bluuebunny/crossref_metadata_2025 huggingface dataset:
Flat Epithelial Atypia of the Breast
Authors: Lerwill Melinda F.
Published: February 2021

Flat epithelial atypia is a presumably neoplastic alteration of terminal duct-lobular units that is characterized by the replacement of the native luminal epithelium by ductal cells demonstrating low-grade cytologic atypia. The atypical cells maintain a “flat” pattern of growth without evidence of architectural atypicality. Morphologic, immunohistochemical, and molecular investigations support that flat epithelial atypia represents an early step in the evolution of low-grade ductal carcinomas. It is frequently seen in association with atypical ductal hyperplasia, low-grade ductal carcinoma in situ, invasive tubular carcinoma, and lobular neoplasia. The risk for subsequent breast carcinoma remains to be defined, but flat epithelial atypia likely represents a nonobligate precursor with an extended time course to progression. Certain benign alterations may superficially mimic its appearance; careful attention to cytologic and architectural characteristics can help one distinguish these unrelated entities from flat epithelial atypia.
The Thyroid Gland: Recurring Problems in Histologic and Cytologic Evaluation
Authors: Faquin William C.
Published: February 2021

Nodules of the thyroid gland are frequently encountered, occurring in up to 7% of the population, and although most of these nodules are benign, carcinomas of the thyroid gland are the most common malignancy of the endocrine system. Although the different types of thyroid carcinoma are few, a wide variety of recurring problems exists in both their histologic and cytologic evaluation. Here, I will review a selected group of problematic areas, including unusual histologic variants of follicular adenoma, criteria for diagnosing minimally invasive follicular carcinoma, the use of fine-needle aspiration as a screening test for follicular neoplasia, challenging variants of papillary carcinoma, and features of poorly differentiated carcinoma.
The Diagnostic Value of Ki-67 and repp86 in Distinguishing Between Benign and Malignant Mesothelial Proliferations
Authors: Taheri Zohreh Mohammad , Mehrafza Mehdi , Mohammadi Forozan , Khoddami Maliheh , Bahadori Moslem , Masjedi Mohammad Reza
Published: February 2021

Context.—The differentiation of benign mesothelial proliferations from malignant mesotheliomas may be difficult, especially when evaluating small specimens from pleural biopsies.

Objective.—To explore the potential value of 2 proliferative cell markers, Ki-67 and restrictedly expressed proliferation–associated protein 86 kDa (repp86), in distinguishing between malignant mesothelioma (MM) and benign reactive mesothelial hyperplasia (MH).

Design.—Thirty-six cases of MM from 26 men and 10 women with a mean age of 62.9 years (range, 36–80 years) and 22 cases of benign reactive MH from 14 male and 8 female patients with a mean age of 51.5 years (range, 15– 88 years) were included in this study. The proliferative status of the lesions was assessed by immunohistochemistry using monoclonal antibodies to Ki-S2 (repp86) and Ki-S5 (Ki-67). The labeling indices were quantified.

Results.—The mean labeling indexes for Ki-67 in MM and benign reactive MH were 24.6% (range, 1%–66%) and 6.23% (range, 0%–25%), respectively. The mean labeling indexes for repp86 in MM and benign reactive MH were 26.3% (range, 0%–50%) and 3.26% (range, 0%– 21%), respectively. The average proliferative cell count was significantly higher in MM compared with benign reactive MH (P < .001). Furthermore, both markers showed a significant correlation in their expression in MM and benign reactive MH (r = 77.5, P < .001). Sensitivities of 88% and 92% and specificities of 92% and 94% were obtained at a cutoff point of 9% for Ki-67 and repp86, respectively.

Conclusions.—Used in combination, Ki-67 and repp86 appear to be useful markers in differentiating MM from benign reactive MH.
Posttransplant Adenoviral Enteropathy in Patients With Small Bowel Transplantation
Authors: Adeyi Oyedele A. , Randhawa Parmjeet A. , Nalesnik Michael A. , Ochoa Erin R. , Abu-Elmagd Kareem M. , Demetris Anthony J. , Wu Tong
Published: February 2021

Transplant patients on immunosuppression represent a risk group for opportunistic infections, including adenoviral infections. The clinical and histopathologic findings of posttransplant adenoviral enteropathy in 3 adult intestinal transplant patients are described. The histopathologic pitfalls for the differential diagnosis between intestinal adenoviral enteropathy and acute rejection are discussed. Adenoviral enteropathy is an opportunistic infection that may follow aggressive treatment for small bowel allograft rejection, but which may require no specific treatment. It is associated with mild mixed inflammation in the lamina propria and slight increase of crypt apoptosis, resembling low-grade acute rejection. The identification of characteristic viral inclusions in the surface or crypt epithelium points to the diagnosis of adenoviral enteropathy, in spite of the increased crypt apoptosis.
Epstein-Barr Virus–Associated Lymphoepithelioma-like Gastric Carcinoma
Authors: Pavithra Herath Chaturika Harshini , Chetty Runjan
Published: February 2021

This article provides an overview of the pathology of Epstein-Barr virus (EBV)–associated lymphoepithelioma-like gastric carcinoma, highlighting its unique morphology and clinical features. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach with a better prognosis than conventional adenocarcinoma. Most lymphoepithelioma-like gastric carcinomas are associated with EBV infection, while a subset is associated with microsatellite instability. Even though there is a very strong association with EBV, its exact role in carcinogenesis still remains to be elucidated in those cancers that harbor EBV. Distinctive histology and demonstration of EBV using in situ hybridization, polymerase chain reaction, or Southern blotting and immunohistochemistry for the DNA mismatch repair genes or polymerase chain reaction analysis of microsatellite loci to assess microsatellite instability helps to make the diagnosis.
A Teaching Database for Diagnosis of Hematologic Neoplasms Using Immunophenotyping by Flow Cytometry
Authors: Nguyen Andy N. D. , De Jitakshi , Nguyen Jacqueline , Padula Anthony , Qu Zhenhong
Published: February 2021

Context.—In the diagnosis of lymphomas and leukemias, flow cytometry has been considered an essential addition to morphology and immunohistochemistry. The interpretation of immunophenotyping results by flow cytometry involves pattern recognition of different hematologic neoplasms that may have similar immunologic marker profiles. An important factor that creates difficulty in the interpretation process is the lack of consistency in marker expression for a particular neoplasm. For this reason, a definitive diagnostic pattern is usually not available for each specific neoplasm. Consequently, there is a need for decision support tools to assist pathology trainees in learning flow cytometric diagnosis of leukemia and lymphoma.

Objective.—Development of a Web-enabled relational database integrated with decision-making tools for teaching flow cytometric diagnosis of hematologic neoplasms.

Design.—This database has a knowledge base containing patterns of 44 markers for 37 hematologic neoplasms. We have obtained immunophenotyping data published in the scientific literature and incorporated them into a mathematical algorithm that is integrated to the database for differential diagnostic purposes. The algorithm takes into account the incidence of positive and negative expression of each marker for each disorder.

Results.—Validation of this algorithm was performed using 92 clinical cases accumulated from 2 different medical centers. The database also incorporates the latest World Health Organization classification for hematologic neoplasms.

Conclusions.—The algorithm developed in this database shows significant improvement in diagnostic accuracy over our previous database prototype. This Web-based database is proposed to be a useful public resource for teaching pathology trainees flow cytometric diagnosis.
Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma Associated With X-Linked Hyperimmunoglobulin M Syndrome
Authors: Malhotra Reenu K. , Li Wei
Published: February 2021

Gastroenteropancreatic neuroendocrine tumors are uncommon tumors representing 2% of all gastrointestinal tumors. We report a case of a 21-year-old man with X-linked hyperimmunoglobulin M (hyper-IgM) syndrome who presented with diarrhea and jaundice. An ultrasound and magnetic resonance imaging showed multiple variable-sized lesions in the liver and peripancreatic lymphadenopathy. The morphologic and immunohistochemical features of the biopsies from the liver and lymph node were consistent with poorly differentiated neuroendocrine carcinoma. Hyper-IgM syndrome is a rare primary immunodeficiency disease characterized by low serum IgG, IgA, and IgE levels with normal or elevated IgM levels. These patients are at a higher risk for developing malignancies, particularly adenocarcinoma of the gastrointestinal tract and lymphoma. A review of the literature of gastroenteropancreatic neuroendocrine tumors is presented with the discussion of a possible relationship of these tumors with immunodeficiency.
Translocations and Amplifications of Chromosome 12 in Liposarcoma Demonstrated by the LSI CHOP Breakapart Rearrangement Probe
Authors: Willmore-Payne Carlynn , Holden Joseph , Turner Kristi C. , Proia Alan , Layfield Lester J.
Published: February 2021

Context.—Liposarcomas display a number of molecular abnormalities involving chromosome 12. Myxoid and round cell liposarcomas are characterized by t(12;16)(q13; p11) or t(12;22)(q13;q12) translocations. Amplifications occur within the 12q13-15 region of atypical lipomatous tumors and well-differentiated liposarcomas but not lipomas.

Objective.—To investigate the performance characteristics of the LSI CHOP Breakapart Rearrangement Probe for the diagnosis of myxoid/round cell liposarcomas and atypical lipomas/well-differentiated liposarcomas.

Design.—We investigated a series of lipomatous neoplasms (5 lipomas, 5 well-differentiated liposarcomas, 22 myxoid/round cell liposarcomas, 2 liposarcomas not otherwise specified, and 2 dedifferentiated liposarcomas) and normal myometrium for abnormalities in the q13-15 region of chromosome 12. Cases were studied for the presence or absence of t(12;16)(q13;p11) or t(12;22)(q13;q12) translocations by the LSI CHOP Breakapart Rearrangement Probe. These probes contain a sequence encompassing the SAS and CDK4 genes. Four or more copies of this sequence were considered to represent amplification of these genes.

Results.—Rearrangement of the CHOP gene was seen in all evaluable myxoid liposarcomas. Rearrangements were seen in 1 dedifferentiated liposarcoma but not in normal myometrium or lipomas. Probe signal amplification was seen in all 5 well-differentiated liposarcomas and 1 myxoid liposarcoma. No signal amplification was seen in lipomas or myometrium.

Conclusions.—Demonstration of translocations t(12; 16)(q13;p11) and t(12;22)(q13;q12) by the LSI CHOP Breakapart Rearrangement Probe appears to correlate with round cell/myxoid liposarcoma. The probe also demonstrated amplification of the 12q13-15 region in well-differentiated liposarcomas, making it useful for the diagnosis of these neoplasms. In a significant percentage of cases, high background fluorescence or poor probe staining made interpretation difficult.
Clinicopathologic Characteristics, CpG Island Methylator Phenotype, and BRAF Mutations in Microsatellite-Stable Colorectal Cancers Without Chromosomal Instability
Authors: Kakar Sanjay , Deng Guoren , Sahai Vaibhav , Matsuzaki Koji , Tanaka Hirofumi , Miura Soichuro , Kim Young S.
Published: February 2021

Context.—The 2 chief pathways implicated in colorectal carcinogenesis, microsatellite instability and chromosomal instability, are not present in 20% to 37% of cases.

Objective.—To determine whether the CpG island methylator phenotype (CIMP) pathway, characterized by simultaneous methylation of several known tumor suppressor genes, is the principal underlying mechanism in cases without chromosomal or microsatellite instability, and to determine the significance of CIMP pathway and BRAF mutations in microsatellite-stable (MSS) cases.

Design.—Clinicopathologic features and chromosomal instability status by loss of heterozygosity analysis were determined in 83 cases of colorectal cancer in which microsatellite instability, CIMP status, BRAF mutations, and KRAS mutations were previously known.

Results.—Microsatellite instability was present in 14 cases (17%). Of the 69 MSS cases (83%), chromosomal instability manifested by LOH involving at least one locus was observed in 53 cases (64%). Hence, 16 (19%) of 83 colorectal cancer cases showed neither microsatellite instability nor chromosomal instability. These cases had a low incidence of CIMP (3/16; 19%) and BRAF mutation (1/16; 6%). The 5-year survival in these cases was significantly better compared with MSS cases with chromosomal instability (80% vs 54%, P = .02). BRAF mutations were identified in 10 MSS cases (15%). BRAF mutation in MSS cases correlated significantly with high-level chromosomal instability (P = .009) and poor 5-year survival (0% vs 70%, P < .001).

Conclusions.—CIMP does not appear to play a key role in colorectal cancer without microsatellite instability and chromosomal instability. These cases have a better survival, probably related to absence of significant chromosomal instability. BRAF mutations in MSS cases are associated with high levels of chromosomal instability that are likely responsible for the adverse outcomes in these cases.
Cytogenetic Studies of 24 Renal Epithelial Tumors With von Hippel-Lindau and Fragile Histidine Triad Protein Expression Correlation
Authors: Gayrard Nathalie , Cacheux Valère , Iborra François , Mourad Georges , Argilés Àngel
Published: February 2021

Context.—Deletion of the short arm of chromosome 3 (3p deletion) is a cytogenetic abnormality generally associated with clear cell renal cell carcinoma, the most aggressive form of renal epithelial tumor.

Objective.—To cytogenetically characterize 24 renal tumors in order to check the incidence and the type of 3p deletions, as well as to identify new genes putatively participating in renal tumorigenesis and test the protein products of the von Hippel-Lindau (VHL) and fragile histidine triad (FHIT) genes.

Design.—We analyzed 24 renal tumors by conventional cytogenetics, comparative genomic hybridization, and fluorescence in situ hybridization. We then performed a comparative expression study of the proteins pVHL and Fhit.

Results.—In our series of 24 renal tumors, the 3p deletion was the most frequent genetic alteration (15/24); the other features were partial trisomy 5q, 8p deletion, and monosomy 9 and 14. The 3p deletion was long and terminal, and no interstitial deletion was identified. By immunohistochemistry, we found that for the 2 genes of interest, VHL and FHIT, loss or decrease in protein expression were very frequently observed in clear cell renal cell carcinoma and not always associated with a 3p deletion (14/20 in clear cell renal cell carcinoma).

Conclusions.—Our studies characterize the 3p deletion as long and terminal and identify no interstitial deletion in that chromosome. Fhit and pVHL protein expression loss appear to be independent, as they can be dissociated. Our data are supportive of a role for FHIT (in addition to VHL) in renal tumorigenesis. No other gene with particular potential interest in renal tumorigenesis could be identified among the selected genes.
Dramatically Elevated Circulating Tumor Cell Numbers in a Patient With Small Cell Neuroendocrine Carcinoma of the Prostate
Authors: Chan Fanny , Goodman Oscar , Fink Louis , Vogelzang Nicholas J. , Pomerantz David , Khoury Joseph D.
Published: February 2021

Detection of circulating tumor cells in whole blood is a useful prognostic tool for patients with castration-resistant prostate cancer, as well as for patients with metastatic breast cancer and colorectal carcinoma. In this report, we present the case of a patient with neuroendocrine small cell prostate cancer with normal prostate-specific antigen levels throughout the course of disease but who had markedly elevated circulating tumor cells, as detected with the CellSearch (Veridex) system.
BRAF Mutation Testing in Colorectal Cancer
Authors: Sharma Shree G. , Gulley Margaret L.
Published: February 2021

Colorectal cancer is the second most common cause of cancer death in the United States. Understanding the biochemical pathways underlying carcinogenesis has paved the way for more effective treatments and better outcomes. BRAF mutation testing has a role in (1) differentiating sporadic colorectal cancer from Lynch syndrome, (2) identifying cancers lacking BRAF mutation that are more likely to respond to epidermal growth factor receptor inhibitor therapy, and (3) conferring worse prognosis in colorectal cancer that is microsatellite stable. Several analytic methods are available to reliably detect BRAF mutations. Real-time polymerase chain reaction identifies the most common BRAF mutation, V600E, in frozen or paraffin-embedded colorectal cancer tissue. Traditional DNA sequencing and the somewhat more-sensitive pyrosequencing method can detect multiple alternative BRAF mutations that are predicted to constitutively activate signaling through the MAPK pathway, promoting tumor growth and survival. Pathologists play an important role in assay validation as well as in consulting with clinicians about indications for testing, ensuring quality of testing, and interpreting results in conjunction with other clinicopathologic factors important in the management of affected patients.
Cardiac Sarcoidosis: A Pathology-Focused Review
Authors: Lagana Stephen M. , Parwani Anil V. , Nichols Larry C.
Published: February 2021

Context.—Sarcoidosis is a granulomatous disease of unclear etiology. It is not commonly fatal, but when sarcoidosis is fatal, it is most often from cardiac involvement and when sarcoidosis involves the heart, it frequently causes death. The disease presents diagnostic challenges both clinically and histologically.

Objectives.—To review the histology of cardiac sarcoidosis and the histologic differential diagnosis of cardiac granulomatous disease and to review the epidemiology and gross pathology of cardiac sarcoid as well as discuss current controversies, clinical diagnostic criteria, and proposed mechanisms of pathogenesis.

Data Sources.—We reviewed the literature searchable on PubMed as well as selected older studies revealed by our review of the recent literature. Photographs were taken from cases on file at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) and Columbia University Medical Center (New York, New York).

Conclusions.—Sarcoidosis is a focal or disseminated granulomatous disease that likely represents the final common pathway of various pathogenic insults in a genetically susceptible host. The type of insult may influence the specific sarcoid phenotype. Controversy still abounds, but many areas of investigation around sarcoidosis are yielding exciting discoveries and bringing us closer to a richer understanding of this puzzling disease.
Implementation and Assessment of a Resident Curriculum in Evidence-Based Transfusion Medicine
Authors: Haspel Richard L.
Published: February 2021

Context.—Given the number of controversial issues in transfusion medicine, an understanding of biostatistics and evidence-based medicine is invaluable. No detailed curricula that address teaching critical appraisal of the transfusion medicine literature have been published or evaluated.

Objective.—To design, implement, and evaluate an evidence-based transfusion medicine curriculum.

Design.—Four hour-long training sessions in journal club format were designed for a 2-month transfusion medicine rotation for clinical pathology residents. A previously validated survey was administered precurriculum and postcurriculum to gauge changes in resident self-reported attitudes and confidence regarding biostatistics methods and critical appraisal of the medical literature. Residents were also asked to evaluate the course regarding content, execution, and utility.

Results.—Seven second-year residents participated in the sessions. Following the curriculum there were statistically significant increases in the residents’ self-reported ability to appraise critically and search the medical literature (P  =  .05). Resident confidence interpreting an article's statistical results also significantly improved (P  =  .01). There was also a significant change in the residents' desire to learn more about statistics (P  =  .02). Resident reviews of the curriculum were overall extremely positive.

Conclusion.—A 4-session curriculum can have a significant effect on resident self-reported ability to appraise critically and understand the medical literature and help foster interest in biostatistics. Although based on small numbers, this study represents one of the first efforts to evaluate the efficacy of a transfusion medicine curriculum and can potentially serve as a starting point to better integrate and evaluate knowledge of evidence-based transfusion medicine during residency training.
Adenocarcinoma in Ectopic Prostatic Tissue at Dome of Bladder: A Case Report of a Patient With Urothelial Carcinoma of the Bladder and Adenocarcinoma of the Prostate
Authors: Gardner Jerad M. , Khurana Hema , Leach Fredrick S. , Ayala Alberto G. , Zhai Jim , Ro Jae Y.
Published: February 2021

We report a case of ectopic prostate tissue with an associated prostatic adenocarcinoma occurring in the dome of the urinary bladder. A 62-year-old man presented with a 4-month history of persistent microscopic hematuria following a urinary tract infection. Other complaints included frequent urination, but there was neither dysuria nor gross hematuria. Digital rectal examination revealed a smooth prostate of normal size. Cystoscopic examination revealed a sessile lesion of the anterior bladder neck and multiple smaller papillary lesions throughout the bladder. Following a transurethral resection of the bladder tumor with a diagnosis of muscle-invasive transitional cell carcinoma grade 3, a radical cystoprostatectomy was performed. The diagnosis of transitional cell carcinoma was confirmed, but in addition, a different lesion was also incidentally found in the dome of the bladder. This incidental lesion showed a prostatic adenocarcinoma arising from ectopic prostatic tissue within the bladder submucosa. The prostate also showed prostatic adenocarcinoma, but this was minimal, low grade, and confined to the prostate gland, and thus it was felt to be unlikely to have metastasized to the bladder dome. Adenocarcinoma arising in ectopic prostatic tissue is a rare finding and to our knowledge only 1 case has been previously described, occurring in the soft tissue adjacent to the prostate. We report the first case of adenocarcinoma arising in ectopic prostatic tissue within the bladder.
Atypical Genital Nevus
Authors: Brenn Thomas
Published: February 2021

Context.—Atypical genital nevus is rare and the only poorly documented melanocytic lesion in the spectrum of nevi of special sites. It is characterized by unique and reproducible histologic features, which may appear alarming and may raise significant concern for a diagnosis of melanoma.

Objectives.—To present the clinical and histologic features of atypical genital nevus with emphasis on distinction from vulvar melanoma.

Data Sources.—The findings are based on a review of the current literature.

Conclusions.—Atypical genital nevus is most often found in the vulva of premenopausal women. Despite the alarming histologic features, its clinical behavior appears benign with only rare local recurrence after incomplete removal. Recognition of this unusual melanocytic lesion and its characteristic histologic features is important to avoid overdiagnosis of invasive melanoma, with subsequent wide excision or sentinel lymph node biopsy, especially in view of the sensitive anatomic location.
Comparison of 10 Indirect Fluorescent Antibodies to Detect and Type Influenza A Specimens
Authors: She Rosemary C. , Taggart Edward W. , Petti Cathy A.
Published: February 2021

Context.—Management of influenza infections relies on rapid, accurate, and sensitive diagnostic techniques. Influenza A (IA) strain typing has become more important since the emergence of highly pathogenic avian and novel influenza strains and the high frequency of oseltamivir resistance in circulating H1N1 isolates.

Objective.—To analyze the performance of indirect fluorescent antibody testing for subtyping a broad range of IA strains.

Design.—Ten indirect fluorescent antibody reagents were used to detect and type 100 archived IA respiratory specimens from 1986 through 1995 and 2006 through 2007 and a reassortant, nonpathogenic H5N1 sample. Both direct specimen and cultured isolates were tested. Reverse transcription-polymerase chain reaction was used to confirm indirect fluorescent antibody results. Three H1N1-, 2 H3N2-, and 1 H1-H2-H3-H5–specific antibodies (Chemicon Diagnostics), an IA pool reagent (Trinity Biotech), and H1, H3, and H1-H3–specific antibodies (Centers for Disease Control and Prevention) were used.

Results.—Reverse transcription-polymerase chain reaction confirmed all 100 isolates as IA and identified 71 as H1, 22 as H3, and 7 as non–H1-H3. Sensitivity of direct specimen testing ranged was 18.3% to 57.7% for the H1 reagents, 36.4% to 50.0% for the H3 reagents, and 40.0% to 53.8% for the pool reagents. Subtyping was more sensitive on cultured isolates than direct specimens. Specificity for all antibodies was 89.7% to 100%. The H5N1 sample was positive by direct testing and culture (reverse transcription-polymerase chain reaction, Centers for Disease Control and Prevention H5N1 pool, Chemicon H1-H2-H3-H5). No cross-reactivity was observed when the 10 antibodies were tested against other common respiratory viruses.

Conclusions.—When positive, IA subtyping antibodies can serve as a useful diagnostic tool when multiple influenza virus subtypes are cocirculating with different susceptibility patterns.
Diagnostic Pitfalls in Syringocystadenocarcinoma Papilliferum: Case Report and Review of the Literature
Authors: Leeborg Nicky , Thompson Michele , Rossmiller Sarah , Gross Neil , White Clifton , Gatter Ken
Published: February 2021

We report the first case, to our knowledge, of syringocystadenocarcinoma papilliferum with p63-verified squamous differentiation and extensive dermal invasion accompanying in situ components. An 86-year-old woman presented with a neoplasm on the neck, and the intralesional heterogeneity typical of these neoplasms led to an initial diagnosis on needle biopsy favoring squamous cell carcinoma. Excision illustrated diverse morphology, raising a broad differential diagnosis, including more common extracutaneous malignancies, such as breast, gastrointestinal, and ovarian primary tumors. Fortuitous sectioning revealed a focal connection to the skin surface with evidence of apocrine differentiation allowing final diagnosis as syringocystadenocarcinoma papilliferum. Our literature review shows the histologic and immunohistochemical features of syringocystadenocarcinoma papilliferum are not well defined outside of their clear morphologic overlap with syringocystadenoma papilliferum. We describe our findings and diagnostic pitfalls to help pathologists encountering this unusual apocrine neoplasm.
Low-Grade Papillary Urothelial Carcinoma of the Urinary Bladder: A Clinicopathologic Analysis of a Post–World Health Organization/International Society of Urological Pathology Classification Cohort From a Single Academic Center
Authors: Miyamoto Hiroshi , Brimo Fadi , Schultz Luciana , Ye Huihui , Miller Jeremy S. , Fajardo Daniel A. , Lee Thomas K. , Epstein Jonathan I. , Netto George J.
Published: February 2021

Context.—Few large cohort studies have addressed outcome in patients with noninvasive low-grade papillary urothelial carcinoma (LG-UrCa) following implementation of the 2004 World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification.

Objective.—To evaluate our cohort of LG-UrCa cases classified according to 2004 WHO/ISUP to reassess outcome and interobserver agreement.

Design.—Files were searched for all patients diagnosed with LG-UrCa between 1998 and 2008. All sections were reevaluated for accuracy of classification.

Results.—A total of 112 cases initially diagnosed as LG-UrCa were identified. Of those, 8 of 55 cases (15%) initially diagnosed by nonurologic pathologists were reclassified as high-grade papillary urothelial carcinoma and were excluded. The mean length of follow-up was 40.1 months (range, 2–113 months). Tumor recurrence was encountered in 56 of 104 patients (53.8%), including 37 (35.6%) with LG-UrCa or lower-grade tumors and 19 (18.3%) with high-grade papillary urothelial carcinoma. Of the 19 patients demonstrating grade progression, 7 (37%) also developed stage progression (invasive carcinoma, n  =  5; metastatic carcinoma, n  =  2). Seven patients eventually underwent radical cystectomy. None of the 104 patients died of bladder cancer. The mean number of recurrence episodes was 3.11. The mean durations of time to first recurrence and time to grade progression were 13.9 months and 25.1 months, respectively. The mean size of initial tumors was 1.73 cm. There was no significant correlation between tumor size, patient age, sex, or smoking history and the likelihood for recurrence or grade progression. A significantly higher rate of recurrence was seen in patients with multiple tumors at initial diagnosis (P  =  .04).

Conclusions.—A tendency to underdiagnose high-grade papillary urothelial carcinoma continues to exist. More than half (53.8%) of patients with LG-UrCa developed recurrence, with an 18.3% incidence of grade progression and a 6.7% incidence of stage progression. Patients with multiple initial tumors had significantly higher risk of developing recurrence.
Melanoma in Children
Authors: Paradela Sabela , Fonseca Eduardo , Prieto Victor G
Published: February 2021

Context.—Cutaneous melanoma in childhood (CMC) is rare; therefore, its prognostic factors and biologic behavior, and the effectiveness of adjuvant techniques for CMC remain mostly unknown.

Objective.—To review the most useful, evidence-based practice criteria for establishing the diagnosis of CMC, for which universally accepted criteria are lacking, in order to facilitate the interpretation and comparison of the results from different institutions, and to perform systematic reviews and meta-analysis.

Data Sources.—A comprehensive review of the most relevant previous single-institution series reported in the literature since 1990, including our cumulative experience of 137 cases of primary cutaneous and mucosal melanoma in patients younger than 18 years. Special characteristics of melanoma in children are discussed, regarding clinical settings and risk factors, helpful histologic features, and immunohistochemical patterns for diagnosis and prognosis.

Conclusions.—Careful analysis of histologic features as well as the additional information provided by immunohistochemistry should allow for a correct diagnosis in most cases of melanoma in children. Although it seems that pediatric patients with melanoma have higher survival probability than adults, still a number of children will develop metastasis and die of their disease, particularly when melanoma is diagnosed after puberty. Until further studies more accurately determine the prognosis, a prudent approach to CMC diagnosis and therapy seems to follow the same principles as those established for adult melanoma.
A Method for Optimizing and Validating Institution-Specific Flagging Criteria for Automated Cell Counters
Authors: Sireci Anthony , Schlaberg Robert , Kratz Alexander
Published: February 2021

Context.—Automated cell counters use alerts (flags) to indicate which differential white blood cell counts can be released directly from the instrument and which samples require labor-intensive slide reviews. The thresholds at which many of these flags are triggered can be adjusted by individual laboratories. Many users, however, use factory-default settings or adjust the thresholds through a process of trial and error.

Objective.—To develop a systematic method, combining statistical analysis and clinical judgment, to optimize the flagging thresholds on automated cell counters.

Design.—Data from 502 samples flagged by Sysmex XE-2100/5000 (Sysmex, Kobe, Japan) instruments, with at least 1 of 5 user-adjustable, white blood cell count flags, were used to change the flagging thresholds for maximal diagnostic effectiveness by optimizing the Youden index for each flag (the optimization set). The optimized thresholds were then validated with a second set of 378 samples (the validation set).

Results.—Use of the new thresholds reduced the review rate caused by the 5 flags from 6.5% to 2.9% and improved the positive predictive value of the flagging system for any abnormality from 27% to 37%.

Conclusions.—This method can be used to optimize thresholds for flag alerts on automated cell counters of any type and to improve the overall positive predictive value of the flagging system at the expense of a reduction in the negative predictive value. A reduced manual review rate helps to focus resources on differential white blood cell counts that are of clinical significance and may improve turnaround time.
Expression Patterns of PAX5, c-Met, and Paxillin in Neuroendocrine Tumors of the Lung
Authors: Song Jie , Li Mei , Tretiakova Maria , Salgia Ravi , Cagle Philip T. , Husain Aliya N.
Published: February 2021

Context.—c-Met is important in the pathogenesis, invasion, and spread of several forms of lung cancer, and multiple c-Met inhibitors are undergoing clinical trials. PAX5 has been shown to upregulate c-Met in small cell lung carcinoma (SCLC), and coinhibiting PAX5 and c-Met had a synergic effect in killing tumor cells. Paxillin is a downstream target of activated c-Met, and its activation leads to enhanced cell motility and tumor spread. The expression patterns of these functionally related proteins have not, to our knowledge, been systemically studied in neuroendocrine tumors of the lung.

Objective.—To investigate the expression patterns of PAX5, paxillin, c-Met, and phosphorylated c-Met in 4 categories of pulmonary neuroendocrine tumors.

Design.—Tissue microarrays of 38 typical carcinoids, 6 atypical carcinoids, 34 SCLCs, and 11 large cell neuroendocrine carcinomas were studied with immunohistochemistry.

Results.—Most of the 4 tumor types expressed c-Met, phosphorylated c-Met, and paxillin. PAX5 was frequently expressed in atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas but tended to be negative in typical carcinoids. Coexpression of PAX5 with c-Met or phosphorylated c-Met was present in most of the atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas. Significant correlation between PAX5 and paxillin was detected in SCLCs and large cell neuroendocrine carcinomas but not in carcinoid tumors.

Conclusions.—The frequent coexpression of PAX5 with c-Met or phosphorylated c-Met in intermediate-grade and high-grade neuroendocrine tumors supports the therapeutic strategy of coinhibiting these proteins. The discrepancy between high-grade and low-grade neuroendocrine tumors in PAX5/paxillin expression correlation may be due to the different underlying molecular genetics of these tumors.
An Update on Tumors of the Anal Canal
Authors: Shia Jinru
Published: February 2021

Context.—The anal canal possesses complex anatomy and histology and gives rise to a variety of tumor types. Challenging issues remain with regard to both the pathologic diagnosis and the clinical management of these tumors.

Objectives.—To provide an updated overview of the histogenesis, clinical and pathologic characteristics, diagnostic terminology, and relevant clinical management of the various types of anal canal tumors.

Data Sources.—Recent literature on clinical and pathologic characteristics of anal canal tumors.

Conclusions.—Although most anal canal tumors are of squamous lineage, a complex variety of other tumors also occurs. Recognition of such diverse tumor entities will allow accurate pathologic diagnosis and most optimal clinical management.
Clinical Examination and Validation of Primary Diagnosis in Anatomic Pathology Using Whole Slide Digital Images
Authors: Jukić Drazen M , Drogowski Laura M , Martina Jamie , Parwani Anil V
Published: February 2021

Context.—Novel anatomic pathology technologies allow pathologists to digitally view and diagnose cases. Although digital pathology advocates champion its strengths and move to integrate it into practice and workflow, the capabilities and limitations of digital slides have not been fully investigated.

Objectives.—To estimate intrapathologist diagnostic discrepancy between glass and digital slides and to determine pathologists' diagnostic certainty when diagnosing with the 2 formats.

Design.—Intrapathologist diagnostic consistency between glass and digital slides was measured. Three pathologists diagnosed 101 cases digitally and with corresponding glass slides. Discrepancies between formats were evaluated, and diagnostic precision and certainty were compared.

Results.—A total of 606 diagnoses were evaluated in pairs (202 per pathologist). Seven cases did not transfer to the database and were eliminated from further study. We report no discrepancies between media in 75%, 87%, and 83% of the cases diagnosed by the 3 pathologists, respectively; significant discrepancies were identified in 3%, 3%, and 7% of cases by each pathologist. In total, we identified significant clinical and therapeutic discrepancies in 13 of 296 cases (4.4%). The certainty values provided by each pathologist were similar between formats.

Conclusions.—This study did not detect significant differences between diagnoses based on digital and glass slides. We believe that this study further supports the integration of digital slides into pathology workflow, particularly considering the low rate of discrepancy documented here.
Cutaneous Protothecosis
Authors: Hillesheim Paul B. , Bahrami Soon
Published: February 2021

Prototheca species are an achlorophyllic algae that cause infections primarily in immunocompromised individuals. At least one-half of infectious cases are cutaneous. Because protothecosis is seldom suspected clinically, patients may be subjected to various treatment modalities for extended periods without satisfactory results. Cutaneous protothecosis shares similar clinical and pathologic findings with deep tissue fungal mycoses. The typical presentation occurs most commonly on the face and extremities as erythematous plaques, nodules, or superficial ulcers. Prototheca spp are spherical, unicellular, nonbudding organisms that are sometimes noted on routine hematoxylin-eosin staining but are best visualized with periodic acid–Schiff and Gomori methenamine-silver histochemical stains. Although protothecosis can be diagnosed on biopsy, culture of the organism on a medium such as Sabouraud dextrose agar is required for definitive diagnosis. Treatment may require a combination of surgical excision and antifungal agents. Therefore, cutaneous protothecosis should be considered in a lesion that appears suspicious for the more-common fungal infections.
Does Routine Repeat Testing of Critical Values Offer Any Advantage Over Single Testing?
Authors: Toll Adam D , Liu Jennifer M , Gulati Gene , Behling Eric M , Kocher William D
Published: February 2021

Context.—Before being communicated to the caregiver, critical laboratory values are verified by repeat testing to ensure their accuracy and to avoid reporting false or erroneous results.

Objective.—To determine whether 2 testing runs offered any advantage over a single testing run in ensuring accuracy or in avoiding the reporting of false or erroneous results.

Design.—Within the hematology laboratory, 5 tests were selected: hemoglobin level, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time. A minimum of 500 consecutive critical laboratory test values were collected retrospectively for each test category. The absolute value and the percentage of change between the 2 testing runs for each critical value were calculated and averaged for each test category and then compared with our laboratory's preset, acceptable tolerance limits for reruns.

Results.—The mean results obtained for the absolute value and the percentage of change between the testing runs were 0.08 g/dL (1.4%) for hemoglobin levels, 50 cells/µL (10.2%) for white blood cell counts, 1500 cells/µL (9.9%) for platelet counts, 0.7 seconds (1.4%) for prothrombin time, and 5.1 seconds (4.4%) for activated partial thromboplastin time (all within our laboratory's acceptable tolerance limits for reruns). The percentage of specimens with an absolute value or a mean percentage of change outside our laboratory's acceptable tolerance limits for reruns ranged between 0% and 2.2% among the test categories. No false or erroneous results were identified between the 2 testing runs in any category.

Conclusions.—Routine, repeat testing of critical hemoglobin level, platelet count, white blood cell count, prothrombin time, and activated partial thromboplastin time results did not offer any advantage over a single run.
Application of Thrombolytic Drugs on Clotted Blood and Bone Marrow Specimens to Generate Usable Cells for Cytogenetic Analyses
Authors: St Antoine Angelique , Ketterling, BA Morgan N. , Sukov William R. , Lowman Josh , Knudson Ryan A. , Sinnwell Jason P. , Wiktor Anne E. , Ketterling Rhett P.
Published: February 2021

Context.—Clotted blood and bone marrow specimens account for a large proportion of failed cytogenetic studies. There are no published protocols describing salvage of clotted specimens such that conventional chromosome or fluorescence in situ hybridization (FISH) studies can be performed.

Objective.—To evaluate the utility of thrombolytic drugs on clotted blood samples to yield intact cells suitable for cytogenetic analysis.

Design.—Five commercially available thrombolytic drugs (alteplase, urokinase, streptokinase, tenecteplase, reteplase) were evaluated in a series of blinded experiments to identify the best drug for lysing clots to produce samples suitable for chromosome and FISH studies. After the selection of alteplase as the drug yielding the most promising results, a comparative study between alteplase (0.75 mg/ml) and a commercially available anticlotting reagent (ACR) was performed. For each sample, mitotic index, chromosome length, and quality of slides prepared for conventional chromosome and FISH analyses were evaluated.

Results.—Alteplase-treated samples produced a higher mitotic index than those treated with ACR while showing equivalent quality in conventional chromosome and FISH studies. We have demonstrated the utility of treating clotted blood samples with alteplase before cell culture to yield cells suitable for cytogenetic analysis. Since clinical implementation, this technique has been applied to more than 250 bone marrow samples, with a 93% success rate.

Conclusions.—We believe the routine use of alteplase on clotted blood and bone marrow specimens should become standard for cytogenetics laboratories and may have similar utility in salvaging clotted specimens for other clinical assays requiring intact cells for analysis.
A Review of Sentinel Laboratory Performance: Identification and Notification of Bioterrorism Agents
Authors: Wagar Elizabeth A. , Mitchell Michael J. , Carroll Karen C. , Beavis Kathleen G. , Petti Cathy Anne , Schlaberg Robert , Yasin Bushra
Published: February 2021

Context.—The anthrax incident of 2001 in the United States prompted the College of American Pathologists (CAP), the Association of Public Health Laboratories, and the Centers for Disease Control and Prevention to develop exercises for Laboratory Response Network (LRN) sentinel laboratories.

Objective.—To provide an overview of the results of the CAP bioterrorism Laboratory Preparedness Survey (LPS, 2007) and Laboratory Preparedness Exercise (LPX, 2008) and assist LRN sentinel laboratories and public health agencies in planning for bioterrorism events.

Design.—Bioterrorism agents and nonbiothreat mimic organisms were provided in 2 mailings per year (2007 and 2008, 20 total challenges). Within each mailing, 2 to 3 agents were category A or category B bioterrorism agents (total of 10 categoric challenges). Some category A/B isolates were modified/vaccine strains. The total number of laboratories participating in these exercises ranged from 1316 to 1381. Isolate characteristics used to identify the organisms were compiled along with the participants' reporting actions. Educational commentary was provided with each exercise.

Results.—Acceptable identification responses were as follows: Bacillus anthracis, 90% (2007) and 99.9% (2008); Yersinia pestis, 83.8% (2007) and 87.6% (2008); and Francisella tularensis subsp Holarctica, 86.6% (2007) and 91.6% (2008). The time interval between specimen receipt and notification of results to an LRN reference laboratory decreased from more than 10 days in 2007 to 3 or 4 days in 2008 for some challenges.

Conclusions.—The bioterrorism challenge program (LPS, LPX) provides important comparative data from more than 1300 sentinel laboratories that can be used by individual laboratories to evaluate their identification and LRN reporting performance.
Definition of the Esophagogastric Junction: A Critical Mini Review
Authors: Huang Qin
Published: February 2021

Context.—Accurate diagnosis of diseases involving the esophagogastric junction (EGJ) is challenging because of difficulty in defining the EGJ endoscopically and histologically. Recent research results have redefined the EGJ, and the endoscopic and histologic diagnostic criteria of the mucosal EGJ have become available.

Objective.—To review the recent literature on endoscopy, histology, and pathology of the EGJ with critical analysis.

Data Sources.—Recently published research articles and guidelines in the peer-reviewed core journals and personal research results in this field.

Conclusions.—At present, the mucosal EGJ can be defined endoscopically as the distal ends of esophageal longitudinal vessels that meet the proximal ends of gastric longitudinal mucosal folds. However, histologic validation of this criterion is needed. The histologic criteria of the EGJ include the distal ends of esophageal squamous mucosa, deep esophageal glands or ducts, or multilayered epithelium. The squamocolumnar junction is not a reliable landmark of the EGJ in patients with diseases involving the EGJ, such as hiatal hernias.
A Fatal Central Nervous System Enterovirus 68 Infection
Authors: Kreuter Justin D. , Barnes Arti , McCarthy James E. , Schwartzman Joseph D. , Oberste M. Steven , Rhodes C. Harker , Modlin John F. , Wright Peter F.
Published: February 2021

The anticipated eradication of poliovirus emphasizes the need to identify other enteroviral causes of severe central nervous system disease. Enterovirus 68 has been implicated only in cases of respiratory illness. We therefore report a case of fatal meningomyeloencephalitis caused by enterovirus 68 in a 5-year-old boy, which required neuropathology, microbiology, and molecular techniques to diagnose.