposed Populations Jerrold L. Abraham, MD Department of Pathology State University of New York Upstate Medical University Syracuse, NY, 13210 USA The term: Asbestosis,
More informationCarcinosarcoma of the Ovary
Carcinosarcoma of the Ovary A Rare Finding Presented By: Kathryn Kiely Anisa I. Kanbour School of Cytotechnology of the University of Pittsburgh Medical Center Pittsburgh, PA Patient History 55 year old
More informationPREPARED FOR: U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702 5012
AD Award Number: W81XWH 07 1 0542 TITLE: Is Nuclear Structure Altered in Breast Cancer Cells? PRINCIPAL INVESTIGATOR: Han Htun, Ph.D. CONTRACTING ORGANIZATION: University of California Los Angeles, CA
More informationMOC-31 Exhibits Superior Reactivity Compared With Ber-EP4 in Invasive Lobular and Ductal Carcinoma of the Breast. A Tissue Microarray Study
RESEARCH ARTICLE MOC-31 Exhibits Superior Reactivity Compared With Ber-EP4 in Invasive Lobular and Ductal Carcinoma of the Breast A Tissue Microarray Study Reetesh K. Pai, MD and Robert B. West, MD Abstract:
More informationImmunohistochemical differentiation of metastatic tumours
Immunohistochemical differentiation of metastatic tumours Dr Abi Wheal ST1. TERA 3/2/14 Key points from a review article written by Daisuke Nonaka Intro Metastatic disease is the initial presentation in
More informationHER2 Status: What is the Difference Between Breast and Gastric Cancer?
Ask the Experts HER2 Status: What is the Difference Between Breast and Gastric Cancer? Bharat Jasani MBChB, PhD, FRCPath Marco Novelli MBChB, PhD, FRCPath Josef Rüschoff, MD Robert Y. Osamura, MD, FIAC
More informationA Cytokeratin- and Calretinin-negative Staining Sarcomatoid Malignant Mesothelioma
A Cytokeratin- and Calretinin-negative Staining Sarcomatoid Malignant Mesothelioma MICHAEL G. HURTUK and MICHELE CARBONE Cardinal Bernadin Cancer Center, Cancer Immunology Program, Department of Pathology,
More informationCytology of Effusion Fluids. Cytology of Effusion Fluids. Types of Effusion Fluids. Anatomy. Causes of Effusions. Sampling of Effusion Fluids
Cytology of Effusion Fluids John W. Wong, MD, FRCPC Sunnybrook Health Sciences Centre Assistant Professor, Laboratory Medicine and Pathobiology Faculty of Medicine, University of Toronto November 10, 2012
More informationMalignant pleural mesothelioma from nonoccupational asbestos exposure in Metsovo (north-west Greece): slow end of an epidemic?
Eur Respir J., 1996, 9, 1206 1210 DOI: 10.1183/09031936.96.09061206 Printed in UK - all rights reserved Copyright ERS Journals Ltd 1996 European Respiratory Journal ISSN 0903-1936 Malignant pleural mesothelioma
More informationP16LossandMitoticActivityPredictPoorSurvivalinPatients with Peritoneal Malignant Mesothelioma
P16LossandMitoticActivityPredictPoorSurvivalinPatients with Peritoneal Malignant Mesothelioma Alain C. Borczuk, 1 Robert N.Taub, 2,4 Mary Hesdorffer, 2,4 Hanina Hibshoosh, 1 John A. Chabot, 3 Mary L. Keohan,
More informationClassificazione anatomo-patologica nei RCC Matteo Brunelli. Department of Pathology and Diagnostic, University di Verona, Italy
Classificazione anatomo-patologica nei RCC Matteo Brunelli Department of Pathology and Diagnostic, University di Verona, Italy WHO 2004 AFIP 2004 = ISUP Vancouver Classification 2013 5 newentities 3 emerging
More informationAbstract. Introduction. Material and Methods
Original Article Expression of Mesothelial Markers in Malignant Mesotheliomas: an Immunohistochemical Evaluation of 173 Cases I.N. Soomro, R. Oliveira*, J. Ronan, Z. R. Chaudry, J. Johnson Department of
More informationProtocol applies to all primary borderline and malignant epithelial tumors, and malignant mesothelial neoplasms of the peritoneum.
Peritoneum Protocol applies to all primary borderline and malignant epithelial tumors, and malignant mesothelial neoplasms of the peritoneum. Protocol revision date: January 2004 No AJCC/UICC staging system
More informationBAP1 germline mutations A new Cutaneous Nevus Melanoma Syndrome. Thomas Wiesner
BAP1 germline mutations A new Cutaneous Nevus Melanoma Syndrome Thomas Wiesner Disclosure Listed as co-inventor US patent application US 61/463,389 BAP1 mutational analysis in determining susceptibility
More informationALTHOUGH excellent accounts have been published in recent years of
THE EXFOLIATIVE CYTOLOGY OF DIFFUSE MALIGNANT MESOTHELIOMA BERNARD NAYLOR Department of Pathology, University of Michigan, Ann Arbor, Michigan, U.S.A. PLATE~ LXXXVI-XCI ALTHOUGH excellent accounts have
More informationCase based applications part III
Case based applications part III Los Angeles Society Of Pathologists January 25, 2014 Sanja Dacic, MD, PhD University of Pittsburgh Medical Center 1 CASE 1 A 44-year-old woman with multiple lung nodules.
More informationThe Diagnostic Value of Pleural Fluid Cytology in Benign and Malignant Pleural Effusions
Med. J. Cairo Univ., Vol. 80, No. 2, June: 95-103, 2012 www.medicaljournalofcairouniversity.com The Diagnostic Value of Pleural Fluid Cytology in Benign and Malignant Pleural Effusions SAMAR A. EL-SHEIKH,
More informationOvarian tumors Ancillary methods
Ovarian tumors Ancillary methods Ovarian tumor course Oslo, 24-25/11/14 Prof. Ben Davidson, MD PhD Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway Division of
More informationCHROMOSOMES Dr. Fern Tsien, Dept. of Genetics, LSUHSC, NO, LA
CHROMOSOMES Dr. Fern Tsien, Dept. of Genetics, LSUHSC, NO, LA Cytogenetics is the study of chromosomes and their structure, inheritance, and abnormalities. Chromosome abnormalities occur in approximately:
More informationMALIGNANT MESOTHELIOMA: A TYPICAL PRESENTATION IN AN ATYPICAL PATIENT
MALIGNANT MESOTHELIOMA: A TYPICAL PRESENTATION IN AN ATYPICAL PATIENT Written by: Karyn Varley MS, SCT(ASCP) The donating laboratory would like to remain anonymous. PATIENT HISTORY 28 year old female Lived
More informationLung cancer and asbestos
Lung cancer and asbestos Bureau Veritas Training Bill Sanderson For the benefit of business and people To begin with.. There are known knowns, that is there are things we know that we know. There are known
More informationYOUR LUNG CANCER PATHOLOGY REPORT
UNDERSTANDING YOUR LUNG CANCER PATHOLOGY REPORT 1-800-298-2436 LungCancerAlliance.org A GUIDE FOR THE PATIENT 1 CONTENTS What is a Pathology Report?...3 The Basics...4 Sections of a Pathology Report...7
More informationUse of a Panel of Markers in the Differential Diagnosis of Adenocarcinoma and Reactive Mesothelial Cells in Fluid Cytology
Anatomic Pathology / IMMUNOCYTOCHEMICAL PANEL FOR FLUID SPECIMENS Use of a Panel of Markers in the Differential Diagnosis of Adenocarcinoma and Reactive Mesothelial Cells in Fluid Cytology Ellen C. Ko,
More informationPersonalized Treatment for Malignant Mesothelioma
Personalized Treatment for Malignant Mesothelioma RN Taub (Onc) J Chabot (Surg) A Borczuk (Path) J Sonnet (Surg) M Kluger (Surg) R Fawwaz (Nuc. Med) E Hare (Onc) Columbia University Mesothelioma Center
More informationValidation of BRAF Mutational Analysis in Thyroid Fine Needle Aspirations: A Morphologic- Molecular Approach
Validation of BRAF Mutational Analysis in Thyroid Fine Needle Aspirations: A Morphologic- Molecular Approach Kerry C. Councilman, MD Assistant Professor University of Colorado Denver Goals: BRAF Mutation
More informationReport series: General cancer information
Fighting cancer with information Report series: General cancer information Eastern Cancer Registration and Information Centre ECRIC report series: General cancer information Cancer is a general term for
More informationBRAF in the diagnostic evaluation of thyroid nodules
Symposium 13 Molecular markers in thyroid cancer: current role in clinical practice BRAF in the diagnostic evaluation of thyroid nodules Laura Fugazzola University of Milan, Italy Papillary carcinoma BRAF
More informationLung Carcinomas New 2015 WHO Classification. Spasenija Savic Pathology
Lung Carcinomas New 2015 WHO Classification Spasenija Savic Pathology ***EXPECTED SPRING 2015*** This authoritative, concise reference book provides an international standard for oncologists and pathologists
More informationTUMORS OF THE TESTICULAR ADNEXA and SPERMATIC CORD
TUMORS OF THE TESTICULAR ADNEXA and SPERMATIC CORD Victor E. Reuter, MD Memorial Sloan-Kettering Cancer Center reuterv@mskcc.org 66 th Annual Pathology Seminar California Society of Pathologists Short
More informationMalignant Mesothelioma Recent Advances
Malignant Mesothelioma Recent Advances Dr AS Paul 04 Aug 06 DM Seminar Malignant mesothelioma A tumour of serosal surfaces Pleura, peritoneum Increasing incidence worldwide Association with asbestos exposure
More informationGeneral Rules SEER Summary Stage 2000. Objectives. What is Staging? 5/8/2014
General Rules SEER Summary Stage 2000 Linda Mulvihill Public Health Advisor NCRA Annual Meeting May 2014 National Center for Chronic Disease Prevention and Health Promotion Division of Cancer Prevention
More informationMesothelioma. 1. Introduction. 1.1 General Information and Aetiology
Mesothelioma 1. Introduction 1.1 General Information and Aetiology Mesotheliomas are tumours that arise from the mesothelial cells of the pleura, peritoneum, pericardium or tunica vaginalis [1]. Most are
More informationCHAPTER 2. Neoplasms (C00-D49) March 2014. 2014 MVP Health Care, Inc.
Neoplasms (C00-D49) March 2014 2014 MVP Health Care, Inc. CHAPTER SPECIFIC CATEGORY CODE BLOCKS C00-C14 Malignant neoplasms of lip, oral cavity and pharynx C15-C26 Malignant neoplasms of digestive organs
More informationMalignant Mesothelioma Electron Microscopy
33 Malignant Mesothelioma Electron Microscopy Raoul Fresco In spite of recent advances in immunocytochemistry, electron microscopy continues to be the gold standard for the differential diagnosis of mesothelioma
More informationObjectives. Mylene T. Truong, MD. Malignant Pleural Mesothelioma Background
Imaging of Pleural Tumors Mylene T. Truong, MD Imaging of Pleural Tumours Mylene T. Truong, M. D. University of Texas M.D. Anderson Cancer Center, Houston, TX Objectives To review tumors involving the
More informationProtocol for the Examination of Specimens From Patients With Tumors of the Peritoneum
Protocol for the Examination of Specimens From Patients With Tumors of the Peritoneum Protocol applies to all primary borderline and malignant epithelial tumors and malignant mesothelial neoplasms of the
More informationAnatomic Pathology / PERITONEAL MESOTHELIOMA AND SEROUS CARCINOMA
Anatomic Pathology / PERITONEAL MESOTHELIOMA AND SEROUS CARCINOMA Immunohistochemical Analysis of Peritoneal Mesothelioma and Primary and Secondary Serous Carcinoma of the Peritoneum Antibodies to Estrogen
More informationAn Update on Lung Cancer Diagnosis
An Update on Lung Cancer Diagnosis Dr Michael Fanning MBBS FRACGP FRACP RESPIRATORY AND SLEEP PHYSICIAN Mater Medical Centre Outline Risk factors for lung cancer Screening for lung cancer Radiologic follow-up
More informationCHAPTER 2: UNDERSTANDING CANCER
CHAPTER 2: UNDERSTANDING CANCER INTRODUCTION We are witnessing an era of great discovery in the field of cancer research. New insights into the causes and development of cancer are emerging. These discoveries
More informationBer-EP4 and Anti-Calretinin Antibodies: A Useful Combination for
Tohoku J. Exp. Med., Differential 2005, 206, Diagnosis 31-40 of Ovarian Cancer Cells and Mesothelial Cells 31 Ber-EP4 and Anti-Calretinin Antibodies: A Useful Combination for Differential Diagnosis of
More informationCase Report Pleural Mesothelioma Presenting as Periumbilical Metastasis: The First Clinical Documentation
Volume 2013, Article ID 198729, 4 pages http://dx.doi.org/10.1155/2013/198729 Case Report Pleural Mesothelioma Presenting as Periumbilical Metastasis: The First Clinical Documentation R. F. Falkenstern-Ge,
More informationRenal Cell Carcinoma: Advances in Diagnosis B. Iványi, MD
Renal Cell Carcinoma: Advances in Diagnosis B. Iványi, MD Department of Pathology University of Szeged, Hungary ISUP Vancouver Classification of Renal Neoplasia Am J Surg Pathol 37:14691489, 2013 13 histologic
More informationPATTERNS OF MORTALITY IN ASBESTOS FACTORY WORKERS IN LONDON*
PATTERNS OF MORTALITY IN ASBESTOS FACTORY WORKERS IN LONDON* M. L. Newhouse TUC Centenary Institute of Occupational Health London School of Hygiene and Tropical Medicine London WCIE 7HT. England G. Berry
More informationMost cases of mesothelioma are caused by occupational
Percutaneous Image-Guided Cutting Needle Biopsy of the Pleura in the Diagnosis of Malignant Mesothelioma* Rosie F. Adams, BM BCh; Winifred Gray, MB BS; Robert J. O. Davies, DM; and Fergus V. Gleeson, MB
More information