The changing landscape of pediatric histiocytoses: Birth, life, and transdifferentiation of pediatric histiocytes.

Histiocytic neoplasms in the children are very rare, and histiocytoses can occur in the perinatal period. The presumed origins and presentation of specific histiocytoses in the pediatric age group are described. Common and newly described histiocytoses are presented including Langerhans cell histiocytosis, Rosai-Dorfman disease, histiocytic sarcoma, ALK positive histiocytosis, and hemophagocytic lymphohistiocytosis. Molecular findings common to pediatric histiocytoses are also discussed.

Overview of Gastrointestinal Lymphoproliferative disorders✰.

Lymphoproliferative processes which occur in the gastrointestinal tract range from benign reactive processes such as follicular hyperplasia (rectal tonsil) to high grade malignant lymphomas and histiocytic sarcoma. The WHO Classification of Tumors: Digestive System Tumors, 5th Edition was published in 2019 and shows several impactful changes as compared to the 4th Edition published in 2010. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 2017 also included detailed changes in hematopoietic neoplasms within the gastrointestinal tract. New entities or renamed hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma, duodenal-type follicular lymphoma, intestinal T-cell lymphoma, NOS and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. A brief overview of WHO classification of digestive tumors and WHO classification of tumors of hematopoietic and lymphoid tissue is discussed focusing on the changes in the most recent WHO texts. In depth discussions will be presented in other papers in this series.

Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups.

Histiocytic sarcoma is a rare malignant neoplasm that may occur de novo or in the context of a previous hematologic malignancy or mediastinal germ cell tumor. Here, we performed whole exome sequencing and RNA-sequencing (RNA-Seq) on 21 archival cases of primary histiocytic sarcoma. We identified a high number of genetic alterations within the RAS/RAF/MAPK pathway in 21 of 21 cases, with alterations in NF1 (6 of 21), MAP2K1 (5 of 21), PTPN11 (4 of 21), BRAF (4 of 21), KRAS (4 of 21), NRAS (1 of 21), and LZTR1 (1 of 21), including single cases with homozygous deletion of NF1, high-level amplification of PTPN11, and a novel TTYH3-BRAF fusion. Concurrent NF1 and PTPN11 mutations were present in 3 of 21 cases, and 5 of 7 cases with alterations in NF1 and/or PTPN11 had disease involving the gastrointestinal tract. Following unsupervised clustering of gene expression data, cases with NF1 and/or PTPN11 abnormalities formed a distinct tumor subgroup. A subset of NF1/PTPN11 wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements. Our findings expand the current understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by NF1/PTPN11 alterations with predilection for the gastrointestinal tract.

T-cell lymphoproliferative processes in the spleen.

T-cell lymphoproliferative processes in the spleen are rare and it is important to study normal T cell subsets in the spleen to understand the splenic milieu in which they arise. True malignant T-cell processes including hepatosplenic T-cell lymphoma and T-cell large granular lymphocytic leukemia occur in the spleen, but other atypical reactive T-cell proliferations and those of uncertain significance also have been described. Proper distinction of florid T cell responses from malignant T-cell neoplasms has important therapeutic implications for the patient.

Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.

Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma.

The diagnosis of lymphoplasmacytic lymphoma is often challenging, especially in extramedullary tissues where the differential diagnosis includes nodal marginal zone lymphoma, splenic marginal zone lymphoma, or other small B-cell neoplasms with plasmacytic differentiation. The MYD88 L265P mutation has been recently identified in >90% of bone-marrow-based lymphoplasmacytic lymphoma, but the incidence of this abnormality and corresponding morphologic correlates in nodal lymphoplasmacytic lymphoma have not been established. We analyzed 87 cases of extramedullary lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, unclassifiable splenic B-cell lymphomas, nodal marginal zone lymphoma with plasmacytic differentiation, and chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation for MYD88 L265P. Eighteen cases (21%) were positive, including 9/9 (100%) lymphoplasmacytic lymphomas with classic histologic features, 5/12 (42%) cases that met 2008 WHO criteria for lymphoplasmacytic lymphoma but with atypical morphologic features, 3/15 (20%) cases initially considered nodal marginal zone lymphoma with plasmacytic differentiation, and 1/6 (17%) unclassifiable splenic B-cell lymphomas. The presence of MYD88 L265P was associated with IgM paraprotein (P<0.001) and a trend for bone marrow involvement (P=0.09). Each of 44 splenectomy-defined splenic marginal zone lymphomas (19 with plasmacytic differentiation) and the chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation were negative for the mutation. Morphologic re-review with knowledge of MYD88 mutation status and all available clinical features suggested all MYD88 mutated cases were consistent with lymphoplasmacytic lymphoma (either classic or variant histology), except for one case which remained most consistent with nodal marginal zone lymphoma with plasmacytic differentiation. These results demonstrate the importance of MYD88 mutational analysis in better defining lymphoplasmacytic lymphoma as a relatively monomorphic small B-cell lymphoma with plasmacytic differentiation that may show total nodal architectural effacement and follicular colonization. Cases previously considered lymphoplasmacytic lymphoma that are more polymorphous and are often associated with histiocytes should no longer be included in the lymphoplasmacytic lymphoma category. Clinicopathologic review suggests that although MYD88 mutated non-lymphoplasmacytic lymphoma small B-cell neoplasms exist, they are very uncommon.

Epstein-Barr virus (EBV)-associated lymphoid lesions of the head and neck.

Epstein Barr virus (EBV)-related lymphoproliferative processes occur in the head and neck ranging from reactive processes such as infectious mononucleosis to high grade malignant lymphomas. EBV is a ubiquitous herpes virus that infects more than 90% of adults worldwide, and is generally transferred though saliva. Primary infection can occur throughout life. EBV is the first virus linked to malignancies, both epithelial and lymphoid. Both T and B cell lymphomas can be associated with EBV and evidence shows that an individual's response to the acute EBV infection may be critical in the development of subsequent lymphoma. Currently, in situ hybridization for EBER is the most sensitive available test to detect EBV and should be routinely performed in lymphoproliferative lesions of the head and neck. Immunohistochemistry for EBV related proteins, such as LMP1, is much less sensitive than EBER in situ hybridization, but can help determine latency patterns of EBV infection. Although relatively rare, primary EBV-related lymphomas must be considered in the differential of atypical lymphoid proliferations in the head and neck. We present selected EBV-related disorders of the head and neck discussing etiology as well as differential diagnosis.

ALK-positive large B-cell lymphoma (ALK + LBCL) with aberrant CD3 expression.

ALK-positive ( +) large B cell lymphoma (ALK + LBCL) is a rare distinct subtype of diffuse large B cell lymphoma presenting with high stage and aggressive behavior. Although B cell markers such as CD20, CD19, and CD22 are generally negative, plasmacytic markers including CD138, CD38, and MUM1 are positive. T cell markers are negative with rare exceptions. We report an unusual case of ALK1 + LBCL in a 58-year-old man with partial expression of CD3 without other T cell antigen expression. The tissue was evaluated with flow cytometry, immunohistochemistry, fluorescent in situ hybridization, and gene rearrangement studies. Gene rearrangement studies for IGH and TCR gamma were performed. Flow cytometry did not demonstrate any abnormal lymphoid populations. Tissue sectioning shows a malignant plasmacytic large cell neoplasm which expresses CD45 but is negative for CD20, CD79a, and PAX5. Plasmacytic markers CD138 and MUM1 are positive with kappa light chain restriction. Strong granular cytoplasmic expression of ALK is present. FISH showing disrupted ALK supports the diagnosis while MYC, BCL6, and BCL2 are intact. Gene rearrangement studies show coexisting IGH and TCR gamma clones; however, the TCR peak was present within a polyclonal background suggesting the disputed cells are likely only a subset of the T cell population. ALK + LBCL can present with an ambiguous immunophenotype, which warrants the use of multiple B cell, T cell, and plasmacytic antibodies. CD3 expression in this entity is rare and of uncertain clinical significance, but warrants further study.

Splenic manifestations of chronic autoimmune disorder: a report of five cases with histiocytic necrotizing change in four cases.

AIMS: Autoimmune diseases (AD) are associated with lymphadenopathy and splenomegaly. Changes in the spleen have not been characterized completely in AD; we describe splenectomy specimens from five patients with chronic AD, highlighting the presence of necrotizing histiocytosis. METHODS AND RESULTS: Of the patients (three males and two females; mean 40 years), four had systemic lupus erythematosus; one had rheumatoid arthritis. All had moderate splenomegaly (213-803 g, mean 421 g). Four cases exhibited necrosis with apoptosis and karyorrhectic debris occurring in the white pulp and minimal acute inflammation; one showed florid follicular hyperplasia. Splenic involvement ranged from focal to extensive. Plasma cells were negative for IgG4. Haematoxylin bodies were not identified. Stains for infectious organisms were negative. Immunohistochemical studies showed that lymphocytes surrounding the necrosis were a mixture of CD4(+) and CD8(+) T cells; CD123-positive plasmacytoid dendritic cells were not present, and staining for kappa and lambda light chains showed no clonality. 16S rDNA PCR was performed; no amplification was seen in three of four cases tested for bacteria specific rDNA. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization studies highlighted rare positive cells in four cases. CONCLUSIONS: Splenomegaly in AD is thought to be hyperplasic, but we present four cases showing histiocytic necrosis, a finding which should be considered part of the spectrum of AD in the spleen.

Sclerosing angiomatoid nodular transformation of the spleen: CT and MRI features with pathologic correlation.

OBJECTIVE: The objective of this study was to describe the CT and MRI features of sclerosing angiomatoid nodular transformation of the spleen with pathologic correlation. MATERIALS AND METHODS: Nine patients with surgically resected and pathologically confirmed sclerosing angiomatoid nodular transformation were included in the study. Clinical history was reviewed to determine patient demographics and symptoms at presentation. Gross pathologic, histologic, and immunohistochemical findings were recorded. CT (n = 9) and MRI (n = 4) examinations were evaluated for lesion shape and margins, intrinsic characteristics, and enhancement pattern. RESULTS: Patients included were six women and three men, with a mean age of 41.2 years. Pathologic features of sclerosing angiomatoid nodular transformation included multiple angiomatous nodules in a radiating pattern with a central stellate fibrous scar and evidence of hemosiderin deposition. On imaging, the lesions were solitary and round, 78% having a lobulated margin. They were heterogeneously hypoenhancing during the arterial and portal venous phases of contrast-enhanced CT or MRI, with peripheral enhancing radiating lines in 88% of lesions. They showed progressive enhancement and were isoenhancing or hyperenhancing in the delayed phase. A hypoenhancing central scar was shown on imaging in 22% of lesions. All lesions were hypointense on T2-weighted images. CONCLUSION: Sclerosing angiomatoid nodular transformation shows characteristic CT and MRI findings reflecting the underlying pathology. Typical features are a solitary, round, lobulated mass with early peripheral enhancing radiating lines and progressive enhancement of the angiomatous nodules; delayed enhancement of the fibrous tissue; and hypo-intense T2 signal intensity from hemosiderin deposition.

Isolated Light Chain-restricted Germinal Centers are Common in Follicular Hyperplasia by Ultrasensitive In Situ Hybridization.

Ultrasensitive bright-field RNA in situ hybridization (BRISH) can be used to detect lower levels of light chain expression than immunohistochemical stains or conventional colorimetric RNA in situ hybridization. In this study, we retrospectively reviewed 77 lymph node specimens with follicular hyperplasia and kappa/lambda BRISH performed as part of the diagnostic evaluation. Thirty-two of the specimens had ≥1 germinal center(s) (GC) showing light chain restriction (14 specimens with lambda-restricted GC, 9 with kappa-restricted GC, and 9 with separate kappa-restricted or lambda-restricted GC). In all but 1 specimen, the light chain-restricted GC represented a minority of the total GC (average: 10%, range: 0.2% to 60%). There was no significant difference in age, sex, type of biopsy (core vs. excision), number of GCs, proportion of cases with a light chain-restricted B-cell population by flow cytometry, or proportion of cases with a positive IgH gene rearrangement study between the specimens with and without restricted GCs. In our cohort of follicular hyperplasia cases, BRISH identified light chain-restricted GC more frequently than flow cytometry identified a monotypic B-cell population. Our findings highlight the potential for overinterpretation of light chain restriction in limited samplings such as fine needle aspiration cell blocks or core needle sampling and reinforce that interpretation of BRISH staining needs to occur in the context of the morphologic features including tissue architecture and results of additional immunohistochemical stains.

Increased IgG4+ plasma cells are common in excised lymph nodes from children and adolescents without IgG4-related disease.

Lymphadenopathy is a common finding in patients with IgG4-related disease (IgG4-RD) and often associated with increased IgG4+ plasma cells in this setting. The histologic features of so-called IgG4-related lymphadenopathy (IgG4-LAD) have seldom been investigated in children and adolescents, and step-wise progression to extranodal IgG4-RD has not been described. This study was performed to further evaluate the frequency, pathologic features, and clinical significance of IgG4-LAD-like histologic changes in the pediatric setting. We analyzed 37 benign lymph nodes collected semi-consecutively from children aged 0-18 years at our institution for both absolute and relative IgG4+ plasma cell abundance and recurrent histomorphologic patterns associated with IgG4-LAD. The combination of IgG4+/IgG+ plasma cell ratio >40% and IgG4+ plasma cell count ≥50 were considered as IgG4-LAD-like per expert consensus guidelines. Seven cases (19%) met both diagnostic criteria. The dominant histomorphologic patterns were follicular hyperplasia (n = 6), interfollicular expansion (n = 3), and progressive transformation of germinal centers (n = 3). Extranodal manifestations of IgG4-RD were not identified in this cohort (38 months average follow-up). Instead, clinical and laboratory findings indicated that lymph node enlargement in most patients could likely be attributed to alternative processes including antecedent dentistry, concurrent infection, and incipient Crohn's disease. Our findings suggest that the histologic features of IgG4-LAD are likely much more common in children and adolescents than previously recognized, often existing in complex with common reactive lymphadenopathies. The diagnostic value of routine immunohistochemical assessment for IgG4+ plasma cells in benign lymph nodes from pediatric patients without established extranodal IgG4-RD and/or other supportive clinical and laboratory data is therefore uncertain.

Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm.

Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1ß enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.

CD5-Negative, CD10-Negative Low-Grade B-Cell Lymphoproliferative Disorders of the Spleen.

CD5-negative, CD10-negative low-grade B-cell lymphoproliferative disorders (CD5-CD10-LPD) of the spleen comprise a fascinating group of indolent, neoplastic, mature B-cell proliferations that are essential to accurately identify but can be difficult to diagnose. They comprise the majority of B-cell LPDs primary to the spleen, commonly presenting with splenomegaly and co-involvement of peripheral blood and bone marrow, but with little to no involvement of lymph nodes. Splenic marginal zone lymphoma is one of the prototypical, best studied, and most frequently encountered CD5-CD10-LPD of the spleen and typically involves white pulp. In contrast, hairy cell leukemia, another well-studied CD5-CD10-LPD of the spleen, involves red pulp, as do the two less common entities comprising so-called splenic B-cell lymphoma/leukemia unclassifiable: splenic diffuse red pulp small B-cell lymphoma and hairy cell leukemia variant. Although not always encountered in the spleen, lymphoplasmacytic lymphoma, a B-cell lymphoproliferative disorder consisting of a dual population of both clonal B-cells and plasma cells and the frequent presence of the MYD88 L265P mutation, is another CD5-CD10-LPD that can be seen in the spleen. Distinction of these different entities is possible through careful evaluation of morphologic, immunophenotypic, cytogenetic, and molecular features, as well as peripheral blood and bone marrow specimens. A firm understanding of this group of low-grade B-cell lymphoproliferative disorders is necessary for accurate diagnosis leading to optimal patient management.

t(11;18)(q21;q21) in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in stomach: a study of 48 cases.

Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MZL-MALT) is speculated to be immune mediated and is notable for responding to treatment by Helicobacter pylori eradication. However, the gastric MZL-MALT with t(11;18)(q21;q21) has been shown to be resistant to treatment by H. pylori eradication. We studied the molecular, immunohistochemical, and histological aspects of 48 cases of gastric MZL-MALT and used a reverse transcription real-time PCR assay to assess the presence of a t(11;18)(q21;q21) in formalin-fixed, paraffin-embedded tissue. Florescence in situ hybridization for t(11:18)(q21;q21) was used to confirm the real-time PCR results. Three distinct morphological subtypes were recognized: monocytoid, small lymphocytic, and plasmacytoid. Morphology, immunophenotype, and immunoglobulin heavy chain (IgH) gene rearrangement were correlated with the results of the t(11:18)(q21;q21) assay. Of the 48 analyzed cases, 15 (31%) were positive for t(11;18)(q21;q21) and 33 (69%) were monoclonal for IgH gene rearrangement. Of the 15, 13 (87%) cases with t(11;18)(q21;q21) translocation showed IgH gene rearrangement by PCR. Of the 33 t(11;18)(q21;q21)-negative cases tested, 20 cases (61%) showed IgH gene rearrangement. The 15 t(11;18)(q21;q21) translocation-positive cases had either monocytoid (12 of 15) or small lymphocytic morphology (3 of 15). Aberrant expression of CD43 was observed in 8 of 15 (53%) t(11;18)(q21;q21)-positive cases and 21 of 31 (68%) t(11;18)(q21;q21)-negative cases. Our data show that t(11;18)(q21;q21)-positive MZL-MALTs frequently show monocytoid morphology, less often small lymphocytic morphology, and not purely plasmacytoid morphology. Identification of a t(11;18)(q21;q21) by reverse transcription real-time PCR is highly specific for MZL-MALT and helps in the diagnosis of MZL-MALT. Studying the correlation between this translocation and morphological features may increase our understanding of the role of this translocation in the pathogenesis and the clinical behavior of gastric MZL-MALT.

Atypical Lymphoid Proliferations and Clonality in Helicobacter-associated Inflammatory Infiltrates in Children.

Helicobacter infection is considered the major predisposing factor for gastric mucosa-associated lymphoid tissue (MALT) lymphoma with initial infection likely occurring in childhood. Primary gastric MALT lymphoma most commonly occurs in patients older than 50 years which is attributed to the lengthy chronic infection time required before the development of MALT lymphoma. Our study analyzes the histologic features and presence of immunoglobulin heavy chain (IGH) clonality in Helicobacter-associated chronic gastritis (62 cases) and Helicobacter-negative chronic gastritis (17 cases) biopsies within the pediatric population, diagnosed between 1996 and 2018. Helicobacter-associated gastritis was more likely to show active inflammation (P=0.01), with no significant difference in number of germinal centers or the strength, linear property, or depth of the inflammatory infiltrate. In total, 47% (29/62) of the Helicobacter-associated cases had at least 1 lymphoepithelial lesion, equivocal or definitive (a modified Wotherspoon score of 3 to 5), compared with 24% (4/17) of the Helicobacter-negative cases (P=0.5). All cases with lymphoepithelial lesions were assessed for IGH clonality, showing the presence of monoclonality in 27% (8/30) of evaluable cases. None of our patients were diagnosed with gastric lymphoma within available follow-up data. Although 4% of our cases could be considered MALT lymphoma in an adult patient based on prominent lymphoepithelial lesions and IGH monoclonality, caution is advised when diagnosing lymphoma in the pediatric population given the good prognosis of Helicobacter-associated gastritis in this age group. It is unclear if these monoclonal lymphoid proliferations require close follow-up.

Practical Applications in Immunohistochemistry: An Immunophenotypic Approach to the Spleen.

CONTEXT.­: Even though immunohistochemistry is routinely used by pathologists, evaluation of immunohistochemistry in splenic lesions remains difficult for many. Classification of benign and splenic lesions often requires a combination of hematoxylin-eosin evaluation, immunophenotyping, and sometimes molecular testing. Immunohistochemical staining is essential in evaluating many splenic lesions, and requires an understanding of the normal compartments of the spleen. OBJECTIVE.­: To address different immunohistochemical features used for identification and subclassification of different lesions of the spleen, as well as in the normal compartments of the spleen. DATA SOURCES.­: The information outlined in this review article is based on our experiences with a variety of spleen cases, on the current World Health Organization classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published during 2018. CONCLUSIONS.­: Features for phenotyping normal spleen as well as a variety of splenic lesions, including littoral cell angioma and splenic marginal zone lymphoma, are discussed. Suggested immunopanels are provided to assist in the diagnosis of different lesions of the spleen.