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The answer is a. The prognosis in neuroblastoma, as in other childhood malignancies, is directly proportional to the extent of disease at presentation. In early (stage I or II) disease, the tumor burden is much smaller than in stage III or IV disease, and the patient can be more easily treated with chemotherapy and surgical excision. The biology of neuroblastoma is highly unusual, with some early stage disease cured with surgery alone or surgery plus 2 to 4 months of chemotherapy. This is in comparison with higher-stage disease that requires surgery, intensive chemotherapy, autologous stem cell transplant, radiation therapy, and possibly biologic therapy. A unique feature of neuroblastoma is that it is an age-dependent prognosis. Children under the age of 1 year have a much better prognosis in all stages than do children past that age. This finding is thought to be related to a temporal loss of older infants’ ability to differentiate embryonic tissue. In a series of autopsies performed on 4-month-old fetuses, approximately 32% of the adrenal glands had neuroblastoma cells. These tissues differentiate or mature in most cases as the fetus reaches term. Histopathology (favorable vs. unfavorable) and number of N-myc oncogene copies are prognostic variables used in tailoring therapy, but outcome is correlated more strongly with age and stage. Gender, presence of ataxia, and 24-hour urine catecholamine levels are not significant predictors of prognosis, although patients presenting with ataxia tend to have lower stage disease at diagnosis.

Neuroblastoma is an excellent example of a childhood cancer with risk-directed or stratified therapy based on cell biology and risk factors present at diagnosis. Long-term survival along this spectrum of disease ranges from >95% to <25%.

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The answer is c. Stage IV disease (metastases to viscera, such as the lungs) is a poor prognostic indicator in most malignancies of childhood. However, the treatment of Hodgkin disease has been very successful since the introduction of MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) and ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) therapy in the 1960s and 1970s. This is also an exquisitely radiosensitive tumor. The judicious use of radiation therapy and chemotherapy has resulted in event-free survival exceeding 80% in patients with stage IV Hodgkin disease. Hodgkin disease therapy is evolving rapidly, as attempts are being made to decrease the intensity of chemotherapy and eliminate radiation therapy in patients with early complete response to chemotherapy. This aims to decrease the incidence of late effects and second malignancies in these survivors. All other stage IV malignancies
have a much lower chance for cure. (A patient with ALL would have the best survival rate at approximately 70%.)

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The answer is c. Wilms tumor, retinoblastoma, osteosarcoma, and Ewing sarcoma are usually brought to the attention of a physician early in their course because of the presenting features. Wilms tumor and hepatoblastoma present with an abdominal mass. Retinoblastoma presents with leukocoria and other visual problems. Ewing sarcoma and osteosarcoma present with progressive bone pain or palpable mass; rhabdomyosarcoma usually presents with a palpable mass. Peripheral adenopathy can be associated with these tumors in progressive, latestage, widely metastatic disease. Neuroblastoma often presents in early stages, but when the presentation is in stage IV, the patient may have widespread lymphadenopathy, and the presentation may be very similar to that of acute leukemia (i.e., generalized lymphadenopathy, bone pain, hepatosplenomegaly, petechiae, fever, easy bruising). All forms of lymphoma may present with significant lymphadenopathy.

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The answer is b. This boy’s symptoms are consistent with a hemolytic process. Of the choices listed that are hemolytic anemias, glucose-6-phosphate dehydrogenase deficiency is most consistent with this patient’s clinical presentation. Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder characterized by hemolytic anemia. The incidence of this disorder is high in African Americans, Italians, Greeks, and individuals of Middle Eastern ancestry. The most likely inducers of hemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency include:

HS is more likely in a white patient and hemolysis tends not to be associated with drugs but rather with viral illnesses. Similarly, autoimmune hemolytic anemia usually develops spontaneously or following a viral illness.

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The answer is b. This child presents with isolated thrombocytopenia but no fever or other clinical manifestations. Therefore, ITP is most likely. This often occurs after an antecedent viral infection (70% of cases) and is characterized by a deficiency of circulating platelets despite adequate numbers of megakaryocytes in the bone marrow. It is likely an immune-mediated process whereby the patient’s immune system mistakes a platelet antigen as foreign. The clinical picture is generally one of an acute onset 1 to 4 weeks after a viral illness. A generalized petechial rash and excessive bruising are common, and mucous membrane hemorrhage can be prominent. The children generally appear well, without lymphadenopathy or hepatosplenomegaly to suggest malignancy. Isolated thrombocytopenia (often dramatic, but usually between 10,000-50,000/mm³), with a normal WBC count and hemoglobin level, is the rule. Examination of the bone marrow, although not necessary for diagnosis, reveals normal granulocytic and erythrocytic series, with normal or increased numbers of megakaryocytes. The prognosis is excellent; 80% to 90% of patients will recover in weeks to a few months, with or without treatment. If ITP lasts greater than 6 months, it is termed chronic ITP and can be quite difficult to manage.

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The answer is a. This child has a microcytic, hypochromic anemia with a low-to-normal RDW. Despite iron therapy, her reticulocyte count is low, and the peripheral smear shows small, hypochromic RBCs. These findings are most consistent with thalassemia. The causes of a microcytic, homogeneous anemia (low MCV, normal RDW) include thalassemia and anemia of chronic disease. Sickle cell disease causes a normocytic, heterogeneous anemia (increased RDW resulting from the presence of reticulocytes). Folate and vitamin B₁₂ deficiencies cause a macrocytic anemia and are very unusual in children in developed countries. It is noteworthy that noncompliance with iron treatment should always be a consideration. Serum iron levels can be helpful in distinguishing thalassemia and iron deficiency, but they may coexist. The Mentzer index (MCV/RBC) can also be useful: <11 suggests thalassemia; >11 suggests iron deficiency.

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The answer is d. Jaundice and splenomegaly, along with a normocytic anemia and reticulocytosis, are characteristic of a hemolytic anemia. In a previously healthy 7-yearold white child, HS would be the most likely diagnosis. HS is transmitted as an autosomal-dominant disorder, but the rate of new mutations is high. It is the most common congenital abnormality of the RBC membrane. Hemolytic disease in children is quite variable (baseline hemoglobin ranging from 9-11 g/dL); it can manifest early in life with severe hemolysis or may not manifest until late in life. Prolonged neonatal jaundice is a common historical finding, and splenomegaly and gallstones are common clinical features. Spherocytes (often microspherocytes) and reticulocytes on the blood smear are characteristic (causing increased mean corpuscular hemoglobin concentration [MCHC] and RDW), and the findings of splenomegaly, reticulocytosis, and spherocytosis are often diagnostic. The osmotic fragility test confirms the presence of spherocytes in the blood. This test incubates patient RBCs with varying concentrations of saline, and the patient’s cells will burst quickly, not withstanding osmotic stress as would a normal biconcave RBC. Splenectomy eliminates most of the hemolysis associated with this disorder.

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The answer is d. Tumor lysis syndrome is an acute metabolic derangement caused by the rapid turnover of dying cancer cells. This can happen spontaneously or as a result of initiation of chemotherapy. As intracellular contents are released, the resulting classic laboratory abnormalities are elevated potassium, phosphorus, and uric acid, and decreased calcium. Renal function may deteriorate quickly, necessitating dialysis if electrolytes are not managed aggressively. Management includes frequent monitoring of laboratory values, aggressive intravenous hydration that does not include potassium, and allopurinol (xanthine-oxidase inhibitor), which lowers the production of uric acid. Calcium should be replaced quickly, and many measures can be used to decrease a rising potassium (Lasix, glucose plus insulin, potassium binders). A nephrologist and pediatric intensivist should be notified of any patient who presents at high risk for tumor lysis syndrome. Burkitt lymphoma is the pediatric diagnosis most closely associated with this oncologic emergency. Acute leukemias that present with a high tumor burden (high WBC count with or without massive organomegaly) are also at risk. Solid tumors do not carry significant risk of tumor lysis syndrome.