Recognition of Common Childhood Malignancies

Author: Guy Young, Allen E. Eskenazi
Date: April 1, 2000

Although cancer has an annual incidence of only about 150 new cases per 1 million U.S. children, it is the second leading cause of childhood deaths. Early detection and prompt therapy have the potential to reduce mortality. Leukemias, lymphomas and central nervous system tumors account for more than one half of new cancer cases in children. Early in the disease, leukemia may cause nonspecific symptoms similar to those of a viral infection. Leukemia should be suspected if persistent vague symptoms are accompanied by evidence of abnormal bleeding, bone pain, lymphadenopathy or hepatosplenomegaly. The presenting symptoms of a brain tumor may include elevated intracranial pressure, nerve abnormalities and seizures. A spinal tumor often presents with signs and symptoms of spinal cord compression. In children, lymphoma may present as one or more painless masses, often in the neck, accompanied by signs and symptoms resulting from local compression, as well as signs and symptoms of systemic disturbances, such as fever and weight loss. A neuroblastoma may arise from sympathetic nervous tissue anywhere in the body, but this tumor most often develops in the abdomen. The presentation depends on the local effects of the solid tumor and any metastases. An abdominal mass in a child may also be due to Wilms' tumor. This neoplasm may present with renal signs and symptoms, such as hypertension, hematuria and abdominal pain. A tumor of the musculoskeletal system is often first detected when trauma appears to cause pain and dysfunction out of proportion to the injury. Primary care physicians should be alert for possible presenting signs and symptoms of childhood malignancy, particularly in patients with Down syndrome or other congenital and familial conditions associated with an increased risk of cancer. (Am Fam Physician 2000;61:2144-54.)

Only about 2 percent of all cancers in western industrialized nations occur in children. Hence, childhood cancer is relatively uncommon, with an annual incidence of 150 new cases per 1 million children in the United States. However, cancer accounts for 10 percent of childhood deaths and is second only to accidents as a cause of death in U.S. children.(1)

Although the incidence of childhood cancers increased slightly in the early 1980s, there has been no substantial change in the incidence of major pediatric cancers since the mid-1980s.(2) Mortality rates for these malignancies have declined significantly as a result of improvements in supportive care and therapy.(3)

The most common childhood malignancies are acute lymphoblastic leukemia, central nervous system (CNS) tumors and lymphomas. Together, these cancers account for 63 percent of cases (Table 1).(2) Childhood cancers occur at a slightly higher rate in males and at a significantly higher rate in whites.(1,3)

Although cancer can develop in children of any age, certain malignancies have a predilection for specific age groups. For example, neuroblastoma, retinoblastoma and Wilms' tumor most commonly occur in children between birth and four years of age, whereas osteosarcoma, Ewing's sarcoma and Hodgkin's disease tend to occur in children more than 10 years of age.

This article reviews the typical presenting features of the more common childhood cancers. Some genetic syndromes requiring increased vigilance for cancer are also discussed.

Difficulties in Diagnosis

Childhood cancer can be difficult to diagnose in the primary care setting. The index of suspicion tends to be low because of the relative rarity of malignancies in children. Furthermore, as shown in Table 2, the presenting signs and symptoms are often nonspecific and mimic those of common childhood conditions such as viral infections. Signs and symptoms that warrant evaluation are summarized in Table 3.

The presenting manifestations of leukemia are related to bone marrow infiltration and resultant pancytopenia. These symptoms include the following: fatigue and pallor secondary to anemia; petechiae, ecchymoses and mucus membrane bleeding secondary to thrombocytopenia; signs of infection secondary to neutropenia; and bone pain secondary to marrow hyperplasia. Constitutional symptoms, including fever, anorexia and weight loss, are also quite common.

The signs and symptoms of solid tumors are related to the presence of a mass lesion. CNS tumors can present with headache alone. (Clearly, however, most childhood headaches are not caused by brain tumors.) Headaches associated with neurologic abnormalities, such as ataxia, gait disturbances, seizures or cranial nerve palsies, merit further investigation.

Abdominal masses can present with pain, vomiting, constipation or, less commonly, intestinal obstruction. It is not unusual for a child with an abdominal mass to present because a family member notices a protuberant mass. For masses in the chest, the presenting symptoms are usually persistent cough or dyspnea.

Extremity lesions usually present with pain subsequent to trauma. It is important to realize that the traumatic event merely leads to careful examination of the extremity (including diagnostic imaging) and may not be causing the pain.

Leukemia

Leukemia is the most common malignancy of childhood, and acute lymphoblastic leukemia is the most common type of leukemia in children. Acute lymphoblastic leukemia typically develops in children between one and 10 years of age, although it can occur at any age. This leukemia is more common in males and in whites.(1)

Diagnosing acute lymphoblastic leukemia can be difficult. Frequently, the diagnosis is delayed because early symptoms are nonspecific and may mimic those of viral infections. Most children who have this cancer present with generalized malaise, loss of appetite and a low-grade fever. Additional symptoms that should prompt concern include pallor, petechiae or ecchymoses, bone pain and significant weight loss.

The physical examination may reveal no abnormalities, but the presence of significant lymphadenopathy or any hepatosplenomegaly should raise suspicion for leukemia. Compared with adults, children normally have more lymphoid tissue in their tonsils, adenoids and cervical regions; however, hepatosplenomegaly is always an abnormal finding.

A prudent approach to the child with any suspicious findings is to obtain a complete blood count (CBC) with a white blood cell differential and a reticulocyte count. The presence of blast cells on the peripheral smear is indicative of leukemia. However, many patients with leukemia only have blast cells in their bone marrow. The finding of anemia, especially if accompanied by reticulocytopenia or a high mean corpuscular volume, thrombocytopenia, leukopenia or leukocytosis, should prompt consultation with a pediatric hematologist or oncologist, because the likelihood of leukemia is high.

The presenting signs and symptoms of childhood leukemia are listed in Table 4.(4) Specific illnesses that often mimic leukemia include infectious mononucleosis caused by Epstein-Barr virus or, less frequently, cytomegalovirus infection, collagen vascular disease and aplastic anemia. The differential diagnosis for an abnormal CBC is given in Table 5.

Central Nervous System Tumors

CNS tumors are the second most common childhood malignancy. Many brain tumors are histologically benign but are considered "malignant" because they cause severe symptoms and require treatment secondary to their anatomic location. CNS tumors are classified as intracranial or spinal. In adults, the majority of intracranial tumors are supratentorial. However, infratentorial lesions account for 60 percent of CNS tumors in children.(5)

Children who have infratentorial lesions usually present with ataxia and other gait disturbances, frequently have hydrocephalus as a result of aqueduct compression and may also have cranial nerve abnormalities from brainstem compression. Figure 1 shows a typical posterior fossa mass (ependymoma) in a six-year-old child.

Supratentorial tumors occur at any age. These lesions can present with signs of elevated intracranial pressure (headache and vomiting, or an enlarging head in infants) and focal neurologic deficits. Less common findings include seizures, endocrine abnormalities and personality changes.

Spinal tumors are more common in older children. Malignancies of the spine frequently present as back pain and signs of spinal cord compression, such as weakness and loss of bladder and bowel function.

(3.) SEER Cancer statistics review, 1973-1996. Retrieved February 7, 2000, from the World Wide Web: http://www-seer.ims.nci.nih.gov/Publications/ CSR1973_1996/.

(4.) Pui CH. Childhood leukemias. In: Murphy GP, Lawrence W, Lenhard RE, eds. American Cancer Society textbook of clinical oncology. 2d ed. Atlanta: American Cancer Society, 1995:501-23.

(5.) Pollack IF. Brain tumors in children. N Engl J Med 1994;331:1500-7.

(6.) Medina LS, Pinter JD, Zurakowski D, Davis RG, Kuban K, Barnes PD. Children with headache: clinical predictors of surgical space-occupying lesions and the role of neuroimaging. Radiology 1997;20: 819-24.

(7.) Pao WJ, Kun LE. Hodgkin's disease in children. Hematol Oncol Clin North Am 1989;3:345-65.

(8.) Raney RB. Hodgkin's disease in childhood: a review. J Pediatr Hematol Oncol 1997;19:502-9.

(9.) Sandlund JT, Downing JR, Crist WM. Non-Hodgkin's lymphoma in childhood. N Engl J Med 1996;334:1238-48.

(10.) Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the U.S. Cancer 1996;78:532-41.

(11.) Brodeur GM, Castleberry RP. Neuroblastoma. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. 3d ed. Philadelphia: Lippincott-Raven, 1977:761-7.

(12.) Stram DO, Matthay KK, O'Leary M, Reynolds CP, Haase GM, Atkinson JB, et al. Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children's Cancer Group studies. J Clin Oncol 1996;14:2417-26.

(13.) Cheung NK, Kushner BH, Cheung IY, Kramer K, Canete A, Gerald W, et al. Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 1998;16:3053-60.

(14.) Paulino AC. Current issues in the diagnosis and management of Wilms' tumor. Oncology [Huntingt] 1996;10:1553-65.

(15.) DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 1998;132:398-400.

(16.) Nichols KE, Li FP, Haber DA, Diller L. Childhood cancer predisposition: applications of molecular testing and future implications. J Pediatr 1998;132: 389-97.

(17.) Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst 1998;90:1039-71.

(18.) Bleyer WA. The impact of childhood cancer on the United States and the world. CA Cancer J Clin 1990;40:355-67.

TABLE 1Incidence of Childhood CancersCancer Incidence (%)Leukemia 30.2Central nervous system tumor 21.7Lymphoma 10.9Neuroblastoma 8.2Soft tissue sarcoma 7.0Renal tumor 6.3Bone tumor 4.7Others 11.0Adapted with permission from Linet MS, Ries LA, Smith MA, Tarone RE, DevesaSS. Cancer surveillance series: recent trends in childhood cancer incidenceand mortality in the United States. J Natl Cancer Inst 1999;91:1051-8.TABLE 2Signs and Symptoms of Childhood Cancers and Conditions That Can Mimic TheseCancersSign or symptom Type of cancerFever Leukemia, lymphomaVomiting Abdominal mass, brain tumorConstipation Abdominal massCough Mediastinal massBone or muscle pain Leukemia, bone tumor, neuroblastomaHeadache Brain tumorLymphadenopathy Leukemia, lymphoma, metastatic disease ([greater than] 2 cm)Hematuria Wilms' tumorVoiding difficulty Rhabdomyosarcoma Common conditionsSign or symptom in the differential diagnosisFever InfectionVomiting Infection, gastroesophageal refluxConstipation Poor dietCough Upper respiratory infection, reactive airway disease, pneumoniaBone or muscle pain Musculoskeletal injury, viral infectionHeadache Tension headache, migraine, infectionLymphadenopathy Lymphadenitis, systemic infection, collagen vascular diseaseHematuria Urinary tract infection, glomerulonephritisVoiding difficulty Congenital urinary tract abnormalitiesTABLE 3When and How to Evaluate Signs and Symptoms for CancerSymptom When to evaluateFever Fever lasts longer than 14 days with no identifiable cause.Vomiting Vomiting lasts longer than 7 days with no identifiable cause. Vomiting is associated with headache during sleep.Constipation Constipation is prolonged ([greater than] 1 month) and does not respond to conventional measures.Cough Cough is prolonged ([greater than] 2 weeks) and has no identifiable cause.Bone or muscle Pain is prolonged ([greater than] 2 weeks) and pain has no identifiable cause.Headache Headache occurs during sleep, is associated with neurologic signs and vomiting, or occurs in the absence of a family history of migraine.Hematuria Evaluate immediately if hematuria has no identifiable cause.Voiding difficulty Evaluate immediately if voiding difficulty has no identifiable cause.Lymphadenopathy Evaluate if lymphadenopathy does not respond to a ([greater than] 2 cm) 7-day course of antibiotic.Symptom TestFever CBC with differentialVomiting Abdominal and head CT scans Head CT scanConstipation Abdominal and pelvic CT scansCough Chest radiographBone or muscle Plain-film radiograph, pain bone and CT scans, CBCHeadache Head CT scanHematuria Abdominal ultrasound examinationVoiding difficulty Abdominal ultrasound examinationLymphadenopathy CBC with differential, lactate ([greater than] 2 cm) dehydrogenase levelCBC = complete blood count; CT = computed tomography.TABLE 4Presenting Signs and Symptomsof Childhood LeukemiaSign or symptom Frequency (%)Hepatomegaly 60Splenomegaly 57Fever 53Malaise 50Bleeding 38Lymphadenopathy 35Bone pain 27Anorexia 19Abdominal pain 10Adapted with permission from Pui CH. Childhood leukemias. In: Murphy GP,Lawrence W, Lenhard RE, eds. American Cancer Society textbook of clinicaloncology. 2d ed. Atlanta: American Cancer Society, 1995:501-23.TABLE 5Differential Diagnosisof Abnormal Complete Blood CountInfectionsNonspecific viral syndromeEpstein-Barr virus infectionCytomegalovirus infectionHuman immunodeficiency virus infectionAutoimmune disordersSystemic lupus erythematosusSystemic-onset juvenile rheumatoid arthritisHematologic disordersAplastic anemiaLeukemiaTABLE 6Childhood Cancers: Comparison of Previous Five-Year Survival Rates withSurvival Rates for 1985-1995 Five-year survival rates (%)Cancer 1960-1963 1975-1984 1985-1995All cancers 28 74Acute lymphoblastic leukemia 4 77Acute myelogenous leukemia 20 42Hodgkin's disease 52 92Non-Hodgkin's lymphoma 56 72Brain tumors 35 66Neuroblastoma 25 65Wilms' tumor 33 90Osteosarcoma 50 64Ewing's sarcoma 42 59Soft tissue sarcomas 68 70Germ cell tumors 77 88Adapted with permission from SEER Cancer statistics review, 1973-1996.Retrieved February 7, 2000, from the World Wide Web: http://www-seer.ims.

nci.nih.gov/Publications/CSR1973_1996/.

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