bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoplasia Without Dysplasia: Lessons From Barrett Esophagus and Other Tubal Gut Neoplasms
Authors: Odze Robert D. , Maley Carlo C.
Published: February 2021

Context.—Classic pathology teaching emphasizes that neoplastic lesions of the gastrointestinal tract are characterized by architectural and cytologic abnormalities that distinguish it from normal tissue. Recent studies suggest that many important—and in some cases clonal—molecular abnormalities that lead to dysregulation of cell proliferation and differentiation (neoplasia) occur before morphologic expression of dysplasia.

Objective.—To summarize the biologic and pathologic features of preneoplastic conditions of the tubal gut that reveal evidence of neoplastic alteration, but without the traditional morphologic features of dysplasia, in order to provide guidance on how to identify these lesions. Particular attention is given to Barrett esophagus, a chronic inflammatory condition in which early molecular and morphologic events that drive carcinogenesis are best understood.

Data Sources.—Selected references and abstracts were obtained by a PubMed (US National Library of Medicine) search by using the search headings neoplasia, preneoplasia, dysplasia, adenoma, serrated polyps, and Barrett's esophagus between the years 1980 and 2009.

Conclusions.—Many types of lesions throughout the tubal gut fulfill the most basic and classic principles of a neoplastic precursor lesion but lack conventional morphologic evidence of dysplasia and/or maintain the capacity for cell differentiation and maturation. All of these lesions, such as squamous dysplasia of the esophagus, dysplasia in Barrett esopahagus, and hyperplastic/serrated polyps of the colon, represent early neoplastic precursor lesions but without conventional histologic features of dysplasia. It is important for pathologists to be aware of these lesions, both for diagnostic and prognostic purposes, but also so that future studies can be performed with regard to risk stratification of patients.
Recommendations for Validating Estrogen and Progesterone Receptor Immunohistochemistry Assays
Authors: Fitzgibbons Patrick L. , Murphy Douglas A. , Hammond M. Elizabeth H. , Allred D. Craig , Valenstein Paul N.
Published: February 2021

Context.—Estrogen receptor and progesterone receptor status is assessed on all newly diagnosed, invasive breast carcinomas and in recurrences to determine patient eligibility for hormonal therapy, but 10% to 20% of estrogen receptor and progesterone receptor test results are discordant when tested in multiple laboratories.

Objective.—To define the analytic (technical) validation requirements for estrogen receptor and progesterone receptor immunohistochemistry assays used to select patients for hormonal therapy.

Data Sources.—Literature review and expert consensus.

Conclusions.—A standardized process for initial test validation is described. We believe adoption of this process will improve the accuracy of hormone-receptor testing, reduce interlaboratory variation, and minimize false-positive and false-negative results. Required ongoing assay assessment procedures are also described.
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Unabridged Version)
Authors: Hammond M. Elizabeth H. , Hayes Daniel F. , Dowsett Mitch , Allred D. Craig , Hagerty Karen L. , Badve Sunil , Fitzgibbons Patrick L. , Francis Glenn , Goldstein Neil S. , Hayes Malcolm , Hicks David G. , Lester Susan , Love Richard , Mangu Pamela B. , McShane Lisa , Miller Keith , Osborne C. Kent , Paik Soonmyung , Perlmutter Jane , Rhodes Anthony , Sasano Hironobu , Schwartz Jared N. , Sweep Fred C. G. , Taube Sheila , Torlakovic Emina Emilia , Valenstein Paul , Viale Giuseppe , Visscher Daniel , Wheeler Thomas , Williams R. Bruce , Wittliff James L. , Wolff Antonio C.
Published: February 2021

Purpose.—To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers.

Methods.—The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.

Results.—Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria.

Recommendations.—The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
Pathology Practice in a Resource-Poor Setting: Mwanza, Tanzania
Authors: Rambau Peter F
Published: February 2021

Practicing pathology in a resource-poor setting presents many challenges that are unfamiliar to pathologists in developed countries. Typically, the number of pathologists in a resource-poor country is small, even as a percentage of the total medical workforce. Although pathology should play a central role in the delivery of appropriate health care to the patient, this role is often hidden and not well recognized by patients, clinical colleagues, or other stakeholders, such as administrators and politicians. The public tends to think of the pathologist as the “Doctor of the Dead.” The financial rewards are also small. Consequently, it is difficult to recruit physicians into pathology. The lack of human and material resources allocated to pathology leads inevitably to a large gap in health care for many patients, with an unmeasured negative effect, at both the individual and societal levels. Correct management of the patient, even when available, is not administered because of the lack of pathologic information. Surgery may be performed without the benefit of preoperative or postoperative pathologic confirmation of the diagnosis, let alone identification of important prognostic information. The pathologist plays a key role as an educator in developing countries to medical students, allied health professionals, and medical colleagues and is, therefore, called upon to provide many hours of teaching. The pathologist is uniquely qualified to provide knowledge and understanding regarding the diseases in the region where he or she practices. Although many of these challenges are universal, they are perhaps nowhere more acute than in resource-poor settings.
Cytopathology Including Fine-Needle Aspiration in Sub-Saharan Africa: A Cameroon Experience
Authors: Guggisberg Kelly , Okorie Chukwudi , Khalil Moosa
Published: February 2021

Context.—Surgical pathology is unavailable in most of sub-Saharan Africa because of equipment costs and lack of expertise. Cytopathology is an inexpensive and reliable alternative.

Objective.—To explore the utility of cytopathology in a rural hospital setting in Africa.

Design.—A cytopathologist and a pathology resident from Calgary, Alberta, Canada, went to Cameroon to provide a cytopathology service at the Banso Baptist Hospital. Both performed the fine-needle aspiration procedures. Direct smears were fixed in alcohol and stained with hematoxylin-eosin. Surgical specimens subsequently obtained from the patients were processed and reported at Calgary Laboratory Services, Canada. The histopathologic diagnoses were the gold standard for determining the accuracy of the cytologic diagnoses.

Results.—Fifty-nine patients were examined during a 5-week period, 33 females (56%) and 26 males (44%). Sixteen (27%) were known to be HIV positive. Forty-four fine-needle aspiration procedures were performed for 43 patients (73%). The cost of each procedure was approximately US $10. Head and neck and breast were the sites most frequently sampled for aspirates. Cervical smears from 5 patients were also assessed, as were 8 fluid specimens and 2 touch preparations of prostatic core biopsies. The most frequent diagnoses for malignancy were carcinoma and lymphoma. Tuberculous lymphadenitis was diagnosed in 6 patients, 4 of whom were HIV positive. Surgical specimens were received from 18 patients (30%). Cytohistologic and clinicopathologic correlation revealed 1 false-positive (1.6%) and 1 false-negative (1.6%) diagnosis.

Conclusion.—Cytopathology is a reliable alternative for tissue diagnosis in low-resource settings.
Malaria in Malawi: Inside a Research Autopsy Study of Pediatric Cerebral Malaria
Authors: White Valerie A
Published: February 2021

Context.—Malaria is still a major cause of death in sub-Saharan Africa.

Objectives.—To describe my participation as a pathologist in a research autopsy study in Malawi and to examine retinal pathologic findings in cerebral malaria and correlate them with those in the brain. To describe the challenges of conducting a research study in sub-Saharan Africa and the personal and scientific benefits resulting from this.

Design.—Children with coma are admitted to the pediatric research ward, classified according to the clinical definition of severe malaria or another cause of coma, evaluated, and treated systematically. The eyes are examined by indirect ophthalmoscopy after dilatation. If a child dies and permission is given, a standardized autopsy is carried out. The patients' condition is then reclassified pathologically.

Results.—Ninety autopsies have been completed, with the cause of death confirmed as cerebral malaria in 64 cases (71.1%). These patients showed heavy parasite sequestration and often extravascular pathologic findings in the brain, retina, gastrointestinal tract, and subcutaneous fat. Clinical and pathologic findings in the retina correlated with those in the brain, and ophthalmoscopy has become a useful tool in the diagnosis and prognosis of children with cerebral malaria. Twenty-eight percent of patients clinically classified as having cerebral malaria showed another cause of death and no malarial pathologic process or retinopathy.

Conclusions.—The human, financial, and transportation resources and organization required for this autopsy project are substantial. The scientific benefits are now becoming evident after sufficient autopsies have been completed for detailed comparisons. Personal benefits include the opportunity to work and travel in an African setting and to develop collaborations world-wide.
External Quality Assurance of Antithrombin, Protein C, and Protein S Assays: Results of the College of American Pathologists Proficiency Testing Program in Thrombophilia
Authors: Cunningham Mark T , Olson John D , Chandler Wayne L , Van Cott Elizabeth M , Eby Charles S , Teruya Jun , Hollensead Sandra C , Adcock Dorothy M , Allison Paul M , Kottke-Marchant Kandice K , Smith Marc D
Published: February 2021

Context.—Hereditary and acquired deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. Proper diagnosis requires high-quality assays for these proteins.

Objective.—To determine the accuracy and interlaboratory precision of AT, PC, and PS assays used by laboratories participating in the United States College of American Pathologists proficiency testing program in thrombophilia and to grade the performance of laboratories.

Design.—Standardized normal plasma with assigned analyte values was sent in 2 separate challenges to participating laboratories. Participants measured AT, PC, and PS levels using local methods.

Results.—When compared with the assigned values for the international standard, the order of assay accuracy from highest to lowest was AT activity, PC antigen, AT antigen, total PS antigen, PC activity, PS activity, and free PS antigen (range of assay bias, 2.6%–8.8%). The order of assay precision from highest to lowest was PC activity, AT activity, AT antigen, total PS antigen, PS activity, free PS antigen, and PC antigen (range of assay coefficient of variation, 6.1%–20.0%). Most testing events (87.8%) could be graded as pass or fail using a target range of ±3 standard deviations from the method-specific mean. The pass rate was 98.2% for all AT, PC, and PS testing events combined.

Conclusions.—Accuracy and precision were higher for AT assays and lower for PC and PS assays. It was feasible to grade individual laboratory performance.
The Movat Pentachrome Stain as a Means of Identifying Microcrystalline Cellulose Among Other Particulates Found in Lung Tissue
Authors: Sigdel Saroj , Gemind J. Todd , Tomashefski Joseph F
Published: February 2021

Context.—Microcrystalline cellulose (MCC) is extensively used as a filler material in pharmaceutical tablets. When injected intravenously in aqueous tablet suspensions, MCC may contribute to embolic pulmonary hypertension and be identified histologically in lung tissue samples. In this study, we evaluated a modified Russell Movat pentachrome stain (MMPS) as a means of recognizing MCC and distinguishing it from other birefringent crystals in lung specimens.

Objective.—To study the staining properties of MCC versus other crystalline materials using the MMPS stain.

Design.—Archival, formalin-fixed, paraffin-embedded lung specimens that contained birefringent crystals, including MCC (3 cases of intravenous drug abuse), talc (2 cases of intravenous drug abuse, 1 talc pleurodesis), mixed silicates (1 case of silicate pneumoconiosis), and calcium oxalate (1 case of aspergillosis from Aspergillus niger infection), were evaluated with MMPS. Crystal identification was confirmed by morphology, other histochemical stains, infrared spectroscopy (1 case), and cellulose controls.

Results.—The MMPS stained the MCC bright yellow in tissue and control specimens. Talc stained light greenish-blue; mixed silicates appeared either greenish-blue or unstained. Oxalate crystals stained sea-green. Crospovidone, a nonbirefringent tablet filler substance, stained yellow to dark green with MMPS and was easily distinguished from MCC. Starch granules were unstained by MMPS.

Conclusions.—The MMPS is an excellent method for the histochemical identification of MCC in tissue and its separation from other birefringent crystals with which MCC might be confused. The MMPS is especially useful in the evaluation of pulmonary foreign body embolization in cases of suspected intravenous substance abuse.
Solitary Fibrous Tumor of the Orbit With Epithelioid Features
Authors: Warraich Irfan , Dunn Dale M. , Oliver Jeffrey W.
Published: February 2021

Extrapleural solitary fibrous tumors have often been confused with other mesenchymal tumors, such as hemangiopericytoma, fibrous histiocytoma, fibrous meningioma, and leiomyoma, because of morphologic similarity and underrecognition, especially if some unusual features are present. Recently, epithelioid solitary fibrous tumor has been reported in the mediastinum. We report a case of solitary fibrous tumor of the orbit with biphasic architecture, including spindle cell and epithelioid components. Both components demonstrated immunohistochemical features of a solitary fibrous tumor. A background of scattered vessels was present. No evidence of significant nuclear atypia or mitotic activity was noted. In this report, we discuss the differential diagnosis of solitary fibrous tumor with unusual epithelioid features. Extrapleural solitary fibrous tumor should be included in the differential diagnosis of tumors of the orbit with a spindle cell appearance even in the presence of some epithelioid morphology.
Update on Pancreatic Endocrine Tumors
Authors: Frankel Wendy L.
Published: February 2021

Endocrine tumors of the pancreas represent 1% to 2% of all pancreatic neoplasms. The tumors tend to have an indolent behavior, and long-term survival is common. There is no gender or age predilection. Patients can present with symptoms due to hormonal excess or a local mass effect or be asymptomatic. The tumors tend to be solid and well circumscribed. Typical microscopic findings include an organoid pattern of growth, with cells containing scant to moderate amounts of cytoplasm, and nuclei with dispersed chromatin and inconspicuous nucleoli. The morphologic spectrum of these tumors can be variable, and the differential diagnosis includes chronic pancreatitis with neuroendocrine hyperplasia, ductal adenocarcinoma, solid pseudopapillary tumor, acinar cell carcinoma, and pancreatoblastoma. The classification of these tumors remains controversial, and prognosis is difficult to predict, but important features include metastasis and invasion of adjacent structures. Resection remains the mainstay of surgical treatment. It is important to be aware that unusual morphologic variants of pancreatic endocrine tumors are common, and immunohistochemical stains can help avoid misdiagnosis.
Accuracy and Cost-Effectiveness of Core Needle Biopsy in the Evaluation of Suspected Lymphoma: A Study of 101 Cases
Authors: Lachar Whitney A. , Shahab Imran , Saad A. Joe
Published: February 2021

Context.—Lymphomas have traditionally been diagnosed on excisional biopsies of lymph nodes in order to evaluate tissue architecture and cytomorphology. Recent lymphoma classification schemes emphasize immunophenotypic, genetic, and molecular aspects in addition to morphology as diagnostic features. Core needle biopsies are increasingly being used to obtain tissue for diagnosis in patients with lymphadenopathy and a clinical suspicion of lymphoma. These procedures are rapid, minimally invasive, well tolerated, and may provide some architectural framework (unlike fine-needle aspirations), as well as material for ancillary studies.

Objective.—To explore the accuracy, utility, and cost-effectiveness of this technique.

Design.—Core needle biopsies of 101 consecutive patients from 2 large community hospitals who were suspected of having primary or recurrent lymphomas were retrospectively reviewed. All patients had hematoxylin-eosin–stained sections of needle cores. Specimens morphologically suspicious for lymphoma were subjected to ancillary studies, including immunohistochemistry, flow cytometry, and/or molecular studies. Core needle biopsy diagnoses were correlated with subsequent excisional biopsies, if performed.

Results.—Core needle biopsies established a definitive pathologic diagnosis for the vast majority of cases. A diagnosis was considered sufficient to begin treatment for primary and recurrent lymphomas in most cases. Compared with an open biopsy, there is a cost savings of greater than 75%.

Conclusion.—The accuracy of this technique, along with the cost savings and decreased morbidity, suggest that this method may be used safely and reliably as a first-line diagnostic technique.
The Contribution of Bifunctional SkipDewax Pretreatment Solution, Rabbit Monoclonal Antibodies, and Polymer Detection Systems in Immunohistochemistry
Authors: Wong Sze Chuen Cesar , Chan John K. C. , Lo Elena S. F. , Chan Amanda K. C. , Wong Manson C. K. , Chan Charles M. L. , Lam Money Y. Y. , Chan Anthony T. C.
Published: February 2021

Context.—In immunohistochemistry, nonstandardized antigen retrieval protocols and fluids, poor-quality antibodies, and the presence of endogenous biotin frequently lead to incorrect results. Recently, advanced reagents including bifunctional SkipDewax pretreatment solution (BSPS), rabbit monoclonal (RM) antibodies, and biotin-free polymer detection systems (PDSs) have been developed, which, it is claimed, resolve these problems.

Objectives.—To determine whether BSPS, RM antibodies, and biotin-free PDSs improve the accuracy of immunohistochemistry; to optimize a new protocol consisting of a combination of BSPS, RM antibodies, and PDSs; and to compare it with a conventional protocol.

Design.—The efficacies of BSPS, RM antibodies, and PDSs were compared with those of their respective conventional reagents using multitissue spring-roll sections. The new protocol was compared with a conventional protocol using Ki-67 immunostaining of 49 colorectal carcinoma specimens.

Results.—For antigen retrieval, BSPS resulted in similar or better tissue staining than an EDTA solution, but the efficacy of BSPS decreased when it was reused. Most RM antibodies resulted in a greater proportion of positive cells than the corresponding non-RM antibodies, which did not produce satisfactory results in the absence of antigen retrieval. The PDSs Bond, ChemMate, and SuperPicture resulted in a high percentage of positive cells, good staining intensities, and low backgrounds. Other PDSs, except that from Ventana, resulted in high backgrounds and false positivity. The new combined protocol resulted in better Ki-67 staining than the conventional assay.

Conclusions.—Bifunctional SkipDewax pretreatment solution, RM antibodies, and PDSs improve staining quality and diagnostic accuracy of immunohistochemistry assays and provide a foundation for standardization.
A Proposal on the Identification, Histologic Reporting, and Implications of Intraductal Prostatic Carcinoma
Authors: Cohen Ronald J. , Wheeler Thomas M. , Bonkhoff Helmut , Rubin Mark A.
Published: February 2021

Context.—Prostatic adenocarcinoma growing within acinar-ductal spaces (intraductal carcinoma) in contrast to high-grade prostatic intraepithelial neoplasia (HG-PIN) impacts negatively on patient outcome. There is currently no generally accepted definition of this lesion nor is it classified in the current prostate cancer grading system (Gleason).

Objective.—To define intraductal carcinoma of the prostate (IDC-P) with major and minor diagnostic criteria that clearly separate it from HG-PIN. The implications of such a lesion are discussed with proposals to incorporate this entity into the Gleason grading system.

Data Sources.—We reviewed all published data referring to intraductal spread of prostate carcinoma. Articles discussing endometrial, endometrioid, and ductal carcinoma are included.

Conclusions.—Intraductal carcinoma of the prostate as defined by major criteria that include enlarged gland structures, neoplastic cells spanning the gland lumen, central comedonecrosis, and further supported by minor diagnostic criteria including molecular biological markers, separate this entity from HG-PIN. Despite its perimeter basal cells, IDC-P should be interpreted as biologically equivalent to Gleason pattern 4 or 5 adenocarcinoma. Several hypotheses are proposed as to the evolution of IDC-P, which is almost always a late event in prostate carcinoma progression. Diagnosis of IDC-P on needle biopsy should prompt therapeutic intervention rather than surveillance or repeat biopsy, as is the case for HG-PIN.
Acute Antibody-Mediated Rejection of Renal Transplant: Pathogenetic and Diagnostic Considerations
Authors: Truong Luan D. , Barrios Roberto , Adrogue Horacio E. , Gaber Lillian W.
Published: February 2021

Context.—Acute antibody-mediated rejection (AMR) has emerged recently as an important cause of graft failure.

Objective.—To review the pathogenetic, clinicopathologic, and diagnostic considerations of AMR.

Data Sources.—Review of literature and the authors' experience.

Conclusions.—Acute antibody-mediated rejection is mediated by antibodies specific for donor antigens, which bind to target antigens and activate the complement system, culminating in tissue injury. The clinical manifestation of AMR is not specific, and transplant biopsy is needed for diagnosis. The glomeruli show thrombosis or neutrophils or mononuclear leukocytes in capillary lumens. The tubulointerstitial compartment shows edema, hemorrhage, necrosis, mild inflammation, and neutrophils or mononuclear leukocytes in the peritubular capillary lumens. The blood vessels show thrombosis, thrombotic microangiopathy, fibrinoid necrosis, or transmural vasculitis. Strong staining for C4d in the peritubular capillaries is characteristic. A definitive diagnosis of AMR requires (1) morphologic evidence of acute tissue injury, (2) immunopathologic evidence for antibody action, and (3) serologic evidence of circulating donor-specific antibodies. Acute antibody-mediated rejection should be suspected if some but not all 3 criteria are met. Since effective treatment is currently available, accurate and timely diagnosis of AMR is essential.
Pulmonary Infections in Transplantation Pathology
Authors: Stewart Susan
Published: February 2021

Context.—Pulmonary infections are common and often life-threatening in solid organ and stem cell transplant recipients. Understanding their pathology is critical to making improvements in care and survival as well as in surgical techniques, immunosuppression management, prophylaxis, and treatment. Pulmonary infections are particularly common and serious in the susceptible population of lung transplant recipients.

Objective.—To summarize recent updates in the field for opportunistic infections and some common pathogens, and to consider the role of the diagnostic pulmonary histopathologist as well as advances in molecular diagnosis.

Data Sources.—This work is based on a selected review of the relevant medical and scientific literature, with emphasis on lung transplantation experience gained during 2 decades of practice.

Conclusions.—Pulmonary infections in transplant recipients present a diagnostic challenge and are a continuing source of mortality and morbidity despite improvement in prophylaxis and treatment. Accurate diagnosis requires multidisciplinary input from clinicians, radiologists, and pathology disciplines as well as complementary molecular methods.
Effect of Indian Ayurvedic Medicine Ashwagandha on Measurement of Serum Digoxin and 11 Commonly Monitored Drugs Using Immunoassays: Study of Protein Binding and Interaction With Digibind
Authors: Dasgupta Amitava , Peterson Amanda , Wells Alice , Actor Jeffrey K.
Published: February 2021

Context.—Ashwagandha, a popular Ayurvedic medicine, is now available in the United States. Alkaloids found in this herb have structural similarity with digoxin.

Objective.—To study potential interference of Ashwagandha with serum digoxin measurement by immunoassays. Potential interference was also investigated with immunoassays for 11 other commonly monitored drugs. In addition, interaction of components of Ashwagandha with the Fab fragment of antidigoxin antibody (Digibind) was investigated.

Design.—Two different brands of liquid extract and 1 dry powdered form of Ashwagandha were used for this investigation. Aliquots of drug-free serum were supplemented with various concentrations of Ashwagandha and apparent digoxin concentrations were measured by 3 digoxin immunoassays. Mice were fed with Ashwagandha and apparent digoxin concentrations were measured 1 and 3 hours after feeding. Potential interference of Ashwagandha with immunoassays of 11 other drugs was also investigated. Interaction of components of Ashwagandha with Digibind was studied in vitro.

Results.—Significant apparent digoxin concentrations were observed both in vitro and in vivo using the fluorescence polarization immunoassay of digoxin, whereas the Beckman and the microparticle enzyme immunoassay digoxin assay demonstrated minimal interference. Immunoassays of 11 other drugs tested were unaffected. When Ashwagandha extract was added to a serum pool containing digoxin, falsely elevated digoxin value was observed with fluorescence polarization immunoassay, but values were falsely lowered when measured by the microparticle enzyme immunoassay. Digibind neutralized digoxin-like immunoreactive components of Ashwagandha in vitro.

Conclusions.—Components of Ashwagandha interfered with serum digoxin measurements using immunoassays. Digibind neutralized free digoxin-like immunoreactive components of Ashwagandha.
Expanding the Pathologic Spectrum of Immunoglobulin Light Chain Proximal Tubulopathy
Authors: Kapur Umesh , Barton Kevin , Fresco Raoul , Leehy David J. , Picken Maria M.
Published: February 2021

Context.—In plasma cell dyscrasias, involvement of the distal tubules is frequent and well characterized. In contrast, proximal tubules have only rarely been reported to show diagnostic pathology such as intracytoplasmic crystals.

Objective.—To look for additional morphologic features that might be helpful in the diagnosis of proximal tubulopathy associated with an underlying plasma cell dyscrasia.

Design.—We examined patients presenting with nonspecific renal symptoms who were found to have light chain restriction limited to proximal tubular epithelium by immunofluorescence. We correlated these results with light microscopy, electron microscopy, and the clinical findings.

Results.—By immunofluorescence, 5 patients had light chain restriction in proximal tubular epithelium. By light microscopy, only 1 patient had focal rhomboid crystals in the proximal tubular epithelium; all other biopsies failed to show any discernible pathology within the proximal tubules or elsewhere in the kidney. By electron microscopy, proximal tubules from 2 patients showed crystals with a latticelike structure, whereas the remaining 3 patients had only prominent phagolysosomes. However, by immunoelectron microscopy, the lysosomal content showed light chain restriction (in 2 cases studied). Post–kidney biopsy, all patients were diagnosed with multiple myeloma or plasma cell dyscrasia. One patient developed renal failure and had recurrence of crystals in the allograft.

Conclusions.—Light chain proximal tubulopathy may be associated with the presence of crystals or with the presence of phagolysosomes with light chain restriction as the sole abnormality. Both κ and λ light chains may be involved. The prognosis is variable and the pathology may recur in transplants.
Prognostic Significance of CD44, Platelet-Derived Growth Factor Receptor α, and Cyclooxygenase 2 Expression in Renal Cell Carcinoma
Authors: Tawfik Ossama W. , Kramer Brandan , Shideler Barbara , Danley Marsha , Kimler Bruce F. , Holzbeierlein Jeffrey
Published: February 2021

Context.—Pathologic stage is the main prognostic factor for predicting outcome in renal cell carcinoma (RCC). Because of its unreliability in predicting tumor progression, other factors are needed to provide additional prognostic information.

Objective.—The expression of CD44, cyclooxygenase 2, and platelet-derived growth factor receptor α (PDGFR-α) was evaluated as a potential prognostic factor for survival in patients with RCC.

Design.—Sixty-two patients (42 men and 20 women; median age, 61 years), undergoing partial (10 cases) or radical (55 cases) nephrectomy for RCC were retrospectively analyzed by immunohistochemical analysis for CD44, cyclooxygenase 2, and PDGFR-α expression. Impact of various factors on disease-specific and overall survival was calculated using Cox proportional hazards models.

Results.—There was a gradual increase in CD44 and cyclooxygenase 2 expression with increasing RCC nuclear grade. In contrast, PDGFR-α expression showed no consistent relationship with nuclear grade. On univariate analysis, metastasis at time of surgery (P < .001), tumor size (P = .004), pathologic stage group (P = .001), and nuclear grade (P = .004) were correlated with disease-specific survival. On multivariate analysis, only the presence of metastasis at diagnosis (P < .001) was significant. For overall survival, metastasis (P < .001), tumor size (P = .02), pathologic stage group (P = .01), nuclear grade (P = .003), and PDGFR-α (P = .03) were significant on univariate analysis. Only metastasis (P = .001) and PDGFR-α (P = .03) were significant on multivariate analysis.

Conclusions.—When combined with other variables, PDGFR-α expression in RCC may provide additional predictive value related to the patient's overall survival. However, CD44 and cyclooxygenase 2 do not seem to be independent prognostic indicators in predicting outcomes for patients with RCC.
Effects of a Pneumatic Tube System on Routine and Novel Hematology and Coagulation Parameters in Healthy Volunteers
Authors: Kratz Alexander , Salem Raneem O. , Van Cott Elizabeth M.
Published: February 2021

Context.—Technologic advances affecting analyzers used in clinical laboratories have changed the methods used to obtain many laboratory measurements, and many novel parameters are now available. The effects of specimen transport through a pneumatic tube system on laboratory results obtained with such modern instruments are unclear.

Objective.—To determine the effects of sample transport through a pneumatic tube system on routine and novel hematology and coagulation parameters obtained on state-of-the-art analyzers.

Design.—Paired blood samples from 33 healthy volunteers were either hand delivered to the clinical laboratory or transported through a pneumatic tube system.

Results.—No statistically significant differences were observed for routine complete blood cell count and white cell differential parameters or markers of platelet activation, such as the mean platelet component, or of red cell fragmentation. When 2 donors who reported aspirin intake were excluded from the analysis, there was a statistically, but not clinically, significant impact of transport through the pneumatic tube system on the mean platelet component. There were no statistically significant differences for prothrombin time, activated partial thromboplastin time, waveform slopes for prothrombin time or activated partial thromboplastin time, fibrinogen, or fibrin monomers.

Conclusions.—Although further study regarding the mean platelet component may be required, transport through a pneumatic tube system has no clinically significant effect on hematology and coagulation results obtained with certain modern instruments in blood samples from healthy volunteers.
The Origin of Reference Intervals
Authors: Friedberg Richard C. , Souers Rhona , Wagar Elizabeth A. , Stankovic Ana K. , Valenstein Paul N.
Published: February 2021

Context.—Standards have been developed for establishing reference intervals, but little is known about how intervals are determined in practice, interlaboratory variation in intervals, or errors that occur while setting reference intervals.

Objectives.—To determine (1) methods used by clinical laboratories to establish reference intervals for 7 common analytes, (2) variation in intervals, and (3) factors that contribute to establishment of “outlier” intervals.

Design.—One hundred sixty-three clinical laboratories provided information about their reference intervals for potassium, calcium, magnesium, thyroid-stimulating hormone, hemoglobin, platelet count, and activated partial thromboplastin time.

Results.—Approximately half the laboratories reported conducting an internal study of healthy individuals to validate reference intervals for adults. Most laboratories relied on external sources to establish reference intervals for pediatric patients. There was slight variation in intervals used by the central 80% of study laboratories, but some laboratories outside the central 80% had surprisingly low and high limits for their reference intervals. In some cases the intervals used by 2 laboratories had no overlap. For example, one laboratory considered a hemoglobin of 13.8 g/dL in a woman to be “low” while another considered the same value to be “high.” Three percent of reference intervals contained a limit that qualified as an “outlier” using standard statistical tests; we could not identify any practice associated with adoption of outlier intervals.

Conclusions.—Many laboratories adopt reference intervals from manufacturers without on-site testing of healthy individuals. Reference intervals used by facilities that forgo on-site testing are not statistically different from intervals validated with on-site studies.
Epithelioid Cell Clusters With an Extensive Lymphoid Background
Authors: Zarka Matthew A.
Published: February 2021

Context.—Fine-needle aspiration of salivary gland lesions can be particularly challenging for pathologists. There are numerous neoplasms that occur in this area and several cytologic variations of each specific lesion.

Objective.—To present and discuss a practical pattern recognition approach to fine-needle aspiration diagnosis, which includes categorizing lesions that share a certain overall cytologic architectural pattern, followed by identifying unique cellular characteristics that are specific to a certain lesion. An extensive discussion of one cytologic common pattern of salivary gland lesions, “epithelioid cell clusters with an extensive lymphoid background,” is presented. The pathologic entities that fall under this architectural pattern group are discussed, with an emphasis on neoplasms.

Data Sources.—Published literature and personal experience.

Conclusions.—A practical cytologic architectural pattern method can aid the pathologist in rendering a correct diagnosis when evaluating salivary gland lesions. One common pattern in salivary gland cytopathology is epithelioid cell clusters with an extensive lymphoid background. This pattern is often associated with Warthin tumor; however, other benign and malignant entities fall under this diagnostic group. Unique cytologic features separate these lesions into their respective diagnostic category.
Anti–Interleukin 8 Autoantibody:Interleukin 8 Immune Complexes Visualized by Laser Confocal Microscopy in Injured Lung
Authors: Allen Timothy Craig , Fudala Rafal , Sandra E Nash , Kurdowska Anna
Published: February 2021

Context.—Anti–interleukin 8 autoantibody:interleukin 8 (anti–IL-8 autoantibody:IL-8) complexes are present in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and levels of these complexes correlate with progression to and the outcome of ARDS. FcγRIIa, an immunoglobulin G (IgG) receptor, mediates proinflammatory activity of the complexes.

Objective.—To evaluate lung tissues from patients with ARDS for presence of anti–IL-8 autoantibody:IL-8 complexes and to establish whether the complexes associate with FcγRIIa.

Design.—Lung tissue sections from 3 patients with ARDS and sections of normal lung tissues from 3 patients were stained with antibodies against IL-8 and IgG to detect immune complexes and with antibody against FcγRIIa. In some experiments, sections were blocked with anti-Fcγ RIIa antibody before staining. Samples were analyzed using confocal microscopy.

Results.—Interleukin 8 costained with IgG and FcγRIIa in lung tissues from patients with ARDS but not in control tissues, suggesting that anti–IL-8 autoantibody:IL-8 complexes are deposited in lungs of patients with ARDS via FcγRIIa. Further, colocalization between IL-8 and FcγRIIa could be blocked by anti-FcγRIIa.

Conclusions.—Our data demonstrate that anti–IL-8 autoantibody:IL-8 complexes are present in lung tissues of patients with ARDS, and are attached to FcγRIIa.
The Medicolegal Aspect of Error in Pathology: A Search of Jury Verdicts and Settlements
Authors: Kornstein Michael J. , Byrne Sean P.
Published: February 2021

Context.—Identifying medical errors is a topic of current attention. Among the various approaches is the study of medical malpractice cases.

Objective.—To identify the most common medical errors involving the practice of pathology from a medicolegal perspective by analysis of published jury verdict and settlement reports.

Design.—Search approximately 50 publications that gather jury verdict and settlement information using LexisNexis, an on-line searchable archive, for pathology-related cases.

Results.—One hundred seventy-one legal cases were identified from 1988 through 2005. Nearly one-half involved surgical pathology; among the remainder, cytology cases slightly outnumbered those pertaining to clinical pathology. Among the surgical pathology cases and overall, based on this database, the most common reason for a medical malpractice lawsuit related to pathology was the alleged missed diagnosis of melanoma on a skin biopsy specimen. Less commonly, the surgical pathology cases involved breast biopsy specimens, gynecological specimens, lung, genitourinary system, technical or preanalytic errors (eg, mixed-up specimens), soft tissue, hematopathology, head and neck, gastrointestinal/hepatobiliary system, or thyroid. Among the 48 cases related to cytology, 37 involved false-negative Papanicolaou smears. Less common were cases related to fine-needle aspirates of the breast or thyroid or cytology specimens of the lung. Among the 36 cases involving clinical pathology, 32 related to the blood bank—usually transfusion-acquired human immunodeficiency virus infection.

Conclusions.—These data are in agreement with other publications as to the most frequent causes of medical malpractice allegations related to pathology. As these issues are addressed, the number of errors should decrease. Studying the jury verdict and settlements data may provide additional insight into medical errors and patient safety.
Metastatic Renal Cell Carcinoma to Hemangioblastoma in von Hippel-Lindau Disease
Authors: Polydorides Alexandros D. , Rosenblum Marc K. , Edgar Mark A.
Published: February 2021

A case of metastatic renal cell carcinoma (RCC) to a capillary hemangioblastoma (HAB) of the central nervous system in a 52-year-old woman with von Hippel-Lindau (vHL) syndrome is described. We review the literature on metastatic RCC to HAB, summarize the histologic and immunohistochemical features that can distinguish between the 2 tumors, and comment on the significance of such a finding in terms of the clinical diagnosis of vHL. We found the expression of CAM 5.2, RCC antigen, and CD10 to be strong in RCC and absent in HAB and, conversely, staining with Leu-7, neural cell adhesion molecule, and inhibin-α was present in HAB but weak or absent in RCC. These antibodies can be used to differentiate these entities, provided one is astute in recognizing the possibility of their coexistence.
Disseminated Coccidioidomycosis in Pregnancy
Authors: Hooper Jody E. , Lu Qun , Pepkowitz Samuel H.
Published: February 2021

Coccidioidomycosis is a fungal infection contracted through the inhalation of airborne spores, which are most frequently present in desert areas of the southwestern United States and Mexico. Primary immune response to infection is by TH1, a subset of helper T cells. Although pulmonary symptoms are most common, hematogenous systemic spread can also occur. Pregnancy is a well-noted risk factor for disseminated Coccidioides infection. The objective of this review is to provide an overview of coccidioidomycosis and to review immunologic and hormonal factors that increase risk of dissemination in pregnancy. Dissemination may occur more frequently in pregnant patients than in nonpregnant women because of shifts in T-cell immunity, changes in cytokine production, and increased hormone levels. There is disagreement regarding the precise incidence of systemic spread in pregnancy, but most sources agree that risk is substantially increased and vigilance must be high in patients with exposures in endemic areas.
Noninfectious Complications of Blood Transfusion
Authors: Eder Anne F. , Chambers Linda A.
Published: February 2021

Context.—Serious noninfectious complications are far more likely to occur than viral disease transmission from blood component transfusion.

Objective.—To compile a comprehensive list of the noninfectious risks of transfusion, examples of published risk estimates, and summaries of recent information regarding cause, prevention, or management of noninfectious transfusion risks.

Data Sources.—Information was obtained from peer-reviewed English-language medical journal publications since 1990.

Conclusions.—Early complications, although potentially more serious, usually occur less frequently (<1 in 1000 transfusions) than late complications, which often affect more than 1% of recipients. Areas of active investigation and discussion include acute hemolytic reactions, transfusion-related acute lung injury, red cell alloimmunization, platelet transfusion refractoriness, and transfusion immunosuppression. Continued effort toward research and education to promote recognition and prevention of noninfectious complications associated with blood components is warranted.
Pathogen Inactivation: The Definitive Safeguard for the Blood Supply
Authors: Bryant Barbara J. , Klein Harvey G.
Published: February 2021

Context.—Pathogen inactivation provides a proactive approach to cleansing the blood supply. In the plasma fractionation and manufacturing industry, pathogen inactivation technologies have been successfully implemented resulting in no transmission of human immunodeficiency, hepatitis C, or hepatitis B viruses by US-licensed plasma derivatives since 1985. However, these technologies cannot be used to pathogen inactivate cellular blood components. Although current blood donor screening and disease testing has drastically reduced the incidence of transfusion-transmitted diseases, there still looms the threat to the blood supply of a new or reemerging pathogen. Of particular concern is the silent emergence of a new agent with a prolonged latent period in which asymptomatic infected carriers would donate and spread infection.

Objective.—To review and summarize the principles, challenges, achievements, prospective technologies, and future goals of pathogen inactivation of the blood supply.

Data Sources.—The current published English-language literature from 1968 through 2006 and a historical landmark article from 1943 are integrated into a review of this subject.

Conclusions.—The ultimate goal of pathogen inactivation is to maximally reduce the transmission of potential pathogens without significantly compromising the therapeutic efficacy of the cellular and protein constituents of blood. This must be accomplished without introducing toxicities into the blood supply and without causing neoantigen formation and subsequent antibody production. Several promising pathogen inactivation technologies are being developed and clinically tested, and others are currently in use. Pathogen inactivation offers additional layers of protection from infectious agents that threaten the blood supply and has the potential to impact the safety of blood transfusions worldwide.