Publications by authors named "Lester J Layfield"

196 Publications

Core needle biopsy for the diagnosis of primary soft tissue lesions: Accuracy and diagnostic challenges.

Diagn Cytopathol 2022 Sep 5;50(9):442-450. Epub 2022 Jul 5.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Background: Core needle biopsy (CNB) and fine needle aspiration (FNA) are currently the most common biopsy methods for investigation of soft tissue lesions. Selection of the method to be used depends on a number of factors including diagnostic accuracy, local expertise with the techniques and the need for ancillary testing. We investigated the diagnostic accuracy of CNB and factors influencing the selection of CNB or FNA.

Methods: An electronic search of the surgical pathology records for all core needle biopsies of soft tissue lesions with subsequent incisional biopsies or excisions between January 1, 2015 and December 31, 2021 was performed. Searches of the literature for publications documenting diagnostic accuracy of core biopsy and FNA were performed using the Pub Med literature data base.

Results: The electronic search yielded 177 CNBs with appropriate follow-up. Six cases were non-diagnostic. The remaining 171 cases showed an accuracy of 90% for separation of benign from malignant with two false-positive and 17 false-negative diagnoses. The literature search revealed 11 series of CNBs with a diagnostic accuracy of 74% to 97%. The literature search revealed 20 series of FNAs with an accuracy of 84.8% to 100% for separation of benign from malignant.

Conclusions: Core needle biopsy is a highly accurate diagnostic technique with an accuracy of 90% for separation of benign from malignant lesions. The percentage of non-diagnostic cases is low (3.4%). No significant biopsy related complications were seen in this study.
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http://dx.doi.org/10.1002/dc.25012DOI Listing
September 2022

Bone and soft tissue tumors at the borderlands of malignancy.

Skeletal Radiol 2022 Jun 29. Epub 2022 Jun 29.

University of Missouri at Columbia, Columbia, MO, USA.

This review examines findings of musculoskeletal neoplasms whose equivocal imaging and/or histopathologic features make it difficult to determine if they will show aggressive behavior. We include both intermediate tumors as defined by the World Health Organization (WHO), and a single low-grade malignancy, low-grade central osteosarcoma, which mimics a benign lesion on imaging and histology. Intermediate tumors are a broad category and are subdivided into tumors that have risk of local recurrence only, and ones that have a risk of distant limb and pulmonary metastases. Difficult intermediate musculoskeletal lesions include atypical cartilaginous tumor/grade 1 chondrosarcoma, atypical lipomatous tumor/grade 1 liposarcoma, and solitary fibrous tumor. We review diagnostic criteria, differential diagnosis, and recommendations for surveillance.
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http://dx.doi.org/10.1007/s00256-022-04099-1DOI Listing
June 2022

Molecular features of pancreaticobiliary neoplasms: Implications for diagnosis, prognostication, and therapy selection.

Diagn Cytopathol 2022 Jun 25. Epub 2022 Jun 25.

The Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Background: Molecular diagnostics has impacted the diagnosis, prediction of prognosis, and selection of targeted therapy for many tumor types. While pulmonary adenocarcinomas and melanomas are among the neoplasms most associated with molecular diagnostics and targeted therapy, malignancies of the pancreaticobiliary system have also been impacted by precision medicine.

Methods: We undertook an electronic search using PubMed and Embase to review the published literature to determine what forms of molecular testing, mutations and oncogenetic pathways are associated with neoplasms of the pancreaticobiliary system. Keywords utilized were pancreas, bile duct, mutations, ERCP, FNA, KRAS, SMAD4, TP53, next-generation sequencing, serous cystadenoma, pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm, cystic mucinous neoplasm, solid pseudo-papillary neoplasm.

Results: A search between 1999 and 2022 yielded 6874 manuscripts. Screening of these yielded 302 more focused manuscripts of which 55 were used for the study. Ductal adenocarcinoma of the pancreas is associated with a progression of mutations beginning wit KRAS mutations and ending with a set of mutations in the TP53, SMAD4, and DPC4 genes. Similar mutations are found in neoplastic mucinous cysts. Specific mutations characterize serous cystadenomas, solid, and pseudo papillary neoplasms and adenocarcinomas of the bile ducts.

Conclusions: Mutational analysis of cytologic specimens obtained by fine-needle aspiration, and duct brushings and washings are helpful in the diagnosis of pancreaticobiliary neoplasms and may supply prognostic information.
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http://dx.doi.org/10.1002/dc.25005DOI Listing
June 2022

A report of an intracortical chondroblastoma of the diaphysis in a skeletally mature patient.

Skeletal Radiol 2022 Jun 16. Epub 2022 Jun 16.

Department of Orthopedic Surgery, University of Missouri, Columbia, USA.

Chondroblastomas characteristically occur in skeletally immature patients, and arise within the medullary canal of the epiphysis. We report a rare case of an intracortical chondroblastoma arising in the diaphysis, and occurring in an adult in his 3 decade of life. Immunohistochemistry results were critical to confirmation of this rare diagnosis, with immunohistochemistry showing S100, DOG1, and H3K36me3 positivity in the neoplastic cells.
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http://dx.doi.org/10.1007/s00256-022-04088-4DOI Listing
June 2022

Immunocytochemistry of effusion fluids: Introduction to SCIP approach.

Cytojournal 2022 31;19. Epub 2022 Jan 31.

Department of Pathology and Anatomical Sciences, University of Missouri, One Hospital Drive, Columbia, Missouri, USA.

Due to the remarkably wide morphologic spectrum of reactive mesothelial cells, some of the effusion fluids may be difficult to interpret with objective certainty by cytomorphology alone. Cytomorphology of well to moderately differentiated adenocarcinomas (responsible for the bulk of malignant effusions) may overlap with floridly reactive mesothelial cells. Even mesotheliomas including diffuse malignant epithelioid mesothelioma, are usually cytomorphologically bland without unequivocal features of malignancy. The intensity of challenge depends on the interpreter's training or experience level, institutional demographics of patients (such as type of prevalent diseases, predominant sex and age group), technical support, and quality of cytopreparatory processing. In general immunocytochemistry is valuable adjunct to facilitate objective interpretation with or without other ancillary techniques as indicated. An increasing number of immunomarkers is further refining the contribution of immunohistochemistry to this field. However, application of immunohistochemistry to effusion fluids is relatively challenging because of many variables. Multiple factors such as delay after specimen collection, specimen processing related factors including fixation and storage; ambient conditions under which paraffin blocks are archived (for retrospective testing); antigen retrieval method; duration of antigen retrieval step; antibody clone and dilution; and antibody application time are identical to application of immunohistochemistry in other areas. The significant challenge related to the potential compromization of the immunoreactivity pattern due to exposure to non-formalin fixatives / reagents is also applicable to effusion fluid specimens. The immunoreactivity results would be compared and corelated with cumulative metadata based on the reported studies performed and validated on formalin-fixed paraffin-embedded tissue sections. Deviating from such protocols may lead to suboptimal results, which is not uncommon in clinical practice with potential compromization of patient care and related liability. Because of this, it is critical to perform immunocytochemistry on formalin-fixed cell-block sections only. In addition, unless the interpretation criteria for immunohistochemical evaluation of effusion fluids are not modified specifically, it may not be productive in resolving some challenging cases. However, this aspect is not well elaborated in the literature. A basic and critical challenge is finding and locating the cells of interest in cell-block sections of effusion fluids. A unique approach is to choose a fundamental immunopanel which highlight the mesothelial and inflammatory cells in reactive effusion fluids to create the basic map. This allows detection of a 'second-foreign' population which can be immunocharacterized further with the help of subtractive coordinate immunoreactivity pattern (SCIP) approach elaborated here.
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http://dx.doi.org/10.25259/CMAS_02_05_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9079320PMC
January 2022

Second CMAS (CytoJournal Monograph/Atlas Series) titled "Cytopathologic Diagnosis of Serous Fluids" (second edition).

Cytojournal 2022 21;19:19. Epub 2022 Mar 21.

Department of Pathology and Anatomical Sciences, University of Missouri, University of Missouri, Columbia, Missouri, United States.

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http://dx.doi.org/10.25259/CMAS_02_00_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9063556PMC
March 2022

Salivary gland neoplasms with basaloid features in the era of the Milan system for reporting salivary gland cytology: Classification and interobserver agreement.

Diagn Cytopathol 2022 Jul 23;50(7):341-349. Epub 2022 Apr 23.

Department of Pathology, University of Utah Health Care and ARUP Laboratories, Salt Lake City, Utah, USA.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has been shown to have moderate to good reproducibility for categorization of salivary gland fine-needle aspiration (FNA) specimens. Less is known of its accuracy and interobserver reproducibility for categorization of the diagnostically difficult group of basaloid neoplasms.

Methods: Forty-five salivary gland specimens with a basaloid morphology (pleomorphic and monomorphic adenomas and adenoid cystic carcinomas) were independently assigned by seven cytopathologists to one of the MSRSGC categories. Interobserver agreement was assessed for average agreement, chance expected agreement and by Cohen's κ and diagnostic accuracy. Correlation of the salivary gland neoplasm of unknown malignant potential (SUMP) category with histologic diagnosis and benign or malignant designation along with interobserver reproducibility were calculated.

Results: Average observed agreement for assignment to the MSRSGC was 46% and Cohen's κ = 0.2%. The SUMP category did not correlate with tumor type or with the benign or malignant nature of the neoplasm. Diagnostic specificity and sensitivity were 92% and 100% for consensus diagnosis, but were 76% and 77% for individual diagnoses.

Conclusion: The interobserver agreement in categorizing basaloid neoplasms by the MSRSGC is poorer than for salivary gland lesions overall. This reflects the difficulty in diagnosing basaloid neoplasms. Nonetheless, diagnostic accuracy appears similar to that of salivary gland neoplasms as a whole.
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http://dx.doi.org/10.1002/dc.24962DOI Listing
July 2022

Approach to Diagnostic Cytopathology of Serous Effusions.

Cytojournal 2021 6;18:32. Epub 2021 Dec 6.

Department of Pathology and Anatomical Sciences, University of Missouri, One Hospital Drive, Columbia, Missouri, USA.

Collection of most serous fluids from various effusions is a relatively simple procedure. Because of this, serous fluids are commonly submitted for pathologic examination including cytopathologic evaluation by various clinical institutions. As a consequence, even a general pathology laboratory which may not have expertise with highly trained cytopathologist would be confronted with serous fluids for cytologic evaluation. However, cytopathologic evaluation of serous fluids is complex as compared to evaluation of fine needle aspiration cytology. This signifies the fact that all pathologists, irrespective of subspeciality cytopathology training and level of subspeciality expertise, should be conversant with the diagnostic challenges and pitfalls of effusion fluid cytology. Although, majority of effusions are due to reactive and non-neoplastic etiologies, cancer is one of the causes of an effusion as a manifestation of advanced cancer. Detecting neoplastic cells in effusion specimens in most of clinical settings is related to the advanced status of the disease, which usually is equivalent to incurable stage. Thus, interpretation of cytopathology as positive for cancer cell is highly critical in planning the trajectory of the clinical management with an obvious negative impact of false positive interpretation. Apart from cancer, effusions may be secondary to hemodynamic pathologies such as heart failure, hypoalbuminemia, cirrhosis etc. in addition to the different inflammatory conditions including parasitic infestations, bacterial, fungal, or viral infections, and other non-neoplastic etiologies including collagen diseases. Due to the cytomorphologic overlap of reactive mesothelial cells with malignant cells, general cytologic criteria for diagnosis of malignancy in single cells cannot be applied in most of the effusion specimens. This challenge is further amplified because of surface tension related phenomenon which 'round up' the cells after exfoliation in serous fluids. As a result, the native shapes of cancer cells cannot be a guiding feature. Thus the cytomorphologic features of cancer cells in serous fluids may not be same as seen in routine cytopathology of exfoliative, brushing, and fine-needle aspiration specimens. The cancer cells may continue to proliferate after exfoliation in the nutrient rich effusion fluids and may form proliferation spheres. It is crucial to consider these factors when interpreting effusion cytology. Amongst malignant effusions, adenocarcinomas are the most common cause of metastatic cancers, but almost any type of malignancy including melanomas, hematopoietic neoplasms, sarcomas, and mesotheliomas may involve serous cavities. The interpreter must be aware of the wide range of the cytomorphologic appearances of reactive mesothelial cells in effusion fluids. It is essential to understand these and other nuances related to effusion fluid cytology. Understanding potential pitfalls during various stages from processing to application of ancillary studies would increase the diagnostic accuracy and minimize atypical interpretations and false positivity.
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http://dx.doi.org/10.25259/CMAS_02_03_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813643PMC
December 2021

Introduction to the second edition of 'Diagnostic Cytopathology of Serous Fluids' as CytoJournal Monograph (CMAS) in Open Access.

Cytojournal 2021 6;18:30. Epub 2021 Dec 6.

Department of Pathology and Anatomical Sciences, University of Missouri, One Hospital Drive, Columbia, Missouri, USA.

Serous fluids are excessive accumulation of fluids in a serous cavity as . However, traditionally this area also covers cytopathologic evaluation of washings of these cavities including pelvic/peritoneal washing. This is the introductory review article in series on this topic with the application of simplified algorithmic approaches. The series would be compiled finally as a book after minor modifications of individual review articles to accommodate the book layout on the topic as second edition of 'Diagnostic Cytopathology of Serous Fluids' book. The approach is primarily directed towards detection of neoplastic cells based on morphology alone or with the help of various ancillary tests, including commonly applied immunocytochemistry to be interpreted as second foreign population with application of SCIP () approach in effusion fluid tapings. As the role of molecular pathology tests is increasing, this component as ancillary testing will also be covered as applicable. Because a picture and sketches are worth a thousand words, illustrations and figures are included generously even at the risk of moderate repetition. The clinically important serous cavities include peritoneal cavity, pericardial cavity, and two pleural cavities. The primary topic of this series is specimens from these cavities as effusion fluids and including cytopathologic evaluation of washing. It is expected that some readers may not read the entire series or the final book from beginning to end, but refer to the individual review articles and chapters sporadically during their clinical practice. Considering this practical limitation, some brief repetition may be observed throughout the book. Some of the important themes will be highlighted as italicized and bolded text for quick reference. Dedicated articles/chapters are assigned for technical and other reference material as appendices. Tables, algorithms, sketches, and combination of pictures are included generously for quick reference. Most of the illustrations are attempted to be labeled appropriately with arrows and other indicators to avoid equivocation, especially for beginners in the field. This introductory review article describes general details under the following three broad headings: Histology and general cytology of serous cavity lining Effusion (general considerations) Ancillary techniques in brief.
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http://dx.doi.org/10.25259/CMAS_02_01_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813611PMC
December 2021

Atypia in pulmonary cytology: Morphologic spectrum and causes.

Diagn Cytopathol 2022 Apr 20;50(4):164-171. Epub 2021 Nov 20.

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: The term "atypical" has had a long history of usage in cytology but has had variable definitions and usage. Most commonly the term was used to indicate a degree of cytomorphologic abnormality greater than that clearly due to reactive or reparative changes but not associated with a high concern on the part of the cytopathologist that a malignancy is present. The Papanicolaou Society of Cytopathology System for Reporting Respiratory Cytology provided a foundation for using the category "Atypical" along with the category "Suspicious for Malignancy" to categorize the spectrum of morphologic changes ranging from those which are clearly benign to those that are clearly malignant. The two intermediate categories of "Atypical" and "Suspicious for Malignancy" have characteristic recommendations resulting in clinical utility for both categories.

Conclusion: The Papanicolaou Society of Cytopathology System for Reporting Respiratory Cytology represents a useful system with defined intermediate categories of Atypical and Suspicious for Malignancy.
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http://dx.doi.org/10.1002/dc.24902DOI Listing
April 2022

Diagnostic sensitivity and risk of malignancy for bile duct brushings categorized by the Papanicolaou Society of Cytopathology System for reporting pancreaticobiliary cytopathology.

Diagn Cytopathol 2022 Jan 20;50(1):24-27. Epub 2021 Nov 20.

Department of Pathology & Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Background: The Papanicolaou Society of cytopathology developed a six-category system for pancreaticobiliary cytology specimens. Each category is associated with a definition, diagnostic criteria, estimated risk of malignancy and management recommendations. Risks of malignancy are well defined for specimens obtained by fine-needle aspiration but are less well defined for brushing specimens.

Methods: Diagnoses of 232 brushing specimens of the pancreatic and bile ducts were correlated with diagnoses from subsequent surgical or cytologic specimens. Sensitivity for the brushing technique was calculated. Risk of malignancy was calculated for each category using the original definitions for nondiagnostic and negative categories and for those of a modified system.

Results: Diagnostic sensitivity was 60%-64%. Risk of malignancy for the nondiagnostic, negative, atypical, suspicious for malignancy, and malignant categories was 28%, 28%, 61%, 91%, and 91%, respectively, when the original category definitions were used.

Conclusions: Diagnostic sensitivity for duct brushings is low in comparison to fine-needle aspiration. Risk of malignancy is comparable to that of needle aspiration for the negative, atypical and suspicious categories but lower for the malignant category. There is a stepwise increase in malignancy risk as one moves from the negative to the atypical to the suspicious for malignancy categories.
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http://dx.doi.org/10.1002/dc.24901DOI Listing
January 2022

The international system for serous fluid cytopathology: Interobserver agreement.

Diagn Cytopathol 2022 Jan 16;50(1):3-7. Epub 2021 Nov 16.

Department of Pathology and Laboratory Medicine, ARUP Laboratories, Salt Lake City, Utah, USA.

Background: A number of categorization systems had been developed for the reporting of cytology specimens with the aim of providing uniform definitions, criteria, and diagnostic terminology. The intention of these systems is to improve reproducibility of diagnostic categorization with standardized estimates of malignancy risk. Required for the success of these systems is a high level of interobserver reproducibility for category assignment. Recently, the international system for serous fluid cytopathology (TIS) was proposed using the categories nondiagnostic, negative for malignancy, atypia of undetermined significance (AUS), suspicious for malignancy, and malignant. Little data exists documenting the interobserver agreement for these categories.

Design: A search of the cytology records at the University of Missouri was performed for all pleural fluid specimens obtained between January 2014 and December 2019. A total of 200 specimens were reviewed independently by three board-certified cytopathologists. Specimens were characterized as nondiagnostic, negative, AUS, suspicious for malignancy, and malignant. Interobserver agreement was analyzed using Cohen's kappa.

Results: Overall observer agreement was 68% and chance-corrected weighted agreement (weighted kappa) was 0.63. Agreement was good for categories negative and malignant, but poor for categories atypia of uncertain significance, and suspicious for malignancy.

Conclusions: The TIS has performance characteristics similar to other cytologic classification schemes. Interobserver agreement is best for the negative (76%) and malignant (81%) categories. Interobserver agreement is poor for the category's AUS, and suspicious for malignancy. This is similar to interobserver agreement associated with other published categorization systems.
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http://dx.doi.org/10.1002/dc.24900DOI Listing
January 2022

PD-L1 expression in sarcomas: An immunohistochemical study and review of the literature.

Ann Diagn Pathol 2021 Dec 4;55:151823. Epub 2021 Sep 4.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO, United States of America. Electronic address:

Background: Immunotherapy is increasingly used for treatment of metastatic melanoma and carcinomas. PD-1 (programmed death 1) and its associated ligand (PD-L1) inhibits the activation of T-lymphocytes. This inhibition can be impacted by a number of drugs. Response to these drugs is predicted by assessment of PD-L1 expression. PD-L1 expression varies between 19% and 92% in melanomas and carcinomas. PD-L1 expression is less well documented for sarcomas.

Design: Fifty-six sarcomas of various histopathologic types were immunohistochemically stained (IHC) for PD-L1 using the antibody clone SP263 (Ventana, Tuscan, AZ). Membrane staining of tumor cells was quantitated as a percentage of total tumor cells. Sarcomas were judged as non-expressors (less than 1%) low-expressors (1 to 50%) and high expressors (greater than 50%). The percentage of each type of sarcoma judged as an expressor was determined.

Results: Table 1 documents the percentage of each type of sarcoma expressing PD-L1. 14% of sarcomas expressed PD-L1. Percentage of sarcomas expressing PD-L1 varied significantly between types but the majority of sarcomas were non-expressors.

Conclusion: PD-L1 IHC expression is valuable in predicting response to immune-modulating drugs. Such therapies may be useful for treatment of metastatic sarcomas. Expression of PD-L1 in carcinomas and melanomas is variable ranging from 19% to 92%. In our study, a minority (14%) of sarcomas expressed PD-L1. Other studies have shown similar results with between 1.4 and 59% (average 24%) of sarcomas expressing PD-L1. Expression appears to be sarcoma type specific. These finding suggest that PD-L1 based therapy may be less useful in sarcomas than in other malignancies.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151823DOI Listing
December 2021

Destructive Arthropathy of the Femoral Head.

Am J Clin Pathol 2022 Feb;157(2):273-278

Department of Radiology, University of Missouri, Columbia, MO, USA.

Objectives: Destructive arthropathy of the hip refers to noninfectious arthropathy causing extensive femoral head bone destruction. It has been described in the surgical literature using a variety of diagnostic criteria, but it remains a poorly defined entity.

Methods: Cases of destructive arthropathy diagnosed at our institution between July 1, 2015, and December 31, 2019, were identified by a free text search of the radiology database. The medical record of each case was reviewed for possible causes of femoral head destruction, clinical presentation, laboratory values, imaging studies, and pathologic diagnoses. Imaging studies and pathology specimens were retrospectively reviewed.

Results: Twenty femoral heads were identified in which there was 25% or greater destruction of the femoral head in the absence of infections, congenital disease, or inflammatory arthritis. Destructive arthropathy was characterized pathologically by fibromyxoid change of the marrow, aggregates of necrotic bone fragments, increased numbers of osteoclasts, increased trabecular destruction, and granuloma-like aggregates.

Conclusions: The histologic findings were distinctive. We postulate that a variety of preexisting conditions set in motion a cascade of tissue factors that led to bone destruction.
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http://dx.doi.org/10.1093/ajcp/aqab127DOI Listing
February 2022

Mast cell infiltration and activation in the gallbladder wall: Implications for the pathogenesis of functional gallbladder disorder in adult patients.

Ann Diagn Pathol 2021 Oct 19;54:151798. Epub 2021 Jul 19.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, USA.

Background: Functional gallbladder disorder (FGD) is characterized by recurrent biliary colic with a decreased gallbladder ejection fraction on cholescintigraphy but absence of visible gallbladder abnormalities on ultrasonography. FGD is generally regarded as a primary gallbladder motility disturbance, however, the underlying pathophysiology remains largely unknown. In this study, we investigated the potential role of mast cells in the pathogenesis of FGD by examining mast cell density and activation in the gallbladder wall.

Design: Twenty adult patients with FGD undergoing cholecystectomy were included in the study. Seven patients with no gallbladder disease were served as controls who were subject to incidental cholecystectomy during abdominal surgery such as partial hepatectomy. The density of mast cells in the gallbladder wall was assessed by immunohistochemistry and by toluidine blue special stain. Mast cell activation was evaluated by calculating the percentage of degranulated mast cells on toluidine blue stain.

Results: Compared to the controls, patients with FGD showed a significant increase in mast cell infiltration in the gallbladder walls. Peak mast cell accumulation was predominantly located in the inner muscular layer of the gallbladder wall. Mast cell activation was also markedly increased in the FGD group as evidenced by significantly enhanced mast cell degranulation.

Conclusions: Mast cell infiltration and activation were significantly increased in the muscular wall of gallbladders from FGD patients, suggesting potential involvement of mast cells in the compromised gallbladder motility in adult patients with FGD.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151798DOI Listing
October 2021

SARS-CoV-2 detection by reverse transcriptase polymerase chain reaction testing: Analysis of false positive results and recommendations for quality control measures.

Pathol Res Pract 2021 Sep 4;225:153579. Epub 2021 Aug 4.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO, United States.

Testing for SARS-CoV-2 has become a critical component for the management of the COVID-19 pandemic. Reverse transcriptase polymerase chain reaction (RT-PCR) assays are currently the predominate method for testing. Quality control (QC) measures utilize known positive and known negative controls to ensure the adequacy of extraction and RT-PCR steps but do not evaluate all components of testing. We have conducted a quality assurance review of our RT-PCR testing for COVID-19 to determine the rate of false positive results in asymptomatic patients and causes for these errors.

Design: We have developed a quality control procedure in which all specimens from asymptomatic unexposed persons with SARS-CoV-2 positive tests were retested. When a second test was "non-detected" a third test was performed and a root cause analysis of the erroneous result undertaken.

Results: In the study period, 24,717 samples were tested and 6251 were from asymptomatic patients. Of the 288 initial positive tests, 20 (6.9%) were negative on retesting. Review of cycle threshold curves, technologists' records, location of specimen on testing plates and relationships with high viral load specimens was undertaken. Analysis revealed technologists' errors (misplacement of specimen in testing plate or contamination) and cross contamination from high viral load specimens in adjacent wells of testing plates were common causes for false positive results.

Discussion: SARS-CoV-2 RT-PCR testing is associated with a small number of false positive results, most easily recognized in asymptomatic non-exposed patients. Implementation of a limited retesting protocol identifies clinically significant testing errors and allows review and improvement of laboratory procedures.
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http://dx.doi.org/10.1016/j.prp.2021.153579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336987PMC
September 2021

Post-arthrogram synovitis: MRI and histopathologic findings.

Skeletal Radiol 2022 Jan 31;51(1):219-223. Epub 2021 Jul 31.

University of Missouri at Columbia, Columbia, MO, USA.

A 57-year-old patient developed severe, persistent pain following MR arthrography with iodinated contrast. MRI 1 week later showed synovitis which was new compared to the prior MRI. Arthroscopy showed severe synovitis. Histopathology showed synovitis characterized by lymphocytes, neutrophils, and necrosis. One out of 4 intraoperative cultures was positive, but ultimately believed to be due to contaminants. CRP normalized within 1 month. Repeat MRI 2 years later showed progressive degenerative findings, but no evidence of ongoing infection, or stigmata of previous infection. We believe this to be an unusually severe case of reactive synovitis. The purpose of the report is to add to knowledge of reactions to intra-articular contrast injection.
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http://dx.doi.org/10.1007/s00256-021-03877-7DOI Listing
January 2022

A modified Papanicolaou Society of Cytopathology system for reporting respiratory cytology specimens: Implications for estimates of malignancy risk and diagnostic accuracy.

Diagn Cytopathol 2021 Nov 28;49(11):1167-1172. Epub 2021 Jul 28.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Background: In 2016, the Papanicolaou Society of Cytopathology (PSC) proposed a classification scheme for reporting cytologic specimens obtained from the respiratory system. Diagnostic sensitivity, specificity, and risk of malignancy were reported for endobronchial ultrasound guided fine needle aspiration but data for other sampling techniques has been poorly documented.

Methods: In 2016, a modified version of the PSC guidelines was adopted at the University of Missouri for classification of sputum, bronchial washing, bronchial brushing, and fine-needle aspiration specimens. Specimens assigned to the negative category included all specimens containing evaluatable inflammatory or epithelial cells including benign appearing respiratory epithelium. Only specimens with marked artifactual distortion or obscuring blood or mucus were placed in the non-diagnostic category.

Results: 672 bronchial washing specimens (479 with histology) and 511 bronchial brushings specimens (324 with histology) were reviewed. Washing specimens were classified as non-diagnostic (3%), benign (73%), atypical (10%), suspicious (4%), and malignant (10%). Bronchial brushing specimens were classified non-diagnostic (0.4%) benign (73%), atypical (6%), suspicious (3%), and malignant (17%). Malignancy risks for bronchial washings were insufficient (50%), benign (38%), atypical (62%), suspicious (83%), and malignant (98%). Risks of malignancy for bronchial brushings were insufficient (0%), benign (32%), atypical (79%), suspicious (75%), and malignant (94%).

Conclusion: Malignancy risks associated with bronchial washings and bronchial brushings are different than those reported for EBUS FNA. When the benign category includes specimens with "normal" appearing cellular elements, the risk of malignancy is substantial (between 32% and 38%).
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http://dx.doi.org/10.1002/dc.24840DOI Listing
November 2021

CytoJournal monographs: First CMAS (CytoJournal Monograph/Atlas Series) on science of cell-block making, titled "CellBlockistry 101 ()".

Cytojournal 2021 17;18:10. Epub 2021 Apr 17.

Department of Pathology and Anatomical Sciences, University of Missouri, University of Missouri, Columbia, Missouri, United States.

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http://dx.doi.org/10.25259/Cytojournal_16_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248243PMC
April 2021

Atypia in pulmonary cytology: A cytomorphometric analysis of the spectrum of changes between benign and malignant.

Diagn Cytopathol 2021 Aug 10;49(8):909-914. Epub 2021 May 10.

Department of Pathology and Laboratory Medicine, ARUP Laboratories, Salt Lake City, Utah, USA.

Background: Cytopathologists reviewing pulmonary specimens are expected to classify samples into clinically useful categories. Clinicians prefer reports to convey a definitively benign or definitively malignant diagnosis. Cytopathologists recognize a spectrum of morphologic features with increasing degrees of atypia between clearly benign and clearly malignant. A variety of terms are used to convey to clinicians how concerned a cytologist is that a malignancy maybe present. These terms include "atypia", "atypical" and "suspicious for malignancy", but have had variable meanings among cytopathologists and clinicians. Categorization schemes have been proffered to include standardization of terminology with many of these systems containing one or more intermediate categories.

Methods: An electronic search of the University of Missouri cytology reporting system was made for all bronchial brushings specimens diagnosed using the Papanicolaou Society of Cytopathology System for Reporting Respiratory Cytology (PSCSR) between January 2019 and December 2019. Slides were reviewed to determine adequate cellularity and preparation quality. From those found to be adequately cellular and of good quality, four bronchial brushing specimens from each PSCSR category were randomly selected. For each case a slide was digitized and at least 70 of the most "atypical" cells were analyzed by the Aperio System for nuclear area and nuclear/cytoplasmic ratio. Distribution of measured parameters among categories was analyzed by the Kruskal-Wallis test.

Results: During the study period, only the PSCSR categories "benign", "atypical" and "malignant" were recorded. A significant difference in distribution of nuclear/cytoplasmic ratio was seen between the "benign" and "atypical" categories but not between the "atypical" and "malignant" categories. The "atypical" category appeared to be bi-modal indicating that it could be divided into two categories, "atypical" and "suspicious for malignancy".

Conclusions: The categories "atypical" and "suspicious for malignancy" served to divide the spectrum of cytomorphologic changes between "benign" and "malignant" into clinically useful groups. The use of these categories is supported by cytomorphometric analysis of bronchial brushing specimens.
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http://dx.doi.org/10.1002/dc.24769DOI Listing
August 2021

Cell-blocks and immunohistochemistry.

Cytojournal 2021 30;18. Epub 2021 Jan 30.

Department of Pathology and Anatomical Sciences, University of Missouri, One Hospital Drive, Columbia, Missouri, United States.

The interpretation of results on immunostained cell-block sections has to be compared with the cumulative published data derived predominantly from formalin-fixed paraffin-embedded (FFPE) tissue sections. Because of this, it is important to recognize that the fixation and processing protocol should not be different from the routinely processed FFPE surgical pathology tissue. Exposure to non-formalin fixatives or reagents may interfere with the diagnostic immunoreactivity pattern. The immunoprofile observed on such cell-blocks, which are not processed in a manner similar to the surgical pathology specimens, may not be representative resulting in aberrant results. The field of immunohistochemistry (IHC) is advancing continuously with the standardization of many immunomarkers. A variety of technical advances such as multiplex IHC with refined methodologies and automation is increasing its role in clinical applications. The recent addition of rabbit monoclonal antibodies has further improved sensitivity. As compared to the mouse monoclonal antibodies, the rabbit monoclonal antibodies have 10 to 100 fold higher antigen affinity. Most of the scenarios involve the evaluation of coordinate immunostaining patterns in cell-blocks with relatively scant diagnostic material without proper orientation which is usually retained in most of the surgical pathology specimens. These challenges are addressed if cell-blocks are prepared with some dedicated methodologies such as NextGen CelBloking™ (NGCB) kits. Cell-blocks prepared by NGCB kits also facilitate the easy application of the SCIP (subtractive coordinate immunoreactivity pattern) approach for proper evaluation of coordinate immunoreactivity. Various cell-block and IHC-related issues are discussed in detail.
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http://dx.doi.org/10.25259/Cytojournal_83_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881511PMC
January 2021

Comparison of Radiographic and Pathologic Diagnosis of Osteonecrosis of the Femoral Head.

AJR Am J Roentgenol 2021 04 3;216(4):1014-1021. Epub 2021 Feb 3.

Department of Pathology, University of Utah, University of Utah Hospital, Salt Lake City, UT.

The purpose of this study was to assess the utility of radiography in diagnosing osteonecrosis of the femoral head with pathologic examination as the reference standard. Radiography and pathology reports of 253 consecutive femoral head resections were reviewed. A subset of 128 cases in which the diagnosis of osteonecrosis was made or suggested radiographically or pathologically were reviewed to evaluate for factors that might influence correlation. A total of 23 patients in this subset had also undergone MRI, and those reports and images were reviewed. There was 93.9% agreement between radiography and pathologic examination overall (κ = 0.67). When grade 3 osteoarthritis was present, 95.0% agreement was found, but because of the large number of patients with severe osteoarthritis, the kappa value decreased to 0.51. In the subset of cases in which osteonecrosis was diagnosed or suspected, radiologic-pathologic correlation decreased as osteoarthritis grade increased, and the diagnostic uncertainty for both evaluation methods increased. One patient without osteoarthritis had osteonecrosis diagnosed in both hips at radiography and MRI, but osteonecrosis was absent at pathologic examination. Radiography depicts osteonecrosis in most patients who have osteonecrosis and subsequently undergo femoral head resection. False-positive and false-negative radiographic findings occur, however. Diagnosis is most difficult in patients with advanced osteoarthritis or subchondral fractures. The number of patients who underwent MRI was not sufficient for evaluation of the accuracy of MRI.
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http://dx.doi.org/10.2214/AJR.20.22930DOI Listing
April 2021

Limited usefulness of classic MR findings in the diagnosis of tenosynovial giant cell tumor.

Skeletal Radiol 2021 Aug 7;50(8):1585-1591. Epub 2021 Jan 7.

University of Missouri, Columbia, MO, USA.

Objective: To determine the frequency with which MRI of tenosynovial giant cell tumor demonstrates hemosiderin, visible intralesional fat signal, and proximity to synovial tissue.

Material And Methods: This is a retrospective study of 31 cases of tenosynovial giant cell tumors which had concomitant MRI. Images were examined for lesion size, morphology, origin, bone erosions, MRI signal characteristics, contrast enhancement, and blooming artifact, comparing prospective and retrospective reports. Histology was reviewed for the presence of hemosiderin and xanthoma cells.

Results: Eight lesions were diffuse and 23 were localized nodules. Three lesions were located in subcutaneous tissue and 4 adjacent to tendons beyond the extent of their tendon sheath. All lesions exhibited areas of low T1- and T2-weighted signal. Blooming artifact on gradient echo imaging was present in 86% of diffuse and only 27% of nodular disease. There was interobserver variability of 40% in assessing blooming. Iron was visible on H&E or iron stain in 97% of cases. Fat signal intensity was seen in only 3% of cases, although xanthoma cells were present on in 48%. The correct diagnosis was included in the prospective radiology differential diagnosis in 86% of diffuse cases and 62% of nodular cases.

Conclusion: Blooming on GRE MRI has low sensitivity for nodular tenosynovial giant cell tumors and is not universal in diffuse tumors. There was high interobserver variability in assessment of blooming. Intralesional fat signal is not a useful sign and may occur adjacent to tendons which lack a tendon sheath and may occur in a subcutaneous location.
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http://dx.doi.org/10.1007/s00256-020-03694-4DOI Listing
August 2021

Myxoid neoplasms of bone and soft tissue: a pattern-based approach.

J Am Soc Cytopathol 2021 May-Jun;10(3):278-292. Epub 2020 Oct 16.

Department of Pathology, Curie Institute, Paris, France.

Introduction: The accurate diagnosis of musculoskeletal neoplasms is difficult but a pattern-based approach combined with ancillary testing has been shown to improve diagnostic accuracy. The pattern-based approach is particularly appropriate for myxoid lesions.

Materials And Methods: The authors reviewed their personal experience of over 3 decades of diagnosing myxoid neoplasms of musculoskeletal lesions.

Results: The authors found that myxoid lesions can be accurately classified based on cell type, nuclear atypia, presence of blood vessel fragments, as well as the results of immunohistochemical and molecular testing.

Conclusions: Musculoskeletal lesions with a prominence of myxoid or chondroid material in the background can be accurately diagnosed using pattern analysis and ancillary testing.
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http://dx.doi.org/10.1016/j.jasc.2020.09.009DOI Listing
January 2022

Axillary lymph node metastasis: Fine-needle aspiration biopsy sensitivity as a function of node size, percent replacement of lymph node by tumor and tumor deposit size.

Diagn Cytopathol 2021 Feb 17;49(2):181-186. Epub 2020 Sep 17.

Department of Pathology and Laboratory Medicine, University of Utah & ARUP Laboratories, Salt Lake City, Utah, USA.

Background: Fine-needle aspiration (FNA) is commonly used to investigate lymphadenopathy of suspected metastatic origin. While diagnostic accuracy of FNA for lymph node disease is well described, the relationship between node size, percent tumor replacement, and size of metastatic deposit with diagnostic accuracy is less well documented.

Methods: All axillary lymph nodes undergoing ultrasound-guided FNA for suspected breast metastases were correlated with subsequent surgical excision specimens. FNAs were judged as positive or negative for malignancy and the percent of false negative FNAs was correlated with node size, percent tumor replacement and size of metastatic deposit RESULTS: Sensitivities were calculated for nodes greater than 15 mm (92%), nodes 11 to 14.9 mm (83%), nodes 7 to 10.9 mm (61%), and for nodes less than 7 mm (60%). Sensitivity increases with increasing node size (P = .001). Percent tumor replacement correlated with sensitivity: 90% or greater replacement (85%) 60% to 89.9% replacement (75%), 40% to 59.9% replacement (75%) and less than 39.9% replacement (64%)(P < .001). Metastases size correlated with sensitivity: metastases greater than 10 mm (94%), 6 to 9.9 mm (70%), 4 to 5.9 mm (54%), and less than 4 mm (72%).

Conclusions: Percentage of false negative FNAs associate with investigation of metastatic disease correlates with node size, size of metastatic deposit and percentage of nodes replaced by tumor. Lymph nodes smaller than 7 mm, deposit diameter less than 6 mm and percentage replacement of less than 40% have the highest percentage of false negative results.
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http://dx.doi.org/10.1002/dc.24617DOI Listing
February 2021

Categorical systems for reporting of cytology specimens: Following the footsteps of Bethesda-like reporting systems.

Diagn Cytopathol 2020 Oct 29;48(10):859-861. Epub 2020 Aug 29.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1002/dc.24598DOI Listing
October 2020

Assessing the diagnostic accuracy for pleomorphic adenoma and Warthin tumor by employing the Milan System for Reporting Salivary Gland Cytopathology: An international, multi-institutional study.

Cancer Cytopathol 2021 01 7;129(1):43-52. Epub 2020 Aug 7.

Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has established distinct diagnostic categories for reporting cytopathological findings, and each is associated with a defined risk of malignancy (ROM). However, the ROM is applied at the overall category level and is not specific for particular morphological entities within a category. Here, the diagnostic performance of the MSRSGC for pleomorphic adenoma (PA) and Warthin tumor (WT) is reported.

Methods: The pathology archives of 11 institutions from 4 countries were retrospectively searched to identify all salivary gland fine-needle aspiration (FNA) biopsies with a differential or definitive diagnosis of PA or WT and all resection specimens with a diagnosis of PA or WT; only paired cases were included. All FNA diagnoses were retrospectively classified according to the MSRSGC.

Results: A total of 1250 cases met the inclusion criteria, and they included 898 PA cases and 352 WT cases. The ROM in the benign neoplasm category was 3.0% and 1.3% for cases with a differential or definitive diagnosis of PA and WT, respectively. The ROM in the salivary gland neoplasm with uncertain malignant potential (SUMP) category was 2.7% and 18.8% for PA and WT, respectively (P = .0277). The diagnostic accuracy for PA and WT was 95.1% and 96.1%, respectively.

Conclusions: The diagnostic accuracy for PA and WT on FNA is high. Furthermore, these findings highlight the difference in the ROMs associated with 2 specific differential diagnoses in the SUMP category: basaloid neoplasms and oncocytoid neoplasms.
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http://dx.doi.org/10.1002/cncy.22339DOI Listing
January 2021

A Bethesda-like system for breast cytopathology: A retrospective assessment two decades on.

Diagn Cytopathol 2020 Oct 7;48(10):870-876. Epub 2020 Jul 7.

Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, USA.

Fine-needle aspiration biopsy (FNAB) has been used for many decades in the investigation of breast lesions. Originally, cases were signed out using the categories benign and malignant. The benign category contained specimens showing fibrocystic change as well as benign neoplasms such as fibroadenoma. The malignant category contained carcinomas, lymphomas, and phyllodes tumors with specific diagnoses often given in place of the term malignant. Categorization was less clear when the cytopathologists could not definitively separate benign from malignant. This led to the use of terms, such as atypical, suspicious for malignancy, and atypical suspicious with variable definitions and utilization among cytopathologists. In 1997, a uniform approach to breast FNAB was proposed with well-defined diagnostic categories and criteria. This system foreshadowed the recent International Academy of Cytology Standardized Reporting System for Breast Fine-Needle Aspiration Biopsy. These two systems are compared and contrasted.
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http://dx.doi.org/10.1002/dc.24483DOI Listing
October 2020

Solitary fibrous tumor of bone developing lung metastases on long-term follow-up.

Skeletal Radiol 2020 Nov 9;49(11):1865-1871. Epub 2020 Jun 9.

University of Missouri at Columbia, Columbia, MO, USA.

Solitary fibrous tumors are rare mesenchymal neoplasms of fibroblastic or myofibroblastic origin. Primary solitary fibrous tumors arising in bone are extremely rare and rarely metastasize. We present a case of solitary fibrous tumor where the diagnosis was delayed due to a failure to recognize the subtle, lytic lesion underlying a fracture of the left humerus. The patient underwent proximal humeral replacement and was followed closely with imaging of humerus and chest. A small lung metastasis was found on CT scan 38 months later and was resected. Two additional small metastases were found and resected 62 months after initial tumor resection. The purpose of this case report is both to highlight the radiologic challenges which can lead to overlooking a lytic lesion underlying a fracture and to show the importance of long-term follow-up in patients with solitary fibrous tumor.
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http://dx.doi.org/10.1007/s00256-020-03493-xDOI Listing
November 2020
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