Publications by authors named "Alberto Marchevsky"

104 Publications

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury.

Front Cell Dev Biol 2021 23;9:733158. Epub 2021 Sep 23.

Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States.

Pulmonary fibrosis is a progressive disease for which no curative treatment exists. We have previously engineered dermal fibroblasts to produce extracellular vesicles with tissue reparative properties dubbed activated specialized tissue effector extracellular vesicles (ASTEX). Here, we investigate the therapeutic utility of ASTEX and in a mouse model of bleomycin-induced lung injury. RNA sequencing demonstrates that ASTEX are enriched in micro-RNAs (miRs) cargo compared with EVs from untransduced dermal fibroblast EVs (DF-EVs). Treating primary macrophages with ASTEX reduced interleukin (IL)6 expression and increased IL10 expression compared with DF-EV-exposed macrophages. Furthermore, exposure of human lung fibroblasts or vascular endothelial cells to ASTEX reduced expression of smooth muscle actin, a hallmark of myofibroblast differentiation (respectively). , intratracheal administration of ASTEX in naïve healthy mice demonstrated a favorable safety profile with no changes in body weight, lung weight to body weight, fibrotic burden, or histological score 3 weeks postexposure. In an acute phase (short-term) bleomycin model of lung injury, ASTEX reduced lung weight to body weight, IL6 expression, and circulating monocytes. In a long-term setting, ASTEX improved survival and reduced fibrotic content in lung tissue. These results suggest potential immunomodulatory and antifibrotic properties of ASTEX in lung injury.
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http://dx.doi.org/10.3389/fcell.2021.733158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512699PMC
September 2021

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Pathol Int 2021 Sep 9;71(9):604-613. Epub 2021 Jul 9.

Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.
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http://dx.doi.org/10.1111/pin.13140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519072PMC
September 2021

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis.

Am J Clin Pathol 2021 Nov;156(6):989-999

Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objectives: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM.

Methods: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions.

Results: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens.

Conclusions: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.
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http://dx.doi.org/10.1093/ajcp/aqab054DOI Listing
November 2021

Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: Case reports.

Medicine (Baltimore) 2021 Apr;100(15):e25255

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Rationale: Fibrinolysis shutdown associated with severe thrombotic complications is a recently recognized syndrome that was previously seldom investigated in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It presents a unique therapeutic dilemma, as anticoagulation with heparin alone is insufficient to address the imbalance in fibrinolysis. And while the use of fibrinolytic agents could limit the disease severity, it is often associated with bleeding complications. There is a need for biomarkers that will guide the timely stratification of patients into those who may benefit from both anticoagulant and fibrinolytic therapies.

Patient Concerns: All 3 patients presented with shortness of breath along with comorbidities predisposing them to severe SARS-CoV-2 infection. One patient (Patient 3) also suffered from bilateral deep venous thrombosis.

Diagnoses: All 3 patients tested positive for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) and were eventually diagnosed with respiratory failure necessitating intubation.

Interventions: All 3 patients required mechanical ventilation support, 2 of which also required renal replacement therapy. All 3 patients were also placed on anticoagulation therapy.

Outcomes: In Patients 1 and 2, the initial D-dimer levels of 0.97 μg/ml fibrinogen equivalent units (FEU) and 0.83 μg/ml FEU were only slightly elevated (normal <0.50 μg/ml FEU). They developed rising D-dimer levels to a peak of 13.21 μg/ml FEU and >20.0 μg/ml FEU, respectively, which dropped to 1.34 μg/ml FEU 8 days later in Patient 1 and to 2.94 μg/ml on hospital day 13 in Patient 2. In Patient 3, the D-dimer level on admission was found to be elevated to >20.00 μg/ml FEU together with imaging evidence of thrombosis. And although he received therapeutic heparin infusion, he still developed pulmonary embolism (PE) and his D-dimer level declined to 5.91 μg/ml FEU. Despite "improvement" in their D-dimer levels, all 3 patients succumbed to multi-system organ failure. On postmortem examination, numerous arterial and venous thromboses of varying ages, many consisting primarily of fibrin, were identified in the lungs of all patients.

Lessons: High D-dimer levels, with subsequent downtrend correlating with clinical deterioration, seems to be an indicator of fibrinolysis suppression. These findings can help form a hypothesis, as larger cohorts are necessary to demonstrate their reproducibility.
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http://dx.doi.org/10.1097/MD.0000000000025255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052008PMC
April 2021

Clinico-pathologic findings in patients with median arcuate ligament syndrome (celiac artery compression syndrome).

Ann Diagn Pathol 2021 Jun 22;52:151732. Epub 2021 Mar 22.

Department of Pathology and Laboratory Medicines, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Median Arcuate Ligament Syndrome (MALS) is a rare entity characterized by severe post-prandial epigastric pain, nausea, vomiting, and/or weight loss. Symptoms have been attributed to vascular compression (celiac artery compression syndrome, CACS), but it remains controversial whether they could be secondary to neural compression. Literature review identified rare description of pathologic findings in surgery journals. The clinico-pathologic findings of four MALS patients who underwent robotic or laparoscopic surgery in our hospital are described. All our patients were female with a median age of 32.5 (range 25-55 years), and a median BMI of 23.5 kg/m. They presented with chronic often post-prandial abdominal pain (4/4), nausea (3/4), emesis (2/4), anorexia (1/4), and weight loss (1/4). Two patients had a history of Crohn's disease. At intraoperative exploration, the celiac artery and adjacent nerves and ganglia were encased and partially compressed by fibrotic tissue in each patient. In each case laparoscopic excision of fibrotic tissue, celiac plexus and ligament division and was performed; celiac plexus nerve block was also performed in one patient. After surgical intervention, symptoms improved in three of the patients whose specimens show periganglionic and perineural fibrosis with proliferation of small nerve fibers. Our findings support neurogenic compression as a contributing factor in the development of pain and other MALS symptoms, and favor the use of MALS rather than CACS as diagnostic terminology. To further study the pathogenesis of this unusual syndrome, surgeons should submit all tissues excised during MALS procedures for histopathologic examination.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151732DOI Listing
June 2021

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Pathology 2021 Jun 26;53(4):446-453. Epub 2021 Mar 26.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.
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http://dx.doi.org/10.1016/j.pathol.2020.12.005DOI Listing
June 2021

Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases.

Mod Pathol 2021 02 15;34(2):380-395. Epub 2020 Oct 15.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.
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http://dx.doi.org/10.1038/s41379-020-00688-4DOI Listing
February 2021

Challenges in Ki-67 assessments in pulmonary large-cell neuroendocrine carcinomas.

Histopathology 2021 Apr 29;78(5):699-709. Epub 2020 Nov 29.

Departments of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Aims: To gather the best available evidence regarding Ki-67% values in large-cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut-off values could serve as a prognostic feature in LCNEC.

Methods And Results: Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki-67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki-67 increments. Using the Kaplan-Meier method, overall (OS) and disease-free survivals (DFS) were compared by AJCC stage, by six Ki-67% classes and with Ki-67% cut-points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1-3. The system measured Ki-67% positivity using 4072-44 533 tumour nuclei per case (mean 16610 ± 8039). Ki-67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki-67% ≥40%. OS ranged from 1 to 298 months (median follow-up = 25 months). DFS ranged from 1 to 276 months (median follow-up = 9 months). OS and DFS differed across AJCC stage (overall log-rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki-67% when six or two classes were used with either ≥20% Ki-67 or ≥40% Ki-67 as cut-point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki-67% ranged from 2% to 100%. Problems contributing to variability in Ki-67% measurements are discussed.

Conclusion: Our findings caution against a blanket use of 20%, 40% or other Ki-67% cut-points for LCNEC diagnosis or prognostication.
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http://dx.doi.org/10.1111/his.14277DOI Listing
April 2021

Pathologists should probably forget about kappa. Percent agreement, diagnostic specificity and related metrics provide more clinically applicable measures of interobserver variability.

Ann Diagn Pathol 2020 Aug 28;47:151561. Epub 2020 Jun 28.

Department of Pathology, UMC, Vrije Universiteit Amsterdam, the Netherlands.

Kappa statistics have been widely used in the pathology literature to compare interobserver diagnostic variability (IOV) among different pathologists but there has been limited discussion about the clinical significance of kappa scores. Five representative and recent pathology papers were queried using clinically relevant specific questions to learn how IOV was evaluated and how the clinical applicability of results was interpreted. The papers supported our anecdotal impression that pathologists usually assess IOV using Cohen's or Fleiss' kappa statistics and interpret the results using some variation of the scale proposed by Landis and Koch. The papers did not cite or propose specific guidelines to comment on the clinical applicability of results. The solutions proposed to decrease IOV included the development of better diagnostic criteria and additional educational efforts, but the possibility that the entities themselves represented a continuum of morphologic findings rather than distinct diagnostic categories was not considered in any of the studies. A dataset from a previous study of IOV reported by Thunnissen et al. was recalculated to estimate percent agreement among 19 international lung pathologists for the diagnosis of 74 challenging lung neuroendocrine neoplasms. Kappa scores and diagnostic sensitivity, specificity, positive and negative predictive values were calculated using the majority consensus diagnosis for each case as the gold reference diagnosis for that case. Diagnostic specificity estimates among multiple pathologists were > 90%, although kappa scores were considerably more variable. We explain why kappa scores are of limited clinical applicability in pathology and propose the use of positive and negative percent agreement and diagnostic specificity against a gold reference diagnosis to evaluate IOV among two and multiple raters, respectively.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151561DOI Listing
August 2020

RE: Spread Through Air Spaces (STAS) is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung.

J Thorac Oncol 2020 07;15(7):e116-e117

Department of Oncology and Hemato-Oncology, University of Milan, Milan, and Inter-hospital Pathology Division, IRCCS Multimedica, Milan, Italy.

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http://dx.doi.org/10.1016/j.jtho.2019.11.027DOI Listing
July 2020

Prognosis in pathology: Are we "prognosticating" or only establishing correlations between independent variables and survival? A study with various analytics cautions about the overinterpretation of statistical results.

Ann Diagn Pathol 2020 Jun 21;46:151525. Epub 2020 Apr 21.

Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

Survival data from 225 patients with resected pulmonary typical carcinoids were analyzed with Kaplan-Meier statistics (K-M) and "deep learning" methods to illustrate the difference between establishing "correlations" and "prognostications". Cases were stratified into G1 and G2 classes using a ≤5% Ki-67% cut-point. Overall survival, number of patients at risk and 95% confidence intervals (CI) were estimated for the two classes. Seven neural network models (NN) were developed with GMDH Shell 3.8.2 and Statgraphics Centurion 18.1 software, using variable prior probabilities and different numbers of training vs testing cases. The NNs used age, sex, and pTNM, G1 and G2 as input neurons and "alive" and "dead" as output neurons. Areas under the curve (AUC) and other performance measures were evaluated for all models. Log-rank test showed a significant difference in overall survival between G1 and G2 (p < 0.001). However, 95% CI estimates showed considerable variability in survival at different time intervals. Including the number of patients at risk at different time intervals showed that most G2 patients had been censored by 100 weeks. The NN models provided variable "prognostications", with AUC ranging from 0.5 to 1 and variability in the sensitivity, specificity, and other performance measures. The results illustrate the limitations of survival statistics and NNs in predicting the prognosis of individual patients. The need for pathologists not to overinterpret the finding of significant correlations as "prognostic" or "predictive" for individual patients is discussed.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151525DOI Listing
June 2020

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

J Thorac Oncol 2020 06 9;15(6):1037-1053. Epub 2020 Mar 9.

MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Cochin-Hotel Dieu, Department of Pathology, Paris, France.

Introduction: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort.

Methods: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors.

Results: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification.

Conclusion: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.
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http://dx.doi.org/10.1016/j.jtho.2020.01.025DOI Listing
June 2020

Evidence-based pathology practice.

Ann Diagn Pathol 2020 Feb 17;44:151447. Epub 2019 Dec 17.

Medical College of Wisconsin, Milwaukee, WI, United States of America.

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http://dx.doi.org/10.1016/j.anndiagpath.2019.151447DOI Listing
February 2020

Pathology in the era of "Personalized Medicine": The need to learn how to integrate multivariate immunohistochemical and "omics" data with clinicopathologic information in a clinically relevant way".

Ann Diagn Pathol 2019 Dec 5;43:151410. Epub 2019 Oct 5.

University of Virginia, Charlottesville, VA, United States of America.

"Personalized medicine" has been proposed as a new paradigm for patient care that, based on the integration of genomics and other "omics" data with clinical and other multidisciplinary information, promises early disease detection, improved outcomes and reduced side effects to therapies. Pathologists have become important participants in this new approach as the guardians of tissues and experts in the performance of molecular and other laboratory tests. Large amounts of new laboratory data in multiple neoplasms and other entities are being reported but there has been limited discussion about how best to evaluate the clinical significance of this information and how to integrate it into currently available diagnostic and therapeutic modalities. This article introduces a variety of epistemological problems presented by the "personalized medicine" paradigm and briefly discusses various topics that will be evaluated in further detail in future articles of this new series on Evidence-Based Pathology.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.151410DOI Listing
December 2019

Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel.

Mod Pathol 2020 02 4;33(2):281-296. Epub 2019 Sep 4.

MESOPATH, Lyon, France.

Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as "mesothelioma", LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.
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http://dx.doi.org/10.1038/s41379-019-0352-3DOI Listing
February 2020

The Use of Screencasts with Embedded Whole-Slide Scans and Hyperlinks to Teach Anatomic Pathology in a Supervised Digital Environment.

J Pathol Inform 2018 14;9:39. Epub 2018 Nov 14.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: There is an increasing interest in using digitized whole-slide imaging (WSI) for routine surgical pathology diagnoses. Screencasts are digital recordings of computer screen output with advanced interactive features that allow for the preparation of videos. Screencasts that include hyperlinks to WSIs could help teach pathology residents how to become familiar with technologies that they are likely to use in their future career.

Materials And Methods: Twenty screencasts were prepared with Camtasia 2.0 software (TechSmith, Okemos, MI, USA). They included clinical history, videos of chest X-rays and/or chest computed tomography images, links to WSI digitized with an Aperio Turbo AT scanner (Leica Biosystems, Buffalo Grove, IL, USA), pre- and posttests, and faculty-narrated videos of the WSI in a manner closely resembling a slide seminar and other educational materials. Screencasts were saved in a hospital network, Screencast.com, YouTube.com, and Vimeo.com. The screencasts were viewed by 12 pathology residents and fellows who made diagnoses, answered the quizzes, and took a survey with questions designed to evaluate their perception of the quality of this technology. Quiz results were automatically e-mailed to faculty. Pre- and posttest results were compared using a paired -test.

Results: Screencasts can be viewed with Windows PC and Mac operating systems and mobile devices; only videos saved in our network and screencast.com could be used to generate quizzes. Participants' feedback was very favorable with average scores ranging from 4.5 to 4.8 (on a scale of 5). Mean posttest scores (87.0% [±21.6%]) were significantly improved over those in the pretest quizzes (48.5% [±31.2%]) ( < 0.0001).

Conclusion: Screencasts with WSI that allow residents and fellows to diagnose cases using digital microscopy may prove to be a useful technology to enhance the pathology education. Future studies with larger numbers of screencasts and participants are needed to optimize various teaching strategies.
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http://dx.doi.org/10.4103/jpi.jpi_44_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289000PMC
November 2018

Procurement and Storage of Pleural and Peritoneal Fluids for Biobanking.

Methods Mol Biol 2019 ;1897:125-133

Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA.

There is limited information regarding the biobanking of pleural and peritoneal fluids that might supplement storage of pulmonary and thoracic tissue biospecimens. Such fluids are sometimes collected for clinical analyses and may have uses that obviate or supplement tissue samples. There has been a growing interest in using liquid biopsies as they are less invasive and may be amenable to analyses that guide targeted therapies. Integrating cytology and biobanking approaches, we describe techniques that may be used for collecting and banking pleural and peritoneal fluids.
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http://dx.doi.org/10.1007/978-1-4939-8935-5_13DOI Listing
June 2019

Carcinoid tumors of the thymus and Cushing's syndrome: Clinicopathologic features and current best evidence regarding the cell of origin of these unusual neoplasms.

Ann Diagn Pathol 2019 Feb 22;38:71-79. Epub 2018 Nov 22.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET. The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p < 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas. The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.
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http://dx.doi.org/10.1016/j.anndiagpath.2018.11.006DOI Listing
February 2019

The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence.

Mod Pathol 2018 10 25;31(10):1523-1531. Epub 2018 May 25.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Although Ki-67 labeling index (Ki-67%) is not a diagnostic or grading criterion in the World Health Organization classification of pulmonary carcinoid tumor, oncologists often request this test. A survey was administered at a North American Society for Neuroendocrine Tumors meeting to understand how Ki-67% is used in oncologic practices. A systematic literature review was performed to gather best evidence regarding the use of Ki-67%. Consecutive pulmonary carcinoids were stratified into pulmonary typical carcinoids with Ki-67% <5% (group A, n = 187), typical carcinoids with Ki-67% ≥5% (group B, n = 38) and atypical carcinoids irrespective of Ki-67% (group C, n = 31). Overall survival, progression-free survival, recurrence proportions and time to recurrence were compared, by group, using the log-rank test, chi-square statistics and ANOVA, respectively. Our survey confirmed that Ki-67% is frequently used by specialists caring for these patients. Ki-67% of 1-7% significantly correlated with overall survival in the literature but we found no information about Ki-67% cut-off values that would accurately distinguish pulmonary typical from atypical carcinoids or estimate the prognosis of patients stratified by World Health Organization diagnosis and Ki-67% cut-off. Overall survival was significantly different in our 3 patient groups (p < 0.001), with survival probabilities decreasing from groups A to C. Progression-free survival was significantly longer in group A than B (p < 0.007). Our results support the concept that by combining World Health Organization diagnosis and Ki-67%, pulmonary carcinoids can be stratified into 3 grades: G1 (typical carcinoids with Ki-67% <5), G2 (typical carcinoids with Ki-67% ≥5%) and G3 (atypical carcinoids) with different prognoses.
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http://dx.doi.org/10.1038/s41379-018-0076-9DOI Listing
October 2018

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

Mod Pathol 2018 04 12;31(4):598-606. Epub 2018 Jan 12.

Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.
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http://dx.doi.org/10.1038/modpathol.2017.170DOI Listing
April 2018

Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung.

J Thorac Oncol 2018 02 7;13(2):205-217. Epub 2017 Nov 7.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen κ statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (κ score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.
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http://dx.doi.org/10.1016/j.jtho.2017.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276791PMC
February 2018

Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces.

Arch Pathol Lab Med 2018 Jan 2;142(1):59-63. Epub 2017 Oct 2.

From the Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Context: - Tumor spread through alveolar spaces (STAS) has been correlated with unfavorable prognosis in lung adenocarcinomas treated with sublobar resection, but it is unknown whether STAS can be reliably identified in frozen section (FS) to help stratify patients for lobectomy or sublobar resection.

Objective: - To evaluate STAS in FS.

Design: - Tumor spread through alveolar spaces was evaluated in hematoxylin-eosin-stained FS, FS control slides, and all additional slides with lung tissue adjacent to tumor (AdLT) from 48 pT1-2 adenocarcinomas operated on using video-assisted thoracotomy (n = 25) or open thoracotomy (n = 23). The samples included lobectomies (n = 27) and sublobar resections (n = 21). The STAS incidences were compared by FS versus FS control versus AdLT, video-assisted thoracotomy versus open thoracotomy, and lobectomy versus sublobar resection. Sensitivity, specificity, and positive and negative predictive values of STAS findings were calculated. The literature was queried for best evidence regarding incidence and predictive value of STAS in FS.

Results: - Tumor spread through alveolar spaces positivity was identified in 46 of 48 cases (95.8%), including 23 FS (47.9%), 32 FS control (66.7%), and 43 AdLT (89.6%). The STAS incidence was significantly higher in AdLT than in FS or FS control. Only 2 of the 25 cases that were STAS in FS were true negatives. Frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and 8% negative predictive value. Systematic literature review identified no evidence regarding STAS identification in FS.

Conclusions: - The sensitivity and negative predictive value of FS for STAS detection are unacceptably low. There are insufficient data to support intraoperative detection of STAS as a useful predictive feature to help stratify patients for lobectomy or sublobar resections.
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http://dx.doi.org/10.5858/arpa.2016-0635-OADOI Listing
January 2018

Next-Generation Sequencing: A Novel Approach to Distinguish Multifocal Primary Lung Adenocarcinomas from Intrapulmonary Metastases.

J Mol Diagn 2017 11 1;19(6):870-880. Epub 2017 Sep 1.

Department of Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Distinguishing between multiple lung primary tumors and intrapulmonary metastases is imperative for accurate staging. The American Joint Committee on Cancer (AJCC) criteria are routinely used for this purpose but can yield equivocal conclusions. This study evaluated whether next-generation sequencing (NGS) using the 50-gene AmpliSeq Cancer Hotspot Panel version 2 can help facilitate this distinction. NGS was performed on known primary-metastatic pairs (8 patients) and multiple lung adenocarcinomas (11 patients). Primary-metastatic pairs had high mutational concordance. Seven pairs shared mutations, and 1 was concordant for having no mutations. Driver mutations in KRAS (n = 4), EGFR (n = 2), and BRAF (n = 1) were always concordant. Multiple lung tumors from 3 patients were completely concordant and predicted by NGS to be intrapulmonary metastases, whereas 8 had completely discordant mutations and were predicted to be independent primary tumors. The NGS prediction correlated with the AJCC (eighth edition) prediction in all patients for whom the latter was unequivocal (8 of 11). Furthermore, it separated patients by overall survival. Patients with predicted multiple independent primary tumors by NGS had better survival than those with distant metastases (P = 0.016, log-rank test), whereas those with predicted intrapulmonary metastases had no difference (P = 0.527). With further validation, the 50-gene panel has the potential to serve as an adjunct to the AJCC criteria.
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http://dx.doi.org/10.1016/j.jmoldx.2017.07.006DOI Listing
November 2017

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.

Hum Pathol 2017 09 4;67:160-168. Epub 2017 Aug 4.

Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France.

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.
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http://dx.doi.org/10.1016/j.humpath.2017.07.015DOI Listing
September 2017

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.

Arch Pathol Lab Med 2018 Jan 7;142(1):89-108. Epub 2017 Jul 7.

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).

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.
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http://dx.doi.org/10.5858/arpa.2017-0124-RADOI Listing
January 2018

The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases.

J Thorac Oncol 2017 02 18;12(2):334-346. Epub 2016 Dec 18.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.

Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise κ scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.

Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).

Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, κ scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.

Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided.
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http://dx.doi.org/10.1016/j.jtho.2016.12.004DOI Listing
February 2017

Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease.

J Thorac Oncol 2017 03 24;12(3):425-436. Epub 2016 Nov 24.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed.
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http://dx.doi.org/10.1016/j.jtho.2016.11.2222DOI Listing
March 2017

Quantitative imaging for development of companion diagnostics to drugs targeting HGF/MET.

J Pathol Clin Res 2016 Oct 1;2(4):210-222. Epub 2016 Jul 1.

Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Department of Pathology and Laboratory MedicineCedars-Sinai Medical CenterLos AngelesCalifornia90048USA.

The limited clinical success of anti-HGF/MET drugs can be attributed to the lack of predictive biomarkers that adequately select patients for treatment. We demonstrate here that quantitative digital imaging of formalin fixed paraffin embedded tissues stained by immunohistochemistry can be used to measure signals from weakly staining antibodies and provides new opportunities to develop assays for detection of MET receptor activity. To establish a biomarker panel of MET activation, we employed seven antibodies measuring protein expression in the HGF/MET pathway in 20 cases and up to 80 cores from 18 human cancer types. The antibodies bind to epitopes in the extra (EC)- and intracellular (IC) domains of MET (MET4, SP44_MET, D1C2_MET), to MET-pY1234/pY1235, a marker of MET kinase activation, as well as to HGF, pSFK or pMAPK. Expression of HGF was determined in tumour cells (T_HGF) as well as in stroma surrounding cancer (St_HGF). Remarkably, MET4 correlated more strongly with pMET ( = 0.47) than SP44_MET ( = 0.21) or D1C2_MET ( = 0.08) across 18 cancer types. In addition, correlation coefficients of pMET and T_HGF ( = 0.38) and pMET and pSFK ( = 0.56) were high. Prediction models of MET activation reveal cancer-type specific differences in performance of MET4, SP44_MET and anti-HGF antibodies. Thus, we conclude that assays to predict the response to HGF/MET inhibitors require a cancer-type specific antibody selection and should be developed in those cancer types in which they are employed clinically.
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http://dx.doi.org/10.1002/cjp2.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068192PMC
October 2016

PD-L1, PD-1, CD4, and CD8 expression in neoplastic and nonneoplastic thymus.

Hum Pathol 2017 02 13;60:16-23. Epub 2016 Oct 13.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048. Electronic address:

The checkpoint protein programmed cell death ligand-1 protein (PD-L1) binds to its receptor (PD-1) activating the PD-L1/PD-1 pathway, an important therapeutic target. There is limited information regarding PD-L1 and PD-1 expression in thymic lesions. Sections from nonneoplastic thymi (n = 20), thymomas World Health Organization types A, AB, B1, B2, and B3 (n = 38) and thymic squamous cell carcinoma (n = 8) were stained for PD-L1 (clone SP142; Spring BioScience), PD-1 (MRQ22; Cell Marque), CD4 (clone SPO32; Cell Marque), and CD8 (JCB117; Ventana). Immunoreactivity for each antibody was classified as focal or diffuse and scored as follows: 0, negative; 1%-5%, 1+; 6%-20%, 2+; and >20%, 3+. The proportions of cases expressing PD-L1, PD-1, CD4, and C8 at score ≥1+ were compared by diagnosis, using χ statistics. PD-L1 was expressed in 90% of nonneoplastic thymi, 92% of thymomas, and 50% of carcinomas, with significantly higher scores (P < .01) in B2 and B3 thymomas and carcinomas than in AB and B1 thymomas; PD-L1 was diffuse in most B2 and B3 thymomas and focal in carcinomas. PD-1 was focally expressed, and mostly with scores 1+, in 55% of nonneoplastic thymi, 63% of thymomas, and 37.5% of carcinomas. CD4+ and CD8+ cells were diffusely distributed with scores 3+ in all lesions other than B3 thymomas and carcinomas. The latter showed CD4+ cells mostly at the interface between neoplastic cells and stroma. PD-L1 and PD-1 are not expressed in similar locations and cellular proportions in thymic lesions, raising a question as to whether the PD-L1/PD-1 pathway is an actionable therapeutic target in these lesions.
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http://dx.doi.org/10.1016/j.humpath.2016.09.023DOI Listing
February 2017

Dataset for reporting of thymic epithelial tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Histopathology 2017 Mar 28;70(4):522-538. Epub 2016 Nov 28.

Department of Cellular Pathology, Birmingham Women's Hospital, Birmingham, UK.

Aims: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists-Association Canadienne des Pathologists in association with the Canadian Partnership Against Cancer, and the European Society of Pathology. Its goal is to produce standardized, internationally agreed, evidence-based datasets for use throughout the world.

Methods And Results: This article describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of thymic epithelial tumours. The dataset includes 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are validated by a review of current evidence and supported by explanatory text. Seven required elements and 12 recommended elements were agreed by the international dataset authoring committee to represent the essential information for the reporting of thymic epithelial tumours.

Conclusions: The use of an internationally agreed, structured pathology dataset for reporting thymic tumours provides all of the necessary information for optimal patient management, facilitates consistent and accurate data collection, and provides valuable data for research and international benchmarking. The dataset also provides a valuable resource for those countries and institutions that are not in a position to develop their own datasets.
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http://dx.doi.org/10.1111/his.13099DOI Listing
March 2017
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