This is a 10 year old boy who presents to the emergency department with a chief complaint of fever and increasing tiredness. He was well until 2 weeks ago when he had an upper respiratory illness (URI). He has been tired with decreased activity since the URI, and has missed school and sports practices for 2 days. He has a decreased appetite and has lost 2 pounds over the last 2 weeks. He has some shortness of breath when he climbs stairs, but his parents deny cough, fever, nausea, emesis, bruising, headache, or visual problems. His past medical health, including birth history, immunizations, and other medical problems is unremarkable. He lives with his two parents and 6 year old brother, all of whom are healthy. The sibling and parents had similar URI symptoms 2 weeks ago, but everyone else is back to normal activity levels. There is no family history of relevant medical problems.

Exam: VS T 38.5 degrees C, P 120, R 32, BP 110/56. Height & weight at the 80th percentile. He is alert, tired and slightly pale appearing, but in no apparent distress. His head is normocephalic without scalp lesions. His hair texture is normal. His ear canals and TMs are normal. Pupils are equal and reactive to light. Conjunctivae are pale. His fundi are normal. His nasal passages are clear. His mucous membranes are dry and pale. His posterior pharynx is erythematous without lesions and no tonsillar enlargement. His dentition and gums are normal. No nuchal rigidity is present. He has bilateral cervical nodes, posterior cervical nodes, axillary nodes, and inguinal nodes palpable (about 1-2 cm), mobile and nontender. His chest exam (breasts, lungs, heart) is normal except for some tachycardia. His abdomen is flat and non-tender with normal bowel sounds. His liver edge is palpable at the costal margin. His spleen is palpable 4 cm below the left costal margin. His back is normal. His skin shows no lesions, bruises or petechiae. Upper and lower extremities are normal. His neurological exam is normal.

Laboratory: CBC Hgb 7, Hct 24, MCV 100, WBC 56,000, Differential 14% lymphoblasts, 80% lymphocytes, 6% atypical lymphocytes. Platelets 23,000. Chest x-ray shows clear lung fields but a wide mediastinum.

He is admitted to the hospital and a diagnostic workup including a bone marrow aspirate and biopsy reveals acute lymphoblastic leukemia.

There are different types of leukemia but the most common leukemia that occurs in children is acute lymphoblastic leukemia (ALL). ALL is the most common cancer in children representing 23% of cancer diagnoses among children younger than 15 years of age and occurring at an annual rate of approximately 31 per million (1). Approximately 2,400 children and adolescents younger than 20 years of age are diagnosed with ALL each year in the USA. There is a sharp peak in ALL incidence among children ages 2 to 3 years. Lymphomas, in general, are divided into two broad categories, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). As a group, it is the third most common childhood malignancy with HD and NHL accounting for approximately 10% of cancers in children less than 20 years of age (2). In the United States, there are about 800 new cases of NHL diagnosed each year. Incidence is approximately 10 per 1,000,000.

For both ALL and lymphoma (HD and NHL), the signs and symptoms may be similar but non-specific. The clinical manifestations may present insidiously or acutely, as an incidental finding on a routine complete blood count analysis or as a life-threatening infection or respiratory distress. Some characteristics which may present at the time of diagnosis are lethargy, fever, joint pain, bleeding, abdominal pain, CNS manifestations, and/or difficulty breathing secondary to a mediastinal mass. On physical examination, there may be pallor, hepatosplenomegaly, petechiae, and/or lymphadenopathy.

Because some rare cases may be difficult to diagnose even with proper diagnostic biopsies, other diagnoses should be entertained. These include viral infections such as Epstein-Barr virus, cytomegalovirus; other malignancies such as neuroblastoma; hematological disorders such as aplastic anemia, histiocytosis, idiopathic (immune) thrombocytopenic purpura (ITP); and juvenile rheumatoid arthritis. In general, the differential diagnosis between ALL and NHL has been debated for years, and the criteria utilized to distinguish between the two categories of diseases have been arbitrary. While both entities can be of B-cell or T-cell phenotype, the distinction between NHL and ALL is currently based on the degree of bone marrow involvement. Children who have more than 25% infiltration of their marrow with blast cells are considered to have ALL.

Treatment and management of ALL and NHL are based on proper diagnosis and staging to determine the extent of disease involvement. Diagnosis is made from either the bone marrow (ALL) or tissue (NHL), and includes immunophenotyping, cytogenetics, flow cytometry, and/or molecular studies such as gene rearrangements. Recommended staging studies include a careful physical examination, complete blood count, bone marrow aspirate or biopsy, lumbar puncture, and radiographic studies including possible nuclear medicine studies to assess the extent of disease.

Prior to instituting specific therapy, measures should be instituted to treat emergent problems, particularly in patients with advanced disease and who may have associated airway compression or superior vena cava obstruction. Measures should also be in place to be able to monitor and intervene for treatment related problems such as tumor lysis. Tumor lysis can occur spontaneously or as a result of chemotherapy leading to serious metabolic complications such as hyperuricemia, hyperkalemia, and hyperphosphatemia. This could ultimately lead to renal failure or cardiac arrest if left untreated.

Successful treatment of children with ALL and NHL requires the control of systemic disease (marrow, liver and spleen, lymph nodes, etc.) as well as the treatment (or prevention) of extramedullary disease particularly in the central nervous system (CNS) (1,3). The main goal of therapy is to begin induction treatment as soon as the diagnosis is made in order to obtain remission. After inducing remission, the next goal is to maintain remission. In general, therapy is based on cytotoxic drugs affecting the rapidly dividing cells during the cell cycle. Multiple drugs are used because each class of drugs acts on a different part of the cell cycle with the intent of interrupting cell division in the majority of malignant cells. The concept of inducing remission initially is to try and rapidly destroy the majority of malignant cells within the first 30 days of treatment. Ongoing and subsequent treatment strategies are based on the concept that malignant cells that "escaped" the induction phase will enter the cell cycle over a period of time and will then be affected by the drugs. Most of the drugs are administered orally, intravenously, or intramuscularly. CNS treatment and/or prophylaxis is administered via a lumbar puncture (intrathecal). Occasionally, emergency treatment has to be considered for life-threatening situations such as airway compression, spinal cord compression, etc. This can be accomplished with the use of radiation to the involved sites. The immune system is compromised throughout the duration of therapy. Therefore one must be attentive to any signs or symptoms of septicemia. Additionally, exposure to infectious agents including live vaccines should be avoided.

In general, there are clinical and laboratory findings present at the time of diagnosis which may correlate with prognosis. A high tumor burden, whether assessed by total white blood cell count for ALL or high stage disease in NHL (or elevated serum LDH) has been consistently found to be an important prognostic factor. Other factors might include specific chromosome abnormalities, age, race, or gender. Recently, the rapidity of response to induction therapy or the presence of residual disease has been examined as a predictor of outcome.

Approximate 75-80% of children and adolescents with ALL and NHL will survive at least 5 years with modern chemotherapy although outcome is variable depending on a number of factors. Since nearly all children will achieve remission with proper treatment, one of the main obstacles today is how to effectively treat bone marrow or CNS relapses. Other challenges are the result of successful treatment and related to screening and treating long term complications from therapy. These include CNS sequelae affecting cognition and learning, growth failure, reproductive sequelae, cardiac sequelae, and secondary malignancies.

Questions

1. You are called to the ER to evaluate a 10 year old boy who has been tired for 2 weeks and his parents noticed that he becomes short of breath when he walks upstairs to go to his bedroom. Upon your physical exam, you note that he has some shortness of breath when he is placed in the supine position. Which of the following procedures might you consider initially ?
. . . . . a. Arrange for a better examination of the lungs and possible diagnostic biopsy under general anesthesia.
. . . . . b. PA and Lateral chest x-ray.
. . . . . c. An MRI of the chest to rule out an enlarged heart.
. . . . . d. Diagnostic fine needle aspirate without general anesthesia to find out why he is short of breath.

2. One of your patients (5 year old female) was diagnosed with ALL 6 months ago and is being treated by a pediatric hematologist/oncologist with chemotherapy. She now wants to start back to school and the school administration tells the parents that she needs to be up to date on her immunizations. They would like her MMR administered. What advice do you offer them?
. . . . . a. Even though the child is on chemotherapy, there is evidence that her immune status is competent, therefore she can be given all of her scheduled immunizations.
. . . . . b. Her immune system will only mount an immune response to live, attenuated vaccines, therefore she can receive the MMR vaccine as scheduled.
. . . . . c. MMR vaccine is contraindicated in a child receiving chemotherapy for cancer.
. . . . . d. The parents should wait until the child recovers from the side effects of the current cycle of chemotherapy and then make an appointment for the MMR vaccine.

3. As the pediatrician of a 7 year old boy who was diagnosed with NHL at 4 years of age and successfully completed chemotherapy, the parents made an appointment to have him see you because they were advised by the boy's teacher that he has not been keeping up academically. You review the boy's medical history, and other than the chemotherapy, you do not see anything that would account for the poor school performance. What is the best advice to the parents?
. . . . . a. You remind the parents that because of the child's past medical situation, he has a feeling of neglect and abandonment therefore will need some remedial attention to overcome the psychological condition, which is causing his poor academic performance.
. . . . . b. There is a high likelihood that the child has a secondary brain tumor, and may need at CT scan of the head.
. . . . . c. Having received therapy which compromised the child's immune status, he most likely has meningitis, therefore should be admitted for therapy.
. . . . . d. Children who have received chemotherapy and/or radiation may experience delays in growth and development, therefore further testing and gathering of information should be suggested.

4. You are the primary pediatric resident on the hematology/oncology team and covering the service over the weekend. A 6 year old was admitted on Thursday, with a history of being tired, shortness of breath, pallor and weight loss. A prompt and efficient workup revealed a diagnosis of T-cell NHL. Following the family conference and consent process to begin the child on a lymphoma protocol, treatment was started by the weekend. The chemotherapy is being administered properly, with attention to tumor lysis precautions, including vigorous hydration. As you make your midnight rounds, you notice that the documentation of fluid input and output shows a large discrepancy. The amount of fluid administered (orally and intravenously) is almost twice the volume as the urine output. You suspect that the patient is experiencing complications from the chemotherapy and think you should do which of the following:
. . . . . a. Increase the hydration because the fluid balance is not equal, and the patient should be receiving more than twice maintenance fluid intake during induction chemotherapy.
. . . . . b. Perform a thorough physical exam, have the patient weighed, repeat the serum electrolytes immediately to determine if the patient is fluid overloaded.
. . . . . c. The patient is experiencing renal failure, and needs immediate consultation by a nephrologist to begin dialysis.
. . . . . d. You decide that the oral fluid intake has not been taken into consideration, which it should be, and estimate the amount the patient has been taking in orally based on what was served on his meal trays. By your calculations, the total fluid intake and output is equal, therefore no further action is needed.

5. The parents of a 5 year old boy bring their son to see you because they are concerned that their son has leukemia. His 3 year old sister had a URI 2 weeks ago, but fully recovered and has been back in school and active. This 5 year old boy has URI symptoms now. They noticed bruising on his legs and arms over the last few days, and their neighbor's daughter had similar findings 2 years ago before she was diagnosed with acute lymphoblastic leukemia. The mother's grandfather died at the age of 80 from leukemia. Your physical exam is unremarkable except for the bruises noted on the anterior legs and on the forearms. He is playful and cooperative. What course of action or advice should you do next?
. . . . . a. Because of the strong family history of ALL and the leukemia case in the neighborhood, you should pursue a presumed workup of ALL and notify the state Cancer Control Division.
. . . . . b. Obtain a complete blood count.
. . . . . c. The bruising strongly makes you suspicious of possible child neglect or abuse. Reassure the parents that you do not suspect them, but you should alert them of your concerns and find out who could possibly be the perpetrator.
. . . . . d. Since the bruises are the only abnormal finding, you are less concerned about leukemia, therefore you alleviate the parents' concerns and tell them that the bruising is most likely related to the child's aggressive activities at school.

References

1. Pui CH. Acute lymphoblastic leukemia in children. Current Opinion in Oncology 2000;12:3-12.

2. Sandlund JT, Downing JR, Crist WM. Non-Hodgkin's lymphoma in childhood. New Engl J Med 1996;334:1238-1248.

3. Magrath IT, Shiramizu B. Biology and treatment of small non-cleaved cell lymphoma. Oncology 1989;3:41-53.

Answers to questions

1. b. The fact that the child is short of breath in the supine position could be related to a mediastinal mass, which can be identified on a chest x-ray. A mediastinal mass could be a potential emergency situation, therefore a chest x-ray should be considered shortly after the history and physical exam are completed.

2. c. Live vaccines are contraindicated throughout the treatment course due to the immunocompromised status of the patient.

3. d. Delays in growth and development may occur as a result of chemotherapy and/or radiation therapy.

4. b. The chemotherapy may have induced tumor lysis causing hyperuricemia, which in turn may be affecting the kidneys.

5. b. As part of the differential diagnosis, you should consider ITP.