Isolated Optic Nerve Relapse in a Pediatric Patient With T-Cell Lymphoblastic Leukemia: A Brief Report.

Isolated optic nerve (ON) relapse is a rare occurrence in lymphoblastic leukemia (LBL). A 10-year-old boy with T-LBL presented 8 months after diagnosis with blurred vision and thickening of right ON on magnetic resonance imaging consistent with relapse. Cerebrospinal fluid and bone marrow were negative for leukemia. He received reinduction chemotherapy (including nelarabine and craniospinal radiation) followed by a myeloablative matched sibling donor bone marrow transplant. He remains in remission 2 years post-transplant with normal vision. We also review the literature for reports of isolated ON relapse in patients with LBL. Our patient's clinical course demonstrates that disease control can be achieved with early detection of ON relapse before disease progression.

A Rare Case of Early T-Precursor Lymphoblastic Lymphoma (ETP-LBL) in a Child With Nijmegen Breakage Syndrome.

Lymphoblastic lymphoma (LBL) with an early T-cell precursor phenotype has only been rarely reported. Nijmegen breakage syndrome (NBS) is an inherited chromosomal instability disorder with known predisposition to malignancies that is very rare as well. We report a case of early T-precursor LBL (ETP-LBL) in a patient with NBS, a rare combination that has not been reported. We raise the question of whether a chromosomal instability disorder such as NBS increases the propensity for early T-precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL), given that ETP-ALL has been shown to have increased genomic instability compared to T-ALL.

Interfollicular Classic Hodgkin Lymphoma: Report of a Case and a Brief Review of Literature.

Interfollicular Hodgkin lymphoma (IHL) has been rarely reported in the literature and is recognized by the WHO Classification as a morphologic pattern sometimes seen in mixed cellularity classic Hodgkin lymphoma (CHL). The changes may be subtle due to preservation of architecture. We report a case of a 9-year-old male with IHL showing preserved follicular architecture but with the presence of interfollicular infiltrates consisting of eosinophils, plasma cells, and Hodgkin-Reed-Sternberg (HRS) cells. Immunophenotyping confirmed the morphologic suspicion for IHL. A discussion and review of the literature are offered. We conclude that IHL is a variant that requires a high index of suspicion, as it may be easily missed due to the subtle morphologic features and preserved architecture seen in most cases. We further emphasize that unexplained interfollicular infiltrates of eosinophils may be clues that should prompt a search of HRS cells and consideration of immunohistochemical staining if needed.

Differentiating fulminant EBV infection complicated by HLH from Lymphoma: report of a case and a brief literature review.

Epstein-Barr virus (EBV) infection may present with fulminant constitutional symptoms, cytopenia(s), and systemic lymphadenopathy, raising clinical suspicion for lymphoma and prompting lymph node and bone marrow biopsies. At the microscopic level, the histopathologic findings in cases of acute EBV lymphadenitis may mimic certain lymphoid neoplasms, creating a range of differential diagnoses and diagnostic pitfalls.We present a case of fulminant EBV infection in an adolescent whose clinical and radiographic findings led to lymph node and bone marrow biopsies to rule out lymphoma. One week after being diagnosed with acute EBV infection (infectious mononucleosis), a 17-year-old Caucasian male presented with worsening symptoms including persistent fever, progressive, painful lymphadenopathy, and splenomegaly. A peripheral blood smear showed lymphocytosis with many reactive lymphocytes, anemia, and thrombocytopenia. Laboratory studies showed elevated ferritin, triglycerides, and soluble IL-2/CD25. A cervical lymph node biopsy demonstrated an EBV-positive, reactive B-immunoblast proliferation with large atypical lymphoid cells mimicking Reed-Sternberg cells of Hodgkin lymphoma, in addition to patchy vasculitis, coagulative necrosis, and prominent hemophagocytic activity. Bilateral bone marrow biopsies showed a hypercellular marrow with patchy infiltrates of similar EBV-positive, large atypical lymphoid cells, as well as prominent hemophagocytic activity. The diagnosis of acute EBV associated lymphoproliferation with concurrent hemophagocytic lymphohistiocytosis (HLH) was rendered.Recognition of common and uncommon clinical presentations of acute EBV infection is essential, particularly when histopathologic findings raise suspicion for a possible hematolymphoid neoplasm. Both the lymph node architectural and viral cytopathic changes observed in EBV lymphadenitis exhibit significant morphologic overlap with classic Hodgkin lymphoma (cHL) and several other lymphomas, including anaplastic large cell lymphoma, diffuse large B cell lymphoma, and angioimmunoblastic T cell lymphoma. Recognition of immunohistochemical staining patterns in EBV lymphadenitis is critical to avoid misdiagnosis. Conversely, bona fide lymphoma, particularly cHL, can masquerade as EBV infection. We provide a concise discussion and tables of the histopathologic differential diagnosis of EBV lymphadenitis, including cHL and other lymphomas. Pathologists should include acute EBV infection within the differential diagnosis when confronted with clinical and pathologic findings concerning for lymphoma, particularly in adolescents and young adults.

Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group.

BACKGROUND: Acute myeloid leukemia (AML) with megakaryocytic differentiation (AMkL) is a rare subtype of AML more common in children. Recent literature has identified multiple fusions associated with this type of leukemia. METHODS: Morphology, cytogenetics, and genomic sequencing were assessed in patients from Children's Oncology Group trials AAML0531 and AAML1031 with central-pathology review confirmed non-Down syndrome AMkL. The 5-year event-free survival (EFS), overall survival (OS), and RR were evaluated in these AMkL subcategories. RESULTS: A total of 107 cases of AMkL (5.5%) were included. Distinct fusions were identified in the majority: RBM15::MRTFA (20%), CBFA2T3::GLIS2 (16%), NUP98 (10%), KMT2A (7%), TEC::MLLT10 (2%), MECOM (1%), and FUS::ERG (1%); many of the remaining cases were classified as AMkL with (other) myelodysplasia-related changes (MRC). Very few cases had AML-associated somatic mutations. Cases with CBFA2T3::GLIS2 were enriched in trisomy 3 (p = .015) and the RAM phenotype, with associated high CD56 expression (p < .001). Cases with NUP98 fusions were enriched in trisomy 6 (p < .001), monosomy 13/del(13q) (p < .001), trisomy 21 (p = .026), and/or complex karyotypes (p = .026). While different 5-year EFS and OS were observed in AMkL in each trial, in general, those with CBFA2T3::GLIS2 or KMT2A rearrangements had worse outcomes compared to other AMkL, while those with RBM15::MRTFA or classified as AMkl-MRC fared better. AMkL with NUP98 fusions also had poor outcomes in the AAML1031 trial. CONCLUSION: Given the differences in outcomes, AMkL classification by fusions, cytogenetics, and morphology may be warranted to help in risk stratification and therapeutic options.

Selective Immunoreactivity for WT1 Carboxy-Terminus Distinguishes Desmoplastic Small Round Cell Tumor From its Histologic Mimics.

Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric round cell sarcoma containing a characteristic EWSR1-WT1 gene fusion. In the absence of genetic data, distinguishing DSRCT from other small round cell tumors of childhood can be problematic due to overlapping histologic and immunohistochemical features. We studied the utility of immunohistochemistry with antibodies targeting both the amino-terminal and carboxy-terminal regions of the Wilms tumor-1 (WT1) protein in differentiating these groups of tumors. The study cohort included 33 cases of genetically confirmed pediatric round cell tumors (10 DSRCTs, 12 Wilms tumors, 10 Ewing sarcomas, and 1 CIC-rearranged sarcoma). Immunoreactivities and immunolocalization of both the WT1 amino-terminus and carboxy-terminus were scored and documented. All DSRCTs displayed selective reactivity for only the WT1 carboxy-terminus (10/10), while dual immunoreactivity for both the WT1 carboxy-terminus (12/12) and amino-terminus antibodies (12/12) were characteristic of Wilms tumors. CIC-rearranged sarcoma showed variable WT1 nuclear immunopositivity (1/1, 1/1) and Ewing sarcomas were consistently WT1-negative for both the WT1 amino-terminus (0/10) and carboxy-terminus (0/10). Dual WT1 amino-terminus and carboxy-terminus immunohistochemistry remains a helpful diagnostic tool in discriminating intraabdominal small round cell tumors, which serves as an adjunct to the genetic information in preventing misdiagnosis.

A Novel Case of Concurrent T-cell and Early T-cell Precursor Lymphoblastic Lymphoma in an Adolescent Female.

In the context of an evolving understanding of early T-cell precursor (ETP) lymphoma and leukemia, we present a case of concurrent T-cell lymphoblastic lymphoma and ETP lymphoma in an adolescent female. To our knowledge, this represents the first reported case of both lymphoblastic lymphoma and ETP lymphoma as distinct and conjoined components of the same neoplasm. As an exception to current literature, our patient had a strictly lymphomatous ETP component with no leukemic manifestation. Her ETP component remained viable following induction, supporting ETP resistance to chemotherapy. The patient remains in remission 4 years postallogeneic matched sibling donor bone marrow transplant.

Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group.

Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.

Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.

Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force.

BACKGROUND: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification. METHODS: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL. RESULTS: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21). CONCLUSIONS: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.

Cytoplasmic Fibrillar Aggregates in Gallbladder Epithelium Are a Frequent Mimic of Cystoisospora in Pediatric Cholecystectomy Specimens.

CONTEXT.­: Cystoisospora belli is an intracellular parasite associated with gastrointestinal disease in immunocompromised hosts. Although infection has been classically associated with intestinal disease, studies have identified Cystoisospora in the gallbladder of immunocompetent patients based on hematoxylin-eosin morphology. Recently, the identity of this histologic finding as Cystoisospora has been questioned based on negative results of nucleic acid studies. OBJECTIVE.­: To determine the prevalence of this histologic feature in pediatric patients, we retrospectively reviewed all cholecystectomy specimens from a pediatric hospital during a 24-month period. DESIGN.­: In 180 cholecystectomy specimens, we identified 11 cases (6.1%) with classical histologic features previously described to represent Cystoisospora organisms. To further investigate these structures, we retrieved tissue from paraffin-embedded blocks and performed electron microscopy. RESULTS.­: Ultrastructural examination identified ovoid perinuclear cytoplasmic structures composed of dense fibrillar aggregates rather than organisms. Patients with positive cases were similar in age to controls (positive cases: mean patient age 13.4 years [range, 2-23 years]; negative cases: mean patient age 14.7 years [range, 12 weeks-31 years]; P = .35). There was no significant association of this finding with cholelithiasis (54.5% versus 65.1%, P = .52), cholesterolosis (0% versus 22.5%, P = .12), acute cholecystitis (9.1% versus 10.1%, P > .99), or chronic cholecystitis (45.5% versus 66.3%, P = .20). CONCLUSIONS.­: To our knowledge, this is the first positive identification of these structures as cytoplasmic fibrillar aggregates rather than parasitic inclusions by ultrastructural examination, and the first study of this histologic finding in pediatric cholecystectomies.