bluuebunny/crossref_metadata_2025 huggingface dataset:
Upper Aerodigestive Tract Squamous Dysplasia: Correlation With p16, p53, pRb, and Ki-67 Expression
Authors: Wayne Sigrid , Robinson Robert A.
Published: February 2021

Context.—Differential expression of cell cycle–associated proteins may correlate with human papillomavirus status and may help delineate degree of dysplasia in upper aerodigestive tract squamous lesions.

Objective.—To determine intraepithelial height of immunohistochemical staining for p16, p53, pRb, and Ki-67 in upper aerodigestive tract lesions with reference to degree of dysplasia. Human papillomavirus status was ascertained to correlate with p16 expression.

Design.—Biopsy specimens of 53 squamous dysplastic and 13 keratotic/hyperplastic lesions were immunohistochemically stained for p16, p53, pRb, and Ki-67. Mean height and proportion of positive staining were quantified and compared for keratotic/hyperplastic, mild, moderate, and severe dysplasia/carcinoma in situ. DNA extracted from paraffin-embedded blocks was evaluated for human papillomavirus by polymerase chain reaction amplification using consensus primers for mucosal viral types.

Results.—Height of Ki-67 staining within the epithelium increased significantly between mild and moderate and between mild and severe dysplasia, with a trend toward increasing height between moderate and severe dysplasia. The percentage of cases with p16 staining decreased significantly with increasing degree of dysplasia; however, no significant trend in staining height or proportion was observed with p16, p53, or pRb in relation to degree of dysplasia, or between dysplastic and keratotic/hyperplastic lesions. Only 1 of 53 dysplastic lesions was positive for human papillomavirus.

Conclusions.—This series of upper airway dysplastic mucosal lesions demonstrated a positive correlation between intraepithelial Ki-67 staining height and degree of dysplasia, offering a diagnostic aid in delineating degree of dysplasia in difficult squamous lesions.
Morphologic Examination of Sequential Bone Marrow Biopsies after Nonmyeloablative Stem Cell Transplantation Complements Molecular Studies of Donor Engraftment
Authors: Lagoo Anand S. , Gong Jerald Z. , Stenzel Timothy T. , Goodman Barbara K. , Buckley Patrick J. , Chao Nelson J. , Gasparetto Cristina , Long Gwynn D. , Rizzieri David A.
Published: February 2021

Context.—Nonmyeloablative stem cell transplantation (NMSCT) is a mode of immunotherapy increasingly employed in treating hematologic, lymphoid, and solid tumors. Patients are monitored principally by molecular analysis of donor engraftment.

Objective.—To determine the role of morphologic examination of bone marrow after NMSCT.

Design.—Seventy-three patients undergoing NMSCT under the Campath 1H (humanized anti-CD52 antibody) protocol were studied. Pretransplant and sequential posttransplant bone marrow specimens were evaluated and the findings were correlated with corresponding engraftment data.

Results.—Pretransplant bone marrow specimens from 43% of the patients were involved by disease, and these marrow specimens were significantly more cellular than those that were free of disease. Morphologically detectable disease was still present in day 14 posttransplant marrow specimens in more than one half of these patients, but there was no difference in engraftment in those with or without marrow disease. Early posttransplant marrow in nearly one half of the patients showed myeloid hyperplasia and atypical localization of immature myeloid precursors. Marrow cellularity for the first 2 months after NMSCT was significantly lower in those patients receiving stem cells mismatched at 1 to 3 loci as compared with those who received fully matched grafts (mean cellularity, 38.1% vs 54.1% at day 14). Marrow failure without recurrent disease at 3 to 6 months after transplant was detected by engraftment study in only approximately 15% of cases. Similarly, early recurrence of disease was detected first by morphologic examination in 4 of 13 cases before a decline in donor engraftment occurred.

Conclusion.—Morphologic examination of bone marrow provides additional information that is complementary to donor engraftment analysis for optimal management after NMSCT.
Evaluation of C4d Staining in Liver and Small Intestine Allografts
Authors: Troxell Megan L. , Higgins John P. , Kambham Neeraja
Published: February 2021

Context.—Antibody-mediated humoral rejection in kidney and heart allografts is well recognized and is often associated with poor outcome. C4d deposition in allograft biopsy specimens occurs at sites of antibody-mediated complement activation and has become one of the histopathologic criteria for diagnosis of humoral rejection in the kidney and the heart.

Objective.—To study immunohistochemical C4d staining as a potential diagnostic marker in liver and small intestine allograft biopsy specimens.

Design.—Thirty-six small intestine and 71 liver specimens, including native specimens, allografts with and without histologic features of acute cellular rejection, and explants, were stained with antisera to C4d using an immunohistochemical method on formalin-fixed, paraffin-embedded tissue.

Results.—In small intestine, C4d labeled capillaries in 27% of cases with no evidence of rejection, 36% of cases with evidence of acute rejection, and 2 (28%) of 7 specimens of native normal small intestine. In liver allograft biopsy specimens, C4d stained endothelium of veins, arteries, and/or sinusoids in 2 (8%) of 25 cases of acute rejection with central vein involvement; C4d staining was negative in biopsy specimens with no evidence of rejection. C4d stained the endothelium in a subset of explanted liver allografts with ductopenic rejection or chronic vascular rejection and strongly stained 1 explant with features of hyperacute rejection.

Conclusions.—The clinical utility of C4d staining in solid organ transplantation may vary by organ. Our data show C4d is unlikely to have utility in small intestine allograft biopsy specimens; however, further study in liver allografts, in conjunction with donor-specific antibody testing, is warranted.
Fetiform Teratoma (Homunculus)
Authors: Weiss Jason R. , Burgess Jeanette R. , Kaplan Keith J.
Published: February 2021

Fetiform teratoma (homunculus) is a term that has been given to a rare form of ovarian teratoma that resembles a malformed fetus. There are very few reported cases of this entity in the English language literature. In this report, we document a case of fetiform teratoma in a 23-year-old woman, gravida 0, who initially presented with a chief complaint of dyspareunia. The clinical and pathologic aspects of this rare entity are presented here, with a review of the English literature. Differentiating fetiform teratoma from the more highly developed fetus-in-fetu and ectopic pregnancy is also discussed.
Epstein-Barr Virus–Associated Posttransplantation Lymphoproliferative Disorder Following Lung Transplantation Is More Commonly of Host Origin
Authors: Peterson Michael R. , Emery Shawn C. , Yung Gordon L. , Masliah Eliezer , Yi Eunhee S.
Published: February 2021

Context.—Posttransplantation lymphoproliferative disorder (PTLD) in patients who have undergone solid organ transplantation is thought to be mostly of host (ie, transplant recipient) origin, as opposed to being predominantly of donor origin, which is observed in patients who have undergone bone marrow transplantation. Donor-origin PTLDs reportedly follow a more indolent course than host-origin PTLDs.

Objective.—To determine the origin of PTLD and its clinical implications in patients who have undergone lung transplantation.

Design.—Patients' medical records were reviewed for clinical data. We performed a molecular study to determine the origin of abnormal lymphoid cells in 4 PTLD cases identified from our autopsy files. Each case underwent restriction fragment length polymorphism analysis using polymerase chain reaction–based genotyping for CYP2D6. Epstein-Barr virus (latent membrane protein 1) immunostaining and polymerase chain reaction analysis were performed on PTLD-involved tissues.

Results.—Three of 4 PTLD cases were of host origin, and the remaining case was of donor origin. Epstein-Barr virus was detected by immunohistochemical and polymerase chain reaction methods in all PTLD-involved tissues that were examined. There was no apparent difference in clinical manifestations between host-origin and donor-origin PTLD cases in our study.

Conclusions.—The PTLDs in our patients who had undergone lung transplantation were Epstein-Barr virus–positive and mostly of host origin, without any notable clinical difference from donor-origin PTLD.
Longitudinal Case-Based Evaluation of Diagnostic Competency Among Pathology Residents: A Statistical Approach
Authors: Ducatman Barbara S. , Ducatman Alan M.
Published: February 2021

Context.—Accreditation Council for Graduate Medical Education guidelines require the evaluation of residents in 6 competencies. Pathology residents demonstrate medical knowledge, patient care, communication, and practice-based learning competencies in their attainment of competency in surgical pathology diagnosis.

Objective.—To implement a prospective case-based approach to longitudinally evaluate the acquisition of competency in surgical pathology diagnosis by trainees.

Design.—Each resident made his or her surgical pathology diagnosis on cases before faculty review of the cases. Faculty members scored each resident diagnosis as to whether they agree, partially agree, or disagree with the diagnosis. Forty-three months of surgical pathology reports (August 2001 through January 2005) and 22 252 surgical pathology cases were analyzed.

Setting.—Pathology residency program.

Participants.—Thirteen faculty members and 21 trainees.

Main Outcome Measure.—Time and training year trends for the number of cases reviewed and the percent agreement between faculty and trainees on the diagnoses.

Results.—A mean of 146 cases (range, 12–327 cases) was reviewed during each month-long rotation. The number of cases reviewed increased through postgraduate year 4. The percent agreement on the diagnoses was 78% (range, 56%– 99%) for all trainees, with improvement by postgraduate year, although the improvement attenuated by postgraduate year 3. Residents were less likely to preview the most complex cases. Faculty rank and sex and resident sex did not significantly affect outcomes. The overall agreement on the diagnoses increased over time. Residents experiencing difficulty could be identified clearly and early.

Conclusions.—Individual resident performance was easily tracked over time. The review of hundreds of reports increases systems accountability and allows more objectivity than traditional evaluations. The use of case-based evaluation fosters earlier identification and remediation of deficiencies.
Utility of CD117 Immunoreactivity in Differentiating Metastatic Melanoma From Clear Cell Sarcoma
Authors: Garcia Joaquin J. , Kramer Miranda J. , Mackey Zachary B. , O'Donnell Richard J. , Horvai Andrew E.
Published: February 2021

Context.—Clear cell sarcoma is a malignant soft tissue tumor with melanocytic differentiation. Molecular methods are sometimes necessary to identify the unique t(12; 22)(q13;q12) translocation and differentiate clear cell sarcoma from melanoma.

Objective.—To determine whether CD117 immunoreactivity may be useful in separating melanoma from clear cell sarcoma.

Design.—We identified 20 tumors listed in our surgical pathology files that were diagnosed as clear cell sarcoma or in which clear cell sarcoma was strongly considered. These were tested for the presence of the t(12;22) translocation by reverse transcriptase/polymerase chain reaction and sequencing from paraffin-embedded tissue. Tumors with a t(12;22) translocation were immunostained with an antibody to CD117 and compared with 16 similarly stained metastatic melanomas.

Results.—Twelve tumors from 9 patients demonstrated t(12;22). No metastatic melanomas demonstrated t(12;22). None of the 12 clear cell sarcomas showed membrane or cytoplasmic staining for CD117. Conversely, 10 (63%) of 16 metastatic melanomas were, at least focally, positive for CD117; this difference was significant (P < .001). Interestingly, 3 tumors in which clear cell sarcoma was initially considered as a diagnosis, but which lacked t(12;22), were also positive for CD117.

Conclusions.—Reverse transcriptase/polymerase chain reaction, performed on paraffin-embedded tissue, is a useful, rapid tool for identifying the presence of t(12;22) in clear cell sarcoma. The CD117 immunoreactivity may prove useful in the differential diagnosis of deep soft tissue or visceral lesions with melanocytic differentiation; positive staining results exclude clear cell sarcoma, but are compatible with metastatic melanoma.
Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea
Authors: Jakate Shriram , Demeo Mark , John Rohan , Tobin Mary , Keshavarzian Ali
Published: February 2021

Context.—In some adult patients with chronic intractable diarrhea, the diagnosis remains elusive even after detailed evaluations, and colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining.

Objectives.—To assess the concentration of mast cells in colonic or duodenal biopsy specimens by immunohistochemical analysis for mast cell tryptase from patients with chronic intractable diarrhea and to evaluate their response to drugs affecting mast cell function.

Design.—Mast cells per high-power field were assessed in biopsy specimens from 47 patients with chronic intractable diarrhea, from 50 control subjects, and from 63 patients with other specific diseases that cause chronic diarrhea (inflammatory bowel disease, celiac disease, collagenous colitis, and lymphocytic colitis). Patients with chronic intractable diarrhea who had more than 20 mast cells per high-power field were administered drugs affecting mast cell mediator function and release.

Results.—The mean ± SD concentration of mast cells in the 50 control subjects was 13.3 ± 3.5 cells per high-power field; hence, patients with more than 20 mast cells per high-power field were considered to have increased mast cells. Thirty-three (70%) of 47 patients with chronic intractable diarrhea had increased mast cells, and symptoms were controlled by drug therapy in 22 (67%) of the 33 patients. No patient had systemic or cutaneous mastocytosis. No increase in mast cells was seen in patients with other common causes of chronic diarrhea.

Conclusions.—In chronic intractable diarrhea, colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining, but increased mast cells may be demonstrated by immunohistochemistry for mast cell tryptase, with the novel term mastocytic enterocolitis describing this condition. Similar increases in mast cells are not apparent in control populations or in patients with other specific diseases that cause chronic diarrhea. The cause of the increased mast cells remains to be elucidated.
Cystic Panfolliculoma
Authors: Hoang Mai P. , Levenson Brian M.
Published: February 2021

Panfolliculoma is a rare follicular neoplasm with differentiation toward both upper (infundibulum and isthmus) and lower (stem, hair matrix, and bulb) segments of a hair follicle. We present an unusual case of cystic panfolliculoma. A 33-year-old Hispanic woman presented with an 8-month history of a 3.0-cm cystic scalp mass. The lesion was excised, and the histologic sections showed a cystic follicular neoplasm that contained corneocytes in basket-woven and laminated array, trichohyalin granules of the inner root sheath, germinative cells, papillae, matrical cells, and “shadow” cells. Cytokeratin 903 and cytokeratin 5/6 immunostains uniformly highlight the tumor cells. Ber-EP4 strongly labels the germinative cells but not the follicular papillae. CD34 labels the surrounding fibrotic stroma and focally the epithelial component.
Communicating Critical Values in Anatomic Pathology
Authors: LiVolsi Virginia A. , Leung Stanley
Published: February 2021

Critical values in anatomic pathology are usually information sensitive, whereas most such values in laboratory medicine are time sensitive. However, there is an important time element in anatomic pathology as well. Pathologists should be aware that many medicolegal actions against radiologists are based on failure to communicate “abnormal” results in a timely manner. Are pathologists the next group that will be targeted? Pathologists can spend much time trying to communicate important data that will affect patient care to someone who will accept the information. This is not an efficient use of pathologists' professional time. Most important, what are our obligations to patients to communicate “critical” abnormal results to the treating physician? What results need to be so communicated? Are pathologists obliged to contact the patient directly if there is a failure to communicate the critical results to a clinician? We explore these questions to promote discussion of these important issues as they relate to pathologists' liability and to patient care.
The Application of Molecular Techniques to the Study of Hospital Infection
Authors: Andrei Anca , Zervos Marcus J.
Published: February 2021

Context.—Nosocomial infections represent an important cause of morbidity and mortality in hospital settings, resulting in high health care costs. The roles of an epidemic investigation are to recognize that a problem exists, to compare characteristics of affected persons with those of similar but unaffected persons (case-control study), and to identify risk factors. Integrating typing methods as part of conventional epidemiologic surveillance is cost-effective and results in a reduction in rates of nosocomial infections. During the past 10 years, there has been unprecedented progress in molecular biology and in the application of nucleic acid technology to the study of the epidemiology of human infections.

Objectives.—To summarize the available molecular tests for determination of the relatedness of microorganisms causing nosocomial infections, emphasizing the most useful applications of the tests to the study of the epidemiology of hospital-acquired infection; and to discuss the appropriate use of these tests in the prevention and control of hospital-associated infection.

Data Source.—Published English-language literature from 1980 to the present.

Conclusions.—Pulsed-field gel electrophoresis is the method of choice for strain delineation. The newest techniques include polymerase chain reaction and multilocus sequence typing, in which various housekeeping genes that are stable markers of strain identity are sequenced. Molecular techniques are broadly applicable to the study of diverse pathogens. Typing data obtained by DNA analysis should always be considered together with epidemiologic information, because only this combination will enable the most accurate epidemiologic evaluation.
Iatrogenic Trichuris suis Infection in a Patient With Crohn Disease
Authors: Kradin Richard L. , Badizadegan Kamran , Auluck Pavan , Korzenik Joshua , Lauwers Gregory Y.
Published: February 2021

We report a case of biopsy-proven iatrogenic infection by the pig whipworm Trichuris suis in a patient with Crohn disease. The deliberate therapeutic ingestion of T suis ova has been adopted as an experimental approach to the treatment of Crohn disease in an effort to promote a switch from the T helper subtype 1 to T helper subtype 2 inflammatory phenotype in vivo. This report examines the morphology of the immature and adult T suis, the effects of this intervention on the immunophenotype of the bowel mucosa, and it also raises the possibility of persistent active infection in man.
Evaluation of Total Serum Calcium Critical Values
Authors: Howanitz Joan H. , Howanitz Peter J.
Published: February 2021

Context.—As a patient safety measure, laboratories are required by regulatory agencies to have a critical values policy. Total serum calcium commonly is included in critical results lists; however, a wide range of values are used and there is scant outcome data justifying inclusion of this analyte in these lists.

Objective.—To evaluate the appropriateness of the critical values for total serum calcium used in our institution.

Design.—We studied all critical total serum calcium results found during a 3-month period. The patients' medical records were evaluated for the presence of documented critical results call for calcium, clinician response, and patient outcome. The patients' outcomes were measured by time of clinical response, length of stay in the hospital, and mortality.

Results.—There were 722 (1.4%) critical results found in a total of 50 402 total serum calcium results. Using our criteria of 7 mg/dL or less as the low and 12 mg/dL or more as the high critical value, we found 171 patients with 608 critically low results and 47 patients with 114 critically high results. Eighty percent of patients with critically low results and 75% of patients with critically high results had length of stays greater than our average (5.58 days). Clinicians responded to 49% of the critical results calls within 4 hours. There was an overall mortality rate of greater than 25%, with more than half the mortality occurring in patients who had results within 0.5 mg/dL of the cutoff values used.

Conclusion.—Although broadening critical values limits would reduce required calls, this does not appear warranted. The disease severity of the patients as measured by length of stay and mortality, as well as the rapidity with which patients were treated, indicate that the current limits are appropriate and should not be widened.
Fatal Hemorrhage Secondary to Ulcerated Epiphrenic Pseudodiverticulum
Authors: Chen Lei , Walser Eric M. , Schnadig Vicki
Published: February 2021

A 47-year-old man was found unconscious after experiencing severe hematemesis. He had a history of alcohol abuse, hepatic cirrhosis, and previous episodes of gastrointestinal bleeding. Imaging studies indicated that the left gastric artery was the probable source of bleeding. A severe coagulopathy was also noted clinically. Angiographic embolization of the left gastric artery failed to staunch bleeding, and the patient died shortly after admission. Autopsy demonstrated a large, ulcerated epiphrenic esophageal pseudodiverticulum, the base of which was in close proximity to an esophageal branch of the left gastric artery. Cystic dilatation of adjacent esophageal submucosal glands was also seen. Gelatin embolic material, without associated thrombus formation, was found within the left gastric artery. Esophageal pseudodiverticulosis is an uncommon disorder that may be associated with dysphagia, stricture, and odynophagia. Bleeding and perforation are very rare complications. This case may be the first fatality proven by autopsy to be secondary to esophageal pseudodiverticulosis.
Prospective Step Sections for Small Skin Biopsies
Authors: Bruecks Andrea K. , Shupe Jill M. , Trotter Martin J.
Published: February 2021

Context.—In our laboratory, for small skin biopsies or curetted specimens, 3 slides are prepared before the case is reviewed by the dermatopathologist.

Objective.—To examine the utility of these “prospective” step sections in improving diagnostic accuracy and turnaround time.

Design.—Five hundred consecutive cases, in which step sections had been cut prior to slide review, were studied. For each specimen, 3 slides, each consisting of 1 ribbon of tissue containing 4 to 6 sections, were obtained at 50-μm intervals from the paraffin block.

Results.—Fifty-eight biopsies (12%) were nondiagnostic using slide 1 alone. Step sections provided a diagnosis in 19 of 58 cases. In an additional 15 cases (3%) in which a diagnosis was possible using slide 1, deeper levels resulted in a change in diagnosis. Thus, in 34 (7%) of 500 biopsies, deeper levels resulted in improved diagnostic accuracy. In addition, the pathologist would have ordered step sections in a further 117 cases (23%) to clarify the diagnosis rendered on level 1 or to exclude other lesions. Thus, 30% of small skin biopsies would have required deeper levels if step sections had not been obtained prior to slide review.

Conclusions.—In our laboratory, the use of prospective step sections is essentially cost-neutral and case turnaround time is improved by 9% to 45%. Step sections result in a changed diagnosis in 7% of small skin biopsy specimens.
Application of a Combined Protocol for Rational Request and Utilization of Antibody Assays Improves Clinical Diagnostic Efficacy in Autoimmune Rheumatic Disease
Authors: Tampoia Marilina , Brescia Vincenzo , Fontana Antonietta , Zucano Antonietta , Morrone Luigi Francesco , Pansini Nicola
Published: February 2021

Context.—Because of a marked increase in the number of requests for antinuclear antibodies, anti–extractable nuclear antigen antibodies, and anti–double-stranded DNA antibodies for the diagnosis of autoimmune rheumatic disease, guidelines have been proposed for their appropriate use.

Objective.—To evaluate in terms of clinical efficacy and cost-benefit ratio the outcome of applying a protocol for the diagnosis of autoimmune rheumatic disease.

Design.—A diagnostic protocol for the rational utilization of second-level tests (anti–extractable nuclear antigen antibodies and anti–double-stranded DNA antibodies) was applied at Hospital Polyclinic beginning January 2004. The appropriateness of 685 consecutive requests received at the clinical pathology laboratory from January to June 2004 was assessed. Patients who underwent these laboratory tests were followed up for 12 months after blood sample drawing.

Results.—Introduction of the protocol led to a significant reduction in the number of second-level tests prescribed (27.9% vs 49.5% for anti–extractable nuclear antigen antibodies; 27.5% vs 56.6% for anti–double-stranded DNA antibodies). After the period of observation, none of the 163 patients who had negative results on the first-level test and were asymptomatic, for whom second-level tests had not therefore been performed, were found to have autoimmune rheumatic disease. In 90.5% (77/85) of patients positive for the second-level tests, clinical confirmation of autoimmune rheumatic disease was obtained.

Conclusions.—Not only did application of the diagnostic protocol reduce the number of second-level tests performed but it also increased their specificity. Our data thus indicate that the use of shared guidelines by clinical and laboratory specialists yields satisfactory results.
Best Practices in Diagnostic Immunohistochemistry: Pleomorphic Cutaneous Spindle Cell Tumors
Authors: Folpe Andrew L. , Cooper Kumarasen
Published: February 2021

Context.—Pleomorphic cutaneous spindle cell tumors can be difficult to distinguish solely on histologic grounds. The use of ancillary immunohistochemical studies can greatly assist in this differential diagnosis.

Objective.—To review histologic and immunohistochemical aspects of cutaneous spindle cell tumors and discuss a basic panel of markers to assist in the differential diagnosis.

Data Sources.—English-language literature published between 1981 and 2005.

Conclusions.—A basic immunohistochemistry panel for high-molecular-weight cytokeratin, melanocytic markers (S100 protein, HMB-45, Melan-A), smooth muscle actin, desmin, and endothelial markers (CD31, CD34) is effective in diagnosing most cutaneous spindle cell tumors.
The Value of Monitoring Human Papillomavirus DNA Results for Papanicolaou Tests Diagnosed as Atypical Squamous Cells of Undetermined Significance: A College of American Pathologists Q-Probes Study of 68 Institutions
Authors: Tworek Joseph A. , Jones Bruce A. , Raab Stephen , Clary Karen M. , Walsh Molly K.
Published: February 2021

Context.—Papanicolaou (Pap) tests are often diagnosed as atypical squamous cells of undetermined significance (ASC-US). Human papillomavirus (HPV) DNA testing has been proposed as a quality metric for this diagnosis.

Objective.—To measure the frequency of HPV positivity in Pap tests diagnosed as ASC-US and to examine laboratory variables that are associated with institutional deviation from the mean percent of HPV positivity.

Design.—As part of a College of American Pathologist Q-Probes program, 68 participating laboratories retrospectively identified approximately 50 consecutive ASC-US Pap tests that had HPV testing results.

Results.—The mean percentage of HPV positivity for ASC-US was 43.74% among institutions surveyed, but it had a broad distribution, with an SD of 17.77%. Associations were found for lower difference of the institutional mean from the surveyed interinstitutional mean percentage of positive HPV with (1) higher numbers of Pap tests in the past year that had HPV testing, (2) in-house HPV testing, and (3) teaching hospitals. All 3 factors correlated with a larger volume of Pap tests per institution. An association was found between patient age and the probability of a positive HPV result, indicating a dependence upon prevalence of HPV.

Conclusions.—Larger volumes of Pap tests may offer an opportunity to gain greater comfort in interpreting Pap tests. While there is significant variability in interinstitutional HPV-positive rates in ASC-US Pap tests, monitoring the HPV-positive rate in ASC-US Pap tests is a valuable broad measure of quality. Performance beyond 2 SDs of the mean should prompt reassessment of diagnostic criteria used in the evaluation of Pap tests and/or investigation of the prevalence of HPV positivity in the population from which the Pap tests are obtained.
Panels of Immunohistochemical Markers Help Determine Primary Sites of Metastatic Adenocarcinoma
Authors: Park Seog-Yun , Kim Baek-Hee , Kim Jung-Ho , Lee Sun , Kang Gyeong Hoon
Published: February 2021

Context.—Although identification of the primary tumor in patients with metastatic adenocarcinoma has a profound clinical impact, diagnosing the organ of origin is frequently difficult. Because none of the individual immunohistochemical markers used for tissue identification are both site specific and site sensitive, multiple markers are needed to improve the prediction of primary sites.

Objective.—To develop an effective approach to immunohistochemically evaluate metastatic adenocarcinoma for the assignment of a likely primary site of origin.

Design.—Expression profiles of CDX2, cytokeratin (CK) 7, CK20, thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), MUC2, MUC5AC, SMAD4, estrogen receptor (ER), and gross cystic disease fluid protein 15 (GCDFP-15) were generated in adenocarcinomas from 7 primary sites, followed by construction of a decision tree and design of multiple-marker panels. Expression of these markers was evaluated immunohistochemically in 314 primary adenocarcinomas (50 cases each of colorectal, gastric, lung, pancreatic, bile duct, and breast, and 14 cases of ovarian origin) using the tissue array method. Results were validated using 60 cases of metastatic adenocarcinoma with known primaries.

Results.—Organ-specific immunostaining profiles using multiple markers provided high sensitivity, specificity, and positive predictive value in detecting primary adenocarcinomas, as follows: colorectal, TTF-1−/CDX2+/CK7−/CK20+ or TTF-1−/CDX2+/CK7−/CK20−/(CEA+ or MUC2+); ovarian, CK7+/MUC5AC+/TTF-1−/CDX2−/CEA−/GCDFP-15−; breast, GCDFP-15+/TTF-1−/CDX2−/CK7+/CK20− or ER+/ TTF-1−/CDX2−/CK20−/CEA−/MUC5AC−; lung, TTF-1+ or TTF-1−/CDX2−/CK7+/CK20−/GCDFP-15−/ER−/CEA−/ MUC5AC−; pancreaticobiliary, TTF-1−/CDX2−/CK7+/ CEA+/MUC5AC+; and stomach, TTF-1−/CDX2+/CK7+/ CK20−. Overall, these combined phenotypes correctly predicted the tester samples (metastatic adenocarcinomas with known primaries) in 75% of cases.

Conclusions.—Determination of tissue-specific immunostaining profiles is valuable in the diagnostic differentiation of metastatic adenocarcinomas from seven common primary sites and should help to correctly predict the organ of primary tumor origin.
Cytology of Nonneoplastic Occupational and Environmental Diseases of the Lung and Pleura
Authors: Laucirica Rodolfo , Ostrowski Mary L.
Published: February 2021

Context.—Cytologic examination of the respiratory tract has been a useful diagnostic tool when evaluating neoplastic lesions of the respiratory tract. However, we have limited experience in the application of this technique in the management of nonneoplastic occupational and environmental diseases of the lung and pleura. This review focuses on the cytologic characteristics of a variety of occupational lung diseases, grouping them into 2 broad diagnostic categories: reactive cellular changes and noncellular elements. The former includes entities such as reactive mesothelial proliferation, goblet cell metaplasia, Creola bodies, and reserve cell hyperplasia, and the latter encompasses Curschmann spirals, Charcot-Leyden crystals, and asbestos bodies.

Objective.—To illustrate the cytologic features of several nonneoplastic occupational and environmental diseases and correlate the cytology with various etiologic agents.

Data Sources.—Case-derived material and literature review.

Conclusions.—The role of cytology in the diagnosis of nonneoplastic occupational and environmental lung diseases is limited. This may be because more than one agent can elicit a similar host reaction and/or the offending agent can be associated with more than one pathologic process. However, in the appropriate clinical and radiographic setting, the cytology can render valuable diagnostic information. Examples include pulmonary alveolar proteinosis in patients with acute silicoproteinosis and asbestos bodies in bronchoalveolar lavage samples of patients with asbestos exposure.
Transformation of Polycythemia Vera to Chronic Myelogenous Leukemia
Authors: Mirza Imran , Frantz Christine , Clarke Gwendolyn , Voth Arnold J. , Turner Robert
Published: February 2021

Transformation of polycythemia vera to chronic myelogenous leukemia is a rare event. We report 2 women with long-standing polycythemia vera who developed chronic myelogenous leukemia. Both patients had no BCR/ABL1 fusion at the time of polycythemia vera diagnosis but were positive for the fusion at chronic myelogenous leukemia onset. Most patients with polycythemia vera have JAK2V617F mutation. Analysis of an archival bone marrow aspirate sample from 1 patient showed a heterozygous mutation status. The blood and bone marrow samples from the other patient showed the presence of homozygous JAK2V617F mutation and BCR/ABL1 fusion. The possible pathogenesis of such an event is discussed in the light of current literature.
A Pilot Study of Vasculogenic Mimicry Immunohistochemical Expression in Hepatocellular Carcinoma
Authors: Guzman Grace , Cotler Scott J. , Lin Amy Y. , Maniotis Andrew J. , Folberg Robert
Published: February 2021

Context.—The “de novo” formation of fluid-conducting patterns by tumor cells, termed vasculogenic mimicry (VM), is associated with increased mortality in many different solid tumors.

Objective.—To identify VM patterns in hepatocellular carcinoma (HCC) and to determine whether these patterns were associated with more rapid tumor recurrence after orthotopic liver transplantation.

Design.—Subjects included 20 patients who underwent orthotopic liver transplantation and were found to have HCC in the liver explant. Samples from 5 normal postmortem livers and 5 explanted livers with hepatitis C virus cirrhosis without HCC served as control tissues. Patterned matrix VM expression in HCC was identified by the presence of laminin-positive loops surrounding packets of tumor cells. Time to HCC recurrence after orthotopic liver transplantation was compared between patients with and without patterned VM expression. The relationships among VM in HCC, cause of chronic liver disease, serum α-fetoprotein level at the time of diagnosis, tissue expression by epidermal growth factor receptor, and endothelial markers including vascular endothelial growth factor and CD31 were assessed.

Results.—Patterned matrix VM was identified in 11 of 20 primary HCC tissue samples. Vasculogenic mimicry was absent in all 10 control cases and was not identified in any area of dysplasia. The expression of VM in HCC lesions in liver explants was associated with more rapid posttransplant recurrence (P = .01). Vasculogenic mimicry was not associated with the cause of liver disease, serum α-fetoprotein level at time of diagnosis, or expression of epidermal growth factor receptor, vascular endothelial growth factor, or CD31.

Conclusions.—Vasculogenic mimicry of the patterned matrix type is present in hepatocellular carcinoma and is associated with tumor recurrence after orthotopic liver transplantation. Vasculogenic mimicry lesions are not associated with endothelial markers in HCC.
Polymorphisms inTGFβandTNFαAre Associated With the Myelodysplastic Syndrome Phenotype
Authors: Powers Martin P. , Nishino Ha , Luo Yamin , Raza Alina , Vanguri Amulya , Rice Lawrence , Zu Youli , Chang Chung-Che(Jeff)
Published: February 2021

Context.—Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis, excessive apoptosis, and the aberrant expression of a number of cytokines. The genes encoding these cytokines are significantly polymorphic. It is unknown whether these cytokine polymorphisms are associated with, and may therefore be playing a role in the pathogenesis of, MDS.

Objective.—To determine if certain polymorphisms in the tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β) cytokines are overrepresented in a cohort of patients with MDSs.

Design.—DNA was isolated from the peripheral blood or bone marrow aspirate of 21 patients with MDS. The genotypes for 4 different polymorphisms, 2 in TNFα and 2 in TGFβ1, were determined using single-specific-primer polymerase chain reaction. The allele and genotype frequencies were compared with similar populations in the National Cancer Institute SNP500 database.

Results.—In our MDS population, the −308A/A genotype of the TNFα gene and the TGFβ1 allele +29T and genotype +29T/T, each associated with higher levels of expression, were overrepresented in our MDS population.

Conclusions.—Polymorphisms associated with increased expression in the cytokines TNFα and TGFβ1 are overrepresented in the MDS population suggesting that increased TNF-α and TGF-β1 activity may contribute to the susceptibility and/or pathogenesis of MDS. Further studies with larger sample sizes are warranted to confirm our observation.
Tissue Handling for Genome-Wide Expression Analysis: A Review of the Issues, Evidence, and Opportunities
Authors: Medeiros Fabiola , Rigl C. Ted , Anderson Glenda G. , Becker Shawn H. , Halling Kevin C.
Published: February 2021

Context.—Molecular diagnostic applications that use microarrays to analyze large numbers of genes simultaneously require high-quality mRNA. As these genome-wide expression assays become more commonly used in medical practice, pathologists and oncologists will benefit from understanding the importance of obtaining high-quality RNA in order to generate reliable diagnostic and prognostic information, especially as these relate to cancer.

Objective.—To review the effects that different tissue preservation techniques have on RNA quality and to provide practical advice on changes in tissue acquisition and handling that may soon be needed for certain clinical situations.

Data Sources.—A review of recent literature on RNA quality, tissue fixation, cancer diagnosis, and gene expression analysis.

Conclusions.—Studies have consistently shown that frozen tissue yields more intact RNA than formalin-fixed, paraffin-embedded tissue. The chemical modification, cross-linking, and fragmentation caused by formalin fixation often render RNA unsuitable for microarray analysis. Thus, when expression analysis involving hundreds or more than 1000 gene markers is contemplated, pathologists should consider freezing a specimen within half an hour (preferably within minutes) of surgical resection and storing it at −80°C or below. In coming years, pathologists will need to work closely with oncologists and other clinicians to determine when saving frozen tissue for microarray expression analysis is both practical and necessary. In select cases, the benefit of implementing a few extra tissue-handling steps may improve diagnostic and prognostic capability.
Thrombotic Microangiopathy in Cocaine Abuse–Associated Malignant Hypertension: Report of 2 Cases With Review of the Literature
Authors: Gu Xin , Herrera Guillermo A.
Published: February 2021

Cocaine is one of the most commonly used illicit drugs. Acute renal failure is an emergent complication in patients with acute cocaine intoxication. It is well known that rhabdomyolysis and vasoconstriction can be important pathogenetic mechanisms resulting in acute renal failure in these patients. Clinically, although cocaine abuse is associated with elevated blood pressure, persistent accelerated hypertension reaching levels diagnostic of malignant hypertension is uncommon. Cocaine-induced malignant hypertension associated with morphologic features of thrombotic macroangiopathy has been rarely mentioned in the literature. We report 2 cases of cocaine abuse–associated malignant hypertension with renal failure. Kidney biopsies revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop acute renal failure and malignant hypertension.
Diffuse Filiform Polyposis With Unique Histology Mimicking Familial Adenomatous Polyposis in a Patient Without Inflammatory Bowel Disease
Authors: Oakley III Gerard J. , Schraut Wolfgang H. , Peel Robert , Krasinskas Alyssa
Published: February 2021

Filiform polyposis is an uncommon entity that is most often encountered in the colon of patients with a history of inflammatory bowel disease (IBD). Filiform polyposis is characterized by a large number of “wormlike” polyps lined by histologically normal colonic mucosa. These polyps can mimic adenomatous polyps. Only rare cases without a history or evidence of IBD have been reported. Neuromuscular and vascular hamartoma of the small bowel is a rare, focal disorder characterized by disorganized smooth muscle fascicles throughout the submucosa accompanied by fibrosis, nerve fibers, ganglion cells, and vessels. To our knowledge, there is only one report of this lesion in the large bowel (cecum), where it presented as a mass. Here we report the case of a 50-year-old man with no known history or symptoms of IBD presenting with filiform polyposis involving the entire colon, clinically mimicking familial adenomatous polyposis, and showing histologic features similar to neuromuscular and vascular hamartoma of the small bowel.
Bernard-Soulier Syndrome: An Inherited Platelet Disorder
Authors: Pham Angie , Wang Jun
Published: February 2021

Bernard-Soulier syndrome is an inherited platelet disorder, which is transmitted in an autosomal recessive manner. This syndrome is characterized by variable thrombocytopenia and large defective platelets. Bernard-Soulier syndrome often presents early with bleeding symptoms, such as epistaxis, ecchymosis, menometrorrhagia, and gingival or gastrointestinal bleeding. Diagnosis can be confirmed by platelet aggregation studies and flow cytometry. The differential diagnosis includes the other inherited giant platelet disorders, as well as von Willebrand disease and immune thrombocytopenia purpura. Treatment is generally supportive with platelet transfusions when absolutely necessary and avoidance of antiplatelet medications. Recombinant activated factor VII and desmopressin have been used in attempts to shorten bleeding times; however, no definitive studies regarding their effectiveness have been reported.
Assessment Monitoring of Laboratory Critical Values: A College of American Pathologists Q-Tracks Study of 180 Institutions
Authors: Wagar Elizabeth A. , Stankovic Ana K. , Wilkinson David S. , Walsh Molly , Souers Rhona J.
Published: February 2021

Context.—Critical laboratory value reporting is a highly visible and essential key activity for clinical laboratories.

Objective.—To measure critical laboratory value reporting in multiple institutions over time and to examine the practice patterns and demographic factors associated with sustained improvement in critical value reporting.

Design.—A longitudinal cohort study of 180 clinical laboratories that provided quarterly critical values reporting data for 2 to 16 quarters was conducted using a uniform definition of successful caregiver notification. Mixed linear model analysis of the 2001 through 2004 dataset was performed.

Results.—A decrease in total and inpatient rates of undocumented critical values per 1000 results was associated with (1) the American Association of Blood Banks inspection within the past 2 years (P = .01, for both total and inpatient rates); (2) unit secretary/clerical staff not authorized to accept inpatient critical value notification (P = .004 [total] and .001 [inpatient]); and (3) the mandatory practice of requiring notification of health care providers when handling inpatients known to have results repeatedly in the critical range (P = .01, for both total and inpatient rates). Continued participation in the Q-Tracks monitoring program was associated with significant and progressive improvement in total, inpatient, and outpatient critical value reporting (P = .02, .01, and .003, respectively).

Conclusions.—Critical value reporting improved as the duration of participation in the Q-Tracks monitoring program increased. Improved total and inpatient critical value reporting was associated with factors that may be markers for institutions with priorities of quality management and enhanced communication with responsible caregivers.
Flow Cytometric Detection of ZAP-70 in Chronic Lymphocytic Leukemia: Correlation With Immunocytochemistry and Western Blot Analysis
Authors: Slack Graham W. , Wizniak Juanita , Dabbagh Laith , Shi Xinzhe , Gelebart Pascal , Lai Raymond
Published: February 2021

Context.—Expression of ZAP-70 in chronic lymphocytic leukemia (CLL) predicts worse clinical outcome in patients with early-stage disease. It has become important to include ZAP-70 in the immunophenotyping panel used to diagnose CLL, commonly performed by flow cytometry (FC). Nevertheless, the methodology used to detect ZAP-70 by FC has not been extensively evaluated.

Objective.—To describe our FC method for detecting ZAP-70 in CLL and assess whether this assay is useful in estimating the ZAP-70 protein level in CLL cells.

Design.—ZAP-70 expression was assessed by FC in 45 consecutive newly diagnosed CLL patients, and the results were correlated with those of immunocytochemistry and Western blot analysis.

Results.—With >25% ZAP-70–positive B cells as the cutoff, the FC results had a perfect concordance with those of immunocytochemistry (39/39, 100%) and Western blot analysis (7/7, 100%). The use of autofluorescence controls was found to be superior to other alternatives. Overall, 19 (42%) of 45 cases were ZAP-70 positive in our series. Since only 7 cases (16%) had >20% to 30% ZAP-70–positive B cells, the cutoff of >25% readily separated CLL into positive and negative groups in most cases. ZAP-70 positivity was significantly associated with atypical morphology but not other laboratory parameters evaluated.

Conclusions.—With proper specimen processing and the use of directly fluorescence-conjugated anti–ZAP-70 antibody, one can readily incorporate ZAP-70 into the routine FC study panel for CLL. Our data suggest that FC is a rapid and useful method to estimate the ZAP-70 protein expression level in CLL.