bluuebunny/crossref_metadata_2025 huggingface dataset:
Interobserver Agreement on Microfollicles in Thyroid Fine-Needle Aspirates
Authors: Renshaw Andrew A. , Wang Edward , Wilbur David , Hughes Jonathan H. , Haja Jennifer , Henry Michael R.
Published: February 2021

Context.—Although microfollicles are a well-known feature of follicular neoplasms in fine-needle aspirates of the thyroid, the level of agreement about classifying groups as microfollicles is not known.

Objective.—To determine what features are present in groups that are consistently classified as microfollicles.

Design.—We showed 45 small groups of follicular cells each composed of fewer than 50 cells from fine-needle aspirates of the thyroid to 12 members of the College of American Pathologists Cytopathology Committee, who then classified the groups into microfollicles, macrofollicles, and indeterminate groups.

Results.—Twenty groups were consistently classified as microfollicles, 7 groups as macrofollicles, and 18 groups as indeterminate. Cases that were consistently classified as microfollicles were composed of fewer than 15 cells (19/ 20 cases), were arranged in a circle with a lumen (13/20 cases) that was at least two-thirds complete (12/20 cases), and were flat (18/20 cases). Cases that were classified as macrofollicular had between 8 and 35 cells, were arranged in sheets composed of at least 15 cells (5/7 cases) or rows of 8 cells (2/7 cases), and were flat (7/7 cases). In contrast, cases that were indeterminate were composed of either 3-dimensional groups (5/18 cases), flat groups of fewer than 10 cells (11/18 cases), or single cells (1/18 cases).

Conclusion.—Not all small groups of follicular cells are consistently classified as microfollicles, and some are more often classified as macrofollicles. The criteria described here for reproducible microfollicles (<15 cells, arranged in a circle that is at least two-thirds complete, and flat) may help improve the agreement in classification of microfollicles and lead to more consistent classification of thyroid fine-needle aspirates.
Hepatic Mesenchymal Hamartoma: A Short Review
Authors: Siddiqui Masood A. , McKenna Barbara J.
Published: February 2021

Hepatic mesenchymal hamartoma is a hamartomatous growth of mesenchymal tissue in the liver of uncertain etiology. It is a space-occupying lesion that can potentially compress adjacent organs resulting in various complications including death. Hepatic mesenchymal hamartoma is characterized by proliferation of variably myxomatous mesenchyme and malformed bile ducts. The differential diagnosis includes other pediatric hepatic masses. The diagnosis is typically made during infancy, and complete resection is invariably curative.
Granulocytic Sarcoma of the Small Intestine
Authors: Kohl Shane K. , Aoun Patricia
Published: February 2021

Granulocytic sarcoma is an extramedullary tumor of myeloblasts and/or immature myeloid cells, which can develop at any anatomic site and is often a forerunner to the development of acute myelogenous leukemia. Granulocytic sarcoma of the gastrointestinal tract most frequently involves the small intestine and most often presents with abdominal pain and obstruction. Pathologists must consider granulocytic sarcoma in any mass of unknown origin with a diffusely infiltrating population of tumor cells, as the diagnosis is often initially unrecognized, especially in nonleukemic patients. Multiple ancillary modalities are available to assist pathologists in making the correct diagnosis so that appropriate therapy can be initiated.
An Algorithmic Approach to the Brain Biopsy—Part II
Authors: Prayson Richard A. , Kleinschmidt-DeMasters B. K.
Published: February 2021

Context.—The formulation of appropriate differential diagnoses for a slide is essential to the practice of surgical pathology but can be particularly challenging for residents and fellows. Algorithmic flow charts can help the less experienced pathologist to systematically consider all possible choices and eliminate incorrect diagnoses. They can assist pathologists-in-training in developing orderly, sequential, and logical thinking skills when confronting difficult cases.

Objective.—To present an algorithmic flow chart as an approach to formulating differential diagnoses for lesions seen in surgical neuropathology.

Design.—An algorithmic flow chart to be used in teaching residents.

Results.—Algorithms are not intended to be final diagnostic answers on any given case. Algorithms do not substitute for training received from experienced mentors nor do they substitute for comprehensive reading by trainees of reference textbooks. Algorithmic flow diagrams can, however, direct the viewer to the correct spot in reference texts for further in-depth reading once they hone down their diagnostic choices to a smaller number of entities. The best feature of algorithms is that they remind the user to consider all possibilities on each case, even if they can be quickly eliminated from further consideration.

Conclusions.—In Part II, we assist the resident in arriving at the correct diagnosis for neuropathologic lesions containing granulomatous inflammation, macrophages, or abnormal blood vessels.
Light-Chain–Mediated Acute Tubular Interstitial Nephritis: A Poorly Recognized Pattern of Renal Disease in Patients With Plasma Cell Dyscrasia
Authors: Gu Xin , Herrera Guillermo A.
Published: February 2021

Context.—Acute renal failure may be the first clinical presentation in patients with plasma cell dyscrasia. Recognition of the unusual interstitial inflammatory lesion associated with monoclonal light chains and renal failure described herein is important to guide clinicians in requesting appropriate tests to confirm plasma cell dyscrasia and providing adequate treatment.

Objective.—To describe an unusual pattern of tubular interstitial nephritis in patients with underlying plasma cell dyscrasia characterized by an interstitial inflammatory reaction associated with deposition of light chains along tubular basement membranes.

Design.—Eight cases of light-chain–mediated acute tubular interstitial nephritis were identified from the archives of 4296 kidney biopsy specimens. In all cases, routine light microscopic examination, direct immunofluorescence, and electron microscopic examination were performed. Ultrastructural immunogold labeling was performed in specimens with inconclusive findings and in specimens from patients with no clinical history of plasma cell dyscrasia.

Results.—All patients presented with acute renal failure. Light microscopy revealed acute tubular interstitial nephritis. In some of the cases, direct immunofluorescence and electron microscopy failed to show definitive evidence of light-chain deposition along tubular basement membranes. Ultrastructural immunogold labeling aided the demonstration of monotypical light chains along some tubular basement membranes. No light chains were present in other renal compartments.

Conclusions.—Accumulation of light chains along tubular basement membranes may induce an interstitial process that mimics acute tubular interstitial nephritis. Recognition of this unusual pattern of renal disease in patients with plasma cell dyscrasia requires ancillary diagnostic techniques.
Patient Safety in the Clinical Laboratory: A Longitudinal Analysis of Specimen Identification Errors
Authors: Wagar Elizabeth A. , Tamashiro Lorraine , Yasin Bushra , Hilborne Lee , Bruckner David A.
Published: February 2021

Context.—Patient safety is an increasingly visible and important mission for clinical laboratories. Attention to improving processes related to patient identification and specimen labeling is being paid by accreditation and regulatory organizations because errors in these areas that jeopardize patient safety are common and avoidable through improvement in the total testing process.

Objective.—To assess patient identification and specimen labeling improvement after multiple implementation projects using longitudinal statistical tools.

Design.—Specimen errors were categorized by a multidisciplinary health care team. Patient identification errors were grouped into 3 categories: (1) specimen/requisition mismatch, (2) unlabeled specimens, and (3) mislabeled specimens. Specimens with these types of identification errors were compared preimplementation and postimplementation for 3 patient safety projects: (1) reorganization of phlebotomy (4 months); (2) introduction of an electronic event reporting system (10 months); and (3) activation of an automated processing system (14 months) for a 24-month period, using trend analysis and Student t test statistics.

Results.—Of 16 632 total specimen errors, mislabeled specimens, requisition mismatches, and unlabeled specimens represented 1.0%, 6.3%, and 4.6% of errors, respectively. Student t test showed a significant decrease in the most serious error, mislabeled specimens (P < .001) when compared to before implementation of the 3 patient safety projects. Trend analysis demonstrated decreases in all 3 error types for 26 months.

Conclusions.—Applying performance-improvement strategies that focus longitudinally on specimen labeling errors can significantly reduce errors, therefore improving patient safety. This is an important area in which laboratory professionals, working in interdisciplinary teams, can improve safety and outcomes of care.
Molecular Detection of Transfusion Transmitted Virus Coinfection With Some Hepatotropic Viruses
Authors: Zaki Maysaa El-Sayed , Hady, MD Nagy Abd El
Published: February 2021

Context.—A novel human DNA virus was isolated from the serum of a patient with posttransfusion hepatitis; it was named transfusion transmitted virus (TTV).

Objective.—To ascertain the influence of TTV (detected by polymerase chain reaction amplification of a conserved region of the viral genome) coinfection in individuals infected with hepatitis viruses (A, B, and C) and to investigate the putative role played by TTV in hepatic dysfunction in individuals with acute non-A-E hepatitis.

Design.—Sixty-two patients with viral hepatitis were included in the study in addition to 18 blood donors. Viral study of 4 hepatotropic viruses (A, B, C, and E) was carried out. Study for TTV DNA was performed by nested polymerase chain reaction.

Results.—The prevalence of TTV was not statistically different between hepatitis patients and blood donors, and it was not correlated to the levels of the hepatic aspartate aminotransferase and alanine aminotransferase between individuals evidencing dual infection with hepatitis B and C viruses and healthy blood donors. However, in the group of patients with viral hepatitis of unknown etiology (non-A-E), those evidencing TTV viremia had statistically significant lower levels of alanine aminotransferase (P = .03) and aspartate aminotransferase (P = .04) than those who were TTV negative.

Conclusions.—We can conclude that TTV is a frequent virus isolated from patients with various types of viral hepatitis, from cases of hepatitis without obvious viral agent, and from the healthy population. TTV has no effect on biochemical markers of associated viral hepatitis. It may be associated with a mild form of non-A-E hepatitis.
Nucleophosmin Gene Mutations in Acute Myeloid Leukemia
Authors: Chen Weina , Rassidakis Georgios Z. , Medeiros L. Jeffrey
Published: February 2021

Context.—Heterozygous mutation of the nucleophosmin gene (NPM1) has recently been described as one of the most frequent genetic lesions in acute myeloid leukemia (AML).

Objective.—(1) To discuss the clinical, morphologic, immunophenotypic, and genetic features of AML with NPM1 gene mutations, along with various detection methods, (2) To explore the mechanisms by which NPM1 gene mutations contribute to leukemogenesis.

Data sources/extraction.—Data were analyzed from 7 recently published papers.

Results.—NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count. There is no significant age difference. NPM1-mutated AML is preferentially associated with AML with monocytic differentiation (in particular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations, and a trend toward favorable clinical outcome, especially in patients without FLT3 gene mutation. NPM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies. These mutations may contribute to leukemogenesis, at least in part, through disruption of the p14ARF (alternative reading frame) MDM2-p53 pathway and centrosomal duplication.

Conclusions.—Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups. Exploring the mechanisms may lead to a better understanding of how mutant NPM protein becomes leukemogenic, thereby providing insights for the development of new chemotherapeutic agents.
Follicular Dendritic Cell Sarcoma Arising in the Dura Mater of the Spine
Authors: Choi Jung Woo , Lee Ju-Han , Kim Aeree , Kim Chul Hwan , Chae Yang Seok , Kim Insun
Published: February 2021

There have been some individual case reports and a few large series of reports describing the clinicopathologic features of follicular dendritic cell sarcoma. This tumor originates from the dendritic cells of lymphoid follicles and is extremely rare in the extranodal location. We report the case of a 68-year-old man who presented with low back pain. A mass was found in the lumbar dura mater and extended to the right epidural space. The tumor was composed of nodules, sheets, and interlacing fascicles of oval-to-spindle cells intermingled with the dense infiltrates of small lymphocytes. Immunohistochemical staining revealed that the tumor cells were positive for CD21, CD23, CD35, and clusterin, and focally positive for CD68, CD20, and CD79a. To our knowledge, this is the first case of follicular dendritic cell sarcoma occurring in the dura mater of the spine.
Vascular Adrenal Cysts: A Brief Review of the Literature
Authors: Carvounis Eleni , Marinis Athanasios , Arkadopoulos Nikolaos , Theodosopoulos Theodosios , Smyrniotis Vassilios
Published: February 2021

Adrenal cysts are rare and form a heterogeneous group of lesions that includes (a) parasitic cysts, (b) epithelial cysts, (c) pseudocysts, and (d) endothelial cysts. There is evidence (immunohistochemical and ultrastructural) that both pseudocysts and endothelial cysts are variants of vascular cysts. Adrenal vascular cysts account for 84% of adrenal cysts. They are more common in women and present clinically with abdominal pain or are incidental findings. Their imaging features are not specific. Grossly, both types of adrenal vascular cysts are encapsulated. Pseudocysts are unilocular, thick-walled, and devoid of endothelial lining, whereas endothelial cysts are thin-walled, multilocular, and lined by endothelium. Adrenal vascular cysts probably originate from a preexisting vascular hamartoma. The treatment of choice is surgical excision. The prognosis is excellent.
Leukemia/Lymphoma in Cerebrospinal Fluid: Distinguishing Between Cases That Performed Well and Poorly in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology
Authors: Renshaw Andrew A. , Hughes Jonathan H. , Wang Edward , Haja Jennifer , Wilbur David , Henry Michael R. , Moriarty Ann T.
Published: February 2021

Context.—Although the cytologic features of leukemia/ lymphoma in cerebrospinal fluid specimens are well known, the correlation of these features with the ability of cytologists to identify this tumor have not been well studied.

Objective.—To identify the morphologic features of leukemia/lymphoma in cerebrospinal fluid that are associated with good performance and poor performance in an educational interlaboratory comparison program; and to identify the morphologic features associated with how well a slide performs with regard to its reference diagnosis.

Design.—The performance of 147 cases of leukemia/ lymphoma in the College of American Pathologists Interlaboratory Comparison Program in Non-gynecologic Cytology was analyzed. The cytologic features of a subset of 31 cases composed of relatively equal numbers of Romanowsky-stained and Papanicolaou-stained specimens were further evaluated, and those that performed poorly (n = 12) were compared with those that performed extremely well (n = 19).

Results.—For all cases of leukemia/lymphoma in the program, the rate of misclassification as benign for cases with Papanicolaou stain was significantly higher than for those with Romanowsky stain (9.5% vs 2.6%, P < .001). Compared with cases that performed well, slides that performed poorly were more likely to have less than 200 abnormal cells (42% vs 5%, P = .02). The size of the tumor cells and preservation were not significant.

Conclusion.—Cases of specimens of leukemia/lymphoma in cerebrospinal fluid are more likely to be misdiagnosed as benign if they are Papanicolaou-stained or have 200 abnormal cells.
Determination of Ultrafilterable Prolactin: Elimination of Macroprolactin Interference With a Monomeric Prolactin-Selective Sample Pretreatment
Authors: Quinn Adam M. , Rubinas Tara C. , Garbincius C. Jean , Holmes Earle W.
Published: February 2021

Context.—Macroprolactin (macroPRL), present in as many as 25% of serum specimens with elevated serum prolactin concentrations, can cause apparent hyperprolactinemia in the absence of clinical features and lead to unnecessary clinical, laboratory, and neuroradiological workups.

Objective.—To develop an ultrafiltration method that eliminates macroPRL interference from PRL immunoassays.

Design.—The method involves centrifugation of undiluted serum in a Centricon-100 filter device followed by a PRL assay of the serum ultrafiltrate.

Results.—Ultrafiltrates prepared by this technique are devoid of gamma globulins and contain (mean ± SE) 19% ± 7% of the albumin concentration of the original serum. These ultrafiltrates contain 85% ± 7% of the total PRL immunoreactivity of serum spiked with 23 kd recombinant human prolactin (rHuPRL) and less than 2% of the 50 kd big PRL (bPRL) of whole serum. The fractional recovery of ultrafilterable PRL (uPRL) from serum samples of 54 female patients was 0.78 (confidence interval 0.73–0.83) of the total. The run-to-run coefficient of variation of the uPRL assay was 4.3%. The uPRL concentration (mean ± SD) in a group of healthy female controls was 8.0 ± 3.1 ng/mL.

Conclusions.—Ultrafiltration is a rapid and simple method for eliminating analytical interference by macroPRL. Ultrafiltrates can be analyzed by most, if not all, currently available PRL immunoassays and represent a practical and precise alternative to gel filtration chromatography for the estimation of the monomeric prolactin concentration of serum.
Blood Transfusions Leading to Apparent Hemoglobin C, S, and O-Arab Hemoglobinopathies
Authors: Kozarski Tzvetan B. , Howanitz Peter J. , Howanitz Joan H. , Lilic Nenad , Chauhan Yeshpal S.
Published: February 2021

Context.—Apparent hemoglobinopathies caused by blood transfusions rarely have been reported in the scientific literature.

Objective.—To interpret the abnormal hemoglobins appearing as small peaks on hemoglobin chromatograms or electrophoresis membranes.

Design.—In the clinical laboratories of a university hospital and a metropolitan hospital affiliated with a medical school, we interpreted hemoglobin chromatograms and electrophoresis membranes; correlated them with patients' medical, laboratory, and transfusion records; and when possible, identified the abnormal hemoglobin in the donors' transfusion segments.

Results.—We detected 52 incidences of apparent hemoglobinopathies in 32 recipients caused by blood transfusion, of which 46 were hemoglobin C, 4 were hemoglobin S, and 2 were hemoglobin O-Arab. When first detected, the abnormal hemoglobins in recipients ranged from 0.8% to 14% (median, 5.6%). Multiple transfusions with abnormal hemoglobins occurred in 11 patients with 2 patients receiving hemoglobin C blood 5 separate times. One patient received hemoglobin C and later S, and another patient received C and later O-Arab.

Conclusions.—Apparent hemoglobinopathies caused by blood transfusions are far more common than previously reported and represent diagnostic challenges. Misdiagnosis could lead to unnecessary testing, treatment, and counseling. If a hemoglobinopathy from a unit of transfused blood is identified in a recipient, we recommend notifying the donor of that abnormality.
Reduced Interference by Phenothiazines in Amphetamine Drug of Abuse Immunoassays
Authors: Melanson Stacy E. F. , Lee-Lewandrowski Elizabeth , Griggs David A. , Long William H. , Flood James G.
Published: February 2021

Context.—Emergency department physicians frequently request urine drug screens, but many are unaware of their limitations, including the potential for false-positive results. Promethazine, a phenothiazine derivative, is used for the treatment of allergies, agitation, nausea, and vomiting. Many patients taking promethazine are subject to urine drug screens and any potential interferences are important to recognize.

Design.—During an 11-month period, all patients presenting to the Massachusetts General Hospital emergency department who had a finding of promethazine in their serum drug screen, and who also had a urine drug screen performed, were selected for inclusion in the study. The urine drug screen results (n = 22 patients/samples) were then studied.

Objective.—To determine if promethazine use can cause false-positive urine amphetamine results in widely used drug of abuse immunoassays.

Results.—Thirty-six percent of patients taking promethazine had false-positive test results for urine amphetamines using the EMIT II Plus Monoclonal Amphetamine/Methamphetamine Immunoassay. Sixty-four percent of patients showed cross-reactivity greater than 20% higher than the blank calibrator rate. In a separate, related study, no promethazine-induced false-positive results were seen with the EMIT II Plus, Triage, and TesTcard 9 amphetamine assays, or the Triage methamphetamine assay. Reduced chlorpromazine interference was also seen with these other assays.

Conclusions.—False-positive urine amphetamine results can be obtained in patients taking promethazine. Promethazine metabolite(s), and not the parent compound, are the likely cause of these urine false-positive results obtained with EMIT II Plus Monoclonal Amphetamine/Methamphetamine Immunoassay. Immunoassays from different manufacturers can have very different “interference” profiles, which the pathologist and laboratory scientist must understand and relay to clinicians.
Pseudallescheriasis: A Summary of Patients From 1980–2003 in a Tertiary Care Center
Authors: Jayamohan Yasodah , Ribes Julie A.
Published: February 2021

Context.—Pseudallescheria boydii is being increasingly isolated in immunocompromised patients.

Objective.—To present 24 years of data on patients from whom P boydii was isolated.

Design.—Retrospective review of archival laboratory data and patient charts at a tertiary care hospital with a full service mycology laboratory. All patients evaluated from whom P boydii was isolated between 1980 and 2003 were included in this study.

Results.—Twenty-four patients from whom P boydii had been isolated were identified. The majority of cases represented pulmonary involvement, particularly in cystic fibrosis patients. Three additional patients had infections in surgical or traumatic lesions of the head and 4 had disseminated disease. Invasive disease was associated with underlying malignancy or transplantation and resulted in death secondary to the fungal infection in the majority of cases.

Conclusions.—Pseudallescheria boydii may cause significant disease in humans. Invasive infections with P boydii are often misdiagnosed and inadequately treated. Aggressive treatment of locally invasive disease may be of value in preventing rapid and fatal dissemination with this organism.
Fine-Needle Aspirates of Hepatocellular Carcinoma That Are Misclassified as Adenocarcinoma: Correlating Cytologic Features and Performance in the College of American Pathologists Nongynecologic Cytology Program
Authors: Renshaw Andrew A. , Haja Jennifer , Wilbur David C. , Miller Theodore R.
Published: February 2021

Context.—The cytologic features of hepatocellular carcinoma in fine-needle aspirates are well described. While some cases are easily distinguished from adenocarcinoma, poorly differentiated tumors can be difficult to differentiate. We reviewed the cytologic findings for 9 aspirates from cases of hepatocellular carcinoma that were frequently misclassified as adenocarcinoma and compared them with another 10 cases of hepatocellular carcinoma that were rarely misclassified.

Objective.—To compare the cytologic features of cases of hepatocellular carcinoma in fine-needle aspirates that were both rarely and frequently misclassified as adenocarcinoma.

Design.—We reviewed a total of 762 interpretations from 19 different cases of hepatocellular carcinoma in liver fine-needle aspiration specimens in the College of American Pathologists Nongynecologic Cytology Program and correlated the cytologic features with performance in the program.

Results.—Overall, cases that were frequently misclassified as adenocarcinoma were misclassified 39% of the time (range, 18%–70%), while cases that were rarely misclassified were classified as adenocarcinoma 2% of the time (range, 0%–8%). The difference was statistically significant (P < .001). On review, 4 cytologic patterns were found. The most common pattern for cases that were rarely misclassified was prominent trabeculae of cells and endothelial cells wrapping the trabeculae (6/10 cases vs 2/9 cases that were frequently misclassified). The most common pattern among cases that were frequently misclassified was clusters of cells with granular cytoplasm and associated stripped nuclei (5/9 cases vs 2/10 cases that were rarely misclassified). However, the distribution of neither pattern was significantly different (P = .16 for both). One case with large atypical granular cells, as seen in the fibrolamellar variant, was rarely misclassified. The remaining 3 cases (2 frequently misclassified, 1 rarely misclassified) had a nonspecific a pattern of cells with granular cytoplasm without obvious trabeculae or stripped nuclei.

Conclusion.—Correctly classifying hepatocellular carcinoma by cytology alone remains a significant challenge. While some patterns are more common in cases that performed well and other patterns are more common in cases that performed poorly, there was no significant difference in the distribution of these patterns. These results suggest that people should support their interpretations of aspirations with either immunologic evidence, biopsy evidence, or review by an experienced cytopathologist. Continued educational efforts in this area may be of value.
Changes and Problematic Areas in Interpretation of the AJCC Cancer Staging Manual, 6th Edition, for Breast Cancer
Authors: Connolly James L.
Published: February 2021

Context.—Tumor stage is an important prognostic factor and guides therapy for patients with breast cancer. The American Joint Committee on Cancer (AJCC) periodically updates the staging standards. This article describes changes and problematic areas in interpretation of the AJCC Cancer Staging Manual, 6th edition, for breast cancer and provides practical advice.

Objectives.—This article reviews the variety of practical problems that can arise during assessment of the pathologic stage and other prognostic/predictive factors included in the College of American Pathologists Checklist for Evaluation of Resected Breast Cancers. Potential practical difficulties that can arise include the classification of lymph nodes, for example, isolated tumor cells, micrometastases, metastases, and the combination of locations. Another difficult area is assignment of a correct size. The use of clinical and imaging studies for optimal pathologic staging is discussed. Finally, the proper use of the TNM descriptors is described.

Conclusions.—The various practical problems that can arise during the assessment of important prognostic and predictive features included in the College of American Pathologists Checklist for Evaluation of Resected Breast Cancers are discussed, and specific recommendations are given.
Problems in Pathologic Staging of Lung Cancer
Authors: Marchevsky Alberto M.
Published: February 2021

Context.—Tumor stage is the most important prognostic and predictive factor for patients with lung cancer, the most lethal neoplasm in the United States. It is used by thoracic surgeons, radiation therapists, and oncologists to determine whether patients with these neoplasms will be treated surgically with curative intent or with palliative radiation therapy and/or chemotherapy.

Objective.—To review the variety of practical problems that can arise during the assessment of the pathologic stage and other prognostic/predictive factors included in the College of American Pathologist checklist for evaluation of resected lung neoplasms.

Data Sources.—Potential practical difficulties that can arise during the pathologic staging of lung cancer patients include the distinction between pT1, pT2, and pT3 lesions based on their location and the presence of visceral pleura and/or parietal pleura invasion; the differential diagnosis between multiple synchronous or metachronous primary lung neoplasms (pT1m) and intrapulmonary metastasis of non-small cell carcinoma of the lung (pT4 or pM1 according to their location); and the role of the recent American Joint Committee on Cancer terminology for the classification of lymph nodes (isolated tumor cells, micrometastases, and metastases).

Conclusions.—The variety of practical problems that can arise during the assessment of important prognostic and predictive features such as resection margin status and evaluation of lymphovascular invasion are reviewed. A brief discussion of the assessment of the effects of neoadjuvant therapy on resected lung neoplasms is also included.
HER-2 Fluorescence In Situ Hybridization: Results From the Survey Program of the College of American Pathologists
Authors: Persons Diane L. , Tubbs Raymond R. , Cooley Linda D. , Dewald Gordon W. , Dowling Patricia K. , Du Emma , Mascarello James T. , Rao Kathleen W. , Wilson Kathleen S. , Wolff Daynna J. , Habegger-Vance Gail
Published: February 2021

Context.—Fluorescence in situ hybridization (FISH) is a common method used to determine HER-2 status in breast cancer. Limited information is available concerning reproducibility of FISH in determining HER-2 gene amplification.

Objective.—To present proficiency testing results of FISH for HER-2 conducted by the Cytogenetics Resource Committee of the College of American Pathologists/American College of Medical Genetics.

Design.—During the past 5 years, unstained sections from 9 invasive breast carcinomas were used for HER-2 FISH proficiency testing, allowing for comparison of FISH results among a large number of laboratories. Additional data were collected using an educational (ungraded) challenge and supplemental questions in the surveys.

Results.—The number of laboratories participating in HER-2 FISH proficiency testing has increased steadily during the past 5 years (from 35 in 2000 to 139 in 2004). Reproducibility of test results among laboratories was excellent for breast tumors with low copy number (no HER-2 amplification) and for breast tumors with high copy number (HER-2 amplification). However, there was considerable variation in interpretation of results for a tumor with low-level HER-2 amplification that was tested on 2 separate occasions. Responses to supplemental questions indicated that there was a need for consensus on the use of a separate equivocal/borderline interpretative category and the need for standardization of cutoff values used to define interpretative categories.

Conclusions.—The College of American Pathologists proficiency survey programs provide useful information concerning the reproducibility of clinical testing for HER-2 by FISH and reflect clinical interpretation of HER-2 FISH analyses from laboratories across the country.
Promoter Hypermethylation of the p16 Gene and Loss of Its Protein Expression Is Correlated With Tumor Progression in Extrahepatic Bile Duct Carcinomas
Authors: Hong Seung-Mo , Choi Jene , Ryu Kyueun , Ro Jae Y. , Yu Eunsil
Published: February 2021

Context.—The p16 gene is one of the tumor suppressor genes, and its inactivation results in abnormal regulation of the cell cycle in human neoplasms. Promoter hypermethylation, a mechanism of p16 gene inactivation, has been reported to play an important role in tumorigenesis and to be related to patient prognosis in several carcinomas.

Objective.—To determine the role of the p16 gene in extrahepatic bile duct (EBD) carcinomas.

Design.—We examined promoter hypermethylation of the p16 gene using a methylation-specific polymerase chain reaction and the expression of the p16 protein using an immunohistochemical staining method in 90 cases of EBD carcinomas. We then compared the data with various clinicopathologic parameters, including survival rate.

Results.—Promoter hypermethylation was observed in 69 (77%) of the 90 cases. Of 69 hypermethylated cases, 32 (46%) demonstrated loss of p16 expression. Promoter hypermethylation of the p16 gene was more commonly observed in tumors with vascular invasion (22 [92%] of 24 cases) than without vascular invasion (71%, P = .03). Furthermore, p16 promoter hypermethylation with loss of p16 expression was more frequently observed in cases with lymph node metastasis (P = .006) and higher tumor stage group (P = .04). However, there was no significant difference in survival rate according to the status of p16 promoter methylation and/or p16 expression.

Conclusion.—Promoter hypermethylation is an important mechanism in the inactivation of the p16 gene in EBD carcinogenesis. Furthermore, the loss of p16 expression, with or without p16 gene promoter hypermethylation, is closely related to the tumor progression in EBD carcinomas.
The Use of Virtual Microscopy for Proficiency Testing in Gynecologic Cytopathology: A Feasibility Study Using ScanScope
Authors: Marchevsky Alberto M. , Khurana Renu , Thomas Premi , Scharre Karen , Farias Paul , Bose Shika
Published: February 2021

Context.—ScanScope software can digitize entire cytology slides.

Objective.—To test the feasibility of using virtual microscopy methods and “virtual Papanicolaou tests” for proficiency testing (PT) in gynecologic cytopathology.

Design.—Two PT exercises were conducted using virtual microscopy. Five cytopathologists and 1 cytotechnologist interpreted images using 2 different schema as follows: (1) the College of American Pathologists graded diagnostic codes (CAP-GDCs) and (2) the Center for Medicare and Medicaid Services test scoring categories (CMS-TSCs). The number of diagnostic errors using the CAP-GDCs and the CMS-TSCs, the mean length of time spent diagnosing each case, and the impressions by the users regarding the facility of the technology and image quality were studied.

Results.—In the first PT exercise, the participants provided incorrect diagnoses in 4 to 8 of the 10 test cases using the CAP-GDCs and in 1 to 4 of the 10 test cases using the CMS-TSCs. In the second PT exercise, the number of errors decreased to 1 to 6 using the CAP-GDCs and to 0 to 6 using the CMS-TSCs. The results did not achieve statistical significance. The mean time of 9.4 minutes spent per case in the second PT exercise was significantly shorter than the 14.4 minutes spent per case in the first PT exercise (P < .001). The ease of use of the software and the image quality were scored by all participants as 3+ or as 4+.

Conclusions.—This preliminary study shows that virtual microscopy and virtual Papanicolaou tests prepared using ScanScope may provide effective tools for PT. Technical issues that require further investigation are discussed.
Metastatic Basal Cell Carcinoma: Four Case Reports, Review of Literature, and Immunohistochemical Evaluation
Authors: Ionescu Diana N. , Arida Muammar , Jukic Drazen M.
Published: February 2021

Context.—Metastatic basal cell carcinoma (BCC) is relatively rare and is seldom considered a complication in the routine treatment and follow-up of patients with BCC. Although multiple studies have tried to distinguish aggressive from nonaggressive BCCs, to our knowledge, no consistent clinical, histopathologic, or immunohistochemical features have yet been reported.

Objective.—To report 4 cases of metastatic BCCs and to evaluate these in addition to known nonmetastatic BCCs with specific immunostains in an attempt to find distinct morphologic or immunohistochemical patterns that could be helpful in identifying aggressive BCCs.

Design.—We reviewed 4 cases of metastatic BCCs and recorded the clinical and morphologic findings. We then searched our archives for 14 cases of BCC that followed the usual nonaggressive course. We evaluated these 18 cases with immunohistochemical stains for Ki-67, p53, and bcl-2.

Results.—In metastasizing BCC, Ki-67 staining was slightly higher in metastatic sites than in primary sites (average 63% and 51%, respectively). p53 was expressed in 3 of 4 primary sites and 2 of 4 metastatic sites. Bcl-2 was positive in both primary and metastatic sites in 3 of 4 cases. In the 14 cases of nonaggressive BCC, staining for Ki-67 averaged 38%, p53 was positive in 11 cases, and Bcl-2 staining was noted in 13 cases.

Conclusions.—Overall, in the small sample that we evaluated, the immunohistochemical markers for Ki-67, p53, and Bcl-2 did not distinguish between metastatic and nonaggressive BCCs.
Adequacy of Physician Documentation of Red Blood Cell Transfusion and Correlation With Assessment of Transfusion Appropriateness
Authors: Friedman Mark T. , Ebrahim Amber
Published: February 2021

Context.—A major function of the hospital transfusion service is to assess the appropriateness of blood transfusion. Inadequate documentation of transfusions may hamper this assessment process.

Objective.—To correlate the level of physician documentation of transfusion with the ability to justify transfusion.

Design.—Retrospective review of red blood cell transfusions in adult patients in 2 hospital facilities during 1-week audit periods of each month from April 2001 to March 2003. Assessment forms were used to classify the level of physician documentation of transfusions into 3 groups: adequately, intermediately, and inadequately documented. Transfusions were deemed justified or not via comparison with hospital transfusion guidelines.

Results.—There were 5062 audited red blood cells transfused to 2044 adult (≥18 years) patients. Medical records from 154 patients transfused with 257 units of red blood cells during 172 transfusion events were reviewed after initial screenings of hemoglobin/hematocrit values failed to justify the transfusions. Nine percent of adequately documented, 50% of intermediately documented, and 73% of inadequately documented transfusion events could not be justified. Transfusion events with suboptimal (intermediate and inadequate) documentation accounted for 49% of all medical record–reviewed transfusion events and 62% could not be justified. The correlation between inadequate documentation and failure to justify transfusion was significant (P < .001), as was the correlation between suboptimal documentation and failure to justify transfusion (P = .03).

Conclusions.—There is a significant correlation between suboptimal documentation and failure to justify transfusions. Educating clinicians to improve documentation along with appropriate indications for transfusions may enhance efficiency of blood utilization assessment and lead to reduced rates of unjustifiable transfusions.
Use of Microsatellite Analysis in Detection of Tumor Lineage as a Cause of Death in a Liver Transplant Patient
Authors: Cankovic Milena , Linden Michael D. , Zarbo Richard J.
Published: February 2021

Malignant tumors are a significant cause of long-term morbidity and mortality in allograft recipients. Most solid tumors in transplant recipients are assumed to arise de novo in the setting of chronic immunosuppressive therapy; however, there have been instances in which malignant tumors have been transplanted in donated tissue from apparently healthy donors. We report a case of a 49-year-old liver transplant patient who presented with metastatic melanoma 9 months after transplantation for hepatocellular carcinoma and who later succumbed to the disease. To investigate the possibility that melanoma was derived from the donor liver, we used a commercially available polymerase chain reaction–based microsatellite marker assay to perform tissue identity testing. The genetic profiles of the patient's original hepatocellular carcinoma and the melanoma from the autopsy specimen were compared with the profile of the normal donor liver tissue, which was still available for testing. The pattern of microsatellite allelic expression strongly suggested that the melanoma detected at autopsy originated from the transplanted liver.
Concurrent Herpes Simplex Viral Lymphadenitis and Mantle Cell Lymphoma: A Case Report and Review of the Literature
Authors: Pilichowska Monika E. , Smouse Jason H. , Dorfman David M.
Published: February 2021

We report a case of localized herpes simplex virus lymphadenitis in a patient with mantle cell lymphoma (MCL). A 43-year-old woman with a 2-month history of lymphadenitis and peripheral lymphocytosis received a diagnosis of stage IV MCL based on histologic, flow cytometric, and immunohistochemical findings. One week after completion of chemotherapy, she presented with rapidly enlarging bilateral cervical lymph nodes, a retropharyngeal mass, and incipient respiratory compromise. Multiple biopsies of the cervical nodes and oropharynx that were submitted for morphologic, flow cytometric, and immunohistochemical studies revealed involvement by MCL with superimposed herpes simplex virus lymphadenitis. The recognition of herpes simplex virus infection with MCL is important for treatment as well as to rule out transformation of MCL to a higher-grade lesion.
Medicolegal Aspects of Error in Pathology
Authors: Troxel David B.
Published: February 2021

Objective.—To discuss the various ways error is defined in surgical pathology. To identify errors in pathology practice identified by an analysis of pathology malpractice claims.

Design.—Three hundred seventy-eight pathology malpractice claims were reviewed. Nuisance claims and autopsy claims were excluded; 335 pathology claims remained and were analyzed to identify repetitive patterns of specimen type and diagnostic category.

Setting.—All pathology malpractice claims reported to The Doctors Company of Napa, Calif, between 1998 and 2003.

Results.—Fifty-seven percent of malpractice claims involved just 5 categories of specimen type and/or diagnostic error, namely, breast specimens, melanoma, cervical Papanicolaou tests, gynecologic specimens, and system (operational) errors. Sixty-three percent of claims involved failure to diagnose cancer, resulting in delay in diagnosis or inappropriate treatment.

Conclusion.—A false-negative diagnosis of melanoma was the single most common reason for filing a malpractice claim against a pathologist. Nearly one third involved melanoma misdiagnosed as Spitz nevus, “dysplastic” nevus, spindle cell squamous carcinoma, atypical fibroxanthoma, and dermatofibroma. While breast biopsy claims were a close second to melanoma, when combined with breast fine-needle aspiration and breast frozen section claims, breast specimens were the most common cause of pathology malpractice claims. Cervical Papanicolaou test claims were third in frequency behind melanoma and breast; 98% involved false-negative Papanicolaou tests. Forty-two percent of gynecologic surgical pathology claims involved misdiagnosed ovarian tumors, and 85% of these were false-negative diagnoses of malignancy. The most common cause of system errors was specimen “mix-ups” involving breast or prostate needle biopsies.
Comparing Methods to Measure Error in Gynecologic Cytology and Surgical Pathology
Authors: Renshaw Andrew A.
Published: February 2021

Context.—Both gynecologic cytology and surgical pathology use similar methods to measure diagnostic error, but differences exist between how these methods have been applied in the 2 fields.

Objective.—To compare the application of methods of error detection in gynecologic cytology and surgical pathology.

Data Sources.—Review of the literature.

Conclusions.—There are several different approaches to measuring error, all of which have limitations. Measuring error using reproducibility as the gold standard is a common method to determine error. While error rates in gynecologic cytology are well characterized and methods for objectively assessing error in the legal setting have been developed, meaningful methods to measure error rates in clinical practice are not commonly used and little is known about the error rates in this setting. In contrast, in surgical pathology the error rates are not as well characterized and methods for assessing error in the legal setting are not as well defined, but methods to measure error in actual clinical practice have been characterized and preliminary data from these methods are now available concerning the error rates in this setting.
9-Color and 10-Color Flow Cytometry in the Clinical Laboratory
Authors: Wood Brent
Published: February 2021

Context.—The development of commercial flow cytometers capable of detecting more than 10 simultaneous fluorescent signals presents opportunities for improved diagnosis and monitoring of patients with leukemia and lymphoma.

Objective.—To describe instrument and reagent characteristics necessary for successful 9-color and 10-color flow cytometry in a clinical setting.

Design.—Systematic review of issues related to instrument settings, reagent performance, and general principles of panel construction.

Results.—Nine-color and 10-color flow cytometry offers the possibility for increased accuracy in population identification, the ability to obtain detailed information from paucicellular specimens, improved laboratory efficiency, and the means to consistently detect abnormal populations at low levels. Careful attention to details of instrument and reagent performance allows for the development of panels suitable for screening of samples for leukemia and lymphoma in a clinical setting.

Conclusions.—The characteristics of this technique are particularly well suited to the analysis of leukemia and lymphoma and have the potential to revolutionize and standardize this type of analysis in the clinical laboratory.