Residency · Residency · Pathology

Pediatric Hematopathology: Unique Entities in Children

Introduction

Pediatric hematopathology encompasses hematologic malignancies and reactive conditions with distinct biologic features, molecular profiles, and clinical behaviors compared to adult counterparts. Understanding these age-specific entities is essential for accurate diagnosis, risk stratification, and treatment planning.

Pediatric Acute Lymphoblastic Leukemia

Overview

Acute lymphoblastic leukemia is the most common childhood malignancy, accounting for approximately 25% of all pediatric cancers. Peak incidence occurs at 2-5 years of age, with B-lymphoblastic leukemia (B-ALL) representing approximately 85% of cases and T-lymphoblastic leukemia (T-ALL) approximately 15%. Overall survival exceeds 90% with modern risk-adapted therapy. Diagnosis requires a bone marrow with more than 20% blasts, flow cytometry immunophenotyping, and cytogenetic and molecular studies that are essential for classification.

Key Genetic Subtypes in B-ALL

ETV6::RUNX1 [t(12;21)] is the most common pediatric translocation, present in approximately 25% of cases, and carries an excellent prognosis. It is cryptic on conventional karyotype and requires FISH or molecular testing for detection. Hyperdiploidy (51-67 chromosomes) accounts for approximately 25% of cases and confers a favorable prognosis, particularly with trisomies of chromosomes 4, 10, and 17. KMT2A (MLL) rearrangements are common in infants under one year, are aggressive, and carry a poor prognosis. BCR::ABL1 [t(9;22)], the Philadelphia chromosome, occurs in approximately 3-5% of pediatric ALL, with outcomes improved by TKI incorporation. TCF3::PBX1 [t(1;19)] carries an intermediate prognosis with CNS relapse risk. Philadelphia-like (Ph-like) ALL harbors ABL-class fusions, JAK/STAT alterations, and CRLF2 rearrangements, carries a poor prognosis, and is targetable with TKIs or JAK inhibitors. iAMP21 (intrachromosomal amplification of chromosome 21) is adverse and requires intensified therapy. DUX4-rearranged ALL is associated with ERG deletion and carries a favorable prognosis.

Minimal Residual Disease (MRD)

MRD is the most powerful prognostic factor in pediatric ALL. It is measured by multiparameter flow cytometry (sensitivity 10^-4) or PCR/NGS-based methods (sensitivity 10^-5 to 10^-6). Day 29 (end of induction) MRD guides risk stratification and treatment intensity, and MRD-negative status (less than 0.01%) is associated with excellent outcomes.

Pediatric Acute Myeloid Leukemia

Key Differences from Adult AML

Pediatric AML comprises approximately 15-20% of pediatric leukemias, with overall survival of approximately 65-70%. Core binding factor AML (RUNX1::RUNX1T1, CBFB::MYH11) is favorable and accounts for approximately 25% of pediatric AML. KMT2A-rearranged AML is more common in infants and young children. NUP98 rearrangements (NUP98::NSD1, NUP98::KDM5A) are adverse and more prevalent in the pediatric population. The RAM immunophenotype (CD56+, dim CD45, dim CD38, low or absent HLA-DR) is associated with NUP98::KDM5A and adverse prognosis. Myeloid sarcoma (chloroma), an extramedullary form of AML, is more common in children and may precede bone marrow disease.

Transient Abnormal Myelopoiesis (TAM)

TAM is unique to neonates with Down syndrome (trisomy 21). Peripheral blood blasts display megakaryoblastic morphology and harbor GATA1 mutations. The condition is self-resolving in most cases within 1-3 months without treatment. However, 10-20% of affected infants subsequently develop myeloid leukemia of Down syndrome (ML-DS) within 1-4 years. ML-DS is GATA1-mutated, highly chemosensitive, and carries an excellent prognosis with reduced-intensity therapy.

Pediatric Lymphomas

Burkitt Lymphoma

Burkitt lymphoma is the most common pediatric non-Hodgkin lymphoma, with endemic (EBV-associated, jaw mass) and sporadic (abdominal) forms. The hallmark is MYC translocation, with t(8;14) being most common and t(2;8) and t(8;22) as variants. Histologically, there are diffuse sheets of intermediate-sized cells with multiple nucleoli, a high mitotic rate, and a "starry sky" pattern created by tingible body macrophages. The Ki-67 proliferation index approaches 100%. Despite being highly aggressive, Burkitt lymphoma is very chemosensitive, with cure rates exceeding 90% with intensive short-duration chemotherapy.

Anaplastic Large Cell Lymphoma (ALCL)

ALCL is predominantly a pediatric and young adult disease. The ALK-positive subtype carries the t(2;5) NPM1::ALK translocation most commonly, is CD30+ and ALK+, and has an excellent prognosis (approximately 90% overall survival). Hallmark cells are large cells with eccentric horseshoe or kidney-shaped nuclei. Presentation may include skin involvement, lymphadenopathy, and systemic symptoms. Breast implant-associated ALCL is a distinct ALK-negative entity seen in adults.

Pediatric Hodgkin Lymphoma

Hodgkin lymphoma accounts for approximately 6% of childhood cancers with peak incidence in adolescence. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) features LP cells (popcorn cells) in a nodular B-cell background that are CD20+, CD15-, and CD30-. It is indolent and more common in young boys. Classic Hodgkin lymphoma features Reed-Sternberg cells that are CD30+, CD15+, weak PAX5+, and usually CD20 negative, with a strong EBV association in younger children.

Pediatric Histiocytic Disorders

Langerhans Cell Histiocytosis (LCH)

LCH is a clonal proliferation of Langerhans-type cells with BRAF V600E mutation in approximately 50-60% of cases. The clinical spectrum ranges from single-system disease (bone, skin) to multisystem involvement (liver, spleen, bone marrow, CNS). Histologically, the cells have characteristic grooved (coffee-bean) nuclei with eosinophilic cytoplasm, accompanied by a mixed inflammatory infiltrate with eosinophils. Immunohistochemistry shows CD1a+, langerin (CD207)+, and S100+ staining. Electron microscopy demonstrates Birbeck granules (pentalaminar rod-shaped structures), which were historically diagnostic but are rarely needed with current immunohistochemical panels. Treatment ranges from observation to chemotherapy depending on the extent of disease.

Juvenile Xanthogranuloma (JXG)

JXG is the most common non-LCH histiocytic disorder of childhood. It presents as benign, often self-resolving skin nodules that are rarely systemic. Histologically, Touton giant cells (characterized by a ring of nuclei with foamy cytoplasm) are present alongside histiocytes and an inflammatory infiltrate. The immunophenotype is CD1a-negative, CD207-negative, and factor XIIIa-positive, which distinguishes it from LCH.

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a life-threatening hyperinflammatory syndrome that may be primary (familial, genetic: PRF1, UNC13D, STX11) or secondary (triggered by infection, malignancy, or autoimmune disease). Diagnostic criteria include fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, low or absent NK cell activity, elevated soluble IL-2 receptor, and hemophagocytosis in bone marrow or other tissues. Bone marrow biopsy shows activated macrophages engulfing blood cells, which may be focal and require careful search. Early recognition and treatment with etoposide-based protocols and dexamethasone is critical, with stem cell transplant indicated for familial forms.

Unique Reactive Conditions

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS results from defective FAS-mediated apoptosis caused by germline FAS, FASL, or CASP10 mutations. It presents with chronic lymphadenopathy, splenomegaly, and autoimmune cytopenias. The characteristic finding is an expansion of double-negative T cells (CD3+, CD4-, CD8-, TCR alpha-beta+) exceeding 2.5% of lymphocytes. Patients have an increased risk of both Hodgkin and non-Hodgkin lymphoma.

Infectious Mononucleosis and EBV-Related Lymphoproliferations

EBV-positive reactive lymphadenopathy shows paracortical expansion with immunoblasts and may mimic lymphoma. Post-transplant lymphoproliferative disorder (PTLD) is EBV-driven in most pediatric cases and spans a spectrum from reactive hyperplasia to monomorphic lymphoma. Chronic active EBV infection involves persistent EBV infection with T-cell or NK-cell proliferation and is more prevalent in East Asian populations.

Clinical Pearls

ETV6::RUNX1 translocation is the most common genetic abnormality in pediatric B-ALL and carries an excellent prognosis, but it is cryptic on conventional karyotyping and requires FISH or molecular methods for detection. Transient abnormal myelopoiesis in neonates with Down syndrome is a self-resolving condition driven by GATA1 mutations, but 10-20% of affected infants will later develop myeloid leukemia of Down syndrome. Langerhans cell histiocytosis is a clonal neoplastic disorder with BRAF V600E mutations in approximately half of cases, and the diagnosis rests on the immunophenotype (CD1a+, langerin+) rather than electron microscopy. Minimal residual disease assessment at end of induction is the single most powerful prognostic factor in pediatric ALL and directly guides risk-adapted therapy intensity.

References

1. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541-1552.
2. Rasche M, et al. Pediatric acute myeloid leukemia: from diagnosis to treatment. J Clin Med. 2021;10(20):4686.
3. Allen CE, et al. Langerhans-cell histiocytosis. N Engl J Med. 2018;379(9):856-868.
4. Cairo MS, et al. Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future. Pediatr Blood Cancer. 2019;66(4):e27594.

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