bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Utility of Factor V Leiden (R506Q) Testing for the Diagnosis and Management of Thromboembolic Disorders
Authors: Press Richard D. , Bauer Kenneth A. , Kujovich Jody L. , Heit John A.
Published: January 2021

Objective.—To review the current state of the art regarding the role of the clinical laboratory in diagnostic testing for the factor V Leiden (FVL) thrombophilic mutation (and other protein C resistance disorders), and to generate, through literature reviews and opinions of recognized thought-leaders, expert consensus recommendations on methodology and diagnostic, prognostic, and management issues pertaining to clinical FVL testing.

Data Sources, Extraction, and Synthesis.—An initial thorough review of the medical literature and of current best clinical practices by a panel of 4 experts followed by a consensus conference review, editing, and ultimate approval by the majority of a panel of 28 additional coagulation laboratory experts.

Conclusions.—Consensus recommendations were generated for topics of direct clinical relevance, including (1) defining those patients (and family members) who should (and should not) be tested for FVL; (2) defining the preferred FVL laboratory testing methods; and (3) defining the therapeutic, prophylactic, and management ramifications of FVL testing in affected individuals and their family members. As FVL is currently the most common recognized familial thrombophilia, it is hoped that these recommendations will assist laboratorians and clinicians caring for patients (and families) with this common mutation.
Laboratory Issues in Diagnosing Abnormalities of Protein C, Thrombomodulin, and Endothelial Cell Protein C Receptor
Authors: Kottke-Marchant Kandice , Comp Philip
Published: January 2021

Objective.—To review the current understanding of the pathophysiology of protein C deficiency and its role in congenital thrombophilia. Recommendations for diagnostic testing for protein C function and concentration, derived from the medical literature and consensus opinions of recognized experts in the field, are included, specifying whom, how, and when to test. The role of related proteins, such as thrombomodulin and endothelial protein C receptor, is also reviewed.

Data Sources.—Review of the published medical literature.

Data Extraction and Synthesis.—A summary of the medical literature and proposed testing recommendations were prepared and presented at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After discussion at the conference, consensus recommendations presented in this manuscript were accepted after a two-thirds majority vote by the participants.

Conclusions.—Protein C deficiency is an uncommon genetic abnormality that may be a contributing cause of thrombophilia, often in conjunction with other genetic or acquired risk factors. When assay of protein C plasma levels is included in the laboratory evaluation of thrombophilia, a functional amidolytic protein C assay should be used for initial testing. The diagnosis of protein C deficiency should be established only after other acquired causes of protein C deficiency are excluded. A low protein C level should be confirmed with a subsequent assay on a new specimen. Antigenic protein C assays may be of benefit in subclassification of the type of protein C deficiency. The role of thrombomodulin and endothelial cell protein C receptor in thrombosis has yet to be clearly established, and diagnostic testing is not recommended at this time.
A Review of the Technical, Diagnostic, and Epidemiologic Considerations for Protein S Assays
Authors: Goodwin Andrew J. , Rosendaal Frits R. , Kottke-Marchant Kandice , Bovill Edwin G.
Published: January 2021

Objectives.—To review the state of the art relating to protein S deficiency as a risk factor for thrombosis and to make recommendations regarding the use of protein S measurements in the assessment of thrombotic risk in individual patients and families.

Data Sources, Extraction, and Synthesis.—Selection criteria were developed for the inclusion of publications from 1985 to 2001 based on the relevant literature concerned with the systematic review of diagnostic tests. Minimal selection criteria were agreed on and the articles stratified into level 1 if they met these criteria and level 2 if they did not meet these criteria. The included articles were reviewed by the authors and abstracted onto predetermined data collection forms. These forms were then scored and recommendations based on level 1 studies. As described elsewhere, results of discussions at the College of American Pathologists Conference XXXVI on Diagnostic Issues in Thrombophilia were used to revise the manuscript into its final form.

Conclusions.—Consensus was reached on 16 recommendations for the use of protein S assays in the assessment of thrombotic risk in individuals and families. Two themes run through the conclusions. First, protein S assays are the most technically problematic of the assays reviewed at this conference. Second, only 2 papers evaluating the diagnostic use of protein S assays met our level 1 inclusion criteria. These 2 problems point out the need for better standardized assays and rigorous studies of the diagnostic utility of these assays.
Factor XIII Polymorphisms and Venous Thromboembolism
Authors: Francis Charles W.
Published: January 2021

Objective.—To review the relationship between factor XIII polymorphisms and venous thromboembolism.

Methods.—Review of the medical literature using computerized databases and secondary sources identified through reviews of bibliographies.

Data Synthesis.—Plasma factor XIII is the precursor of a transglutaminase that cross-links fibrin, thereby altering its properties, including resistance to fibrinolysis. It is, therefore, biologically plausible that alterations in factor XIII activity could affect thrombosis risk. There are 4 common polymorphic forms of factor XIII that differ among ethnic groups. The Val34Leu polymorphism results in an amino acid change near the thrombin cleavage site that may alter the rate of activation. Several case-control studies have investigated the relation of the Val34Leu polymorphism to venous thromboembolism. Some have shown a potentially protective effect of this polymorphism, but the association is not consistent.

Conclusion.—Evidence is conflicting regarding the association of the factor XIII Val34Leu polymorphism with risk of venous thromboembolism, and further studies are needed before screening for this polymorphism can be recommended for evaluation of thrombophilia.
Elevated Hemostatic Factor Levels as Potential Risk Factors for Thrombosis
Authors: Chandler Wayne L. , Rodgers George M. , Sprouse Jason T. , Thompson Arthur R.
Published: January 2021

Objectives.—To review the state of the art relating to elevated hemostatic factor levels as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of specific measurements of hemostatic factor levels in the assessment of thrombotic risk in individual patients.

Data Sources.—Review of the medical literature, primarily from the last 10 years.

Data Extraction and Synthesis.—After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the conference. Recommendations were accepted if a consensus of the 27 experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form.

Conclusions.—Consensus was reached on 8 recommendations concerning the use of hemostatic factor levels in the assessment of thrombotic risk in individual patients. Detailed discussion of the rationale for each of these recommendations is presented in the article. This is an evolving area of research. While routine use of factor level measurements is not recommended, improvements in assay methodology and further clinical studies may change these recommendations in the future.
Platelet Count Monitoring and Laboratory Testing for Heparin-Induced Thrombocytopenia
Authors: Warkentin Theodore E.
Published: January 2021

Objective.—Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that paradoxically is associated with a brief but dramatically increased risk for thrombosis (transient acquired thrombophilia). The objective of this article is to provide practical recommendations for platelet count monitoring in patients receiving heparin, as well as for selection of laboratory assays to detect pathogenic HIT antibodies.

Study Selection.—Relevant literature that focused on frequency and timing of HIT in various clinical settings and that dealt with laboratory testing for HIT antibodies was critically appraised.

Data Extraction and Synthesis.—The author prepared a preliminary manuscript including recommendations that was presented to participants at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia (November 10, 2001). Support of at least 70% of conference participants was required for recommendations to be adopted.

Conclusions.—The risk of immune HIT varies depending on the type of heparin (unfractionated heparin greater than low-molecular-weight heparin) and patient population (surgical greater than medical). Thus, the intensity of platelet count monitoring should be stratified depending on the clinical situation. Platelet count monitoring should focus on the period of highest risk (usually days 5 to 10 after starting heparin) and should use an appropriate platelet count baseline (generally, the highest platelet count beginning 4 days after start of heparin). However, earlier platelet count monitoring is appropriate if the patient received heparin within the past 100 days, as already circulating HIT antibodies can cause rapid-onset HIT with heparin reexposure. Although both antigen and (washed platelet) activation assays are very sensitive for detecting clinically significant HIT antibodies, activation assays have greater diagnostic specificity for clinical HIT.
Trophoblast Apoptosis in Human Placenta at Term as Detected by Expression of a Cytokeratin 18 Degradation Product of Caspase
Authors: Austgulen Rigmor , Chedwick Lisa , Isaksen Christina Vogt , Vatten Lars , Craven Catherine
Published: January 2021

Context.—Apoptosis occurs in the normal placenta. The monoclonal antibody M30 is directed against a novel epitope of cytokeratin 18 (CK18) that is formed by caspase cleavage early in the apoptotic cascade, and this antibody may therefore be useful for evaluating trophoblast apoptosis.

Objective.—We undertook the present study to evaluate the use of monoclonal antibody M30 to assess trophoblast apoptosis in placenta at term.

Methods.—We stained paraffin-embedded placental tissues from 15 deliveries at term with M30. We compared positive M30 staining and CK18 staining (as detected by a monoclonal antibody directed against CK18) of trophoblasts in serial slides. We also compared apoptotic rates as detected by M30 and TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling) in 7 of the placentas.

Results.—In fields of villous tissue, most M30-positive cells were CK18-positive syncytiotrophoblasts. Approximately half of M30-positive cells occurred as focal positive staining in the syncytial layer, and half occurred as abundant staining of syncytiotrophoblasts in areas with increased intervillous or perivillous fibrinoid. We found very few M30-positive cells in villous stroma. In decidual/basal plate tissues, most (two thirds) of the M30-positive cells were CK18-positive extravillous trophoblasts, whereas one third were syncytiotrophoblasts of anchoring villi. Since TUNEL detects apoptosis in both epithelial and nonepithelial cells, more cells were positively stained with TUNEL than with M30 in some tissue fields. However, our observations suggest that M30 was more sensitive than TUNEL in recognizing apoptotic trophoblasts and had less nonspecific staining than TUNEL.

Conclusion.—We recommend the use of monoclonal antibody M30 for apoptosis studies in placental tissues. This antibody is easy to handle, the staining obtained seems specific, and the nonspecific staining seems negligible.
Positive Predictive Value of a Point-of-Care Testing Strategy on First-Draw Specimens for the Emergency Department–Based Detection of Acute Coronary Syndromes
Authors: Kratz Alexander , Januzzi James L. , Lewandrowski Kent B. , Lee-Lewandrowski Elizabeth
Published: January 2021

Context.—The rapid and accurate diagnosis of the etiology of chest pain is of central importance in the triage of patients presenting to emergency departments. The “first-draw” sensitivity of serum cardiac markers is known to be low on initial presentation; however, less is understood regarding the predictive value of a positive test in this situation.

Objective.—To determine the ability of a critical pathway combining medical history and physical examination, electrocardiographic findings, point-of-care testing, and central laboratory data to accurately predict the presence of acute coronary ischemia.

Methods.—We investigated the positive predictive value of a testing algorithm for first-draw specimens in clinical practice, combining a qualitative, point-of-care, triple-screen testing panel for cardiac markers, including myoglobin, creatine kinase–MB, and cardiac troponin I, with confirmation of the rapid assay in the central hospital laboratory by quantitative assays for creatine kinase–MB and cardiac troponin T.

Results.—While a positive result on any of the individual cardiac markers of the point-of-care test had a positive predictive value for the acute coronary syndrome of only 36% (creatine kinase–MB, 41%; myoglobin, 36%; and troponin I, 65%), the positive predictive value for the diagnosis of acute coronary syndrome increased to 76% if all 3 point-of-care markers were simultaneously positive. The positive predictive value for acute coronary syndrome for a positive confirmatory result in the hospital laboratory for either creatine kinase–MB or cardiac troponin T was 61%. Among those patients with a positive marker on both the point-of-care test and the laboratory test, a careful retrospective review of the clinical history (with exclusion of patients with nonischemic cardiac pathologies and renal insufficiency) increased the positive predictive value of this algorithm to 98%.

Conclusions.—Our data suggest that qualitative, point-of-care, triple-screen cardiac marker testing of patients with chest pain at initial presentation may exhibit relatively low positive predictive values. Positive predictive value can be significantly improved by rapid confirmation in the hospital laboratory and careful review of clinical findings.
Evaluation of a Dual Hemoglobin A2/A1c Quantitation Kit on the Bio-Rad Variant II Automated Hemoglobin Analyzer
Authors: Lafferty John D. , McFarlane Andrew G. , Chui David H. K.
Published: January 2021

Context.—Quantitation of hemoglobin (Hb) A1c and investigation of hemoglobinopathy on the Bio-Rad Variant analyzers require a switch between 2 separate kits that is time consuming and causes errors.

Objective.—Evaluation of a new Variant II HbA2/HbA1c Dual kit capable of both Hb A1c quantitation and hemoglobinopathy investigation on a single kit.

Design.—We evaluated Hb A1c, Hb A2, and Hb F quantitation for precision, linearity, and correlation with current methodology. We also evaluated detection of Hb variants and correlation of Hb Barts quantitation.

Setting.—Hamilton Regional Laboratory Medicine Program, Provincial Hemoglobinopathy Laboratory, St Joseph's Healthcare Site, Hamilton, Ontario.

Patients.—Patient blood samples submitted for Hb A1c quantitation or hemoglobinopathy investigation.

Main Outcome Measures.—Precision, linearity, linear regression, and reference interval validation.

Results.—We provide tables and figures illustrating precision, linearity, linear regression, and quantitation of Hb variants. We validated reference intervals for Hb A1c, Hb A2, and Hb F.

Conclusions.—The dual kit provides precise Hb A1c, Hb A2, and Hb F quantitation. The results show good linearity and correlate well with the results of current methods. We detected all clinically important Hb variants and a wide variety of rare variants. The dual kit has several advantages: it eliminates the need for extensive kit switch over; improves utility for newborn screening because of its quantification of Hb Barts; permits quantification of Hb A1c using the β-Thal method; and eliminates the need for separate Hb A2 reference intervals for patients with Hb S because of its accurate quantitation of Hb A2 in the presence of Hb S.
Adult Rhabdoid Renal Cell Carcinoma
Authors: Shannon Beverley , Wisniewski Zdzisilaw Stan , Bentel Jacqueline , Cohen Ronald J.
Published: January 2021

Background.—Pediatric rhabdoid tumor of the kidney is regarded as a distinct neoplasm, whereas rhabdoid differentiation in adult renal cell carcinoma is usually found in association with conventional (clear cell) tumor, from which it is thought to evolve.

Objective.—To further characterize the rhabdoid phenotype in adult renal cell carcinoma and to determine its origin by genetic analysis.

Design.—We performed histologic, immunophenotypic, and genetic analyses on 5 cases of adult renal cell carcinoma with rhabdoid differentiation, 3 samples of adjacent conventional (clear cell) tumor, and 6 conventional (clear cell) control tumors.

Results.—Rhabdoid tumors differed from conventional (clear cell) carcinoma as follows: (1) macroscopically, rhabdoid tumors were solid white uniform masses; (2) microscopically, they had large rhabdoid cells with abundant eosinophilic cytoplasm, reduced lipid content, and the absence of a branching vascular pattern; and (3) biologically, they had a high metastatic potential. Despite these differences, loss of chromosome 3p in both the rhabdoid and clear cell carcinoma samples from 1 patient suggested a clonal origin. An identical mutation of the VHL gene in both rhabdoid and clear cell tumor samples from 2 patients confirmed a clonal origin for the histologically distinct tumor types in those cases.

Conclusion.—Adult rhabdoid renal cell carcinoma can in some cases arise from conventional (clear cell) renal carcinoma and should be considered a clinically important form of renal cell carcinoma separate from, but analogous to, sarcomatoid change.
Parathyroid Gland Involvement by Papillary Carcinoma of the Thyroid Gland
Authors: Tang Weihua , Kakudo Kennichi , Nakamura Yasushi , Nakamura Misa , Mori Ichiro , Morita Shinji , Miyauchi Akira
Published: January 2021

Objective.—To describe the phenomenon of parathyroid gland involvement by thyroid carcinoma and to explore its clinicopathologic significance.

Design.—We reviewed the clinicopathologic features and described the histopathologic characteristics of 20 cases of parathyroid involvement found in a series of 911 papillary thyroid carcinomas.

Results.—Parathyroid involvement occurred in 3 patterns: (1) direct invasion from the main tumor with an infiltrative growth, (2) invasion of the parathyroid gland with an expansive growth and formation of a pseudocapsule between the carcinoma and the parathyroid gland, and (3) metastatic deposition within the parathyroid gland itself. Among the 20 cases, 6 (30%) had primary tumors measuring 1 cm or less, and 14 (70%) had primary tumors measuring more than 1 cm. The cases with smaller primary tumors had a comparatively lower rate of nodal metastasis (50% vs 100%, P = .02). Furthermore, none of the cases with smaller primary tumors had invasion of extrathyroid structures other than parathyroid gland, but such invasion was common among the cases with larger primary tumors (0% vs 71%, P = .01).

Conclusion.—To the best of our knowledge, this is the first report showing that parathyroid involvement occurs in papillary thyroid carcinomas even in the early stage of the disease.
Allergic Transfusion Reactions
Authors: Domen Ronald E. , Hoeltge Gerald A.
Published: January 2021

Context.—Allergic reaction to transfusion is common. However, the review of a large series of allergic transfusion reactions has not been performed.

Objective.—To review a large series of allergic transfusion reactions.

Design.—A retrospective review of all reported and evaluated transfusion reactions during a 9-year period at 1 institution was performed. Associated clinical signs and symptoms were evaluated.

Setting.—Large, tertiary-care teaching hospital.

Results.—A total of 1613 adverse reactions to transfusion were evaluated. Allergic transfusion reactions accounted for 17% (273 of 1613) of the transfusion reactions. Severe allergic reactions (anaphylaxis, anaphylactoid signs and symptoms, and/or hypotension) were observed in 21 patients (7.7% of allergic reactions, or 1.3% of all transfusion reactions). Serum tryptase, a marker for anaphylaxis, was measured in 1 patient and determined to be borderline elevated. Five patients experienced allergic transfusion reactions to autologous red cell transfusions. One patient experienced hives during the transfusion of a major ABO mismatched red blood cell. A wide variety of skin manifestations were observed, but 26 (9.5%) patients did not have skin manifestations. Allergic transfusion reactions were estimated to occur in approximately 1 in 4124 blood components transfused, or 1 in 2338 transfusion episodes. Severe allergic reactions occurred in approximately 1 in 30 281 transfusions. No deaths directly attributable to transfusion were observed in this patient group.

Conclusions.—The clinical presentation of allergic transfusion reactions was quite variable, and the pathophysiology remains unclear. Recommendations for clinical evaluation and therapy remain problematic and often empirical.
The Relationship Between p63 and p53 Expression in Normal and Neoplastic Breast Tissue
Authors: Ribeiro-Silva Alfredo , Ramalho Leandra N. Zambelli , Garcia Sérgio Britto , Zucoloto Sérgio
Published: January 2021

Context.—p63 is a recently described p53 homologue. Despite structural homology, they have different activities.

Objectives.—To obtain new insights into the role of p63 in normal and neoplastic breast tissue and to verify the possible association between p63 and p53 in breast carcinomas.

Design.—Immunohistochemistry in 85 breast carcinomas using p63, smooth muscle actin (1A4), p53, estrogen receptor, and progesterone receptor. The p63-positive cases were submitted to a double-immunolabeling study using p63 with 1A4, cytokeratin 7, and 34βE12. Clinical data were retrieved from medical files.

Results.—p63, like 1A4, stained a single and continuous layer surrounding normal breast ductal and alveolar epithelium. In carcinomas, p53 was expressed in 21.17% of carcinomas, whereas p63 was expressed only in poorly differentiated ductal carcinomas (11.76% of cases). p63-positive cells coexpressed 1A4 and 34βE12, but not cytokeratin 7. Expression of p63 correlated with pathologic staging, tumor size, histologic grading, nodal metastasis, and estrogen receptor negativity.

Conclusions.—p63 is a specific myoepithelial cell marker in normal breast tissue and is expressed in a minority of breast carcinomas, being seen only in grade III ductal carcinomas. In ductal carcinomas, malignant p63-positive cells have an immunophenotype similar to that of myoepithelial cells, suggesting that these cells originate from a primary progenitor cell that underwent divergent differentiation to ductal and myoepithelial cells during clonal expansion. Our study argues against a direct role in mammary tumorigenesis. However, p53 is rarely coexpressed with p63, suggesting that p63 could act indirectly as an oncogene by inhibiting p53. This hypothesis could also explain why p63 correlated with several other indicators of poor prognosis.
Sinus Histiocytosis With Massive Lymphadenopathy and Langerhans Cell Histiocytosis Express the Cellular Adhesion Molecule CD31
Authors: Slone Stephen P. , Fleming Donald R. , Buchino John J.
Published: January 2021

Context.—We investigated expression of the adhesion molecule CD31 in sinus histiocytosis with massive lymphadenopathy (SHML) and Langerhans cell histiocytosis (LCH) because (1) SHML and LCH cells express a variety of cellular adhesion molecules and (2) SHML has been characterized as a reactive histiocytic proliferation, and tissue macrophages (histiocytes) are known to express CD31.

Objective.—The purpose of this study was to determine whether SHML and LCH cells express CD31 and whether dual staining with CD31 and S100 facilitates diagnosis of these disease states.

Methods.—Formalin-fixed, paraffin-embedded archival tissues were immunohistochemically stained via the labeled streptavidin-biotin method using antibodies against CD31 and S100 protein after heat-induced epitope retrieval. Archival tissues included SHML (n = 2), LCH (n = 10), malignant melanoma (n = 5), sinus hyperplasia (n = 4), granulomas (n = 4), granular cell tumor (n = 6), and normal skin (n = 4).

Results.—Normal Langerhans cells in the epidermis were CD31−/S100+; neoplastic Langerhans cells in LCH were CD31+/S100+. Histiocytes in granulomas and in sinus hyperplasia were CD31+/S100−; abnormal histiocytes in SHML were CD31+/S100+. S100+ tumors (malignant melanoma and granular cell tumor) were CD31−.

Conclusions.—The spectrum of cell types that express CD31 is expanded to include SHML and LCH. We speculate that up-regulation of CD31 in neoplastic Langerhans cells contributes to the migratory capability of LCH cells. CD31 may be a useful nonlysosomal marker of macrophages and their neoplastic counterparts (true histiocytic sarcomas). An immunohistochemical staining panel that includes CD31 and S100 facilitates the diagnosis of SHML and LCH.
Effect of Marathon Running on Total and Free Serum Prostate-Specific Antigen Concentrations
Authors: Kratz Alexander , Lewandrowski Kent B. , Siegel Arthur J. , Sluss Patrick M. , Chun Kelly Y. , Flood James G. , Lee-Lewandrowski Elizabeth
Published: January 2021

Context.—Prostate-specific antigen (PSA) is an important tumor marker for the most frequently diagnosed cancer in the United States. A major limitation of this marker is falsely elevated results in patients who are found not to have prostate cancer. The effects of vigorous physical exertion on PSA concentrations are controversial.

Objective.—To determine the effects of marathon running on PSA levels.

Design.—Measurement of total and free PSA levels in the sera of participants in a marathon before and within 4 and 24 hours after the race.

Results.—None of the participants had elevated total PSA levels before the race. Although we found no statistically significant changes in average total or free PSA concentrations at either time point, after the marathon, 2 (11%) of 18 runners had total PSA concentrations outside the standard reference range. Changes in total PSA levels did not correlate with age or prerace PSA concentrations. Free PSA levels were not statistically significantly changed after the race and did not allow a reliable determination of exercise-induced PSA elevations.

Conclusions.—Although it may not be necessary for men to abstain from exercise involving running before blood draws for PSA analysis, elevated PSA concentrations may be observed in some individuals after participation in a major sporting event. In these cases, repeat measurements should be considered at a time significantly removed from such exercise.
Factors Affecting Transfusion of Fresh Frozen Plasma, Platelets, and Red Blood Cells During Elective Coronary Artery Bypass Graft Surgery
Authors: Covin Randal , O'Brien Maureen , Grunwald Gary , Brimhall Bradley , Sethi Gulshan , Walczak Steven , Reiquam William , Rajagopalan Chitra , Shroyer A. Laurie
Published: January 2021

Context.—The ability to predict the use of blood components during surgery will improve the blood bank's ability to provide efficient service.

Objective.—Develop prediction models using preoperative risk factors to assess blood component usage during elective coronary artery bypass graft surgery (CABG).

Design.—Eighty-three preoperative, multidimensional risk variables were evaluated for patients undergoing elective CABG-only surgery.

Main Outcome Measures.—The study endpoints included transfusion of fresh frozen plasma (FFP), platelets, and red blood cells (RBC). Multivariate logistic regression models were built to assess the predictors related to each of these endpoints.

Setting.—Department of Veterans Affairs (VA) health care system.

Patients.—Records for 3034 patients undergoing elective CABG-only procedures; 1033 patients received a blood component transfusion during CABG.

Results.—Previous heart surgery and decreased ejection fraction were significant predictors of transfusion for all blood components. Platelet count was predictive of platelet transfusion and FFP utilization. Baseline hemoglobin was a predictive factor for more than 2 units of RBC. Some significant hospital variation was noted beyond that predicted by patient risk factors alone.

Conclusions.—Prediction models based on preoperative variables may facilitate blood component management for patients undergoing elective CABG. Algorithms are available to predict transfusion resources to assist blood banks in improving responsiveness to clinical needs. Predictors for use of each blood component may be identified prior to elective CABG for VA patients.
Cost-Effectiveness of Laboratory Testing
Authors: Hernandez James S.
Published: January 2021

Objective.—To illustrate how laboratorians and pathologists must demonstrate accountability for efficiency (how well something is done), effectiveness (what is done), and cost-effectiveness (a proxy for value, in which value equals quality per cost).

Data Sources.—A literature search was conducted, including documents in the National Library of Medicine.

Study Selection.—The literature on cost-effectiveness of laboratory testing was reviewed.

Conclusions.—The demand for proving the value of newer and more expensive medical technologies, including newer medical tests, will increase substantially. Payers, including Medicare, commercial insurers, and employers, will demand accountability and elimination of the abuse and misuse of ineffective testing strategies. Pathologists and laboratorians play a key role in guiding the most cost-effective use of testing strategies, including the judicious use of algorithms.
The Potential Role of Flow Cytometry in the Diagnosis of Small Cell Carcinoma
Authors: Cornfield Dennis , Liu Zach , Gorczyca Wojciech , Weisberger James
Published: January 2021

Context.—Virtually no information exists in the medical literature on the immunophenotyping of small cell carcinoma by flow cytometry. CD56, or neural cell adhesion molecule, is widely expressed by small cell carcinoma and easily measured by flow cytometry.

Objective.—To determine the potential usefulness of flow cytometry in the diagnosis of small cell carcinoma.

Design and Setting.—Retrospective data and archival material on 27 patients were obtained from community hospitals. Specimens (needle aspirations and tissue biopsies) from all patients demonstrated cytomorphologic and flow cytometric features consistent with small cell carcinoma. All measurements were performed at a large reference laboratory. Routine 3- and 4-color flow cytometry using a lymphoma antibody panel, including anti-CD56, was performed. Anti-cytokeratin antibody was also used in the last 12 cases. Immunohistochemical staining with a panel of conventional markers for neuroendocrine neoplasms was performed on available tissue for purposes of confirmation of small cell carcinoma.

Patients.—Twenty-seven patients whose tissue specimens showed a clearly defined population of CD45−CD56+ cells by flow cytometry and cytomorphologic features consistent with small cell carcinoma.

Interventions.—Needle aspiration (n = 3) and tissue biopsy (n = 24) from a variety of sites.

Results.—CD56 positivity by flow cytometry was 100 to 1000 times that of the matched isotype control in 25 cases and 10 to 100 times that of the control in 2 cases. Cytokeratin positivity by flow cytometry was found in 12 of 12 cases. Immunohistochemical staining showed positivity for at least 1 cytokeratin and 1 or more neuroendocrine markers in 26 of 27 cases and confirmed the diagnosis of small cell carcinoma.

Conclusions.—Routine flow cytometry can identify a neuroendocrine phenotype that shows a strong correlation with confirmatory immunohistochemical markers in cases exhibiting cytomorphologic features of small cell carcinoma. Flow cytometry appears to complement and may possibly be a satisfactory alternative to immunohistochemical staining when small cell carcinoma is suspected.
Cytokeratin 19 Immunolocalization in Cell Block Preparation of Thyroid Aspirates
Authors: Khurana Kamal K. , Truong Luan D. , LiVolsi Virginia A. , Baloch Zubair W.
Published: January 2021

Context.—Immunohistochemical staining for cytokeratin 19 (CK-19) is a useful ancillary technique for diagnosing papillary thyroid carcinoma (papillary carcinoma) in histologic specimens. Although similar results have been obtained on aspirate smears, to our knowledge the utility of CK-19 immunolocalization in cell block preparations as an adjunct to fine-needle aspiration diagnosis of papillary carcinoma has not been examined.

Objective.—The purpose of this study was to determine whether CK-19 immunostaining of cell block preparations of thyroid aspirates is a useful ancillary technique for diagnosing papillary carcinoma.

Materials and Methods.—Using a monoclonal antibody to CK-19 and a standard avidin-biotin complex technique, immunostaining was performed on paraffin-embedded cell blocks of 57 cases with the following cytologic diagnoses: (a) papillary carcinoma (20 cases); (b) atypical cytology, cannot exclude papillary carcinoma (19 cases); and (c) nonneoplastic thyroid (18 cases). The staining reaction in each case was graded on the basis of percentage of epithelial cells stained (1+, <10%; 2+, <10%–50%; 3+, >50). Tissue follow-up was available in all cases.

Results.—Nineteen (95%) of 20 cases with an unequivocal diagnosis of papillary carcinoma were positive for CK-19 (3+). Tissue follow-up confirmed papillary carcinoma in all 20 cases. Of the 19 cases with a diagnosis of atypical cytology, cannot exclude papillary carcinoma, 7 (37%) cases displayed 3+ immunostaining and subsequent excision confirmed papillary carcinoma in all 7 cases. The remaining 12 cases with 1+ immunostaining included surgically confirmed goiter (6 cases), adenoma (2 cases), lymphocytic thyroiditis (3 cases), and papillary carcinoma (1 case). The follicular cells in 18 cases with a cytologic diagnosis of nonneoplastic thyroid showed 1+ immunostaining. Histologic follow-up of these cases confirmed the nonneoplastic cytologic diagnoses.

Conclusions.—Cytokeratin 19 immunostaining of cell block preparations of thyroid aspirates serves as a useful tool for the diagnosis of papillary carcinoma. Strong immunostaining (3+) for CK-19 aids in accurate diagnosis of malignancy in cytomorphologically equivocal cases of papillary carcinoma.
Molecular Monitoring of Cerebrospinal Fluid Can Predict Clinical Relapse in Acute Lymphoblastic Leukemia With Eosinophilia
Authors: Nuñez Cesar A. , Zipf Theodore F. , Roberts W. Mark , Medeiros L. Jeffrey , Hayes Kimberly , Bueso-Ramos Carlos E.
Published: January 2021

In a patient with precursor B-cell acute lymphoblastic leukemia (ALL) associated with eosinophilia that completely responded to induction chemotherapy, we assayed serial remission cerebrospinal fluid and bone marrow specimens for minimal residual disease using a quantitative polymerase chain reaction assay to assess for clone-specific immunoglobulin heavy-chain gene cluster (IGH) gene rearrangement. Cerebrospinal fluid eosinophilia and minimal residual disease were detected on day 406, preceding the morphologic diagnosis of central nervous system relapse on day 578. By day 841, the bone marrow had 35% blasts. Despite aggressive therapy, including unrelated umbilical cord blood transplantation, the patient developed testicular and bone marrow relapses and died of disease. We conclude that increasing levels of minimal residual disease in cerebrospinal fluid can predict recurrence of ALL prior to clinical and morphologic relapse. Furthermore, we demonstrate a novel translocation in this tumor, the t(5;9)(q31;p24), that possibly led to fusion of the interleukin-3 (IL3) (5q31) and JAK2 (9p24) genes and may explain the concomitant appearance of eosinophilia and ALL.
Comparative Analysis of Conventional Papanicolaou Tests and a Fluid-Based Thin-Layer Method
Authors: Limaye Anjali , Connor Amsy J. , Huang Xiaohua , Luff Ronald
Published: January 2021

Context.—A fluid-based, direct-to-vial method of thin-layer gynecologic cytology (ThinPrep Pap Test) is reported to be more effective than the conventional Papanicolaou test in the detection of squamous intraepithelial lesions.

Objective.—This retrospective analysis evaluated the validity of the findings on the thin-layer method using case material at a large independent laboratory and represented a comparison of performance of both methods over an identical period.

Methods.—Data for conventional and ThinPrep tests were compared for 2 periods. Period 1 included 1 421 080 conventional and 56 835 ThinPrep specimens, and period 2 included 564 270 conventional and 109 784 ThinPrep specimens. Squamous intraepithelial lesions were used to determine detection of disease. These 2 sets of data were also analyzed to eliminate effects of any selection bias toward ThinPrep for high-risk patients.

Results.—Use of ThinPrep showed a greater than 100% increase in the detection rate of squamous intraepithelial lesions (1.3%–3.4% in period 1 and 1.3%–2.9% in period 2), which was statistically significant after correcting for selection bias. We also found a significant decrease in the false-negative proportion (57% in period 1 and 35% in period 2). There was a marked improvement (233%) in the detection of high-grade squamous intraepithelial lesions in high-risk cases and a decrease in the atypical squamous cells of undetermined significance to squamous intraepithelial lesion ratio from 3.1 to 1.5 in period 2.

Conclusion.—ThinPrep is better than the conventional Papanicolaou test in detecting squamous intraepithelial lesions and is a superior screening test in detection of precancerous changes of the cervix.
Expression of p53, c-Myc, or Bcl-6 Suggests a Poor Prognosis in Primary Central Nervous System Diffuse Large B-Cell Lymphoma Among Immunocompetent Individuals
Authors: Chang Chung-Che , Kampalath Bal , Schultz Christopher , Bunyi-Teopengco Ellen , Logan Brent , Eshoa Camellia , Dincer Ayse P. , Perkins Sherrie L.
Published: January 2021

Context.—Primary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) in immunocompetent individuals, although rare, has been rising in incidence. Currently, no reliable prognostic markers are available for these individuals.

Objective.—To study the implications of expression of a panel of oncogenic proteins (Bcl-2, Bcl-6, and c-Myc) and p53 for predicting clinical outcome, particularly overall survival, in immunocompetent individuals with primary CNS DLBCL.

Design.—Fourteen primary CNS DLBCL cases were retrospectively studied by immunohistochemistry on formalin-fixed, paraffin-embedded sections for the expression of c-Myc, Bcl-2, Bcl-6, and p53.

Results.—The overall frequencies of expression for p53, c-Myc, Bcl-2, and Bcl-6 in these cases were 29%, 50%, 71%, and 57%, respectively. Cases with expression of p53, c-Myc, or Bcl-6 had a poorer overall survival than those without (Kaplan-Meier survival analysis: 50% cumulative overall survival, 2 months vs 30–60 months, P = .02, log-rank test; 9–16 months vs 21–60 months, P = .03, log-rank test; and 9–16 months vs 21–60 months, P = .16, log-rank test, respectively). The expression of Bcl-2 or proliferation activity by MIB-1 showed no correlation with overall survival. Likewise, the clinical parameters, including age, location of tumors, multiplicity of tumor lesions, and lactase dehydrogenase levels revealed no impact on overall survival.

Conclusion.—Our results suggest that patients with expression of p53, c-Myc, or Bcl-6 have a poorer overall survival than those without. Since traditional prognostic markers in non-CNS DLBCL, such as staging and International Prognostic Index scores, are not applicable to primary CNS DLBCL, evaluation of p53, c-Myc, and Bcl-6 by immunohistochemistry may be warranted as part of prognostic evaluation in immunocompetent patients with primary CNS DLBCL. Further studies are indicated to confirm our observations.
A Microdissection and Molecular Genotyping Assay to Confirm the Identity of Tissue Floaters in Paraffin-Embedded Tissue Blocks
Authors: Hunt Jennifer L. , Swalsky Patricia , Sasatomi E. , Niehouse Laura , Bakker Anke , Finkelstein Sydney D.
Published: January 2021

Context.—A recurring problem in surgical pathology practice is specimen mix-up and floater contamination. While many cases can be resolved histologically, a significant number remain unclear and may have serious clinical and medicolegal implications.

Objectives.—To design a microdissection and genotyping assay to identify contaminating floater tissues in paraffin-embedded tissues that is optimized for small samples, and to use the assay to resolve a series of clinical cases with floater tissues.

Materials and Methods.—Twenty-one cases of possible tissue floater contamination in paraffin-embedded tissue blocks were included. Using 4 unstained, 4-μm-thick histologic sections, multiple sites were microdissected under direct visualization either by hand or by laser capture microdissection. Nonneoplastic and neoplastic tissues were sampled. Polymerase chain reaction was performed for a panel of 10 polymorphic microsatellite markers at 1p34, 3p26, 5q21, 9p21, 10q23, and 17p13. Allele size and content were analyzed semiquantitatively by fluorescent capillary electrophoresis, and the genotypes for the tissues in the paraffin-embedded tissue blocks were compared for identity.

Results.—Tissue identification was successful in all cases, despite small tissue sample size and fixation effects. Comparative analysis of neoplastic tissue floaters and the presumptive source tumor was performed when possible to control for possible allelic loss or microsatellite instability.

Conclusions.—Microdissection and genotyping are effective and reliable means to objectively resolve problems of possible floater contamination. Even minute tissue samples provide sufficient DNA template for polymerase chain reaction microsatellite analysis. Because of the potential clinical implications of floaters, we recommend that all suspected floaters that would change a diagnosis from benign to malignant be subjected to genotyping assay to confirm the identity of the floater tissue.
Human Parainfluenza Virus Giant Cell Pneumonia Following Cord Blood Transplant Associated With Pulmonary Alveolar Proteinosis
Authors: Butnor Kelly J. , Sporn Thomas A.
Published: January 2021

Giant cell pneumonia secondary to human parainfluenza virus 3 has been reported only rarely in immunocompromised hosts. The few cases documented after bone marrow transplant have resulted in significant morbidity and mortality. To our knowledge, this entity has not been described following umbilical cord blood transplant. Pulmonary alveolar proteinosis, a rare condition that has been reported with increasing frequency in association with immunocompromise and infections, has not been documented in the setting of either umbilical cord blood transplant or human parainfluenza viral infection. We report what we believe is the first documented case of giant cell pneumonia caused by human parainfluenza virus 3 in an umbilical cord blood transplant recipient. To our knowledge, a unique associated feature of this case, a pulmonary alveolar proteinosis–like reaction, has not been reported previously in association with human parainfluenza virus pneumonia.
Flow Cytometric Analysis of Acute Leukemias
Authors: Kaleem Zahid , Crawford Eric , Pathan M. Hanif , Jasper Leah , Covinsky Michael A. , Johnson Lawrence R. , White Glenda
Published: January 2021

Context.—Acute leukemia displays characteristic patterns of surface antigen expression (CD antigens), which facilitate their identification and proper classification and hence play an important role in instituting proper treatment plans. In addition to enzyme cytochemical analysis, multiparameter flow cytometric analysis has become commonplace in most laboratories for that purpose. The essential role and caveats of flow cytometry in that regard, however, have received little scrutiny.

Objective.—To evaluate the expression of commonly used immunomarkers and patterns in various acute leukemias to help define the best use and role of multiparameter flow cytometry in the diagnosis and proper classification of acute leukemias.

Design.—We have retrospectively analyzed the immunophenotypic data from 508 de novo adult and pediatric acute leukemia patients, as studied using multiparameter flow cytometry in addition to routine morphologic and enzyme cytochemical analysis. Cytogenetic and/or molecular data were correlated in all 41 cases of acute promyelocytic leukemia (APL) and in 203 other cases of acute leukemia where those data were available. We have also determined the positive and negative predictive values of a combined CD34 and HLA-DR expression pattern for the differentiation of APL from other myeloid leukemias.

Results.—In acute myeloid leukemia (AML) other than APL, expression of CD34 was seen in 62% and expression of HLA-DR in 86% of all cases. Twenty-six (10%) of 259 cases of non-APL AML were negative for both CD34 and HLA-DR as opposed to 33 (80%) of 41 cases of APL. None of the cases of APL were positive for both CD34 and HLA-DR in contrast to 149 (58%) of 259 cases of non-APL AML. Fifty-three cases were found to be examples of minimally differentiated AML (AML M0) based on the lack of expression of cytoplasmic CD3 and cytoplasmic CD79a and expression of one or more myelomonocytic-associated antigens and/or myeloperoxidase. Expression of CD20 was seen in 40 (24%) of 168 cases of precursor B-cell acute lymphoblastic leukemia (pB-ALL) and 52 (29%) lacked CD34 expression. Five of 180 cases of pB-ALL and 2 cases of precursor T-cell ALL (pT-ALL) were negative for terminal deoxynucleotidyl transferase (TdT). Aside from cytoplasmic CD3, CD5 and CD7 were the most sensitive antigens present in all 21 cases of pT-ALL. CD33 was more sensitive but less specific than CD13 for myeloid lineage.

Conclusion.—Aside from identification of blasts, flow cytometry was found to be especially useful in the correct identification of AML M0, differentiation of APL from AML M1/M2, and correct identification of TdT-negative ALL and unusual variants, such as transitional B-cell ALL and undifferentiated and biphenotypic acute leukemias.