15.3 Leukemia & Childhood Malignancies (incl. Wilms Tumor)
Key Takeaways
- Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy overall, peaks at age 2-5 years, and classically presents with fever, pallor, bruising/petechiae, bone pain, and hepatosplenomegaly/lymphadenopathy from marrow infiltration and extramedullary spread.
- Acute leukemia requires a bone marrow blast count >=20-25%; ALL lymphoblasts are TdT-positive, while AML myeloblasts are TdT-negative and may show Auer rods -- acute promyelocytic leukemia (APL) with t(15;17) causes DIC and requires urgent all-trans retinoic acid (ATRA).
- Neuroblastoma arises from sympathetic neural crest tissue (most often the adrenal medulla), typically presents before age 5 as an abdominal mass that CROSSES the midline, and is associated with elevated urinary catecholamine metabolites (VMA/HVA) and opsoclonus-myoclonus syndrome.
- Wilms tumor (nephroblastoma) arises from the kidney, typically presents at age 2-5 as a smooth, unilateral abdominal mass that does NOT cross the midline, and is associated with WAGR, Denys-Drash, and Beckwith-Wiedemann syndromes.
- Red-flag features that should trigger urgent oncology referral include unexplained persistent fever, unintentional weight loss, night sweats, a palpable abdominal mass, unexplained lymphadenopathy (especially fixed, >2 cm, or supraclavicular), and new bone pain with a limp or refusal to bear weight.
Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy overall and the most common childhood leukemia, accounting for roughly three-quarters of pediatric leukemias. Incidence peaks between ages 2 and 5 years, with a second, smaller rise in adolescence. ALL arises from malignant proliferation of a lymphoid progenitor cell that crowds out normal hematopoiesis in the bone marrow and can infiltrate extramedullary sites (central nervous system, testes, lymph nodes, liver, spleen).
Clinical Presentation
The presentation of ALL is best understood as the direct consequence of marrow failure (from leukemic cell crowding-out of normal hematopoietic elements) plus organ infiltration:
| Mechanism | Clinical Findings |
|---|---|
| Anemia (↓ RBC production) | Pallor, fatigue, tachycardia |
| Thrombocytopenia (↓ platelet production) | Petechiae, bruising, mucosal bleeding |
| Neutropenia (↓ functional WBC production, despite high total WBC from blasts) | Fever, recurrent/severe infections |
| Bone marrow infiltration/expansion | Bone pain, limp, refusal to walk (can mimic juvenile idiopathic arthritis) |
| Organ infiltration | Hepatosplenomegaly, lymphadenopathy, mediastinal mass (more typical of T-cell ALL), testicular enlargement |
| CNS infiltration | Headache, vomiting, cranial nerve palsies (uncommon at diagnosis, always assessed by lumbar puncture) |
Exam trap: A child with ALL and marrow infiltration can present with bone pain and a limp that looks like a musculoskeletal or rheumatologic complaint (mimicking juvenile idiopathic arthritis) -- an unexplained cytopenia, disproportionate pain (especially nocturnal), or an elevated LDH/uric acid should prompt consideration of leukemia before an arthritis workup is pursued.
Diagnosis
CBC classically shows anemia, thrombocytopenia, and a variable white cell count (can be low, normal, or markedly elevated) with circulating lymphoblasts on peripheral smear. Diagnosis is confirmed by bone marrow aspirate/biopsy, with acute leukemia defined by a blast count of at least 20-25% of marrow cellularity. Immunophenotyping (flow cytometry) distinguishes lymphoblasts from myeloblasts: lymphoblasts are TdT-positive and express lineage markers such as CD19/CD10 (B-cell ALL, the majority of cases) or CD3/CD7 (T-cell ALL); myeloblasts are TdT-negative and may show Auer rods (a feature of acute myeloid leukemia, not ALL). Cytogenetics/molecular studies (e.g., ETV6-RUNX1, hyperdiploidy as favorable markers; BCR-ABL1, hypodiploidy as unfavorable) guide risk stratification and are increasingly tested as the exam emphasizes precision-medicine markers.
Management Overview
Treatment follows risk-stratified multi-agent chemotherapy in phases: induction (achieve remission), consolidation/intensification, maintenance (over ~2 years), with CNS-directed therapy (intrathecal chemotherapy +/- cranial radiation in select high-risk cases) given the CNS acts as a pharmacologic sanctuary site. Overall cure rates for standard-risk B-cell ALL now exceed 90%, one of the great success stories of pediatric oncology.
Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is the second most common childhood leukemia and becomes proportionally more common in adolescence. Presentation overlaps with ALL (marrow failure, fever, bleeding, organomegaly), but AML blasts are myeloblasts -- TdT-negative cells that may contain Auer rods (needle-like azurophilic cytoplasmic inclusions pathognomonic for myeloid lineage). Acute promyelocytic leukemia (APL, formerly M3) carries the t(15;17) translocation and is a board favorite because leukemic promyelocytes release procoagulant granules, causing disseminated intravascular coagulation (DIC) at presentation. APL is treated urgently with all-trans retinoic acid (ATRA) plus arsenic-based therapy (and supportive blood products for DIC), not standard induction chemotherapy alone. Overall pediatric AML cure rates (~60-70%) remain lower than ALL, reflecting greater chemotherapy intensity and relapse risk.
Neuroblastoma vs. Wilms Tumor
These two abdominal tumors of early childhood are a classic "compare and contrast" exam pairing, and distinguishing them is high yield.
Neuroblastoma arises from primitive sympathetic neural crest cells anywhere along the sympathetic chain, most commonly the adrenal medulla, but also paraspinal ganglia (which can cause spinal cord compression). It is the most common extracranial solid tumor of childhood and the most common malignancy diagnosed in infancy.
Wilms tumor (nephroblastoma) arises from embryonal renal precursor (metanephric blastema) tissue within the kidney and is the most common pediatric renal malignancy.
| Feature | Neuroblastoma | Wilms Tumor |
|---|---|---|
| Origin | Sympathetic neural crest tissue (adrenal medulla most common) | Kidney (metanephric blastema) |
| Peak age | <2 years (median ~18 months); most diagnosed before age 5 | 2-5 years |
| Abdominal mass character | Irregular, firm, often crosses the midline | Smooth, well-circumscribed, unilateral, does NOT cross the midline |
| Key labs | Elevated urinary VMA (vanillylmandelic acid) and HVA (homovanillylmandelic acid) -- catecholamine metabolites | Usually no specific tumor marker; hematuria and hypertension can occur |
| Associated syndrome | Opsoclonus-myoclonus-ataxia syndrome ("dancing eyes, dancing feet") -- paraneoplastic | WAGR syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome |
| Other features | Periorbital ecchymoses ("raccoon eyes") from orbital metastases; can present with Horner syndrome if cervical/thoracic | Aniridia, genitourinary anomalies, hemihypertrophy (when syndromic) |
| Prognosis driver | Age at diagnosis, stage, MYCN amplification (unfavorable) | Favorable vs. unfavorable (anaplastic) histology, stage |
Exam trap on "crossing the midline": This is one of the single most tested discriminators on the entire oncology topic. A firm, irregular abdominal mass that crosses the midline is neuroblastoma; a smooth mass that stays confined to one side, respecting the midline, is Wilms tumor.
Associated syndromes to memorize for Wilms tumor:
- WAGR syndrome: Wilms tumor, Aniridia, Genitourinary anomalies, Range of developmental delay/intellectual disability (11p13 deletion, WT1 gene)
- Denys-Drash syndrome: Wilms tumor, progressive nephropathy (early renal failure), male pseudohermaphroditism (WT1 mutation)
- Beckwith-Wiedemann syndrome: Wilms tumor, macroglossia, omphalocele, hemihypertrophy, neonatal hypoglycemia (11p15 alteration)
Children with these syndromes require serial abdominal ultrasound screening (typically every 3 months until age 8 for Wilms tumor risk) given their markedly elevated tumor risk.
Red-Flag Presentations of Childhood Cancer
The exam frequently tests recognition of when a common pediatric complaint should trigger concern for underlying malignancy rather than a benign explanation:
- Persistent, unexplained fever without a source, especially with weight loss or night sweats
- Unintentional weight loss or growth faltering
- Painless, persistent lymphadenopathy -- especially nodes that are fixed/matted, >2 cm, supraclavicular, or progressively enlarging over 2-4 weeks without response to antibiotics
- Palpable abdominal mass in a young child -- always warrants prompt imaging (do not simply observe)
- Bone pain with a limp or refusal to walk, particularly if nocturnal, disproportionate to exam findings, or accompanied by cytopenias
- Easy bruising/petechiae with pallor and fatigue -- think marrow infiltration (leukemia) rather than isolated immune thrombocytopenic purpura when multiple cell lines are affected
- New-onset headache with early morning vomiting, or new neurologic deficits -- concern for a central nervous system tumor
- Periorbital ecchymoses in a young child without trauma history -- think metastatic neuroblastoma
A 3-year-old presents with pallor, easy bruising, low-grade fever, and bone pain with a limp. CBC shows anemia, thrombocytopenia, and circulating blasts. Bone marrow biopsy shows 60% lymphoblasts. What is the diagnosis?
An 18-month-old is found to have a firm, irregular abdominal mass that crosses the midline on exam, along with periorbital ecchymoses. Urine studies show elevated VMA and HVA. What is the most likely diagnosis?
A 4-year-old boy with aniridia and genitourinary anomalies is found to have a smooth, unilateral abdominal mass that does not cross the midline. Which syndrome and tumor are most consistent with this presentation?
Which presentation should most urgently prompt concern for an underlying childhood malignancy rather than a benign cause?