MAYA A. JONES
HISTORY OF PRESENT ILLNESS
A 2-year-old boy presented with a 2-week history of difficulty walking. Initially, the parents noticed that he would no longer run while playing with his siblings. Then during the past week he began walking with a limp and refused to climb stairs. The patient has had no fever, cough, rhinorrhea, throat pain, diarrhea, trauma, and there are no sick contacts. The patient lives with his parents and siblings and they have one dog.
The parents brought the patient to his pediatrician who detected splenomegaly and tenderness over the right hip on physical examination. Therefore, hip radiographs and laboratory studies were obtained after which the patient was immediately referred to the emergency department.
The patient was born at term without complications. He had one hospitalization at 4 months of age for wheezing and had pneumonia at 12 months of age which was treated as an outpatient. He was not receiving any medications and had no allergies. Family history was remarkable for a maternal aunt with rheumatic heart disease.
T 37.3°C; P 104 bpm; RR 34/min; BP 98/43 mmHg
Height and Weight both 25th percentile for age
On examination the child was pale and appeared tired. His sclerae were anicteric. The heart and lung sounds were normal. On abdominal examination, the spleen tip was palpable just below the left costal margin and the liver edge was palpable 3 cm below the right costal margin. There was mild discomfort with passive flexion of the right hip but he had full range of motion and there was no overlying erythema or warmth. The left hip was unremarkable. The testes were in normal position and were not enlarged, swollen, or tender. There were numerous petechiae scattered on his lower extremities bilaterally. There were multiple small lymph nodes palpable in the anterior cervical and inguinal regions.
Complete blood count revealed a white blood cell (WBC) count of 4300/mm3 with 3% band forms, 8% segmented neutrophils, and 85% lymphocytes, and an absolute neutrophil count of 473/mm3. The hemoglobin was 8.0 g/dL with a reticulocyte count of 1.3%, platelet count was 31 000/mm3. C-reactive protein and erythrocyte sedimentation rate were 2.6 mg/dL and 60 mm/h, respectively. Serum lactate dehydrogenase (LDH), uric acid, transaminases, and electrolytes were normal. The hip radiographs performed earlier were reviewed (Figure 5-2A).
FIGURE 5-2. A. Hip radiograph. B. Peripheral blood smear.
COURSE OF ILLNESS
Results of the hip radiographs combined with results of the peripheral blood smear (Figure 5-2B) suggested a diagnosis.
DISCUSSION CASE 5-2
Infectious causes of hip pain in a young boy include septic arthritis of the hip, osteomyelitis of the femur or pelvis, and psoas abscess. The prolonged duration of symptoms with recent worsening in conjunction with an elevated C-reactive protein and erythrocyte sedimentation may indicate osteomyelitis of the femur with extension of infection into the hip joint. However, the mild rather than severe hip pain on examination and the subacute rather than acute nature makes septic arthritis of the hip unlikely. Children with pancytopenia in the context of osteomyelitis are usually critically ill. Toxic synovitis can cause hip pain in this age group. While pancytopenia can be caused by viral-mediated bone marrow suppression, the mild degree of pain is not consistent with joint effusion.
Causes of pancytopenia, hepatosplenomegaly, and bone pain include leukemia, epiphyseal tumors, neuroblastoma, infectious mononucleosis, hemophagocytic syndrome, and Gaucher disease. The normal uric acid and lactate dehydrogenase (LDH) do not exclude malignancy.
The hip radiographs revealed dense metaphyseal lines bilaterally with adjacent metaphyseal lucency, a finding suggestive of leukemia (Figure 5-2A). The peripheral blood smear revealed numerous cells with scant cytoplasm and finely dispersed to variably condensed chromatin morphologically consistent with lymphoblasts (Figure 5-2B). Morphologic, cytochemical, and immunophenotypic features of the bone marrow aspirate were diagnostic of acute lymphocytic leukemia. The child was initially treated with vincristine, dexamethasone, and intrathecal ara-C.
Leukemia results from malignant transformation and clonal expansion of hematopoietic cells that have stopped at a particular stage of differentiation and are unable to progress to more mature forms. Leukemias are divided into acute and chronic subtypes and further classified on the basis of leukemic cell morphology into lymphocytic leukemias (lymphoid lineage cell proliferation) and nonlymphocytic leukemias (granulocyte, monocyte, erythrocyte, or platelet lineage cell proliferation). Acute leukemias constitute more than 95% of all childhood leukemias and are subdivided into acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia, also known as acute myelogenous leukemia (AML). The following discussion focuses on ALL.
ALL, the most common pediatric malignancy, accounts for approximately 25% of all childhood cancers and 75% of all childhood leukemias. Most children are diagnosed between 2 and 5 years of age. In the United States, the incidence of ALL is higher in whites compared to blacks and in boys compared to girls. Genetic factors also affect the risk of ALL which occurs in siblings of children with ALL two to four times more often than in unrelated children. The concordance of ALL in monozygotic twins is approximately 25%. Children with chromosomal abnormalities, including trisomy 21, and syndromes characterized by chromosomal fragility, such as Bloom syndrome and Fanconi anemia, also have a substantially higher risk of leukemia.
The presenting signs and symptoms of children with ALL reflect both the degree of bone marrow infiltration with leukemic cells and the extent of extramedullary disease spread. Symptoms may be present for days or months and include fever, anorexia, fatigue, and pallor. Bone pain occurs with leukemic involvement of the periosteum and bone. Young children often develop a limp or refuse to walk. Headache, vomiting, and seizures suggest central nervous system (CNS) involvement. Rarely, children present with oliguria due to acute renal failure precipitated by hyperuricemia.
On examination, painless lymphadenopathy (50%) and hepatosplenomegaly (68%) result from extramedullary spread of the disease. Pete-chiae and purpura are more common but some children may also have subconjunctival and retinal hemorrhages. Children may also have focal bone tenderness. Testicular enlargement due to leukemic infiltration is present in 5% of boys. In addition to these physical examination findings, there are three life-threatening presentations of ALL, infection/neutropenia, tumor lysis syndrome, and hyperleukocytosis (summarized in Table 5-4) which require immediate attention and intervention.
TABLE 5-4. Life-threatening presentations of ALL.
Complete blood count. The WBC is between 10 000/mm3 and 50 000/mm3 in 30% of children with ALL and greater than 50 000/mm3 in approximately 20%. Neutropenia, defined as an absolute neutrophil count less than 500/mm3, is common at presentation. Other findings include moderate to severe anemia and an inappropriately low reticulocyte count. The platelet count is less than 100 000/mm3 in approximately 75% of patients, however isolated thrombocytopenia rarely occurs. Leukemic cells may be noted on the peripheral blood smear, particularly if the WBC count is normal or high.
Bone marrow aspirate or biopsy. A bone marrow aspirate or biopsy definitively establishes the diagnosis of ALL since the morphology of blasts seen on peripheral smear may not reflect the true bone marrow morphology. Monoclonal antibody testing of the bone marrow for specific cell surface antigens identifies lymphocytes and granulocytes at different stages of development. When this immunopheno-typing is combined with cytochemical staining and molecular genotyping, the diagnostic classification, treatment, and prognosis become more specific.
Other laboratory studies. Other laboratory abnormalities reflect either leukemic cell infiltration or excessive proliferation and destruction of leukemic cells. Serum transaminases may be mildly abnormal with liver infiltration but coagulation abnormalities are uncommon. Hypercalcemia results from leukemic infiltration of bone. Cell lysis leads to elevated phosphorus, LDH, and serum uric acid, reflecting increased purine catabolism.
Radiographs. Long bone radiograph abnormalities include transverse radiolucent metaphyseal growth arrest lines, periosteal elevation with reactive subperiosteal cortical thickening, and osteolytic lesions.
Computed tomography (CT). CT may reveal diffuse lymphadenopathy and hepatosplenomegaly. Approximately 5% to 10% of newly diagnosed patients have an anterior mediastinal mass detected on chest imaging.
Although specific treatment strategies may vary between hospitals, all modern approaches treat leukemia, the complications of leukemia, and manage treatment-related complications. Acute management involves blood product transfusions and treatment of infection, hyperviscosity, compressive symptoms, and metabolic abnormalities. Tumor lysis syndrome describes the constellation of metabolic abnormalities resulting from spontaneous or treatment-induced tumor necrosis. Acute tumor cell destruction releases intracellular contents into circulation leading to hypocalcemia, hyper-phosphatemia, hyperkalemia, and hyperuricemia. Management of tumor lysis syndrome includes vigorous hydration, urine alkalinization, uric acid reduction, and diuretic therapy.
Specific therapy for ALL is instituted in three distinct phases. Remission induction therapy lasts approximately 4 weeks during which most children have a complete remission, defined as the absence of clinical signs and symptoms of disease, recovery of normal blood cell counts, and recovery of normocellular bone marrow. Agents currently used for remission induction include dexamethasone or prednisone, vincristine, and L-asparaginase. Other agents may be used if the patient is considered high-risk or has CNS involvement. Consolidation therapy aims to kill additional leukemic cells with further systemic therapy and prevent CNS relapse with intrathecal chemotherapy. Maintenance therapy continues remission achieved by the first two phases. It is required because shorter treatment protocols are associated with a high rate of relapse. Methotrexate and 6-mercaptopurine are often used for consolidation and maintenance therapy.
Children with high WBC counts (>50 000/mm3), younger than 2 years of age, or older than 10 years of age at the time of diagnosis have the worst prognosis. However, between 95% and 98% of children diagnosed with ALL achieve complete remission after induction therapy. Relapse occurs in 20% to 30% either during subsequent treatment or within the first 2 years after its completion. Relapse affects virtually any site of the body, though bone marrow relapse is most common. Since the introduction of effective CNS-directed therapy, the frequency of CNS relapse has decreased to approximately 5%. Isolated testicular relapse occurs in 1% of boys. Bone marrow relapse is often treated with intense chemotherapy combined with bone marrow transplantation. The event-free survival rate after relapse ranges from 30% to 60%.
Late sequelae of ALL therapy include second neoplasms, neuropsychologic effects, endocrine dysfunction, and other organ-specific complications. Second neoplasms occur in 2.5% of patients, CNS tumors being the most common. Children less than 5 years of age at ALL diagnosis and those who received cranial irradiation are at highest risk of second neoplasms. Short stature occurs due to cranial irradiation-induced growth hormone deficiency. Some late complications are related to specific chemotherapeutic agents such as cardiomyopathy from anthracycline or bladder fibrosis from cyclophosphamide therapy. Chemotherapy may also have long-term effects on the child’s immune system. Recovery of the immune system usually occurs within 1-2 years after the completion of chemotherapy; however, some children may have low antibody titers of clinically significant viruses to which they have been previously immunized.
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