IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia.

BACKGROUND: Compared to other ethnicities, Hispanics/Latinos (H/L) have a high incidence of acute lymphoblastic leukemia (ALL), enrichment of unfavorable ALL genetic subtypes, and worse outcomes, even after correcting for socioeconomic factors. We previously demonstrated increased incidence of the high-risk genetic drivers IKZF1 deletion and IGH::CRLF2 rearrangement in H/L compared to non-H/L children with B-ALL. Here in an expanded pediatric cohort, we sought to identify novel genetic drivers and secondary genetic alterations in B-ALL associated with H/L ethnicity. PROCEDURE: Comprehensive clinicopathologic data from patients with B-ALL treated from 2016 to 2020 were analyzed. Subtype was determined from karyotype, fluorescence in situ hybridization (FISH), chromosome microarray (CMA), and our next-generation sequencing (NGS) panel (OncoKids). Non-driver genetic variants were also examined. p-Values less than .05 (Fisher's exact test) were considered significant. RESULTS: Among patients with B-ALL at diagnosis (n = 273), H/L patients (189, 69.2%) were older (p = .018), more likely to present with CNS2 or CNS3 disease (p = .004), and NCI high-risk ALL (p = .014) compared to non-H/L patients. Higher incidence of IGH::CRLF2 rearrangement (B-ALL, BCR::ABL1-like, unfavorable; p = .016) and lower incidence of ETV6::RUNX1 rearrangement (favorable, p = .02) were also associated with H/L ethnicity. Among secondary (non-subtype-defining) genetic variants, B-ALL in H/L was associated with IKFZ1 deletion alone (p = .001) or with IGH::CRLF2 rearrangement (p = .003). The IKZF1PLUS profile (IKZF1 deletion plus CDKN2A/2Bdel, PAX5del, or P2RY8::CRLF2 rearrangement without DUX4 rearrangement) was identified as a novel high-risk feature enriched in H/L patients (p = .001). CONCLUSIONS: Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.

B-cell acute lymphoblastic leukemia and juvenile xanthogranuloma in a patient with ETV6 thrombocytopenia and leukemia predisposition syndrome: novel clinical presentation and perspective.

Not available.

Updates on lymphoblastic leukemia/lymphoma classification and minimal/measurable residual disease analysis.

Lymphoblastic leukemia/lymphoma (ALL/LBL), especially certain subtypes, continues to confer morbidity and mortality despite significant therapeutic advances. The pathologic classification of ALL/LBL, especially that of B-ALL, has recently substantially expanded with the identification of several distinct and prognostically important genetic drivers. These discoveries are reflected in both current classification systems, the World Health Organization (WHO) 5th edition and the new International Consensus Classification (ICC). In this article, novel subtypes of B-ALL are reviewed, including DUX4, MEF2D and ZNF384-rearranged B-ALL; the rare pediatric entity B-ALL with TLF3::HLF, now added to the classifications, is discussed; updates to the category of B-ALL with BCR::ABL1-like features (Ph-like B-ALL) are summarized; and emerging genetic subtypes of T-ALL are presented. The second half of the article details current approaches to minimal/measurable residual disease (MRD) detection in B-ALL and T-ALL and presents anticipated challenges to current approaches in the burgeoning era of antigen-directed immunotherapy.

Survival of pediatric Hodgkin lymphoma patients treated with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) at a single institution.

BACKGROUND: Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), the de facto standard of care in adult-onset Hodgkin lymphoma (HL), has not been directly compared to doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC), a pediatric-aimed regimen designed to reduce late effects. We aimed to describe the single-institution experience of using both regimens in patients with pediatric HL. METHODS: This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children's Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n = 46) or ABVE-PC (n = 47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student's t-test or Fisher's exact test. Survival analysis used the Kaplan-Meier method. Events included death, relapse, and secondary malignancy. We also describe the use of radiation therapy, pulmonary toxicity, and cardiomyopathy determined by shortening fraction <29%. Analyses followed an intention-to-treat principle. RESULTS: There was no difference in baseline characteristics between the patients receiving ABVE-PC or ABVD in regard for stage, risk group, or prognostic variables, such as the presence or absence of "B" symptoms, bulky disease, and extra-nodal involvement. A greater proportion of patients treated with ABVE-PC received consolidating external beam radiation treatment (XRT) either by randomization or by response compared to ABVD (59.6% vs. 32.6%, respectively, p = .01). While not statistically significant, response to therapy, assessed by positron emission tomography/computerized tomography (PET/CT) where available, mirrored the use for radiation (rapid response 58.3% vs. 90.0%, n = 34, p = .11). The median dose of anthracycline (doxorubicin) was the same in patients receiving ABVE-PC versus ABVD (200 vs. 200 mg/m2 , interquartile range 200-250 vs. 200-300 mg/m2 , p = .002). There was no difference in event-free survival (p = .63) or overall survival (p = .37) with a median follow-up length of 3.9 years. CONCLUSIONS: ABVD and ABVE-PC achieved similar survival outcomes in our single-institution cohort.

Civatte Bodies in Pediatric Esophageal Biopsies: Does Lichen Esophagitis Pattern Occur in Children?

PURPOSE AND CONTEXT: Civatte bodies (CB) are associated with cutaneous and mucosal lichen planus in adults. They are a distinct feature of Lichen Esophagitis Pattern, which is not well described in children. We characterized clinicopathologic associations of archival esophageal CB at our Children's Hospital to determine whether lichen planus or Lichen Esophagitis Pattern occurs in children. METHOD: Pathology records were queried for pediatric esophageal biopsy diagnoses containing "CB," "apoptosis, "necrosis," or "dyskeratosis." Cases with concurrent eosinophilic/acute esophagitis were excluded. H&E slides and clinical reports were reviewed. KEY RESULTS: Biopsies with CB or similar were identified from 19 patients and had been termed "dyskeratotic cells" in 8 reports. Patients had variable age and presenting symptoms, male predominance (74%), and frequent clinical history of polypharmacy (47%), Crohn disease (42%), and/or celiac disease (21%). Civatte bodies were prominent in the distal esophagus (95%), as few isolated cells (63%), and with variable chronic inflammation (absent, pauci-inflammatory, and lichen planus-like in approximately one-third of cases each). CONCLUSIONS: We show that esophageal CB from pediatric patients are under-recognized and may have different features and implications compared to Lichen Esophagitis Pattern in adults. Recognition and documentation of pediatric esophageal CB is needed to understand their clinical significance.

Ingested Foreign Bodies Can Cause Appendicitis and Perforation: A Multi-Institutional Case Series.

INTRODUCTION: Appendicular foreign bodies are a rare, under-described cause of appendicitis. We performed this study to determine the varied causes and consequences of foreign-body appendicitis. METHODS: On retrospective review of the pathology archives of seven institutions, we identified 56 appendix specimens containing a foreign body (defined as ingested, non-digestible material). We recorded the type of foreign body, patient age and sex, and other findings, as available. RESULTS: Mean patient age was 7.7 years (range: 1 day-18 years). The foreign bodies included hair, plant material, magnets, other metallic material, BB pellets, foreign material not otherwise specified, and other miscellaneous objects. Of 48 cases with available clinical information, 31 patients presented with abdominal pain, and 22 were preoperatively diagnosed as having appendicitis/appendicular inflammation. Seven patients had appendiceal perforation (13%). The foreign body was grossly identified in 34/47 cases with available gross descriptions. Twenty-seven cases had an identifiable foreign body microscopically; 10 were associated with giant cell reaction. DISCUSSION: Hair and plant materials were the most common foreign objects found in the appendix; they often cause mucosal damage and giant cell reaction. Metallic objects were less common. Although appendicular foreign bodies in children are rare and sometimes asymptomatic, they may lead to perforation.

Pediatric hematolymphoid pathology in the gastrointestinal tract.

Hematolymphoid processes involving the gastrointestinal tract in the pediatric and adolescent young adult (AYA) populations include processes occurring primarily within the gastrointestinal tract as well as systemic diseases with predilection for gastrointestinal involvement. Here, we present a focused review of reactive and neoplastic entities occurring in the pediatric and AYA age groups.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Low-grade Appendiceal Mucinous Neoplasm and Endometriosis: Incidental Coincident Pathologies at Cesarean Section.

Incidental pathologic findings at the time of Cesarean section are exceedingly uncommon. Similarly, occult low-grade appendiceal mucinous neoplasms and other noninflammatory, non-neoplastic appendiceal pathologies are rare, although appendiceal neoplasia, most commonly well-differentiated neuroendocrine tumors, may be found during evaluation of acute appendicitis. Here we report the first case of incidental coincident low-grade appendiceal mucinous tumor and endometriosis involving the appendix at the time of Cesarean section. We highlight pitfalls in the histopathologic evaluation of these processes, particularly given the setting of decidualization of ectopic endometrial stroma, as well as the prognostic implications of low-grade appendiceal mucinous tumors to emphasize the importance of clinicopathologic correlation and careful intraoperative examination of the appendix and other visible structures during Cesarean section.

Ectopic Fetal Hepatic Tissue in the Placenta.

When an unusual intraplacental lesion is identified during pathologic examination, it becomes of substantial import to determine whether it represents a normal structure, metastasis from the mother, or a primary benign tumor, including those secondary to abnormal embryologic development versus a primary malignant placental tumor. In this case report, we identified an incidental nest of intraplacental cells with nondiagnostic morphology and negative initial Glypican-3 stain in a healthy 35-wk gestation. This negative result prompted a broadening of the differential before ultimately determining this lesion was indeed ectopic liver with positive Arginase-1 and HepPar-1 staining. This may represent the mature hepatocyte phenotype within the lesional cells of this near-term birth, a dichotomy not previously discussed in the literature, which focuses on the fetal hepatocyte phenotype, also rarely seen. In this report, we summarize the previous literature regarding intraplacental ectopic liver, and we propose a sensitive approach to suspected ectopic liver of the placenta that may be sufficient to capture both the fetal and mature hepatocyte immunophenotypes. This approach may extend to other related pathologies including assessment of suspected intraumbilical hepatocytes.

Correlation of Endoscopic and Histologic Severity Scores in Pediatric Ulcerative Colitis at First Presentation.

Detailed histologic scoring systems have been developed for the assessment of disease activity in ulcerative colitis. Literature from adult patients has shown some correlation between endoscopy and histology, and reproducibility of histologic scoring systems has also been supported. The effectiveness of endoscopic appearance at predicting histologic scores in pediatric patients has not been well studied, and none of the histologic scoring systems used in adults have had interobserver reproducibility assessed in pediatric patients. We reviewed endoscopic images and concurrent biopsies using Mayo and Geboes scores from the distal colon and rectum in untreated pediatric patients at the presentation of presumed ulcerative colitis based on clinical and endoscopic findings. Interobserver concordance was calculated by weighted-kappa statistic. The averaged histologic scores were compared to endoscopy scores using Spearman's coefficient. Correlation between endoscopic score and each histologic score was weakly to moderately positive, whereas interobserver agreement for histologic scores was fair to moderate, suggesting that the Geboes scoring system has value in pediatric patients. For each histologic parameter, the average score was lower than the average endoscopic score. Examination of larger pediatric cohorts, treated patients, correlations of clinical outcomes with individual histologic parameters, and alternate scoring systems may contextualize these findings.

R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis.

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R-CHOP versus DA-R-EPOCH. 132 patients were identified from 11 contributing centres (56 R-CHOP and 76 DA-R-EPOCH). The primary outcome was overall survival. Secondary outcomes included progression-free survival, complete response (CR) rate, and rates of treatment-related complications. Demographic characteristics were similar in both groups. DA-R-EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA-R-EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA-R-EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment-related toxicities. At 2 years, 89% of R-CHOP patients and 91% of DA-R-EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R-CHOP to DA-R-EPOCH for PMBCL.

Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.

Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers.

Mutually exclusive extracellular signal-regulated kinase pathway mutations are present in different stages of multi-focal pulmonary Langerhans cell histiocytosis supporting clonal nature of the disease.

AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is an idiopathic cigarette smoking-related disorder of the lung. Molecular changes in cellular or fibrotic stages of PLCH have not been investigated. We studied the prevalence of extracellular signal-regulated kinase (ERK) pathway mutations in different PLCH stages and other non-PLCH smoking-related lung diseases. METHODS AND RESULTS: The cohort included 28 PLCH with cellular (n = 10), mixed cellular/fibrotic (n = 4) and fibrotic histology (n = 14). Seven cases had concurrent multi-focal/multi-lobar tumours. Respiratory bronchiolitis interstitial lung disease (RB-ILD, n = 2), desquamative interstitial pneumonia (DIP, n = 4) and mixed RB-ILD/DIP (n = 2) were included for comparison. BRAF(V) (600E) immunohistochemistry, next-generation sequencing (NGS) and peptide nucleic acid (PNA) clamp polymerase chain reaction (PCR) with high analytical sensitivity (<0.1-0.2%) were used to analyse RAS, BRAF and MAP2K1 genes. Of 26 cases with gene mutation data, BRAF(V) (600E) was identified in eight of 12 (67%) cellular cases and in one of 14 (7%) fibrotic cases. MAP2K1 or KRAS mutations were observed in four of 14 (29%) fibrotic cases and three of the 12 (25%) cellular cases. Multi-focal/multi-lobar specimens carried identical BRAF (n = 5) or non-hotspot MAP2K1 (n = 2) mutations. The other smoking-related disorders were negative for mutations. Patients with cellular lesions or BRAF mutation were significantly younger than patients with fibrotic or BRAF wild-type PLCH. CONCLUSION: The presence of identical but mutually exclusive ERK pathway mutations in multi-focal PLCH supports a neoplastic/clonal origin for this disease. Patient age and mutation type differed between cellular and fibrotic histology and may indicate a natural progression or a mutation-specific pathogenicity.

Diagnostic utility of cerebrospinal fluid flow cytometry in patients with and without prior hematologic malignancy.

Flow cytometry (FCM) is an adjunct study to routine analysis of cerebrospinal fluid (CSF) to investigate for involvement by a hematologic malignancy. However, in our experience, FCM only infrequently detects abnormalities in CSF. To help optimize resources without forfeiting clinically important data, we sought to determine evidence-based indications and criteria for performing FCM on CSF. FCM results of 316 consecutive CSF specimens were retrospectively reviewed and correlated with clinical history, total nucleated cell (TNC) counts, and results of concurrent cytologic review. Of 255 samples adequate for analysis, 54% were from patients with a prior history of hematologic malignancy, of which 12% (17 cases) were abnormal by FCM. Corresponding TNC counts among samples with abnormal FCM ranged from 0-1050 cells/µL, and only 44% showed abnormal morphology on concurrent cytology. Of the remaining 46% of samples from patients with no known history of hematologic malignancy who had CSF sampling for neurological indications, only one (1%) was abnormal by FCM. This specimen had an elevated TNC count (39 cells/µL) but lacked clearly abnormal findings on concurrent cytology. These results support the use of CSF FCM only in patients with a history of hematologic malignancy or, in the absence of such a history, in samples showing pleocytosis. If these criteria were applied to the current cohort using a TNC count cut-off of >5 cells/µL, 23% of samples would have been deferred from testing, resulting in decreased cost, improved efficiency, and reduction in the need for unnecessary testing without a negative impact on clinical care.

Transcriptome Sequencing Allows Comprehensive Genomic Characterization of Pediatric B-Acute Lymphoblastic Leukemia in an Academic Clinical Laboratory.

Studies have shown the power of transcriptome sequencing [RNA sequencing (RNA-Seq)] in identifying known and novel oncogenic drivers and molecular subtypes of B-acute lymphoblastic leukemia (B-ALL). The current study investigated whether the clinically validated RNA-Seq assay, coupled with a custom analysis pipeline, could be used for a comprehensive B-ALL classification. Following comprehensive clinical testing, RNA-Seq was performed on 76 retrospective B-ALL cases, 28 of which had known and 48 had undetermined subtype. Subtypes were accurately identified in all 28 known cases, and in 38 of 48 unknown cases (79%). The subtypes of the unknown cases included the following: PAX5alt (n = 12), DUX4-rearranged (n = 6), Philadelphia chromosome-like (n = 5), low hyperdiploid (n = 4), ETV6::RUNX1-like (n = 3), MEF2D-rearranged (n = 2), PAX5 P80R (n = 2), ZEB2/CEBP (n = 1), NUTM1-rearranged (n = 1), ZNF384-rearranged (n = 1), and TCF3::PBX1 (n = 1). In 15 of 38 cases (39%), classification based on expression profile was corroborated by detection of subtype-defining oncogenic drivers missed by clinical testing. RNA-Seq analysis also detected large copy number abnormalities, oncogenic hot-spot sequence variants, and intragenic IKZF1 deletions. This pilot study confirms the feasibility of implementing an RNA-Seq workflow for clinical diagnosis of molecular subtypes in pediatric B-ALL, reinforcing that RNA-Seq represents a promising global genomic assay for this heterogeneous leukemia.

An Exome Capture-Based RNA-Sequencing Assay for Genome-Wide Identification and Prioritization of Clinically Important Fusions in Pediatric Tumors.

This study reports the development of an exome capture-based RNA-sequencing assay to detect recurring and novel fusions in hematologic, solid, and central nervous system tumors. The assay used Twist Comprehensive Exome capture with either fresh or formalin-fixed samples and a bioinformatic platform that provides fusion detection, prioritization, and downstream curation. A minimum of 50 million uniquely mapped reads, a consensus read alignment/fusion calling approach using four callers (Arriba, FusionCatcher, STAR-Fusion, and Dragen), and custom software were used to integrate, annotate, and rank the candidate fusion calls. In an evaluation of 50 samples, the number of calls varied substantially by caller, from a mean of 24.8 with STAR-Fusion to 259.6 with FusionCatcher; only 1.1% of calls were made by all four callers. Therefore a filtering and ranking algorithm was developed based on multiple criteria, including number of supporting reads, calling consensus, genes involved, and cross-reference against databases of known cancer-associated or likely false-positive fusions. This approach was highly effective in pinpointing known clinically relevant fusions, ranking them first in 47 of 50 samples (94%). Detection of pathogenic gene fusions in three diagnostically challenging cases highlights the importance of a genome-wide and nontargeted method for fusion detection in pediatric cancer.