Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin- and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed non-polypoid lesions. Seven (88%) showed multifocal GI disease, including five with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single-system), with the remaining 14 (36%) exhibiting multi-system disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multi-system LCH more frequently presented with GI symptoms (92%, P<0.001), non-colorectal GI site involvement (50%, P=0.02), multifocal GI lesions (43%, P=0.005), non-polypoid lesions (71%, P<0.001), infiltrative histologic growth pattern (78%, P=0.04), and persistent disease (57%, P<0.001). Adult multi-system LCH patients appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrate that adults with single-system LCH involving the GI tract have an excellent prognosis, while multi-system LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, non-colorectal GI involvement, multifocal GI disease, non-polypoid lesions, and infiltrative growth pattern.

Idiopathic multicentric Castleman disease with TAFRO clinical subtype responsive to IL-6/JAK inhibition: A pediatric case series.

TAFRO (thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, and organomegaly) clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare lymphoproliferative disease characterized by systemic inflammation. First-line treatment for iMCD-TAFRO includes steroids and interleukin (IL)-6 blockade. Many patients have refractory disease, which is associated with significant morbidity and mortality, and treatment remains challenging. We present two pediatric cases of iMCD-TAFRO. One patient responded to IL-6 blockade; the other was refractory to siltuximab and chemotherapy, ultimately responding to JAK inhibition with ruxolitinib. This is the first reported pediatric case of refractory iMCD-TAFRO responding to JAK inhibition.

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.

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.

Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids.

BACKGROUND: Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones. METHODS: Patients 1 and 2 are identical twins, who presented with red blood cell transfusion-dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next-generation sequencing (NGS) on an in-house bone marrow failure syndrome panel. RESULTS: The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion. CONCLUSION: We report three Caucasian siblings from non-consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two-compound heterozygous pathogenic variants of TBXAS1.

Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.

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.

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists.

CONTEXT.­: Myeloid neoplasms with familial occurrence have been rarely reported in the past. With the advance of molecular technology and better understanding of the molecular pathogenesis of myeloid neoplasms, investigating the genetic causes of familial acute myeloid leukemia or myelodysplastic syndrome has become feasible in the clinical setting. Recent studies have identified a rapidly expanding list of germline mutations associated with increased risks of developing myeloid neoplasm in the affected families. It is important to recognize these entities, as such a diagnosis may dictate a unique approach in clinical management and surveillance for the patients and carriers. OBJECTIVE.­: To raise the awareness of myeloid neoplasms arising in the setting of familial inheritance among practicing pathologists. DATA SOURCES.­: Based on recent literature and the 2016 revision of the World Health Organization classification of hematopoietic neoplasms, we provide an up-to-date review of myeloid neoplasm with germline predisposition. CONCLUSIONS.­: This short review focuses on the clinical, pathologic, and molecular characterization of myeloid neoplasm with germline predisposition. We emphasize the important features that will help practicing pathologists to recognize these newly described entities.

Expanding the Spectrum of EBV-positive Marginal Zone Lymphomas: A Lesion Associated With Diverse Immunodeficiency Settings.

Traditionally low-grade B-cell lymphomas have been excluded from the category of monomorphic posttransplant lymphoproliferative disorders. However, recent reports identified Epstein-Barr virus-positive (EBV) extranodal marginal zone lymphomas (MZL), almost exclusively seen in the posttransplant setting. Some reported cases responded to reduced immunosuppression, suggesting that they should be considered as a form of posttransplant lymphoproliferative disorders. We identified 10 cases of EBV MZL, 9 in extranodal sites and 1 presenting in lymph node. Two cases arose following solid organ transplantation, but other settings included iatrogenic immunosuppression for rheumatoid arthritis (2); prior chemotherapy (2); congenital immune deficiency (1); and increased age (3), as the only potential cause of immune dysfunction. There were 4 males and 6 females; age range 18 to 86. The atypical plasmacytoid and/or monocytoid B cells were positive for EBV in all cases, with either latency I or II in all cases tested. Monotypic light chain expression was shown in all with 6 cases positive for IgG, and 2 for IgM, undetermined in 2. Clonal immunoglobulin gene rearrangement was positive in all cases with successful amplification. MYD88 L265P was wild type in the 6 cases tested. We show that EBV MZLs can arise in a variety of clinical settings, and are most often extranodal. Treatment varied, but most patients had clinically indolent disease with response to reduction of immune suppression, or immunochemotherapy.

Genome-wide analysis reveals TNFAIP8L2 as an immune checkpoint regulator of inflammation and metabolism.

The interplay between inflammation and metabolism is widely recognized, yet the underlying molecular mechanisms remain poorly characterized. Using experimental database mining and genome-wide gene expression profiling methods, we found that in contrast to other TNFAIP8 family members, TNFAIP8L2 (TIPE2) was preferentially expressed in human myeloid cell types. In addition, Tnfaip8l2 expression drastically decreased in lipopolysaccharide (LPS)-stimulated macrophages. Consequently, Tnfaip8l2 deficiency led to heightened expression of genes that were enriched for leukocyte activation and lipid biosynthesis pathways. Furthermore, mitochondrial respiration rate was increased in Tnfaip8l2-deficient macrophages, as measured by Seahorse metabolic analyzer. Taken together, these results indicate that Tnfaip8l2 serves as a "brake" for immunometabolism, which needs to be released for optimized metabolic reprogramming as well as mounting effective inflammatory responses. The unique anti-inflammatory and metabolic-modulatory function of TNFAIP8L2 renders it a novel therapeutic target for cardiovascular diseases and cancer.