bluuebunny/crossref_metadata_2025 huggingface dataset:
FLT3 Mutations at Diagnosis and Relapse in Acute Myeloid Leukemia: Cytogenetic and Pathologic Correlations, Including Cuplike Blast Morphology
Authors: McCormick Stanley R. , McCormick Matthew J. , Grutkoski Patricia S. , Ducker Gregory S. , Banerji Nilanjana , Higgins Rodney R. , Mendiola John R. , Reinartz John J.
Published: February 2021

Context.—Acquired mutations in the fms-like tyrosine kinase 3 gene (FLT3) adversely impact relapse risk after chemotherapy in patients with acute myeloid leukemia (AML). The FLT3 mutation status may differ at diagnosis and relapse, suggesting a potential role in chemoresistance, yet few reports have addressed the cytogenetic and pathologic correlates of FLT3 mutations in relapsed AML.

Objectives.—To determine FLT3 mutations at diagnosis and relapse in a cohort of adult patients with chemoresistant AML and to correlate mutation status with multiple variables.

Design.—We retrospectively determined FLT3 internal tandem duplication (FLT3/ITD) and FLT3 tyrosine kinase domain mutations in 50 diagnosis/relapse pairs. We correlated FLT3 status with karyotype, World Health Organization 2008 subtype, white blood cell count, biopsy cellularity, blast percentage, and the presence of invaginated (“cuplike”) blast nuclei.

Results.—In 11 of 50 patients (22%) the FLT3 mutation status differed at relapse and diagnosis, with a trend toward gain of FLT3/ITD (n  =  7) and loss of FLT3 tyrosine kinase domain (n  =  5) mutations. FLT3-mutated AMLs correlated with the World Health Organization 2008 subtype, AML, not otherwise specified, hyperproliferative features at diagnosis and relapse, and cytogenetic evolution. FLT3-wild type AMLs correlated with the subtype AML with myelodysplasia-related changes and frequently had adverse presentation karyotypes. Cuplike blast morphology was associated with FLT3/ITD+ status and with high mutation levels. Four of 7 patients with relapse-only FLT3/ITD mutations exhibited cuplike blasts at relapse after being noncuplike at diagnosis.

Conclusions.—In addition to well-known correlates in pretreatment specimens, FLT3 mutation status has pathologic and cytogenetic significance at relapse. A shift to cuplike blast morphology at relapse may herald emergence of a previously undetected FLT3/ITD mutation.
The Use of Autopsy in Preclinical Medical Education: A Survey of Pathology Educators
Authors: Talmon Geoffrey
Published: February 2021

Context.—Declining rates and increased competition for student contact hours pose challenges to integrating autopsies into preclinical curricula. Some have stated that the practice is minimally used with few students having the opportunity to observe necropsies.

Objective.—To determine the degree to and manner in which autopsies are used in the preclinical medical education.

Design.—A survey was distributed to the membership of the Group for Research in Pathology Education, an organization of preclinical pathology educators, assessing the nature of preclinical student exposure to postmortem examinations, how the experience was integrated in curricula, and attitudes toward the practice.

Results.—Fifty-one of 131 instructors (38.9%) responded. Most (86.2%) integrated autopsy material into coursework, usually in pathology education (63.1%) with 10.7% using it in discussions on end-of-life issues. The majority (74.5%) furnish students the opportunity to observe autopsies, typically in small groups. Volume was the only variable significantly related to whether the opportunity was provided (P < .001). The experience was required in 56.3% of schools and usually less than 10% of students attended voluntarily. Although most educators felt it was important in general and pathology curricula, responses were mixed regarding autopsy's utility in discussions on death and dying. Common challenges were low autopsy numbers and busy class schedules.

Conclusions.—Most surveyed schools formally offer the opportunity to observe autopsies and incorporate autopsy themes in curricula. However, as only 41% of these institutions require the practice and most medical students did not view an autopsy voluntarily, less than half of preclinical students actually observe postmortem examinations.
Cellular Heterogeneity in Vertical Growth Phase Melanoma
Authors: Laga Alvaro C. , Murphy George F.
Published: February 2021

Context—Melanoma growing as a tumorigenic nodule is one of the most virulent neoplasms to which the flesh is heir. At a considerably small tumor size, it incurs significant risk for widespread metastatic dissemination. There are no effective means of surgical intervention, chemical therapy, or immunologic therapy for advanced and metastatic melanoma.

Objective—To review the literature and highlight recent cardinal advances in the understanding of melanoma vertical growth, with specific emphasis on how its recognition and characterization may be applied to diagnostic practice and development of novel investigative approaches.

Data Sources—Literature review, archival material, personal experience, and research collaborators.

Conclusions—The study of tumorigenic melanoma, both in primary lesions and in metastases, is the key to the eventual eradication of this highly virulent neoplasm that may disseminate widely when only occupying the volume of a grain of rice. Morphology often provides the first insight into structure and function. A growing database using meticulous and inclusive criteria to define tumor stem cells in the context of clinically relevant models now indicates that the key to melanoma heterogeneity may reside in a small subpopulation with the ability to self-renew and form tumors despite most cells present being significantly less virulent. Hopefully, from these insights into melanoma tumor progression from radial growth phase to heterogeneous and tumorigenic vertical growth phase will come additional answers to how smart therapies may be developed that specifically target those vertical growth phase cells that most pertain to patient survival.
Can Features Evaluated in the Routine Pathologic Assessment of Lymph Node–Negative Estrogen Receptor–Positive Stage I or II Invasive Breast Cancer Be Used to Predict the Oncotype DX Recurrence Score?
Authors: Auerbach Jena , Kim Mimi , Fineberg Susan
Published: February 2021

Context.—Oncotype DX is a multigene reverse transcription–polymerase chain reaction assay used to quantify recurrence risk in patients with stage I or II estrogen receptor–positive, lymph node–negative invasive breast cancer. The results are reported as a Recurrence Score (RS). The 16 cancer genes evaluated include a proliferation set, hormone receptor set, and HER2 set. The activity of these genes is addressed by pathologic assessment of breast cancers.

Objective.—To determine if factors evaluated in pathologic evaluation of breast cancer could be used to predict Oncotype DX results.

Design.—We studied 138 cases of invasive breast cancer for which Oncotype DX results and pathology data were available. Grading was performed by using Nottingham grading system. For hormone receptor immunostaining, 10% nuclear staining was considered a positive result.

Results.—Oncotype DX RS was low in 81 cases, intermediate in 44 cases, and high in 13 cases. All 6 cases with both a negative progesterone receptor (PR) and a mitotic count score of 3 had a high RS. All 12 cases with both a negative PR and a mitotic count score greater than 1 had either an intermediate or high RS. Although Nottingham grade, PR status, mitotic count score, tumor size, and nuclear grade were each significantly associated with RS, in bivariate analyses the only variables that remained independently predictive of an intermediate or high RS score in a multivariate logistic regression model were negative PR and mitotic count score greater than 1.

Conclusions.—Our study suggests that a mitotic count score greater than 1 combined with a negative PR result, as determined by pathologic assessment, could serve as a marker for an intermediate or high Oncotype DX RS.
Ocular Melanoma
Authors: Laver Nora V. , McLaughlin Margaret E. , Duker Jay S.
Published: February 2021

Context—Intraocular melanoma of the ciliary body and choroid is the most common primary ocular malignant tumor in adults and the most common noncutaneous melanoma.

Objective—To describe the most salient clinical features, histopathologic findings, and treatment modalities of intraocular melanoma, as well as the novel therapies currently being tested.

Data Sources—Clinically, it is important to determine which lesions carry a worse prognosis so as to offer patients the best treatment modalities available. Tumor location, size, histopathology, cytogenetic abnormalities, and tumor profiling are all used in determining the risk of death from metastatic disease of uveal melanocytic lesions. Despite successful local tumor control, up to 50% of patients have metastatic disease within 15 years of diagnosis; there is no effective treatment for metastatic disease.

Conclusions—Pathologists should be aware of the importance of tumor gross description, cellular histopathology classification, the use of fine-needle aspiration biopsy coupled with cytogenetics, and the new classification of uveal malignant melanomas that is based on chromosome 3 status.
Primary Mediastinal (Thymic) Large B-Cell Lymphoma: A Short Review With Brief Discussion of Mediastinal Gray Zone Lymphoma
Authors: Hutchinson Charles Blake , Wang Endi
Published: February 2021

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). It commonly presents as a bulky lesion in the anterior-superior mediastinum with symptoms related to local invasion or compression. Microscopic examination typically shows infiltration of medium-large cells surrounded by collagen fibrosis. The neoplastic cells express B-cell markers, and CD30 often shows heterogeneous staining. Comparative genomic hybridization has identified gains in loci of 9p24 and 2p15 as well as Xp11.4-21 and Xq24-26. Amplification of REL and BCL11A at 2p as well as elevated expression of JAK2, PDL1, and PDL2 at 9p has been demonstrated. Nodular sclerosis classic Hodgkin lymphoma needs to be differentiated from PMBCL and cases with overlapped features have been described as mediastinal gray zone lymphoma. Primary mediastinal (thymic) large B-cell lymphoma carries a favorable prognosis in comparison to conventional DLBCL.
Proficiency Survey-Based Evaluation of Clinical Total and Allergen-Specific IgE Assay Performance
Authors: Hamilton Robert G.
Published: February 2021

Context.—The diagnostic algorithm for human allergic disease involves confirmation of sensitization by detection of allergen-specific immunoglobulin E (IgE) antibody in individuals suspected of having allergic disease because of a history of allergic symptoms after known allergen exposure. Previous studies showed wide disparity among clinically reported allergen-specific IgE levels from different serologic assays.

Objective.—To validate the relative analytic performance (sensitivity, interassay reproducibility, linearity/parallelism, intermethod agreement) of clinically used total and allergen-specific IgE assays by using College of American Pathologists' Diagnostic Allergy “SE” Proficiency Survey data.

Design.—Data from 2 SE survey cycles were used to assess relative analytic performance of the ImmunoCAP (Phadia), Immulite (Siemens Healthcare-Diagnostics), and HYTEC 288 (HYCOR-Agilent Technologies) total and allergen-specific IgE assays. In each cycle, 2 recalcified plasma pools from atopic donors were diluted twice with IgE-negative serum and evaluated in approximately 200 federally certified clinical laboratories for total IgE and IgE antibody to 5 allergen specificities. Statistical analysis evaluated analytic sensitivity, linearity, reproducibility, and intermethod agreement.

Results.—Interlaboratory intramethod, intermethod, and interdilution agreement of all 6 clinically used total serum IgE assays were excellent, with coefficients of variation (CVs) below 15%. Interlaboratory intramethod, and interdilution agreement of 3 clinically used allergen-specific IgE assays were also excellent with CVs below 15%. However, intermethod CVs identified between-assay disagreement greater than 20% in 80% of allergen-specific IgE measurements. Allergen reagents and patients' immune response heterogeneity are suggested probable causes.

Conclusions.—Clinical total and allergen-specific IgE assays display excellent analytic sensitivity, precision, reproducibility, and linearity. Marked variability in quantitative estimates of allergen-specific IgE from clinically used automated immunoassays is a concern that may be ameliorated with component allergen use.
Utilization of Fluorescence In Situ Hybridization in the Diagnosis of 230 Mesenchymal Neoplasms: An Institutional Experience
Authors: Tanas Munir R. , Rubin Brian P. , Tubbs Raymond R. , Billings Steven D. , Downs-Kelly Erinn , Goldblum John R.
Published: February 2021

Context—Mesenchymal neoplasms harbor characteristic translocations and amplification of gene regions amenable to evaluation by fluorescence in situ hybridization (FISH).

Objective—To determine the utility of FISH in the diagnosis of mesenchymal neoplasms.

Design—Two hundred thirty soft tissue cases analyzed by FISH were reviewed retrospectively.

Results—Morphologic patterns where FISH was used included high-grade round cell sarcomas (n  =  67), nonmyogenic spindle cell sarcomas (n  =  40), low-grade myxoid neoplasms (n  =  34), adipocytic neoplasms (n  =  20), and melanocytic neoplasms (n  =  19). Fifty cases did not fit into the previously mentioned categories. SYT FISH (96% of monophasic synovial sarcomas were positive; 0% of malignant peripheral nerve sheath tumor were positive) and DDIT3 FISH (100% of myxoid/round cell liposarcomas; no other neoplasm positive) were very sensitive and specific. EWSR1 FISH was very sensitive and specific in the differential diagnosis of melanocytic neoplasms (88% of clear cell sarcomas were positive; all melanomas were negative). EWSR1 FISH was sensitive among high-grade round cell sarcomas (positive in 100% of desmoplastic small round cell tumors and 96% of Ewing sarcoma/primitive neuroectodermal tumors) but not specific because clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of round cell liposarcomas also harbor rearrangements of EWSR1. FUS FISH was very sensitive in detecting low-grade fibromyxoid sarcomas (91% positive) but not specific because most myxoid/round cell liposarcomas also contain rearrangements of FUS. All atypical lipomatous tumors were positive for amplification of MDM2, whereas all lipomas were negative. FOXO1A FISH was positive in ∼70% of cases of alveolar rhabdomyosarcoma.

Conclusion—FISH is a useful adjunct in the diagnosis of mesenchymal neoplasms.
Parathyroid Pathology: Hyperparathyroidism and Parathyroid Tumors
Authors: Carlson Diane
Published: February 2021

Context.—Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Parathyroid adenomas are common, unlike other parathyroid tumors. This review presents a brief summary of current updates in parathyroid pathology.

Objective.—To review parathyroid development and discuss issues in hyperparathyroidism and diagnosis of parathyroid lesions, including the application of immunohistochemistry and molecular biology.

Data Sources.—Current texts, PubMed (National Library of Medicine) articles, and Memorial Sloan-Kettering Cancer Center archives.

Conclusions.—Primary hyperparathyroidism is most commonly seen with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. Autosomal dominant familial hyperparathyroidism syndromes should be considered in the evaluation of patients with parathyroid lesions, particularly in association with parathyroid carcinoma. While the incidence of parathyroid carcinoma is quite low, it is seen with a greater frequency in those patients with hyperparathyroidism-jaw tumor syndrome. Inactivation of the tumor suppressor gene HRPT2 can be identified in a large number of parathyroid carcinomas. Hence, germline HRPT2 gene mutations may reflect unrecognized syndromic patients.
Use of a Linear Array for the Detection of Human Papillomavirus Genotypes in Head and Neck Cancer
Authors: Black Candice C. , Bentley Heather A. , Davis Thomas H. , Tsongalis Gregory J.
Published: February 2021

Context—Tumors of the head and neck commonly arise from the squamous and respiratory mucosa that lines the nasal and oral cavity, sinuses, pharynx, and larynx. The rate of oropharyngeal cancers diagnosed among Americans younger than 50 years is increasing. Infection of the oropharynx and tonsils by the human papillomavirus (HPV) has been linked to preneoplasia and cancer.

Objectives—To evaluate the Roche Linear Array HPV Genotyping test kit to identify, and then specifically genotype, HPV in formalin-fixed, paraffin-embedded tissues.

Design—We evaluated the performance of this assay for accuracy, for intra-assay and interassay precision, and for its limit of detection, using materials with known HPV status. Sixteen tumor tissues with the following origins were evaluated: 1 ocular, 1 hypopharynx, 8 tonsil, 1 retromolar trigone, 3 tongue, 1 anal, and 1 lymph node. DNA from formalin-fixed, paraffin-embedded tumor sections was isolated and amplified in duplicate, with positive and negative controls, using primers specific to the polymorphic L1 region of the HPV genome. Thirty-seven genotypes were tested using the linear array. The amplified product (450 base pairs) was visualized by gel electrophoresis and, if positive, reflexed to HPV genotyping.

Results—Nine of the 16 tumors analyzed were HPV positive. The detected genotypes included HPV 6, 16, and 69.

Conclusions—The Roche Linear Array HPV Genotyping test is an easy-to-use method for determining HPV genotype in the routine analysis of formalin-fixed, paraffin-embedded tumors. This assay is robust and can be performed routinely in a clinical laboratory setting.
Molecular Diagnostics in Melanoma: Current Status and Perspectives
Authors: Dadras Soheil S.
Published: February 2021

Context.—In the current “molecular” era, the advent of technology, such as array-based platforms, systems biology, and genome-wide approaches, has made it possible to examine human cancers, including melanoma, for genetic mutations, deletions, amplification, differentially regulated genes, and epigenetic changes. Advancement in current technologies is such that one can now examine ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and protein directly from the patient's own tumor.

Objective.—To apply these new technologies in advancing molecular diagnostics in melanoma has historically suffered from a major obstacle, namely, the scarcity of fresh frozen, morphologically defined tumor banks, annotated with clinical information. Recently, some of the new platforms have advanced to permit utilization of formalin-fixed, paraffin-embedded (FFPE) tumor specimens as starting material.

Data Sources.—This article reviews the latest technologies applied to FFPE melanoma sections, narrowing its focus on the utility of transcriptional profiling, especially for melastatin; comparative genomic hybridization; BRAF and NRAS mutational analysis; and micro ribonucleic acid profiling.

Conclusion.—New molecular approaches are emerging and are likely to improve the classification of melanocytic neoplasms.
Epithelioid Angiomyolipoma: A Morphologically Distinct Variant That Mimics a Variety of Intra-abdominal Neoplasms
Authors: Mete Ozgur , van der Kwast Theodorus H.
Published: February 2021

This review examines the histopathologic, immunohistochemical, ultrastructural, and molecular biologic features of epithelioid angiomyolipoma (EAML), with an emphasis on the differential diagnosis of intra-abdominal EAML. Epithelioid angiomyolipoma is an uncommon mesenchymal tumor with malignant potential, frequently associated with tuberous sclerosis complex. Histologically, EAML is characterized by sheets or nests of large polygonal epithelioid cells with abundant eosinophilic or occasionally clear cytoplasm, often with prominent nucleoli, and EAML may include multinucleated and markedly pleomorphic forms. As these tumors share a distinctive perivascular epithelioid cell phenotype, they belong to the PEComa tumor family. Nearly all EAMLs show immunoreactivity for both melanocytic and myoid markers. Ultrastructurally, EAMLs show evidence of melanogenesis by the presence of premelanosomes. Epithelioid angiomyolipoma can pose significant diagnostic challenges as it mimics morphologically a variety of neoplasms including renal cell carcinoma, renal oncocytoma, adrenal cortical neoplasm, epithelioid smooth muscle tumor, epithelioid peripheral nerve sheath tumor, epithelioid gastrointestinal stromal tumor, epithelioid melanoma, hepatoblastoma, and hepatocellular carcinoma. The variation in immunophenotype in these tumors requires a prudent use of immunohistochemistry, which may occasionally need complementation by electron microscopy to establish the correct diagnosis.
Blood Bank Safety Practices: Mislabeled Samples and Wrong Blood in Tube—A Q-Probes Analysis of 122 Clinical Laboratories
Authors: Grimm Erin , Friedberg Richard C. , Wilkinson David S. , AuBuchon James P. , Souers Rhona J. , Lehman Christopher M.
Published: February 2021

Context.—Although a rare occurrence, ABO incompatible transfusions can cause patient morbidity and mortality. Up to 20% of all mistransfusions are traced to patient misidentification and/or sample mislabeling errors that occur before a sample arrives in the laboratory. Laboratories play a significant role in preventing mistransfusion by identifying wrong blood in tube and rejecting mislabeled samples.

Objectives.—To determine the rates of mislabeled samples and wrong blood in tube for samples submitted for ABO typing and to survey patient identification and sample labeling practices and sample acceptance policies for ABO typing samples across a variety of US institutions.

Design.—One hundred twenty-two institutions prospectively reviewed inpatient and outpatient samples submitted for ABO typing for 30 days. Labeling error rates were calculated for each participant and tested for associations with institutional demographic and practice variable information. Wrong-blood-in-tube rates were calculated for the 30-day period and for a retrospective 12-month period. A concurrent survey collected institution-specific sample labeling requirements and institutional policies regarding the fate of mislabeled samples.

Results.—For all institutions combined, the aggregate mislabeled sample rate was 1.12%. The annual and 30-day wrong-blood-in-tube aggregate rates were both 0.04%. Patient first name, last name, and unique identification number were required on the sample by more than 90% of participating institutions; however, other requirements varied more widely.

Conclusions.—The rates of mislabeled samples and wrong blood in tube for US participants in this study were comparable to those reported for most European countries. The survey of patient identification and sample labeling practices and sample acceptance policies for ABO typing samples revealed both practice uniformity and variability as well as significant opportunity for improvement.
Pathologic Evaluation of Axillary Dissection Specimens Following Unexpected Identification of Tumor Within Sentinel Lymph Nodes
Authors: Gutierrez Jessica , Dunn Daniel , Bretzke Margit , Johnson Eric , O'Leary John , Stoller Diane , Fraki Sally , Diaz Leslie , Lillemoe Tamera
Published: February 2021

Context—Axillary lymph node dissection has been the standard of care after identification of a positive sentinel lymph node for breast cancer patients.

Objective—To determine the likelihood of non–sentinel lymph node involvement for patients with negative sentinel node by frozen section, who are subsequently found to have tumor cells in the sentinel node by permanent section levels and/or cytokeratin immunohistochemistry.

Design—One hundred three patients with invasive breast cancer exhibiting negative frozen section evaluation of their sentinel node, but later found to have isolated tumor cells (n  =  46), micrometastasis (n  =  46), or metastases (n  =  11) in their sentinel node by permanent sections or immunohistochemistry, were enrolled in this prospective cohort study and underwent completion axillary dissection.

Results—Six of 46 patients (13%) with isolated tumor cells in their sentinel node, 15 of 46 patients (33%) with micrometastasis in their sentinel node, and 2 of 11 patients (18%) with metastasis in their sentinel node had additional findings in the nonsentinel nodes. These findings resulted in a pathologic stage change in 2 patients. Predictors of positive nonsentinel nodes were 2 or more positive sentinel nodes (P  =  .002), sentinel nodes with micrometastasis versus isolated tumor cells (P  =  .03), and those with angiolymphatic invasion (P  =  .04).

Conclusions—Our findings lend support to axillary node dissection for patients with micrometastasis or metastasis in their sentinel nodes. However, studies with clinical follow-up are needed to determine whether axillary node dissection is necessary for patients with isolated tumor cells in sentinel nodes.
The Impact of Specially Designed Digital Games-Based Learning in Undergraduate Pathology and Medical Education
Authors: Kanthan Rani , Senger Jenna-Lynn
Published: February 2021

Context—The rapid advances of computer technologies have created a new e-learner generation of “Homo-zappien” students that think and learn differently. Digital gaming is an effective, fun, active, and encouraging way of learning, providing immediate feedback and measurable process. Within the context of ongoing reforms in medical education, specially designed digital games, a form of active learning, are effective, complementary e-teaching/learning resources.

Objective—To examine the effectiveness of the use of specially designed digital games for student satisfaction and for measurable academic improvement.

Design—One hundred fourteen students registered in first-year pathology Medicine 102 had 8 of 16 lecture sessions reviewed in specially designed content-relevant digital games. Performance scores to relevant content sessions were analyzed at midterm and final examinations. Seventy-one students who registered in second-year pathology Medicine 202 were exposed to the games only during the final examination, with the midterm examination serving as an internal matched-control group. Outcome measures included performance at midterm and final examinations. Paired 2-tailed t test statistics compared means. A satisfaction survey questionnaire of yes or no responses analyzed student engagement and their perceptions to digital game-based learning.

Results—Questions relevant to the game-play sessions had the highest success rate in both examinations among 114 first-year students. In the 71 second-year students, the examination scores at the end of the final examination were significantly higher than the scores on the midterm examination. Positive satisfaction survey noted increased student engagement, enhanced personal learning, and reduced student stress.

Conclusions—Specially constructed digital games-based learning in undergraduate pathology courses showed improved academic performance as measured by examination test scores with increased student satisfaction and engagement.
Expression and Phosphorylation of Eukaryotic Translation Initiation Factor 4E Binding Protein 1 in B-Cell Lymphomas and Reactive Lymphoid Tissues
Authors: Kodali Dhatri , Rawal Ajay , Ninan Mary J , Patel Manish R , Mesa Hector , Knapp Dennis , Schnitzer Bertram , Kratzke Robert A , Gupta Pankaj
Published: February 2021

Context.—Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated.

Objective.—To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues.

Design.—Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues.

Results.—Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N  =  10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N  =  50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous.

Conclusions.—The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.
Xanthogranulomatous Pyelonephritis
Authors: Li Li , Parwani Anil V.
Published: February 2021

Xanthogranulomatous pyelonephritis is an uncommon chronic destructive granulomatous process of renal parenchyma in association with long-term urinary tract obstruction and infection. It affects females more often than males, with a wide range of age, from newborn to elderly. Almost all patients are symptomatic and the most common symptoms are flank or abdominal pain, lower urinary tract symptoms, fever, palpable mass, gross hematuria, and weight loss. The common laboratory findings are leukocytosis and anemia. Urine cultures most often reveal Escherichia coli and Proteus mirabilis. Computed tomography is the mainstay of diagnostic imaging for xanthogranulomatous pyelonephritis. Imaging studies may demonstrate diffuse or focal form. Histologically, xanthogranulomatous pyelonephritis presents a granulomatous inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, xanthomatous histiocytes, and multinucleated giant cells. The differential diagnosis includes clear cell renal cell carcinoma, papillary renal cell carcinoma, sarcomatoid renal cell carcinoma, leiomyosarcoma, malakoplakia, and megalocytic interstitial nephritis. Both antibiotics and surgery can be treatment options depending on the patient's disease status.
Expression of AIF and HtrA2/Omi in Small Lymphocytic Lymphoma and Diffuse Large B-Cell Lymphoma
Authors: Li Shaoying , Wan Mei , Cao Xu , Ren Yongsheng
Published: February 2021

Context.—The pathogenesis of non-Hodgkin lymphoma may involve deregulation of apoptosis. In response to apoptotic stimuli, several proapoptotic proteins are released into the cytoplasm from the mitochondria, including second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low pI (Smac/DIABLO), apoptosis-inducing factor (AIF), and high temperature requirement protein A2 (HtrA2/Omi). Apoptosis-inducing factor promotes apoptosis through a caspase-independent pathway, while Smac/DIABLO and HtrA2/Omi do so through both caspase-dependent and caspase-independent pathways. Smac/DIABLO was reported to be strongly positive in diffuse large B-cell lymphoma (DLBCL) and virtually absent in small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Little is known about the expression of AIF and HtrA2/Omi in lymphomas.

Objective.—To evaluate the expression of AIF and HtrA2/Omi in SLL and DLBCL.

Design.—Twenty-three DLBCLs, 20 SLLs/CLLs, and 10 benign lymph nodes were evaluated for AIF and HtrA2/Omi expression by immunohistochemical staining.

Results.—Apoptosis-inducing factor was strongly and diffusely expressed in 19 of 23 (83%) cases of DLBCL with comparable expression pattern between germinal center–like and non-germinal center–like subgroups. Apoptosis-inducing factor was weakly positive in 15 of 20 (75%) cases of SLL/CLL with increased intensity in pseudofollicles. In contrast, HtrA2/Omi was weakly expressed in SLL/CLL (17 of 20; 85%) and DLBCL (18 of 23; 78%).

Conclusions.—The different expression level and pattern of AIF and HtrA2/Omi in SLL/CLL and DLBCL may suggest different apoptotic mechanisms involved in the pathogenesis and prognosis of these diseases. HtrA2/Omi does not appear to be a major player in the regulation of apoptosis of DLBCL and SLL/CLL.
Maintaining Clinical Tissue Archives and Supporting Human Research: Challenges and Solutions
Authors: Giannini Caterina , Oelkers Michael M , Edwards William D , Aubry Marie Christine , Muncil Maureen M , Mohamud Koshin H , Sandleback Sara G , Nowak John M , Bridgeman Andrew , Brown Marie E , Cheville John C
Published: February 2021

Context.—The increasing number of requests for use of clinically archived tissue in translational research poses unique challenges. Conflicts may arise between pathologists who are responsible for overseeing and preserving the tissues and investigators who need these materials for research purposes.

Objectives.—To evaluate the status of our institution's Tissue Registry Archive and to develop updated written policies and procedures to support a new modern and robust tracking system with features of a library loan system.

Design.—An observational study was performed.

Results.—We found the existing process for managing loans of tissue (slides and paraffin blocks) to be insufficient for the complexity and volume of this task. After extensive customization, a new tracking system was implemented in January 2008. Analysis of the first year of the system's use (2008) showed that of the 206 330 slides and 51 416 blocks loaned out in 2008, 92% and 94%, respectively, were returned by the due date. These rates were markedly improved from those before the new system: 61% and 47%, respectively, in 2005. Material permanently “lost” in 2008 represented only 0.02% of slides and 0.05% of blocks, none of which was the only diagnostic material for the case.

Conclusions.—With expanding needs for archived tissues for clinical care and growing demands for translational research, it is essential that pathology departments at institutions with large tissue-based research endeavors have a tracking and management system in place to meet clinical, educational, and research needs, as well as legal requirements.
Progressive Genetic Alterations of Adenoid Cystic Carcinoma With High-Grade Transformation
Authors: Seethala Raja R. , Cieply Kathleen , Barnes E. Leon , Dacic Sanja
Published: February 2021

Context—Although genome-wide imbalances have been characterized in conventional adenoid cystic carcinoma, other than p53 mutational status, the molecular profile of adenoid cystic carcinoma with high-grade transformation has not been explored.

Objective—To evaluate progressive genetic alterations in adenoid cystic carcinoma with high-grade transformation using array comparative genomic hybridization.

Design—Five adenoid cystic carcinomas with high-grade transformation (4 primary tumors and 1 paired metastasis) were selected and characterized at the DNA level by array comparative genomic hybridization on formalin-fixed paraffin-embedded tissue. Select alterations were validated by fluorescence in situ hybridization.

Results—Chromosomal gains were mostly confined to the areas of high-grade transformation while losses were seen only in the conventional areas. Chromosomal regions with significant gains included 8q24, 17q11.2-q12, 17q23, and 15q11-13. Regions that showed the significant losses included 9q34, 4p16, 1p36.1, and 11q22. Fluorescence in situ hybridization analysis demonstrated increases in C-MYC (8q24.12-q24.13) and a low level increases in ERBB2 (formerly HER2/neu) (17q11.2-q12) in cases showing gains by array comparative genomic hybridization in these regions. However, no tumor showed HER2/neu immunopositivity.

Conclusions—High-grade transformation in adenoid cystic carcinoma is a complex process that is reflected by several chromosomal alterations. Our findings implicate C-MYC amplification in this progression, although the role of HER2/neu is still unclear. Other candidate oncogenes, particularly on chromosome 17q23, warrant investigation in this rare tumor.
Serum Levels of Interleukins 6, 10, and 13 Before and After Treatment of Classic Hodgkin Lymphoma
Authors: Gaiolla Rafael D , Domingues Maria A. C , Niéro-Melo Lígia , de Oliveira Deilson Elgui
Published: February 2021

Context.—Interleukins (ILs) 6, 10, and 13 seem to be important in the pathogenesis of Hodgkin lymphoma (HL), but there is insufficient data on the serum levels of these cytokines in patients with HL.

Objectives.—To evaluate serum levels of IL-6, IL-10, and IL-13 before and after HL treatment and to determine their potential association with clinical and laboratory parameters.

Design.—Serum IL-6, IL-10, and IL-13 levels were quantified in the serum of 27 patients with HL by enzyme-linked immunosorbent assay. Results were evaluated against clinical and laboratory parameters, response to treatment, and presence of infection by the Epstein-Barr virus. As a control group, serum samples from 26 healthy blood donors were evaluated the same way.

Results.—Pretreatment serum levels of IL-6 and IL-10 were significantly higher in patients with HL (P < .001), and a significant decrease was observed after treatment (P < .001). Serum IL-13 was undetectable in both patient and control groups. Serum IL-6 was higher in patients with abdominal involvement (P  =  .02), hepatomegaly (P  =  .03), B symptoms (P  =  .02), and anemia (P  =  .02). Serum IL-10 levels were higher in patients with hypoalbuminemia (P  =  .04). No association with EBV status was observed. Lymphocytopenia and B symptoms were accurate predictors of IL-6 serum levels before treatment, and higher pretreatment levels of IL-6 were observed in patients with treatment failure (P  =  .03).

Conclusions.—Serum levels of IL-6 and IL-10 were frequently elevated in patients with HL and decreased substantially after conventional chemotherapy. The association of elevated IL-6 and IL-10 levels in serum with some clinical and laboratory features suggests those ILs may be useful biomarkers for monitoring the HL disease and its response to chemotherapy.
Epithelial Neoplasms of the Appendix
Authors: Tang Laura H.
Published: February 2021

Context.—The appendix gives rise to an array of epithelial neoplasms showing glandular or neuroendocrine differentiation, and some tumors with elements of both cell types. Although some appendiceal neoplasms resemble their counterparts in the small and large intestines (conventional adenocarcinoma and carcinoid tumor), the appendix also gives rise to relatively unique entities including mucinous neoplasms and goblet cell carcinoid tumors, which present a challenge in pathologic classification and clinical management.

Objective.—To review clinical and diagnostic issues for 3 pathologic types of epithelial neoplasms of the appendix: (1) adenocarcinoma, with specific focus on mucinous neoplasm; (2) goblet cell carcinoid tumor and associated adenocarcinoma; and (3) typical carcinoid tumor.

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

Conclusions.—The most important issue in pathologic assessment of epithelial tumors of the appendix is to understand the clinical implications inherent in the diagnosis.
Aberrant CpG Island Hypermethylation in Pediatric Gastric Mucosa in Association With Helicobacter pylori Infection
Authors: Shin So-Hyun , Park Seog-Yun , Ko Jae-Sung , Kim Nayoung , Kang Gyeong Hoon
Published: February 2021

Context.—Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion.

Objectives.—To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues.

Design.—We analyzed pediatric (n  =  47) and adult (n  =  38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori–positive and H pylori–negative sample results and between pediatric and adult samples.

Results.—The average number of methylated genes was significantly higher in H pylori–infected pediatric samples than in H pylori–negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori–infected adult samples than in H pylori–negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori–infected pediatric samples than in H pylori–negative pediatric samples (all values were P < .05).

Conclusions.—These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori–associated hypermethylation were similar in pediatric and adult samples.
Clinical Implications of Margin Involvement by Pleomorphic Lobular Carcinoma In Situ
Authors: Downs-Kelly Erinn , Bell Diana , Perkins George H. , Sneige Nour , Middleton Lavinia P.
Published: February 2021

Context.—The appropriate treatment for patients with pleomorphic lobular carcinoma in situ (PLCIS) is unknown. When diagnosed on core biopsy, excision is recommended; however, management of PLCIS when it involves margins has not been addressed.

Objective.—To evaluate the significance of PLCIS that is located close to, or at, a resection margin.

Design.—We identified 26 patients with resection specimens containing PLCIS, all of whom were offered chemoprevention and radiation therapy. The margin status in these patients was subdivided as PLCIS cells at the margin without obvious truncation of lesion; PLCIS less than or equal to 1 mm from, but not involving, the margin; PLCIS 1.1 to 2 mm from the margin; and PLCIS at least 2.1 mm from the margin.

Results.—Patient age ranged from 35 to 76 years (mean, 58 years), and length of follow-up ranged from 4 to 108 months (mean, 46 months). Six of the 26 patients (23%) received chemoprevention, 4 of 26 patients (15%) received radiation therapy, and 6 of 26 patients (23%) received both. The remaining 10 patients received no further therapy. Pleomorphic lobular carcinoma in situ was at the margin in 6 of the 26 cases (23%), 1 mm from the margin in 7 of 26 cases (27%), 1.1 to 2 mm from the margin in 4 of 26 cases (15%), and was at least 2.1 mm from the margin in 9 of 26 cases (35%). In 1 of the 26 patients, recurrent PLCIS was identified 18 months after initial surgery, for an overall recurrence rate of 3.8%. All other patients were clinically and radiologically free of disease at last follow-up.

Conclusions.—This is the first series, to our knowledge, that evaluates margin status in patients with PLCIS and documents recurrence. Recurrent PLCIS was identified at a rate similar to low- or intermediate-grade ductal carcinoma in situ. Therefore, known methods of local control, including surgical excision with negative margins (2 mm), may be the appropriate treatment in these patients.
Nodular Lymphocyte Predominant Hodgkin Lymphoma: Diagnostic Pearls and Pitfalls
Authors: Smith Lauren B.
Published: February 2021

Context.—The diagnosis of nodular lymphocyte predominant Hodgkin lymphoma involves key histopathologic and immunophenotypic findings. Appropriate classification is essential owing to the unique therapeutic and prognostic implications of this diagnosis.

Objective.—To define the histologic and immunophenotypic features useful in diagnosing nodular lymphocyte predominant Hodgkin lymphoma and to identify the important differential diagnostic considerations. Diagnostic difficulty can arise in differentiating nodular lymphocyte predominant Hodgkin lymphoma from classical Hodgkin lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma (floral variant), and follicular hyperplasia with progressive transformation of germinal centers.

Design.—Discussion of illustrative cases including morphologic and immunophenotypic findings.

Results.—With the morphologic and immunophenotypic methods described, a diagnosis of nodular lymphocyte predominant Hodgkin lymphoma can be made on excisional biopsies.

Conclusion.—Clinical, histologic, and immunophenotypic features are invaluable in reaching an accurate diagnosis.
Bronchioloalveolar Carcinoma and the Significance of Invasion: Predicting Biologic Behavior
Authors: Schmidt Lindsay , Myers Jeffrey
Published: February 2021

A resected adenocarcinoma illustrates challenges in diagnosing bronchioloalveolar carcinoma (BAC). Bronchioloalveolar carcinoma is defined by lack of invasion, something that may be difficult to assess in scars. Small (≤0.5 cm) invasive foci have little impact on the good prognosis associated with low-stage tumors. The term microinvasive adenocarcinoma or minimally invasive adenocarcinoma has been proposed for otherwise typical BACs and small invasive foci measuring 0.5 cm or less. Larger areas of invasion are associated with a more aggressive course and more reliably distinguish BAC from other variants of adenocarcinoma. Separating BAC from other forms of adenocarcinoma is important owing to differences in prognosis and emerging therapeutic strategies.
Acral Junctional Nevus Versus Acral Lentiginous Melanoma In Situ: A Differential Diagnosis That Should Be Based on Clinicopathologic Correlation
Authors: Puccio Francisco Bravo , Chian Cesar
Published: February 2021

Context.—Acral lentiginous melanoma is the most prevalent clinical presentation of melanoma in ethnic groups other than whites and also occurs in significant numbers in North America and Europe. Despite a clear-cut clinical picture, histologic findings seen in partial biopsies may be too subtle and deceive pathologists dealing with such cases.

Objectives.—To make pathologists aware of the histologic findings during early phases of acral lentiginous melanoma (including the in situ phase), to compare those findings with what is seen in acral junctional nevus, and to highlight their similarities and differences. This review will also emphasize the important clinical and dermatoscopic findings to be considered when diagnosing acral lentiginous melanoma.

Data Sources.—Review of published articles on the epidemiology; the clinical, dermatoscopic, and histopathologic findings; and the molecular biology of acral lentiginous melanoma as well as the personal experience of the authors when dealing with such cases.

Conclusions.—Acral lentiginous melanoma is a clinicopathologic entity with a clear-cut clinical picture: a diameter larger than 0.7 mm; ill-defined, darkly pigmented, flat lesion with irregular borders on acral locations; and the presence of mostly single-cell proliferations of melanocytes along the dermo-epidermal junction. Along with a few additional criteria, these findings should be sufficient to allow the pathologist to make the diagnosis and to recommend complete excision. Fluent communication between clinician and pathologist will facilitate a correct diagnosis.