bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Herpesvirus 8 Reactivation and Human Immunodeficiency Virus Type 1 gp120
Authors: Lu Chun , Gordon Gabriel M. , Chandran Bala , Nickoloff Brian J. , Foreman Kimberly E.
Published: January 2021

Context.—Human herpesvirus 8 (HHV-8) is the presumed etiologic agent of Kaposi sarcoma (KS), the most common neoplasm in patients with acquired immunodeficiency syndrome. Current evidence indicates HHV-8 is necessary, but not sufficient, for KS development without the involvement of other cofactors. One potentially important cofactor is human immunodeficiency virus type 1 (HIV-1). Although HIV-1 is not essential for development of KS, studies have shown factors released from HIV-1–infected cells, including HIV-1 proteins and cytokines, promote the growth of KS cells in vitro. Recently, studies have shown that coculture of HIV-1–infected T cells with HHV-8–infected primary effusion lymphoma cell lines results in HHV-8 reactivation. This response was due, in part, to cytokines. However, only a portion of induced HHV-8 replication could be accounted for by cytokine stimulation, indicating that other factors, including HIV-1–associated proteins, may also be involved.

Objective.—To investigate a possible role for HIV-1 gp120 in HHV-8 reactivation.

Design.—Using an in vitro model system, we examined the effect of recombinant HIV-1 gp120 protein on HHV-8 replication in latently infected primary effusion lymphoma cell lines.

Main Outcome Measures.—Reactivation of HHV-8 was analyzed using Northern blot analysis and quantitative polymerase chain reaction for ORF26 messenger RNA expression, a gene encoding for the HHV-8 minor capsid protein produced only during reactivation. The results were extended and confirmed using a luciferase reporter construct driven by the HHV-8 ORF50 promoter, the first promoter activated during HHV-8 replication.

Results.—No evidence of enhanced HHV-8 replication was found following treatment with HIV-1 gp120. In addition, HIV-1 gp120 was unable to act synergistically with interferon-γ or hepatocyte growth factor/scatter factor to enhance reactivation of the virus in infected primary effusion lymphoma cell lines.

Conclusions.—HIV-1 gp120 does not appear to be responsible for the reactivation of HHV-8 demonstrated in our previous studies. Further studies are necessary to determine if other HIV-associated proteins, particularly Tat, gp160, and/or gp41, which are also released from infected cells, may be important in inducing HHV-8 reactivation.
pH Effects on Measurements of Ionized Calcium and Ionized Magnesium in Blood
Authors: Wang Sihe , McDonnell Elizabeth H. , Sedor Frank A. , Toffaletti John G.
Published: January 2021

Context.—It is well known that the concentration of ionized calcium in blood is affected by the pH of the specimen, since hydrogen ions compete with calcium for binding sites on albumin and other proteins. However, the relationship between pH and ionized magnesium concentration is not as well characterized.

Objective.—To determine the effects of pH on ionized magnesium concentration over a wide range of pH values in serum or plasma.

Design.—Both ionized calcium and ionized magnesium concentrations were measured in 3 sets of samples. (1) Pools of serum or whole blood at different pH values (7.20–7.60) achieved by adding a constant volume of acid or base (diluted solutions of either hydrochloric acid or sodium hydroxide) plus saline. These pools consisted of 2 serum and 3 heparinized whole blood pools collected from leftover blood remaining in clinical specimens in the Clinical Chemistry and Blood Gas Laboratories, respectively, at Duke University Medical Center. (2) Five whole blood specimens obtained from apparently healthy individual donors. (3) Twenty-six whole blood specimens obtained from individual patients (leftover blood from the Blood Gas Laboratory) in which pH was varied by in vitro loss or gain of carbon dioxide.

Results.—Both ionized calcium and ionized magnesium concentrations decreased as the pH in the specimen increased, indicating the stronger binding of these ions with proteins in the more alkaline environment.

Conclusion.—We conclude that the rate of change of ionized magnesium concentration with pH change (0.12 mmol/L per pH unit) is significantly less than that of ionized calcium (0.36 mmol/L per pH unit). Furthermore, our findings indicate that if adjustment to pH 7.40 is necessary, the ionized magnesium test results need to be adjusted when pH is markedly abnormal, as is sometimes done for ionized calcium.
CD10 Expression in Primary Intestinal Large B-Cell Lymphomas
Authors: Go Jai Hyang , Yang Woo Ick , Ree Howe J.
Published: January 2021

Objective.—To determine the prevalence and clinical significance of a follicular origin in primary intestinal large B-cell lymphomas.

Design.—We performed immunohistochemistry for detection of CD10 and Bcl-6 in paraffin-embedded tissue sections from 32 patients who had surgically resected primary intestinal lymphomas. We then correlated the expression of CD10 protein with various clinical parameters.

Results.—Fifteen of 32 cases (47%) were CD10+, and CD10 positivity was correlated with intense Bcl-6 positivity. There were no significant differences in age, sex, serum lactate dehydrogenase level, and performance status between the CD10+ and CD10− groups. Patients with CD10+ lymphoma more frequently presented with stage I2 disease compared with those with CD10− lymphoma (P = .03). The response to treatment was significantly better in the CD10+ group than in the CD10− group (P = .02). An analysis of survival rates showed a trend for a longer overall survival duration in the CD10+ group compared with the CD10− group, although this was not statistically significant (P = .05).

Conclusions.—We propose that more than half of primary intestinal large B-cell lymphomas have a germinal center cell origin. We also suggest that CD10 expression may be a prognostic indicator in patients with primary intestinal large B-cell lymphomas.
Primary Cutaneous Alveolar Rhabdomyosarcoma of the Perineum
Authors: Gong Yun , Chao Jerome , Bauer Bruce , Sun Xiaoping , Chou Pauline M.
Published: January 2021

Primary alveolar rhabdomyosarcoma (RMS) involving perineal skin is extremely rare, particularly in the infant age group. We report a case of an alveolar RMS in a newborn with abnormal symmetrical perineal overgrowth, causing ambiguous morphologic structure of the genitalia. Clinical and imaging studies were suggestive of Proteus syndrome with lymphatic malformation. Histologic examination of the mass showed cutaneous alveolar RMS with areas of embryonal and pleomorphic RMS features. Multiple superficially located, cystic-dilated spaces with loose edematous-mucoid hypocellular stroma gave a gross morphologic structure similar to that of lymphatic-type excrescences.
Q-Tracks
Authors: Zarbo Richard J. , Jones Bruce A. , Friedberg Richard C. , Valenstein Paul N. , Renner Stephen W. , Schifman Ron B. , Walsh Molly K. , Howanitz Peter J.
Published: January 2021

Context.—Continuous monitoring of key laboratory indicators of quality by hundreds of laboratories in a standardized measurement program affords an opportunity to document the influence of longitudinal tracking on performance improvement by participants focused on that outcome.

Objective.—To describe the results of the first 2 years of participation in a unique continuous performance assessment program for pathology and laboratory medicine.

Design.—Participants in any of 6 modules in the 1999 and 2000 College of American Pathologists (CAP) Q-Tracks program collected data according to defined methods and sampling intervals on standardized input forms. Data were submitted quarterly to CAP for statistical analysis. Interinstitutional comparison reports returned in 6 weeks provided each laboratory with its performance profile of key indicators and its percentile ranking compared with all participants in that quarter. This also included longitudinal comparisons of performance during previous cumulative quarters. Control charts graphically displayed data with flags identifying performance points that were out of statistical control.

Setting.—Hospital-based laboratories in the United States (98%), Canada, and Australia.

Participants.—Voluntary subscriber laboratories in the CAP Q-Tracks performance measurement program: roughly 70% from hospitals of 300 occupied beds or fewer, 65% from private, nonprofit institutions, slightly more than half located in cities, one third from teaching hospitals, and 20% with pathology residency training programs.

Main Outcome Measures.—Each module measured several major and additional minor quality indicators and unbenchmarked individualized data for internal use.

Results.—Participants in 4 of 6 Q-Tracks continuous monitors demonstrated statistically significant performance improvement trends in 1999 and 2000, which were most marked for laboratories that continued participation throughout both years. These monitors were wristband patient identification, laboratory specimen acceptability, blood product wastage, and intraoperative frozen section consultation.

Conclusions.—Key continuous indicators chosen on the basis of a decade's experience in the CAP Q-Probes quality improvement program are useful measurement and benchmarking tools for laboratories to improve performance. In general, measures in which there is a broad range of demonstrable performance initially are most optimal for subsequent improvement using continuous monitoring. These studies have shown that quality is not static, but rather is a moving benchmark of performance as seen in the redefinition of benchmarks over time by participants in the first 2 years of the CAP Q-Tracks program.
Intraoperative Parathyroid Hormone Testing
Authors: Hortin Glen L. , Carter Alexis B.
Published: January 2021

Objective.—To examine the number and testing characteristics of laboratories that offer intraoperative testing of intact parathyroid hormone (PTH).

Design.—Laboratories (n = 355) that participated in 2001 in PTH proficiency testing with the College of American Pathologists Special Ligand Survey were surveyed about intraoperative PTH testing.

Results.—Of the 320 laboratories that responded to the survey, 92 performed intraoperative PTH testing. Testing practices were divided nearly equally among laboratories that performed intraoperative PTH testing for all parathyroidectomies (40%), most but not all cases (31%), and less than half of cases (30%). Testing frequency usually was low, with about two thirds of laboratories reporting 5 or fewer cases per month. A surprising finding was that, although intraoperative PTH testing originally became widely practiced as a point-of-care test, 71% of laboratories performed testing in a central laboratory, 6% in satellite laboratories, and only 23% in operating suites. A survey of methods showed that 33% used the manual QuiCk-Intraoperative test, 47% used the automated Immulite Turbo intact PTH assay, and 20% used other methods.

Conclusions.—Intraoperative testing of intact PTH, although relatively new, has come into widespread practice during parathyroid surgery. Service delivery has evolved from a point-of-care model toward a central laboratory model, with this test serving as an illustrative example of factors that affect the balance between point-of-care and laboratory testing.
Colonic Adenocarcinoma Metastatic to the Urinary Tract Versus Primary Tumors of the Urinary Tract With Glandular Differentiation
Authors: Tamboli Pheroze , Mohsin Syed K. , Hailemariam Seife , Amin Mahul B.
Published: January 2021

Objective.—To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols.

Design.—We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns.

Results.—Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative.

Conclusions.—We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.
ras Gene Mutations and Expression of Ras Signal Transduction Mediators in Gastric Adenocarcinomas
Authors: Yoo Jinyoung , Park Sonya Y. , Robinson Robert A. , Kang Seok Jin , Ahn Woong Shick , Kang Chang Suk
Published: January 2021

Objective.—To investigate ras gene alteration in human gastric adenocarcinomas and its potential relationship to ras signal transduction mediators.

Design.—Genomic DNA from 104 gastric tumors were analyzed by sequencing of polymerase chain reaction–amplified products for the presence of ras mutations. All the samples were further investigated with the use of immunohistochemical analysis for ERK1 and ERK2.

Setting.—Tertiary care teaching hospital.

Patients.—Seventy patients from a Korean population and 34 from a Midwestern US population composed of white Americans and African Americans.

Results.—Fifteen tumors (14%) were positive for either H-ras or K-ras mutation: 9 (13%) of 70 Korean patients and 6 (18%) of 34 US patients. Seven (78%) of the 9 mutated tumors from Korean patients and all 6 (100%) from the US patients were intestinal-type lesions. Either ERK1 and/or ERK2 was overexpressed in 68 samples (65%). No association was established between ras mutations and overexpression of ERK1/2. However, the correlation between ERK1/2 and progression (early vs late) was statistically significant (P = .007).

Conclusions.—These data suggest that ras mutations are uncommon in gastric adenocarcinomas and that differing racial and/or geographic mechanisms may not underlie ras gene alteration. Most ras mutations were, however, observed in the group of intestinal-type samples, supporting the different genetic mechanisms of carcinogenesis between the intestinal- and diffuse-type tumors. It is noteworthy that enhanced ERK1/2 activity could be one of the characteristics of tumor invasiveness in gastric cancers.
Immunohistochemical Localization of Cdc6 in Squamous and Glandular Neoplasia of the Uterine Cervix
Authors: Bonds Lian , Baker Paige , Gup Carol , Shroyer Kenneth R.
Published: January 2021

Context.—Cdc6 has been extensively studied as a marker for cellular proliferation that is expressed during the normal cell cycle. Recent studies indicate that Cdc6 may be a marker for cervical intraepithelial neoplasia (CIN) and carcinoma; however, the histologic distribution of Cdc6 has not been explicitly defined. Expression of Cdc6 in the endocervical mucosa also remains unexplored.

Objective.—The goal of the current study was to evaluate the distribution of Cdc6 protein, MIB-1 protein, and human papillomavirus (HPV) DNA in a broad range of cervical tissues, including normal, potentially premalignant, and malignant lesions of the ectocervical and endocervical mucosa.

Methods.—We used an indirect immunoperoxidase method to stain formalin-fixed, paraffin-embedded tissues and frozen tissues, including biopsy and hysterectomy specimens, for Cdc6 and MIB-1 proteins, and we used in situ hybridization to detect HPV DNA in a subset of cases.

Results.—Cdc6 staining was exclusively nuclear and was present in both squamous and glandular epithelial cells of histologic sections. Cdc6 staining was rarely present in specimens of normal cervical squamous mucosa (2/84, 2.4%) or in specimens with squamous metaplasia (3/59, 5.1%) and was not detected in normal endocervical glands (0/84). Staining was present in most cases of CIN I (31/48, 65%). Staining was present in the majority of cases of CIN II (25/28, 89%) and in all cases of CIN III (36/36) and squamous cell carcinomas (34/34). The proportion of cells staining for Cdc6 increased with the grade of dysplasia, and the proportion of stained cells in squamous cell carcinomas was similar to that in lesions of high-grade dysplasia. Cdc6 staining was present in the majority of cases in glandular lesions including adenocarcinoma in situ (11/14, 79%) and adenocarcinoma (8/10, 80%). The histologic distribution of Cdc6-immunoreactive cells was similar to that of cells with a strong signal for HPV DNA, but Cdc6 protein and HPV DNA did not colocalize at the level of individual cells.

Conclusion.—Cdc6 expression is a marker for high-grade cervical squamous and glandular dysplasia and carcinoma and is associated with HPV infection. The mechanistic basis of the association between HPV infection and Cdc6 immunopositivity remains to be determined but may represent either up-regulation of Cdc6 expression or stabilization of the Cdc6 protein.
Number of Levels Needed for Diagnosis of Cervical Biopsies
Authors: Luo Yehung Vivian , Prihoda Thomas J. , Sharkey Francis E.
Published: January 2021

Context.—Three levels of histologic sections are routinely prepared for small biopsies in many surgical pathology laboratories. The first level is superficial and may not be representative of the entire biopsy, and may therefore represent wasted resources and time for technologists and pathologists alike.

Objective.—To determine if disposing of the first of 3 standard levels materially affects the diagnosis of cervical biopsies.

Design.—We retrospectively reviewed levels 2 and 3 of 241 cervical biopsies and compared the review diagnosis with the original diagnosis, using 6 diagnostic categories: I, benign lesions; II, human papillomavirus–associated changes or low-grade dysplasia; III, high-grade dysplasia/carcinoma in situ; IV, invasive carcinoma; V, insufficient tissue for diagnosis; and VI, further workup needed. If there was a discrepancy between the original and review diagnostic categories, then we examined level 1 to determine if this would resolve the disagreement.

Setting.—The surgical pathology laboratory.

Patients.—Women undergoing cervical biopsy.

Interventions.—None.

Main Outcome Measures.—The frequency with which level 1 information changed the diagnostic category determined with levels 2 and 3 only.

Results.—After review of levels 2 and 3, the diagnosis in 42 (17%) of 241 cases was in disagreement with the original diagnosis. Upon review of level 1, the review category was changed to that of the original diagnosis in only one case.

Conclusions.—The first of 3 levels contributed little to reaching a diagnosis in these cervical biopsies. Control of interobserver variation would seem to be superior to preparation of additional levels as a strategy for reducing diagnostic error.
Evaluation of a Diagnostic Polymerase Chain Reaction Assay forNeisseria meningitidisin North America and Field Experience During an Outbreak
Authors: Pollard Andrew J. , Probe Gary , Trombley Colleen , Castell Annette , Whitehead Sue , Bigham J. Mark , Champagne Sylvie , Isaac-Renton Judy , Tan Rusung , Guiver Malcolm , Borrow Ray , Speert David P. , Thomas Eva
Published: January 2021

Context.—Meningococcal infection has a high public profile because of its dramatic presentation, high fatality rate, and propensity to occur in outbreaks and clusters of cases. Use of a diagnostic polymerase chain reaction (PCR) assay could enhance laboratory confirmation of cases and guide the public health response in North America.

Objective.—To assess the performance of a PCR assay for the diagnosis of meningococcal disease after its implementation in a North American setting and to evaluate sensitivity and specificity of the assay for the detection of prevalent bacterial isolates.

Design.—Laboratory evaluation of the sensitivity and specificity of a PCR assay for Neisseria meningitidis and observational study of a series of cases comparing molecular diagnosis against the criterion standard of conventional laboratory diagnostic tests.

Setting.—A Canadian province with a population of 4 million people.

Patients.—Children and adults presenting with suspected meningococcal disease in British Columbia.

Main Outcome Measures.—The sensitivity and specificity of the PCR assay when compared against standard laboratory methods.

Results.—The PCR assay correctly identified all of 38 Canadian isolates of Neisseria meningitidis and correctly assigned the serogroup to each isolate. None of 57 other gram-positive or gram-negative bacteria or yeasts were detected by the PCR assay. In a clinical evaluation, for diagnosis of meningococcal disease, the PCR assay had a sensitivity and specificity of 91% and 76%, respectively, against conventional methods of diagnosis. Use of the PCR assay increased the laboratory confirmation of clinically suspected cases by 36%. During an outbreak, the PCR assay allowed serogroup determination in 3 of 7 cases, aiding in the public health decision to launch an immunization campaign.

Conclusions.—The PCR assay is more sensitive than conventional methods for the diagnosis of meningococcal disease, and enhanced surveillance may help direct the public health response to the changing epidemiology of disease in North America.
Primary Large Cell Neuroendocrine Carcinoma of the Urinary Bladder
Authors: Evans Andrew J. , Al-Maghrabi Jaudah , Tsihlias John , Lajoie Ginette , Sweet Joan M. , Chapman William B.
Published: January 2021

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases. We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease. Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy. Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.
Phyllodes Tumor Metastatic to Thyroid HürthleCell Adenoma
Authors: Giorgadze Tamar , Ward Richard M. , Baloch Zubair W. , LiVolsi Virginia A.
Published: January 2021

We present a case of a malignant phyllodes tumor metastasizing to a Hürthle cell adenoma of the thyroid. A 55-year-old woman underwent mastectomy for a malignant phyllodes tumor. Two years later, she presented with a left thyroid mass, which was a single, circumscribed, soft, deep red-brown nodular lesion with an eccentric area of firmer consistency. Histologically, the thyroid tumor was composed of 2 distinct types of cellular proliferation. Atypical spindle cells were infiltrating between the Hürthle cell cords and follicles in a fibrosarcomatous pattern. A battery of immunohistochemical stains was applied to both the thyroid and breast tumors for comparison. Based on the histologic and immunophenotypic features of the fibrosarcomatous components of both the breast and thyroid tumors, we rendered a diagnosis of cystosarcoma phyllodes metastatic to Hürthle cell adenoma. To the best of our knowledge, this unusual case is a first report of tumor-to-tumor metastasis of a sarcoma to a primary thyroid neoplasm.
Clinical and Laboratory Management of the Prothrombin G20210A Mutation
Authors: McGlennen Ronald C. , Key Nigel S.
Published: January 2021

Objective.—To make recommendations regarding the appropriate evaluation for the prothrombin G20210A mutation, as reflected by published evidence and the consensus opinion of recognized experts in the field.

Data Sources.—Review of the medical literature, primarily since 1996.

Data Extraction and Synthesis.—After an initial assessment of the literature, key points defining the condition, and review of the clinical study design, a draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference on Diagnostic Issues in Thrombophilia before the meeting. Each of the key points and associated recommendations were then presented for discussion at the conference. Recommendations were accepted if a consensus of 70% of 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 several recommendations concerning the criteria for testing for the prothrombin G20210A mutation and for the method of testing. First, a major point of consensus was that the prothrombin G20210A mutation is a significant risk factor for venous thromboembolism (VTE) and that testing should be considered in the initial evaluation of suspected inherited thrombophilia. Second, although several analytic methods are commonly used for genetic testing for the prothrombin mutation, all are generally robust and reliable. The recommendations for testing for the prothrombin mutation parallel those for the factor V Leiden mutation and include patients with a history of recurrent VTE, a first episode of VTE before the age of 50 years, a history of an unprovoked VTE at any age, thromboses in unusual anatomic sites, or an affected first-degree relative with VTE. A history of VTE related to pregnancy or estrogen use and unexplained pregnancy loss during the second or third trimesters were also considered to be indications for testing. Other scenarios remain controversial or not recommended, including general population screening.
Hyperhomocyst(e)inemia and Thrombophilia
Authors: Key Nigel S. , McGlennen Ronald C.
Published: January 2021

Objective.—To review the role of an elevated total plasma homocysteine level (hyperhomocyst[e]inemia) in patients with venous or arterial thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field.

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

Data Extraction and Synthesis.—The literature was reviewed to identify key points defining the condition, and the clinical study design of each article was examined. A draft manuscript was prepared and circulated prior to the conference to every participant in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. Each of the key points and associated recommendations was then presented for discussion at the conference. Recommendations were accepted if a consensus of the 70% of the 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 9 recommendations concerning the criteria for diagnosis, the method of testing, and the approach for clinical management. A major point of consensus was that no causal role of hyperhomocyst(e)inemia in venous or arterial thrombosis is yet established. Testing methods used to measure homocysteine directly are sensitive and reliable, and provide more information than does genotyping for markers linked to abnormal plasma homocysteine.
Antiphospholipid Antibodies
Authors: Triplett Douglas A.
Published: January 2021

Objective.—To review the role of lupus anticoagulants in the pathogenesis of both venous and arterial thromboembolic events, as well as in recurrent spontaneous abortions. The pathophysiology of lupus anticoagulants and associated antiphospholipid antibodies (eg, anticardiolipin antibodies) is also discussed.

Data Sources.—Review of the recent medical literature.

Data Extraction and Synthesis.—Key articles in the recent medical literature dealing with lupus anticoagulants and their role in pathogenesis of thromboembolic events were reviewed. Plasma proteins that have an affinity for binding to “perturbed cellular membranes” have been identified as the antigenic targets for antiphospholipid antibodies. Thus, the concept of antiphospholipid antibodies needs to be reevaluated. Perhaps a better term is antiprotein-phospholipid antibodies. The principal antigenic protein targets are β2-glycoprotein I, prothrombin, and a wide range of additional proteins that interact with activated cellular membranes, including protein C, protein S, annexin V, etc. Most research reported in the literature has focused on β2-glycoprotein I and human prothrombin.
Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome
Authors: Moake Joel L.
Published: January 2021

Objective.—To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies.

Data Sources.—Articles published in the medical literature.

Data Extraction and Synthesis.—In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP.

Conclusions.—The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.
Proficiency Testing for Laboratories Performing Fluorescence In Situ Hybridization With Chromosome-Specific DNA Probes
Authors: Mascarello James T. , Brothman Arthur R. , Davison Keri , Dewald Gordon W. , Herrman Marille , McCandless Danette , Park Jonathan P. , Persons Diane L. , Rao Kathleen W. , Schneider Nancy R. , Vance Gail H. , Cooley Linda D.
Published: January 2021

Objective.—To assess laboratory performance, use, and limitations in the joint College of American Pathologists and American College of Medical Genetics proficiency testing program for laboratories performing cytogenetic tests based on fluorescence in situ hybridization (FISH).

Data Sources.—Eight proficiency surveys dealing with FISH detection of microdeletions or microduplications, aneuploidy in interphase cells, gene amplification, and neoplasm-specific translocations. Participating laboratories used their own DNA probes (commercial or home-brew), hybridization methods, and analytic criteria to answer clinical questions about cases represented by slides included in the survey materials. They also described their test results according to the International System for Human Cytogenetic Nomenclature (ISCN) and answered supplementary questions relating to their experience with the subject test systems.

Data Extraction.—In addition to evaluating diagnostic accuracy, we evaluated survey use, laboratory experience, variation in methodologic approach, and the practicality of using ISCN nomenclature for describing test results.

Synthesis and Conclusions.—With the exception of one challenge, at least 80% of the participants reached the correct diagnostic conclusion. In the sole exception, there was still a consensus of 91.7% of participants with the same (albeit erroneous) diagnostic conclusion. The overall outstanding performance of participating laboratories clearly shows the reliability of current FISH methods. Despite the fact that a large number of laboratories reported little or no experience with the specific test systems, the overwhelming majority performed very well. This result shows that the program's strategy of targeting classes of abnormalities (vs a single abnormality associated with a specific disease) did not put at a disadvantage participants who did not routinely perform all of the potential tests in the class. The extraordinary variation in ISCN descriptions submitted by participants showed that the existing system for human cytogenetic nomenclature is not suitable for facile communication of FISH test results.
Proteomic Approaches to Tumor Marker Discovery
Authors: Rai Alex J. , Zhang Zhen , Rosenzweig Jason , Shih Ie-ming , Pham Thang , Fung Eric T. , Sokoll Lori J. , Chan Daniel W.
Published: January 2021

Context.—Current tumor markers for ovarian cancer still lack adequate sensitivity and specificity to be applicable in large populations. High-throughput proteomic profiling and bioinformatics tools allow for the rapid screening of a large number of potential biomarkers in serum, plasma, or other body fluids.

Objective.—To determine whether protein profiles of plasma can be used to identify potential biomarkers that improve the detection of ovarian cancer.

Design.—We analyzed plasma samples that had been collected between 1998 and 2001 from patients with sporadic ovarian serous neoplasms before tumor resection at various International Federation of Gynecology and Obstetrics stages (stage I [n = 11], stage II [n = 3], and stage III [n = 29]) and from women without known neoplastic disease (n = 38) using proteomic profiling and bioinformatics. We compared results between the patients with and without cancer and evaluated their discriminatory performance against that of the cancer antigen 125 (CA125) tumor marker.

Results.—We selected 7 biomarkers based on their collective contribution to the separation of the 2 patient groups. Among them, we further purified and subsequently identified 3 biomarkers. Individually, the biomarkers did not perform better than CA125. However, a combination of 4 of the biomarkers significantly improved performance (P ≤ .001). The new biomarkers were complementary to CA125. At a fixed specificity of 94%, an index combining 2 of the biomarkers and CA125 achieves a sensitivity of 94% (95% confidence interval, 85%–100.0%) in contrast to a sensitivity of 81% (95% confidence interval, 68%–95%) for CA125 alone.

Conclusions.—The combined use of bioinformatics tools and proteomic profiling provides an effective approach to screen for potential tumor markers. Comparison of plasma profiles from patients with and without known ovarian cancer uncovered a panel of potential biomarkers for detection of ovarian cancer with discriminatory power complementary to that of CA125. Additional studies are required to further validate these biomarkers.
Reactivity of Resident Immunocytes in Normal and Prepsoriatic Skin Using an Ex Vivo Skin-Explant Model System
Authors: Curry Jonathan L. , Qin Jian-Zhong , Robinson June , Nickoloff Brian J.
Published: January 2021

Context.—While it is well known that both exogenous and endogenous stimuli can trigger appearance of psoriatic lesions, the initial cellular and molecular events mediated by immunocompetent cells normally resident in prepsoriatic (PN) skin are not well understood. Moreover, it is unclear whether there are any fundamentally important differences in the innate immune response of normal healthy skin (NN skin) versus PN skin. Since acute tissue responses to stimuli involve both resident cells and immunocytes recruited rapidly from circulation, it is difficult to discern the contribution of endogenous cells normally present in skin.

Objective.—To solely characterize the reactivity of resident immunocytes using an experimental system.

Design.—To probe the activation potential of resident immunocytes in NN (n = 18) and PN skin (n = 10), a short-term ex vivo organ culture system containing interleukin (IL)-2 was established and characterized. To mimic exogenous or environmental trigger factors, bacteria-derived superantigens and lipopolysaccharide were added to the skin-explant assays, whereas endogenous trigger factors were investigated using heat shock proteins.

Results.—Using this skin-explant assay, both NN and PN skin gave rise to an expansion of various T-cell subsets, which could differentially produce various cytokines and a growth factor (keratinocyte growth factor), depending on the stimulus and source of skin. Bacterial superantigens were relatively potent inducers of interferon-γ, and natural killer–T cells were observed proliferating from PN skin.

Conclusions.—Despite relatively few T cells normally residing in either NN or PN skin, initiation of skin explants from both sets of individuals in the presence of IL-2 triggered vigorous T-cell proliferation and cytokine/growth factor release. These results demonstrate the utility of this skin-explant assay system to further investigate quantitative and qualitative immune responses of NN and PN skin.
Pulmonary Expression of Vascular Endothelial Growth Factor in Sepsis
Authors: Tsokos Michael , Pufe Thomas , Paulsen Friedrich , Anders Sven , Mentlein Rolf
Published: January 2021

Context.—Vascular endothelial growth factor (VEGF), an angiogenic and chemotactic peptide, is abundantly expressed in normal lung tissue, especially in alveolar and bronchial epithelium, glandular cells of the bronchi, and activated alveolar macrophages.

Objective.—To investigate the role of VEGF in progressively impaired lung function as the major complication and cause of death in septic patients.

Materials and Methods.—We evaluated pulmonary VEGF expression in lung autopsy material from septic patients who had been cared for by intensive care medicine using enzyme-linked immunosorbent assay (ELISA), reverse transcriptase–polymerase chain reaction (RT-PCR), and immunohistochemical methods.

Results.—Compared with expression in nonseptic control individuals (n = 10), pulmonary VEGF expression as determined by ELISA was significantly (P < .001) decreased in septic patients (n = 8). As monitored by RT-PCR, mRNA for the 2 splice variants, VEGF121 and VEGF165, and for VEGFR-2/KDR were expressed in both groups, the yields being lower in the sepsis group. Samples from septic patients lacked or showed only sparse immunoreaction on bronchial and alveolar epithelium, whereas this reaction was strong in all control samples. However, alveolar macrophages were similarly immunopositive in both groups.

Conclusions.—The precise underlying mechanisms for the distinctly different expression of pulmonary VEGF in septic patients and nonseptic control individuals are not clear at present. Particularly the role of VEGF in the development of sepsis-induced lung injury and acute respiratory distress syndrome in mechanically ventilated patients suffering from severe sepsis remains to be clarified.
Pleomorphic Adenoma of the Breast
Authors: Reid-Nicholson M. , Bleiweiss I. , Pace B. , Azueta V. , Jaffer S.
Published: January 2021

Pleomorphic adenoma of the breast is a rare, benign tumor accounting for 68 cases in the literature. It is most commonly seen in postmenopausal women and is characterized by an admixture of epithelial and myoepithelial cells embedded in abundant myxomatous stroma. Its clinical and histologic appearance can be challenging and may lead to a misdiagnosis of invasive carcinoma. We report a case of mammary pleomorphic adenoma in an asymptomatic 59-year-old woman and briefly discuss its distinction from mucinous carcinoma through the use of special stains.
Audit of Transfusion Procedures in 660 Hospitals
Authors: Novis David A. , Miller Karen A. , Howanitz Peter J. , Renner Stephen W. , Walsh Molly K.
Published: January 2021

Context.—Hemolytic transfusion reactions are often the result of failure to follow established identification and monitoring procedures.

Objective.—To measure the frequencies with which health care workers completed specific transfusion procedures required for laboratory and blood bank accreditation.

Design.—In 2 separate studies, participants in the College of American Pathologists Q-Probes laboratory quality improvement program audited nonemergent red blood cell transfusions prospectively and completed questionnaires profiling their institutions' transfusion policies.

Setting and Participants.—A total of 660 institutions, predominantly in the United States, at which transfusion medicine services are provided.

Main Outcome Measures.—The percentages of transfusions for which participants completed 4 specific components of patient and blood unit identifications, and for which participants monitored vital signs at 3 specific intervals during transfusions.

Results.—In the first study, all components of patient identification procedures were performed in 62.3%, and all required patient vital sign monitoring was performed in 81.6% of 12 448 transfusions audited. The median frequencies with which institutions participating in the first study performed all patient identification and monitoring procedures were 69.0% and 90.2%, respectively. In the second study, all components of patient identification were performed in 25.4% and all patient vital sign monitoring was performed in 88.3% of 4046 transfusions audited. The median frequencies with which institutions participating in the second study performed all patient identification and monitoring procedures were 10.0% and 95.0%, respectively. Individual practices and/or institutional policies associated with greater frequencies of patient identification and/or vital sign monitoring included transporting units of blood directly to patient bedsides, having no more than 1 individual handle blood units in route, checking unit labels against physicians' orders, having patients wear identification tags (wristbands), reading identification information aloud when 2 or more transfusionists participated, using written checklists to guide the administration of blood, instructing health care personnel in transfusion practices, and routinely auditing the administration of transfusions.

Conclusions.—In many hospitals, the functions of identification and vital sign monitoring of patients receiving blood transfusions do not meet laboratory and blood bank accreditation standards. Differences in hospital transfusion policies influence how well health care workers comply with standard practices. We would expect that efforts designed to perfect transfusion policies might also improve performance in those hospitals in which practice compliance is substandard.
Conference Summary, Strategic Science Symposium
Authors: Zarbo Richard J. , Hammond M. Elizabeth H.
Published: January 2021

Context.—Practicing pathologists often encounter controversial clinical issues and nonstandardized laboratory approaches to the evolving science of predictive/prognostic tumor marker assays. This dilemma becomes especially acute when the assay is the sole determinant for selection of a specific therapy.

Objectives.—To summarize the areas of practical agreement and identify opportunities for improvement in Her-2/neu testing of breast cancer.

Design.—The College of American Pathologists created a new comprehensive education model, called Strategic Science, with expert speakers integrating new and evolving basic, clinical, and scientific issues of Her-2/neu testing with aspects of laboratory management.

Setting.—Symposium held May 4 and 5, 2002, in Rosemont, Ill.

Participants.—Ten speakers and more than 100 attendees.

Results.—Components addressed were new technology assessment, practice guidelines, quality assurance, regulatory compliance, risk and liability, billing and coding, cost analysis, consultation, information management, and results reporting.

Conclusions.—This Strategic Science symposium derived areas of practical agreement, defined the current state-of-the-art, and identified areas for improvement in Her-2/neu testing.
Cystic Sebaceous Neoplasms in Muir-Torre Syndrome
Authors: Abbott Jared J. , Hernandez-Rios Pablo , Amirkhan Robin H. , Hoang Mai P.
Published: January 2021

Cystic sebaceous neoplasms have been seen only in patients with Muir-Torre syndrome (MTS) and have recently been characterized as marker lesions of MTS. Histologically, these lesions form a spectrum of tumors ranging from benign cystic adenomas to proliferative cystic sebaceous tumors. We describe 2 proliferative cystic sebaceous tumors in a 53-year-old man whose workup revealed colonic adenocarcinoma and other sebaceous tumors consistent with MTS. Both the chest wall and the left thigh masses were grossly cystic, measuring 1.0 and 1.5 cm, respectively. Histologic sections demonstrated well-circumscribed cystic neoplasms located in the deep dermis and subcutaneous tissue. Each had a focally infolded cyst wall composed of immature basaloid cells with prominent nucleoli and mitoses, consistent with a proliferative cystic sebaceous tumor. Recognition of cystic sebaceous neoplasm by pathologists and communication to clinicians of its strong association with MTS is of diagnostic importance.