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Mesothelioma: HELP
Articles by Sanja Dacic
Based on 14 articles published since 2008
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Between 2008 and 2019, Sanja Dacic wrote the following 14 articles about Mesothelioma.
 
+ Citations + Abstracts
1 Guideline Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. 2018

Husain, Aliya Noor / Colby, Thomas V / Ordóñez, Nelson G / Allen, Timothy Craig / Attanoos, Richard Luther / Beasley, Mary Beth / Butnor, Kelly Jo / Chirieac, Lucian R / Churg, Andrew M / Dacic, Sanja / Galateau-Sallé, Françoise / Gibbs, Allen / Gown, Allen M / Krausz, Thomas / Litzky, Leslie Anne / Marchevsky, Alberto / Nicholson, Andrew G / Roggli, Victor Louis / Sharma, Anupama K / Travis, William D / Walts, Ann E / Wick, Mark R. ·From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Drs Husain and Krausz) · the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Colby, emeritus) · the Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston (Dr Ordóñez) · the Department of Pathology, University of Texas Medical Branch, Galveston (Dr Allen) · the Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, South Glamorgan, Wales (Dr Attanoos) · the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley) · the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Butnor) · the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Chirieac) · the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic) · Centre National Référent MESOPATH Departement de Biopathologie, Lyon Cedex, France (Dr Galateau-Sallé) · the Department of Pathology, University Hospital of Wales, Penarth, South Glamorgan, Wales (Dr Gibbs) · the Department of Pathology, PhenoPath Laboratories, Seattle, Washington (Dr Gown) · the Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, (Dr Litzky) · the Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Drs Marchevsky and Walts) · the Department of Histopathology, Royal Brompton & Harefield National Health Service Foundation Trust and the National Heart and Lung Institute, Imperial College, Chelsea, London, England (Dr Nicholson) · the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli) · the Department of Pathology, University of Pittsburgh, and the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (Dr Sharma) · the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Travis) · and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick). ·Arch Pathol Lab Med · Pubmed #28686500.

ABSTRACT: CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

2 Guideline Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. 2013

Husain, Aliya N / Colby, Thomas / Ordonez, Nelson / Krausz, Thomas / Attanoos, Richard / Beasley, Mary Beth / Borczuk, Alain C / Butnor, Kelly / Cagle, Philip T / Chirieac, Lucian R / Churg, Andrew / Dacic, Sanja / Fraire, Armando / Galateau-Salle, Francoise / Gibbs, Allen / Gown, Allen / Hammar, Samuel / Litzky, Leslie / Marchevsky, Alberto M / Nicholson, Andrew G / Roggli, Victor / Travis, William D / Wick, Mark / Anonymous2710735. ·Department of Pathology, University of Chicago, Chicago, IL 60637, USA. aliya.husain@uchospitals.edu ·Arch Pathol Lab Med · Pubmed #22929121.

ABSTRACT: CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

3 Review Recent Advances in the Diagnosis of Malignant Mesothelioma: Focus on Approach in Challenging Cases and in Limited Tissue and Cytologic Samples. 2018

Monaco, Sara / Mehrad, Mitra / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh, Pittsburgh, PA. · Department of Pathology, Vanderbilt University, Nashville, TN. ·Adv Anat Pathol · Pubmed #29227332.

ABSTRACT: Mesothelial proliferations can be diagnostically challenging in small specimens, such as body fluid cytology and small tissue biopsies. A great morphologic challenge for pathologists is the separation of benign reactive mesothelial proliferations from malignant mesotheliomas. Reactive mesothelial proliferations may have histologic features that resemble malignancy including increased cellularity, cytologic atypia, and mitoses. Recent advances in mesothelioma genetics resulted in identification of BAP1 mutations and p16 deletions as features of malignant mesotheliomas. Hence, BAP1 immunohistochemistry and fluorescence in situ hybridization for p16 emerged as 2 most common diagnostically helpful ancillary studies used on limited samples when the question is whether the proliferation is malignant or benign. In contrast, separation of mesothelioma from other malignancies is relatively straight forward using morphology and immunohistochemical stains. The choice of antibody panel to be applied in an individual case is driven by morphology, either epithelioid or sarcomatoid. This brief review will focus on morphology and ancillary testing of mainly pleural mesothelial proliferations.

4 Review The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. 2017

Marchevsky, Alberto M / LeStang, Nolwenn / Hiroshima, Kenzo / Pelosi, Giuseppe / Attanoos, Richard / Churg, Andrew / Chirieac, Lucian / Dacic, Sanja / Husain, Aliya / Khoor, Andras / Klebe, Sonja / Lantuejoul, Silvie / Roggli, Victor / Vignaud, Jean-Michel / Weynard, Birgit / Sauter, Jennifer / Henderson, Douglas / Nabeshima, Kasuzi / Galateau-Salle, Francoise. ·Department of Pathology Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: Alberto.Marchevsky@cshs.org. · Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. · Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. · Interhospital Pathology Division, Università degli Studi di Milano and IRCCS MultiMedica Group, Milan, Italy. · Department of Pathology University of Wales and Cardiff University, Cardiff, U.K. · Department of Pathology, University of British Columbia, Vancouver, BC. · Department of Pathology, Brigham and Women's Hospital, Boston, MA. · Department of Pathology UPMC-PUH, Pittsburgh, PA. · Department of Pathology, Chicago University, Chicago, IL. · Department of Pathology, Mayo Clinic, Jacksonville, FL. · SA Pathology at Flinders Medical Cemtre, Bedord Park, SA. · Department of Pathology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. · Department of Pathology Duke University, Durham, NC. · Department of Pathology, CHU de Nancy, Nancy, France. · University Hospital Leuven, Leuven, Belgium. · Department of Pathology Sloan Kettering Memorial Cancer Center, New York, NY. · Department of Pathology Fukuoka University Hospital, Fukuoka, Japan. ·Hum Pathol · Pubmed #28782639.

ABSTRACT: Immunohistochemistry is used to distinguish sarcomatoid malignant mesotheliomas (SMM) from spindle cell and pleomorphic carcinomas (SPC) but there are no guidelines on how to interpret cases that show overlapping or equivocal immunohistochemical findings. A systematic literature review of the immunophenotype of these lesions was performed and the experience with 587 SMM and 46 SPC at MESOPATH was collected. Data were analyzed with Comprehensive Meta-Analysis 2.0 software (Biostat, Englewood, NJ). There were insufficient data to evaluate the differential diagnosis between SPC and localized SMM or peritoneal SMM. Meta-analysis showed considerable overlap in the immunophenotype of these neoplasms and significant data heterogeneity amongst many of the results. Survival data from MESOPATH patients showed no significant differences in overall survival between SMM and SPC patients. Best available evidence was used to formulate several evidence-based guidelines for the differential diagnosis between pleural SMM and SPC. These guidelines emphasize the need to correlate the histopathological findings with clinical and imaging information. Diffuse SMM can be diagnosed with certainty in the presence of malignant spindle cell pleural lesions showing immunoreactivity for cytokeratin and mesothelial markers and negative staining for epithelial markers. Criteria for the interpretation of various other combinations of immunoreactivity for cytokeratin and mesothelial and/or epithelial markers are proposed. Localized sarcomatoid mesotheliomas can only be diagnosed in the presence of spindle cell malignancies that exhibit immunoreactivity for cytokeratin and mesothelial markers and negative immunoreactivity for epithelial lesions, in patients that show no multifocal or diffuse pleural spread and no evidence for extrapleural lesions.

5 Article Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas. 2018

Berg, Kyra B / Dacic, Sanja / Miller, Caitlyn / Cheung, Simon / Churg, Andrew. ·From the Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Berg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic and Ms Miller) · and the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg and Mr Cheung). ·Arch Pathol Lab Med · Pubmed #30059257.

ABSTRACT: CONTEXT.—: The separation of reactive from malignant mesothelial proliferations is often a difficult morphologic problem. There is contradictory information in the literature on whether methylthioadenosine phosphorylase (MTAP) immunohistochemistry can be used for this purpose. OBJECTIVE.—: To determine the utility of MTAP immunohistochemistry in distinguishing reactive from malignant mesothelial proliferations. DESIGN.—: We stained a tissue microarray containing 20 epithelioid malignant mesotheliomas and 17 reactive mesothelial proliferations. For the mesotheliomas, comparisons were made between MTAP staining and BRCA-associated nuclear protein 1 (BAP1) immunohistochemistry, cyclin-dependent kinase inhibitor 2A ( CDKN2A) fluorescence in situ hybridization, and neurofibromin 2 ( NF2) fluorescence in situ hybridization, which are established techniques for making this separation. RESULTS.—: Loss of MTAP was seen in 0 of 17 reactive mesothelial proliferations and 13/20 (65%) malignant mesotheliomas. Almost all cases with loss showed loss in 100% of mesothelial cells. Background inflammatory and stromal cells served as a positive internal control. CDKN2A fluorescence in situ hybridization on the mesotheliomas showed concordance with MTAP staining in 14 of 17 evaluable cases. BAP1 immunohistochemistry showed loss of nuclear staining in 11 of 20 mesotheliomas (55%). No cases showed loss of NF2. A total of 18 of 20 mesotheliomas (90%) showed loss of either MTAP or BAP1. CONCLUSIONS.—: In the context of a mesothelial proliferation, loss of MTAP staining is 100% specific for malignant mesothelioma. In this study the combination of MTAP and BAP1 immunohistochemical staining allowed separation of reactive from epithelial malignant mesothelial proliferations in 90% of cases.

6 Article Malignant mesothelioma in situ. 2018

Churg, Andrew / Hwang, Harry / Tan, Larry / Qing, Gefei / Taher, Altaf / Tong, Amy / Bilawich, Ana M / Dacic, Sanja. ·Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada. · PhenoPath Laboratories, Seattle, WA, USA. · Division of Thoracic Surgery, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. · Department of Pathology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. · Department of Pathology, Memorial University of Newfoundland, St John's, NF, Canada. · Department of Medicine, Memorial University of Newfoundland, St John's, NF, Canada. · Department of Radiology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Histopathology · Pubmed #29350783.

ABSTRACT: AIMS: The existence of malignant mesothelioma in situ (MIS) is often postulated, but there are no accepted morphological criteria for making such a diagnosis. METHODS AND RESULTS: Here we report two cases that appear to be true MIS on the basis of in-situ genomic analysis. In one case the patient had repeated unexplained pleural unilateral effusions. Two thoracoscopies 9 months apart revealed only visually normal pleura. Biopsies from both thoracoscopies showed only a single layer of mildly reactive mesothelial cells. However, these cells had lost BRCA1-associated protein 1 (BAP1) and showed loss of cyclin-dependent kinase inhibitor 2 (CDKN2A) (p16) by fluorescence in-situ hybridisation (FISH). NF2 was not deleted by FISH but 28% of the mesothelial cells showed hyperploidy. Six months after the second biopsy the patient has persisting effusions but no evidence of pleural malignancy on imaging. The second patient presented with ascites and minimal omental thickening on imaging, but no visual evidence of tumour at laparoscopy. Omental biopsy showed a single layer of minimally atypical mesothelial cells with rare tiny foci of superficial invasion of fat. BAP1 immunostain showed loss of nuclear BAP1 in all the surface mesothelial cells and the invasive cells. There was CDKN2A deletion, but no deletion of NF2 by FISH. CONCLUSIONS: These cases show that morphologically bland single-layered surface mesothelial proliferations with molecular alterations seen previously only in invasive malignant mesotheliomas exist, and presumably represent malignant MIS. More cases are need to understand the frequency of such changes and the time-course over which invasive tumour develops.

7 Article Reproducibility for histologic parameters in peritoneal mesothelioma. 2017

Hartman, Douglas J / Borczuk, Alain / Dacic, Sanja / Krasinskas, Alyssa. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. Electronic address: hartmandj@upmc.edu. · Department of Pathology, Weill Cornell Medical College, New York, NY 10021. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. · Department of Pathology, Emory University, Atlanta, GA 30322. ·Hum Pathol · Pubmed #28712777.

ABSTRACT: Histologic subtype is recognized as a prognostic factor in malignant pleural mesothelioma. Specifically, epithelial morphology is associated with a better prognosis than other subtypes, and the same association is observed in peritoneal malignant mesothelioma. Recently, prognostic differences based on morphologic subtypes of epithelial peritoneal malignant mesothelioma were reported. Herein, we report the interobserver variability across four pathologists at three institutions. The authors independently reviewed 67 cases of malignant peritoneal epithelioid mesotheliomas and subclassified them according to their epithelial subtype: papillary, tubulopapillary, trabecular, micropapillary, solid and/or pleomorphic. The cases were also evaluated by each author for several other histopathologic parameters including depth of invasion, nuclear grade, lymphocytic host response, mitotic count/index, presence of lymphovascular invasion, and stromal desmoplasia. The interobserver agreement for histopathologic parameters was highest for mitotic rate (κ=0.36) and primary epithelial subtype (κ=0.32). The interobserver variability for solid subtype pattern was moderate (κ=0.49). We found that the interobserver variability for most histopathologic parameters is poor.

8 Article The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. 2016

Singhi, Aatur D / Krasinskas, Alyssa M / Choudry, Haroon A / Bartlett, David L / Pingpank, James F / Zeh, Herbert J / Luvison, Alyssa / Fuhrer, Kimberly / Bahary, Nathan / Seethala, Raja R / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Mod Pathol · Pubmed #26493618.

ABSTRACT: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n=25, 29%), hemizygous NF2 loss (n=30, 35%), and/or loss of BAP1 protein expression (n=49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival (P<0.02) and poor overall survival (P<0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (P<0.01) and overall survival rate of 18% with a median of 8 months (P<0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

9 Article Prognostic significance of morphological growth patterns and mitotic index of epithelioid malignant peritoneal mesothelioma. 2016

Krasinskas, Alyssa M / Borczuk, Alain C / Hartman, Douglas J / Chabot, John A / Taub, Robert N / Mogal, Ashish / Pingpank, James / Bartlett, David / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Pathology and Cell Biology, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Surgery, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Oncology, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Histopathology · Pubmed #26272336.

ABSTRACT: AIMS: The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has been recently reported, but similar data are lacking for peritoneal mesotheliomas. The aim of this study was to investigate possible relationships between histological growth patterns of epithelioid peritoneal mesotheliomas, clinicopathological features, and patient outcome. METHODS AND RESULTS: Eighty-four cases of chemotherapy-naive epithelioid peritoneal mesothelioma were classified into tubulopapillary, micropapillary, papillary, tubular, solid and trabecular growth patterns. Pathological features such as depth of invasion, lymphocytic host response, mitotic count, nuclear grade, lymphovascular invasion, lymph node metastasis and stromal desmoplasia were analysed. The most common histological patterns were solid (n = 37, 44%), tubulopapillary (n = 24, 29%), and micropapillary (n = 11, 13%). The overall median survival was 36 months. Patients with solid mesothelioma had shorter overall survival (median, 29 months) than patients with tubulopapillary and micropapillary growth patterns (median, 51 and 53 months, respectively; P = 0.053). A high mitotic index (>5 in 50 high-power fields) was found to be associated with poor survival (P < 0.03). A moderate to severe lymphocytic host response was associated with longer median survival (P = 0.13). CONCLUSIONS: Our study highlights the prognostic importance of the solid growth pattern among diffuse epithelioid peritoneal mesotheliomas, and reaffirms mitotic index as a predictor of overall survival.

10 Article p16 Deletion in sarcomatoid tumors of the lung and pleura. 2013

Tochigi, Naobumi / Attanoos, Richard / Chirieac, Lucian R / Allen, Timothy Craig / Cagle, Philip T / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ·Arch Pathol Lab Med · Pubmed #23627453.

ABSTRACT: CONTEXT: The diagnosis of sarcomatoid neoplasms of the lung and pleura can be challenging. Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas that is of potential diagnostic and prognostic significance. OBJECTIVES: To evaluate the frequency of 9p21 deletion by fluorescence in situ hybridization in the primary sarcomatoid neoplasms of the lung and pleura and to determine its potential diagnostic utility. DESIGN: Ninety-two sarcomatoid neoplasms of the lung and pleura (32 sarcomatoid mesotheliomas, 15 sarcomatoid carcinomas, 32 solitary fibrous tumors, and 13 high-grade sarcomas) were examined for 9p21 deletion by fluorescence in situ hybridization. RESULTS: Deletion of 9p21 was most frequently seen in malignant mesotheliomas (81%), followed by sarcomatoid carcinomas (53%), sarcomas (25%), and solitary fibrous tumors (12.5%). Malignant mesotheliomas showed mostly homozygous deletion, whereas sarcomatoid carcinomas showed either homozygous or hemizygous deletion. None of the sarcomas showed homozygous deletion. There was a trend toward more frequent occurrence of 9p21 deletion in recurrent solitary fibrous tumors, but this did not reach statistical difference. CONCLUSIONS: Deletion of 9p21 is common in sarcomatoid tumors of the lung and pleura. Despite statistically significant differences in the frequency of 9p21 deletion, and because of the large overlap among the study groups, this genetic abnormality cannot be used as a reliable diagnostic tool in the assessment of sarcomatoid lesions of the lung and pleura. A potential use of p16 deletion in predicting the biology of solitary fibrous tumors should be further explored.

11 Article The diagnostic utility of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations. 2011

Monaco, Sara E / Shuai, Yongli / Bansal, Mona / Krasinskas, Alyssa M / Dacic, Sanja. ·Dept of Pathology, University of Pittsburgh Medical Center, PA 15232, USA. ·Am J Clin Pathol · Pubmed #21411785.

ABSTRACT: Two promising ancillary tests used in the diagnosis of mesothelioma include GLUT-1 immunohistochemical analysis and fluorescence in situ hybridization (FISH) testing for the p16 deletion. This study compared the diagnostic usefulness of p16 FISH and GLUT-1 immunohistochemical analysis in the diagnosis of mesothelial proliferations in 158 cases with a diagnosis of benign (45.4%), atypical (10.4%), or malignant/mesothelioma (44.2%). Of the 70 benign cases, none had a deletion of p16 and 5 cases (7%) were positive for GLUT-1. Of the 68 mesotheliomas, 40 (59%) had a deletion of p16 (sensitivity, 59%; specificity, 100%) and 27 (40%) were positive for GLUT-1 (sensitivity, 40%; specificity, 93%). GLUT-1 showed lower sensitivity in pleural (56% vs 70%) and peritoneal (29% vs 51%) mesotheliomas (P = .004). Our results demonstrate that p16 FISH is a more sensitive and specific test than GLUT-1 immunohistochemical analysis and can be a more reliable ancillary tool to support the diagnosis of mesothelioma.

12 Article CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival. 2010

Krasinskas, Alyssa M / Bartlett, David L / Cieply, Kathleen / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2546, USA. krasinskasam@upmc.edu ·Mod Pathol · Pubmed #20081810.

ABSTRACT: Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P=0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P=0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.

13 Article Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas. 2008

Dacic, Sanja / Kothmaier, Hannelore / Land, Stephanie / Shuai, Yongli / Halbwedl, Iris / Morbini, Patrizia / Murer, Bruno / Comin, Camilla / Galateau-Salle, Françoise / Demirag, Funda / Zeren, Handan / Attanoos, Richard / Gibbs, Alan / Cagle, Philip / Popper, Helmut. ·Department of Pathology-PUH A610, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213, USA. dacics@upmc.edu ·Virchows Arch · Pubmed #18958493.

ABSTRACT: Homozygous deletion of p16/CDKN2A is the most common genetic abnormality in malignant mesotheliomas. The aim of this study was to determine prognostic significance of p16/CDKN2A loss in malignant pleural mesotheliomas (MPM) as defined by immunohistochemistry and fluorescence in situ hybridization (FISH). High-density tissue microarrays were constructed from archival formalin-fixed paraffin-embedded samples of 48 MPM. Long survival (LS) was defined as survival greater than 3 years from the time of diagnosis, and short survival was defined as less than 3 years from the time of diagnosis. Both loss of p16 protein expression by immunohistochemistry and homozygous deletion of p16 by FISH were associated with adverse prognosis. Female gender, positive p16 immunoexpression, and lack of p16/CDKN2A deletion significantly predicted the survival for the LS group. Statistical analysis showed a very strong correlation of immunohistochemistry and FISH data. Cases positive for p16 immunoexpression and negative for 9p21 deletion showed the best survival time. Our study is the first to demonstrate decreased frequency of homozygous deletion of 9p21 and loss of p16 immunoreactivity in pleural mesotheliomas from patients with long-term survival of greater than 3 years in contrast to patients with rapidly fatal mesotheliomas. A possible implementation of these tests into preoperative prognostication of MPM and therapeutic decisions should be considered.

14 Article Diagnostic importance of 9p21 homozygous deletion in malignant mesotheliomas. 2008

Chiosea, Simion / Krasinskas, Alyssa / Cagle, Philip T / Mitchell, Kisha A / Zander, Dani S / Dacic, Sanja. ·Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, PA 15213, USA. ·Mod Pathol · Pubmed #18327208.

ABSTRACT: Definitive diagnosis of malignant mesothelioma in small specimens can be extremely difficult based on morphology alone. Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas. Recent studies demonstrated that this alteration may be useful for differentiating benign from malignant mesothelial proliferations in cytology specimens. The aim of this study was to evaluate the diagnostic utility of homozygous deletion of 9p21 assessed by fluorescence in situ hybridization (FISH) in mesothelial proliferations involving serosal surfaces in paraffin-embedded tissue. p16 protein immunoexpression was also explored as a potential diagnostic aid. FISH analysis demonstrated homozygous deletion of the 9p21 locus in 35 of 52 cases (67%) of pleural mesothelioma and in 5 of 20 cases of peritoneal mesothelioma (25%) (P<0.005). None of 40 cases of reactive pleural mesothelial proliferations showed p16 deletion (P<0.005). Loss of immunoexpression of p16 was observed in 71% of the peritoneal mesotheliomas, 40% of the pleural malignant mesotheliomas and 15% of the reactive mesothelial cells. Homozygous deletion did not correlate with p16 protein expression in any of the studied groups. Our study suggests that 9p21 homozygous deletion assessed by FISH on paraffin-embedded tissue may be helpful for differentiating between malignant mesotheliomas and reactive mesothelial proliferations. A discrepancy between p16 protein expression and homozygous deletion suggests that other molecular mechanisms may play a role in p16 protein expression in mesothelial proliferations.