Reactive Lymphadenopathy in the Pediatric Population with a Focus on Potential Mimics of Lymphoma.

Benign lymphadenopathy is common in the pediatric population and may be clinically striking. As in adults, lymph node evaluation in pediatric patients requires careful morphologic and immunohistochemical assessment and clinical contextualization of the findings. It is important for the pathologist to be familiar with benign and reactive conditions that may mimic malignancy. This review presents non-neoplastic or indolent processes or patterns of lymphoid hyperplasia that may be confused with or raise the differential of lymphoma, with a focus on those more commonly encountered in the pediatric/adolescent population.

The influence of biofertilizers on leaf economics spectrum traits in a herbaceous crop.

Microbial inoculations or 'biofertilizers' represent novel contributions to sustainable agriculture. While belowground mechanisms surrounding how biofertilizers enhance crop production are well described, their role in aboveground trait expression remains less well explored. We quantified infraspecific variation in leaf economics spectrum (LES) traits in response to 10 biofertilizer treatments in basil (Ocimum basiclicum) cultivated under hydroponic conditions. Multiple physiological (i.e. maximum photosynthesis rates (A), dark respiration (R), and leaf-level light compensation points) and morphological (i.e. leaf mass per area (LMA) and leaf thickness) traits varied significantly across microbial treatments. Following treatments, basil plants differentiated from one another along an infraspecific LES, with certain plants expressing more resource-acquiring LES trait values (i.e. high A, R, leaf N, and low LMA), versus others that expressed the opposite suite of resource-conserving LES trait values. Infraspecific trait covariation largely matched LES patterns observed among plants globally. Bivariate and multivariate trait analyses further revealed that certain treatments-namely those including closely related Bacillus and Brevibacillus species strains-increased leaf resource capture traits such as A and leaf N. Biofertilizers influence plant performance through a role in moderating infraspecific leaf trait variation, thereby suggesting aboveground leaf traits may be used to diagnose optimal biofertilizer formulations in basil and other crops.

Peripheral Blood Smear Detection of Asymptomatic Central Line Infection in a Patient With Sickle Cell Disease.

Sickle cell disease is a lifelong disorder which may be managed by chronic red cell transfusion including exchange transfusion. Chronic indwelling vascular catheters including ports offer convenient and reliable access for red cell exchange but confer risk of complications including infection and thrombosis. Detection of these complications is essential for preserving vascular access and relies on both clinical and laboratory observation. Here we describe a case of asymptomatic port infection detected by manual screening of a peripheral blood smear.

Morphologic and Immunophenotypic Differences in Juvenile Myelomonocytic Leukemias With CBL and Other Canonical RAS-pathway Gene Mutations: A Single Institutional Experience.

The diagnostic criteria for juvenile myelomonocytic leukemia have recently been revised to include clinical findings and RAS-pathway gene mutations per the 2016 World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Differing clinical behaviors have been observed in cases with CBL versus other RAS-pathway gene (RAS-p) mutations, notably the patients with CBL mutations can be self-limiting with spontaneous resolution. Additional clinical characteristics and histopathologic findings between these subsets are less well-described. We performed a retrospective search and identified cases with either CBL or RAS-p mutations, as per targeted and/or massively parallel sequencing. Eight patients had sufficient material for review, including cytogenetic studies and peripheral blood, bone marrow aspirate, and/or biopsy with flow cytometry analyses. Three patients showed CBL mutations and lower percentages of hemoglobin F and peripheral blood absolute monocyte counts, lesser degrees of leukocytosis compared with the RAS-p cohort, and normal megakaryocyte morphology and myeloblast immunophenotypes. Two of these patients were managed with observation only and experienced resolution of their disease. The patients with RAS-p mutations had severe thrombocytopenia, moderate to severe anemia, and experienced variable clinical outcomes. Abnormal megakaryocyte morphology and decreased numbers of megakaryocytes were seen in cases with RAS-p mutations. In addition, 3 of 4 cases with flow cytometry data demonstrated aberrant CD7 expression in myeloblasts. Our study is the first to identify morphologic and immunophenotypic differences between juvenile myelomonocytic leukemia cases with CBL or RAS-p mutations, and further supports previous reports of significantly different clinical behaviors between these subsets of patients.

EBV-Positive Plasmacytomas Involving a Nasopharyngeal Angiofibroma in an Adolescent.

We report comprehensive characterization of an unusual collision tumor comprising extramedullary plasmacytomas and nasopharyngeal angiofibroma in a pediatric patient, which has yet to be reported. Histologically, the nasopharyngeal angiofibroma showed typical morphology with a diffuse, dense plasmacytic infiltrate in the stroma. The neoplastic plasma cells showed a spectrum of well-differentiated, plasmablastic, and anaplastic morphology, Epstein-Barr virus encoded RNA (EBER) positivity, and aberrant immunophenotype. Fluorescence in situ hybridization using a plasma cell myeloma targeted panel detected gains of 1q21.3 (CKS1B, x3), 3q27 (BCL6, x4), and 11q22.3 (ATM, x3), but no rearrangement of ALK and MYC. A 50-gene next generation sequencing lymphoma panel failed to detect any pathogenic mutation. Plasmacytoma with EBER positivity and plasmablastic morphology must be distinguished from plasmablastic lymphoma due to different clinical management and prognosis. This case highlights the importance of a thorough pathological evaluation of a mass lesion with synchronous neoplastic processes.

Bilateral Lung Metastases From a Phalangeal Giant Cell Tumor of Bone.

We describe a rare pediatric case of a phalangeal giant cell tumor of bone with extensive bilateral lung metastases following curettage, wide resection, and amputation. Concurrent peripheral blood eosinophilia and pleural effusion with marked eosinophilia (47%) were present. To discover genetic changes driving tumor metastasis, genomic and transcriptome profiling of the metastatic lung mass as well as germline analysis were performed. Whole exome sequencing detected a histone H3F3A p.G35V missense mutation in tumor cells. RNA sequencing revealed overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL). The patient is alive with no residual disease and uncompromised respiratory function 29 months after amputation of primary tumor and 19 months after surgical resection of his metastatic lung disease.

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. METHODS: We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. RESULTS: 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). CONCLUSION: We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.

Inv(11)(q21q23); KMT2A-MAML2, a Recurrent Genetic Abnormality in T-Cell Therapy-related Acute Lymphoblastic Leukemia.

T-cell therapy-related acute lymphoblastic leukemia (T-t-ALL) is a rare condition associated with previous cytotoxic therapy for another disease. Here we report T-t-ALL with inv(11)(q21q23), which involves KMT2A and MAML2, a transcriptional coactivator of NOTCH proteins, that occurred after chemotherapy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. This case describes the youngest patient with T-t-ALL harboring inv(11)(q21q23) and is the first independent report following an initial series also occurring in children. Our results lend further support to the observation that the KMT2A-MAML2 fusion gene resulting from inv(11)(q21q23) is likely a recurrent cytogenetic abnormality in T-t-ALL and appears to be associated with pediatric cases.

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: Should it also be reclassified in children?

BACKGROUND: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (noniEFVPTC) has low risk of adverse outcome in adults, warranting reclassification as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In children, thyroid nodules have higher risk of malignancy and it is unknown if encapsulated FVPTC (EFVPTC) and infiltrative FVPTC (IFVPTC) tumors have different behavior. We analyzed the clinicopathologic features of follicular variant of papillary thyroid carcinoma (FVPTC) subtypes in our pediatric population to determine if noniEFVPTC has an indolent course as reported in adults. PROCEDURE: We retrospectively studied all patients diagnosed with FVPTC at our institution. The clinicopathologic characteristics of the histologic subtypes were compared. RESULTS: Eighteen patients were identified, all treated with total thyroidectomy. No significant differences in age, sex, tumor size, focality, or prior malignancy were detected between subtypes. Extrathyroidal extension had significantly higher incidence in IFVPTC (5/8) compared with EFVPTC (1/10, P = 0.03), translating in significantly more T3 tumors within IFVPTC subtype (5/8), whereas most EFVPTC cases had T1 staging (6/10, T1 vs. T3, P = 0.05). EFVPTC had significantly lower rate of lymph node involvement (N1 in 2/8) compared with IFVPTC (N1 in 8/8, P = 0.003). Only one patient diagnosed with IFVPTC developed extranodal recurrence. When noniEFVPTC and iEFVPTC were separately compared, the noninvasive form showed no propensity for invasive growth (T3 staging: 0/4 vs. 2/6), lymph node metastasis (N1: 0/3 vs. 2/5) or extranodal recurrence. CONCLUSION: In children, noniEFVPTC/NIFTP has indolent behavior, warranting consideration of less aggressive management, similar to adults.

Intraspecific Leaf Trait Variation across and within Five Common Wine Grape Varieties.

Variability in traits forming the Leaf Economics Spectrum (LES) among and within crop species plays a key role in governing agroecosystem processes. However, studies evaluating the extent, causes, and consequences of within-species variation in LES traits for some of the world's most common crops remain limited. This study quantified variations in nine leaf traits measured across 90 vines of five common wine grape (Vitis vinifera L.) varieties at two growth stages (post-flowering and veraison). Grape traits in these varieties covary along an intraspecific LES, in patterns similar to those documented in wild plants. Across the five varieties evaluated here, high rates of photosynthesis (A) and leaf nitrogen (N) concentrations were coupled with low leaf mass per area (LMA), whereas the opposite suite of traits defined the "resource-conserving end" of this intraspecific LES in grape. Variety identity was the strongest predictor of leaf physiological (A) and morphological traits (i.e., leaf area and leaf mass), whereas leaf chemical traits and LMA were best explained by growth stage. All five varieties expressed greater resource-conserving trait syndromes (i.e., higher LMA, lower N, and lower Amass) later in the growing season. Traits related to leaf hydraulics, including instantaneous water-use efficiency (WUE), were unrelated to LES and other resource capture traits, and were better explained by spatial location. These results highlight the relative contributions of genetic, developmental, and phenotypic factors in structuring trait variation in the five wine grape varieties evaluated here, and point to a key role of domestication in governing trait relationships in the world's crops.

National-scale changes in crop diversity through the Anthropocene.

Expansion of crops beyond their centres of domestication is a defining feature of the Anthropocene Epoch. This process has fundamentally altered the diversity of croplands, with likely consequences for the ecological functioning and socio-economic stability of agriculture under environmental change. While changes in crop diversity through the Anthropocene have been quantified at large spatial scales, the patterns, drivers, and consequences of change in crop diversity and biogeography at national-scales remains less explored. We use production data on 339 crops, grown in over 150 countries from 1961 to 2017, to quantify changes in country-level crop richness and evenness. Virtually all countries globally have experienced significant increases in crop richness since 1961, with the early 1980s marking a clear onset of a ~ 9-year period of increase in crop richness in countries worldwide. While these changes have increased the similarity of diversity of croplands among countries, only half of countries experienced increases in crop evenness through time. Ubiquitous increases in crop richness within nearly all countries between 1980 and 2000 are a unique biogeographical feature of the Anthropocene. At the same time, we detected opposing changes in crop evenness, and only modest signatures of increased homogenization of croplands among countries. Therefore context-dependent and, at least, national-scale assessments are needed to understand and predict how changes in crop diversity influence agricultural resistance and resilience to environmental change.

Higher antibody, but not cell-mediated, responses to vaccination in high physically fit elderly.

The purpose of this study was to examine whether cardiovascular fitness, independent of confounding factors, was associated with immune responsiveness to clinically relevant challenges in older adults (60-76 yr). Thirteen sedentary, low-fit (LF; maximal O(2) uptake = 21.1 +/- 1.1 ml.kg(-1).min(-1)) and 13 physically active, high-fit (HF; maximal O(2) uptake = 46.8 +/- 3.4 ml.kg(-1).min(-1)) older adults participated in this study. Dietary intake was assessed, and a battery of psychosocial tests was administered. In vivo antibody and ex vivo proliferative and cytokine responses to influenza (Fluzone) and tetanus toxoid (TT) vaccination and delayed-type hypersensitivity skin tests were performed. HF elderly individuals displayed a higher antibody response to two of the three strains included in the Fluzone vaccine as measured by hemagluttination inhibition, but there was no difference between groups in influenza-specific ex vivo proliferation or IFN-gamma or IL-10 production. HF elderly individuals exhibited a lower IgG(1) response and a tendency for a higher IgG(2) response to the TT vaccine. There were, however, no differences in TT-specific ex vivo proliferation or IFN-gamma or IL-10 production. In contrast, HF subjects had higher proliferative responses to phytohemagluttinin. In addition, there were no differences in delayed-type hypersensitivity responses to fungal antigens between groups. These results suggest that, after accounting for confounding factors, HF elderly individuals have higher antibody responses to Fluzone vaccine and a Th2 skewing of the antibody response to TT. There was little evidence that HF mounted better cell-mediated immune responses to the Fluzone or TT vaccine measured in peripheral blood cells or to other recall antigens in vivo.

Effects of a Taiji and Qigong intervention on the antibody response to influenza vaccine in older adults.

Previous studies have suggested that Taiji practice may improve immune function. This study was intended to examine whether 5 months of moderate Taiji and Qigong (TQ) practice could improve the immune response to influenza vaccine in older adults. Fifty older adults (mean age 77.2 +/- 1.3 years) participated in this study (TQ N = 27; wait-list control [CON] N = 23). Baseline pre-vaccine blood samples were collected. All subjects then received the 2003-2004 influenza vaccine during the first week of the intervention. Post-vaccine blood samples were collected 3, 6 and 20 weeks post-intervention for analysis of anti-influenza hemagglutination inhibition (HI) titers. We found a significant (p < 0.05) increase in the magnitude and duration of the antibody response to influenza vaccine in TQ participants when compared to CON. The vaccination resulted in a 173, 130, and 109% increase in HI titer at 3, 6, and 20 weeks post-vaccine, respectively, in the TQ group compared to 58, 54, and 10% in CON. There was a significant between group difference at 3 and 20 weeks post-vaccine and at 20 weeks the TQ group had significantly higher titers compared to the pre-vaccine time point, whereas the CON group did not. A higher percentage of TQ subjects also responded to the influenza A strains with a protective (> 40HI) antibody response (37% TQ vs. 20% CON for the H1N1 strain and 56% TQ vs. 45% CON for the H3N2 strain), but the differences between groups were not statistically significant. Traditional TQ practice improves the antibody response to influenza vaccine in older adults, but further study is needed to determine whether the enhanced response is sufficient to provide definitive protection from influenza infection.

Copper deficiency mimicking myelodysplastic syndrome.

Copper deficiency is a rare cause of pancytopenia that may be mistaken for myelodysplastic syndrome. Cytoplasmic vacuolization in erythroid and myeloid precursors is found on bone marrow examination. Patients with a history of abdominal surgery who present with anemia and neutropenia with dysplastic changes should have copper levels checked.

Can we improve the positive predictive value of atypical glandular cells not otherwise specified?

The category of atypical glandular cells (AGC) in gynecologic cytopathology presents many well-documented diagnostic challenges, the most significant related to high interobserver variability, low specificity, and low positive predictive value. The current Bethesda System provides criteria for specific glandular categories including atypical endocervical cells not otherwise specified (AEC-NOS), AEC favor neoplastic, and atypical endometrial cells. The Bethesda System does, however, acknowledge that in some cases AGC cannot be categorized based upon cell of origin, in which case the generic term "atypical glandular cells" (AGC) may be used. We sought to determine whether further refinement of the current Bethesda System criteria for AEC-NOS might increase the positive predictive value of the general category of AGC. Fifty-three cases of AGC with documented histologic follow-up at the University of Illinois Hospital were reviewed. The cases were graded on each of the eight specific cytologic criteria recommended by the current Bethesda System for AEC-NOS using a study-developed three-tier grading system. Multiple regression analysis showed that four of the cytologic criteria in combination--nuclear enlargement, nuclear pleomorphism, increased nuclear-to-cytoplasmic (N/C) ratio, and cells occurring in sheets and strips with cell crowding and nuclear overlap--discriminated positive histologic outcome slightly better than any single criterion alone. In addition, simple logistic regression analysis showed nuclear enlargement to have a marginal independent association with positive histologic outcome (P = 0.0566). No other criterion was independently associated with outcome. Ancillary methods seem indicated to increase the positive predictive value of AGC at this time.

Lymphangitic pulmonary metastases in castrate-resistant prostate adenocarcinoma.

A 63-year-old man with castrate-resistant metastatic prostate adenocarcinoma with known osseous and pelvic nodal involvement presented with progressive dyspnea for one week. Complete cardiopulmonary evaluation revealed a restrictive lung defect that could not be attributed to any of his previous therapies. On presentation, physical examination revealed coarse breath sounds diffusely with hypoxemia. Computed tomography of the chest showed severe bilateral airspace opacities and ground-glass appearance most consistent with interstitial pneumonitis. The patient was intubated due to progressive hypoxemia and worsening respiratory status despite empiric antibiotics and high dose steroids. Subsequent emergent bronchoscopy with transbronchial biopsies revealed atypical intralymphatic cells that stained positively for prostate-specific antigen and prostatic-specific acid phosphatase, confirming the diagnosis of intralymphatic pulmonary metastasis from prostate adenocarcinoma. Lymphangitic pulmonary metastasis from prostate adenocarcinoma is exceedingly rare, with few reported cases that are biopsy-proven. Herein, we describe a rare case of biopsy-proven lymphangitic pulmonary metastasis in the setting of castrate-resistant prostate adenocarcinoma and provide a comprehensive literature review.