CHAPTER 152

Cancer in Children

Eduard H. Panosyan, MD; Moran Gotesman, MD; and Joseph L. Lasky III, MD, FAAP

Epidemiology

Childhood cancer is rare. Approximately 12,400 children and adolescents younger than 20 years are diagnosed with cancer each year in the United States. The likelihood of a child developing cancer before the age of 20 years is 1 in 300 for males and 1 in 333 for females. The overall incidence of childhood cancer has been slowly increasing since the mid-1970s, but death rates have declined dramatically for most childhood cancers and survival rates have improved markedly since the 1970s. Cancer remains the leading disease-related cause of death in children younger than 15 years, however. The prevalence of cancer is higher in children younger than 5 years and in children between the ages of 15 and 19 years. Acute hematologic malignancies, sarcomas, and embryonic neoplasms with fewer mutations are more typical in the pediatric age group compared with adults, who develop genetically more complex cancers and carcinomas of epithelial origin. Acute leukemia is the most common childhood cancer, followed by brain tumors, lymphomas, neuroblastoma, Wilms tumor (ie, nephroblastoma), and other less common pediatric solid tumors (Figure 152.1).

Environmental factors, genetic predisposition, and developmental processes may all play a role in influencing the cancer risk of a child. Case-control epidemiology studies looking for the causes of pediatric cancer have evaluated foods, prenatal exposures of parents and affected offspring, electromagnetic fields, radon, and various other environmental factors with no conclusive evidence of causality to date. Although many environmental factors are known to induce carcinogenesis, current evidence does not support a major causative role for exogenous factors in childhood cancer. Most childhood cancers result from aberrations in early developmental processes. Some known risk factors for selected childhood cancers include infectious agents, such as Epstein-Barr virus (eg, B-cell lymphomas, Hodgkin lymphoma, nasopharyngeal carcinoma), HIV (eg, B-cell lymphomas, Kaposi sarcoma, leiomyosarcoma), and hepatitis B and C (eg, hepatocellular carcinoma); ionizing radiation (eg, leukemia, osteosarcoma, brain tumors); chemotherapeutic agents (eg, leukemia, osteosarcoma); immunodeficiency (eg, non-Hodgkin lymphoma); and genetic conditions. Approximately 4% to 10% of childhood cancer results from known inherited genetic mutations that result in a cancer predisposition. Children with trisomy 21 syndrome (ie, Down syndrome) have an increased risk of leukemia (eg, lymphoid and myeloid). Beckwith-Wiedemann syndrome is associated with an increased risk for hepatoblastoma, Wilms tumor, rhabdomyosarcoma, and neuroblastoma and warrants appropriate surveillance screening. Inheritance of mutations in tumor suppressor genes, such as the retinoblastoma gene or the p53 gene, predispose affected children in families with these mutations (eg, Li-Fraumeni syndrome) to particular malignancies at a greater frequency and an earlier age than in unaffected individuals. Some children with tuberous sclerosis or neurofibromatosis 1 will develop multiple types of brain tumors.

Clinical Presentation

Signs and symptoms of childhood cancer are varied, are often nonspecific initially, and can mimic many common pediatric conditions (Table 152.1). Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 80% of pediatric leukemia cases. Acute myeloid leukemia accounts for the remaining 15% to 20% of cases. The child with acute leukemia presents with signs and symptoms that reflect leukemic infiltration of the bone marrow and extramedullary locations. Presentation with generalized bone pain and signs and symptoms related to pancytopenia (ie, fever, fatigue, pallor, bleeding, bruising, infections) is common. Disseminated intravascular coagulation is more characteristic of acute myeloid leukemia, especially acute promyelocytic leukemia. Leukemic infiltration of extramedullary sites can result in hepatosplenomegaly, lymphadenopathy, chloroma (ie, a green-colored tumor of myeloid cells), central nervous system (CNS), and sometimes testicular involvement. The child with high white blood cell counts at presentation, as in leukocytosis, can present with signs and symptoms of leukostasis typically involving the lung or brain. Tumor lysis syndrome can occur spontaneously or with the initiation of intravenous (IV) hydration or chemotherapy. Tumor lysis syndrome occurs as a result of breakdown of leukemic blasts that results in the release of metabolic by-products. It is characterized by a metabolic triad of hyperuricemia, hyperkalemia, and hyperphosphatemia, which places a child at risk for renal dysfunction or failure secondary to precipitation of urate or calcium phosphate crystals within the renal tubules. Involvement of the CNS by leukemia can result in signs of increased intracranial pressure (ICP), such as headache, vomiting, hypertension, seizures, and cranial neuropathies.

Figure 152.1. Cancer incidence rates for patients aged 0 through 14 years and 15 through 19 years in the Surveillance, Epidemiology, and End Results (SEER) Program from 2009 through 2012 by International Classification of Childhood Cancer group and subgroup and age at diagnosis, including myelodysplastic syndrome and group III benign brain/central nervous system tumors for all races for males and females. Incidence rates are age-adjusted and age-specific and are shown for leukemia, lymphoma, central nervous system (CNS) tumors, neuroblastoma, retinoblastoma, renal tumors, hepatic tumors, bone tumors, soft tissue tumors, germ cell tumors, carcinomas and melanomas, and other cancers. Retinoblastoma occurs infrequently in adolescents aged 15 through 19 years. Reprinted from Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version. National Cancer Institute website. https://www.cancer.gov/types/childhood-cancers/hp/unusual-cancers-childhood-pdq#_105. Accessed November 26, 2019.

T-cell ALL or T-cell lymphoblastic lymphoma can present with a large anterior mediastinal mass and symptoms related to compression by the mediastinal mass on the trachea and blockage of venous return and lymphatic drainage, that is, superior vena cava syndrome (SVC syndrome). The child with SVC syndrome can present with wheezing, dyspnea, dysphagia, plethora, and cyanosis. Pleural or pericardial effusions may also be present. Superior vena cava syndrome can rapidly progress and constitutes a true oncologic emergency that requires prompt intervention.

Lymphomas in children can be divided pathologically into Hodgkin or non-Hodgkin lymphoma. The child with Hodgkin lymphoma typically has a prolonged history (often ≥2–3 months’ duration) of painless enlarging cervical or supraclavicular lymphadenopathy. Affected lymph nodes can be firm, immobile, rubbery, and nontender. In two-thirds of cases, mediastinal adenopathy may be present, resulting in cough or wheeze. Constitutional symptoms, such as fatigue, pruritus, and anorexia can occur, as well as the classic “B” symptoms (ie, fever, night sweats, and weight loss ≥10% of body weight). Non-Hodgkin lymphoma can be distinguished as lymphoblastic or nonlymphoblastic. The child with lymphoblastic lymphoma often presents with supradiaphragmatic disease and may have cervical or supraclavicular lymphadenopathy, sometimes in association with a mediastinal mass or SVC syndrome (as previously described for T-cell lymphoblastic lymphoma). Central nervous system disease in such children is associated with signs of increased ICP. The patient with nonlymphoblastic lymphoma of the Burkitt or non-Burkitt type often presents with intra-abdominal disease that can manifest as intussusception, abdominal obstruction, hepatosplenomegaly, or obstructive jaundice. The child with sporadic Burkitt lymphoma can present with a rapidly enlarging abdominal mass associated with tumor lysis syndrome. Endemic Burkitt lymphoma (ie, African lymphoma) presents with facial or isolated jaw tumors. Additionally, the patient with lymphoma is at risk for developing 1 or more paraneoplastic syndromes. These include idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, nephrotic syndrome, and peripheral neuropathies, which may be mediated by abnormal and lymphoma-driven humoral or cell-mediated processes. The child with lymphoma is also at risk for tumor lysis syndrome as described for leukemia. Generally, a patient may have entirely normal blood cell counts or a mild anemia, but occasionally the bone marrow may be infiltrated, giving a clinical picture similar to leukemia with anemia, thrombocytopenia, or neutropenia.

The child with brain tumor can present with diverse signs and symptoms, depending on the anatomic location of the tumor (ie, subtentorial, supratentorial, or brain stem), age of the child (eg, infants with open sutures), and presence and degree of increased ICP. Subtentorial tumors, which are more common in children than adults, typically present with gaze palsies, cerebellar signs (especially truncal ataxia), dysmetria, or vomiting. Supratentorial tumors can cause seizures, upper motor neuron signs (ie, hemiparesis, asymmetrical hyperreflexia, and clonus), sensory changes, behavioral changes, decreased school performance, and disorders of the midbrain (eg, Parinaud syndrome [ie, paralysis of upward gaze]). Signs and symptoms of ICP are often in the forefront of complaints. Recurrent morning headaches, headaches that awaken the child at night, intense headaches, vomiting (often followed by temporal relief of morning headaches), lethargy, setting sun sign (ie, eyes deviating downward like a sun setting on the horizon), increasing head circumference and loss of developmental milestones in infants, and change in school performance in older children all warrant close evaluation. Certain conditions, such as tuberous sclerosis and neurofibromatosis 1, should increase the index of suspicion for brain tumor. Primary tumors intrinsic to the brain, that is, those of glial, neural, or choroid plexus origin, and extrinsic to the brain (ie, craniopharyngioma, germ cell tumor) are encountered most often in the pediatric population. Neural/embryonic tumors, such as medulloblastomas and primitive neuroectodermal tumors, are more typical for childhood age group. Metastatic brain lesions are less common in children than adults but may be encountered with neuroblastomas, lymphomas, or some renal tumors.

The child with spinal cord involvement from a primary spinal tumor or a paraspinal tumor (eg, neuroblastoma, Ewing sarcoma, leukemic chloroma) may present with persistent back pain, intense radicular pain, local bony tenderness of the affected vertebrae, abnormal reflexes, abnormal dermatomal sensory examination, weakness/evolving paralysis, and subtle symptoms of bowel or bladder dysfunction (ie, constipation, difficulty urinating). Suspicion of a spinal cord compression is an oncologic emergency for which timely, appropriate consultation must be sought.

Neuroblastoma is a malignancy of sympathetic ganglionic cell origin and can arise anywhere along the sympathetic nervous system. Most tumors arise in the adrenal or paraspinal region of the abdomen; additional sites include the neck, chest, pelvis, and, rarely, CNS. At presentation, tumors may be localized, with or without regional lymph node extension, or disseminated involving bone, bone marrow, liver, and CNS. The child with localized disease often is asymptomatic and the tumor is detected when radiographic imaging is performed for other medical purposes. The child with disseminated disease is ill-appearing and may present with fever, bone pain, and irritability. Paraneoplastic syndromes may also be present at diagnosis, with a variety of features, such as opsomyoclonus/ myoclonus/ataxia (ie, random dysconjugate eye movements, myoclonic jerking), cerebellar ataxia, and diarrhea. Proptosis and hemorrhage caused by metastases involving the periorbital region can result in periorbital swelling and ecchymoses (ie, raccoon eyes). A cervical tumor may be associated with unilateral Horner syndrome (ie, unilateral ptosis, miosis, and anhidrosis). Central nervous system metastasis may present with signs and symptoms of increased ICP.

Nephroblastoma or Wilms tumor, an embryonic tumor of the kidney, usually presents as a painless abdominal mass, often detected by a parent while bathing the child. Associated symptoms may include fever, abdominal pain, or hematuria. Abdominal trauma can result in rupture and hemorrhage of these bulky masses, and a child may present with acute abdominal pain and swelling. On examination, the child may have hypertension, stigmata of associated genetic syndromes (eg, Beckwith-Wiedemann, Denys-Drash), or another isolated congenital anomaly, such as aniridia, hemihy-pertrophy, or hypospadias.

Bone sarcomas that occur in children include Ewing sarcoma, osteosarcoma, and other rarer sarcomas. These tumors are most common in adolescents and rarely occur in young children. Bone tumors can present with pain at the site of tumor, with or without an associated soft tissue mass. Osteosarcomas classically involve the metaphyseal portions of the long bones, with the distal femur and proximal tibia being the most frequently involved sites. Metastatic disease, which is present in 15% to 20% of cases, primarily involves the lung, although other sites of bone can be involved. Ewing sarcomas that occur in bone most commonly involve the flat bones of the axial skeleton. When affecting the long bones, they tend to arise in the diaphyseal region (unlike osteosarcoma). Twenty-five percent of cases will have metastatic disease at presentation involving lung, bone, or bone marrow. The child with Ewing sarcoma may also have associated constitutional symptoms, such as low-grade fever, fatigue, and weight loss. Extraosseous soft tissue components are also more common with Ewing sarcomas than osteosarcomas.

Rhabdomyosarcomas, which account for approximately one-half of the soft tissue sarcomas in children, present with signs and symptoms dependent on the location of the primary tumor. Sites include the head, neck, chest, abdomen, genitourinary tract, or extremities. Less than 25% of children will present with metastatic disease, but when present it can involve lymph nodes, lungs, bone marrow, and bone. Head and neck sarcomas commonly arise in parameningeal and orbital sites and can present with recurrent headache, vomiting, visual problems, and proptosis. Abdominal and pelvic primary tumors can present with a palpable abdominal mass, pain, constipation, urinary obstruction, or dysuria. Genitourinary tract tumors most often involve the bladder or prostate and can present with pain, constipation, and urinary obstruction. One classic presentation occurs in girls who present with a grape-like mass at the introitus and vaginal bleeding; this is caused by tumor involving the vagina or uterus and is known as sarcoma botryoides. Primary tumors involving an extremity present with swelling at the site of tumor that can be painful and tender on palpation.

Pathophysiology

Although the macroscopic causes of pediatric cancer are not well elucidated, significant progress has been made in determining some of the cellular and molecular events that actively trigger or fail to prevent malignancy. Growth factors are responsible for stimulation of cellular proliferation, and growth factor receptors transduce this signal into the cell via cytoplasmic secondary messengers, which in turn transmit the signal to nuclear regulatory factors. These factors ultimately regulate transcription of new RNA and protein, resulting in the desired cellular response of stimulation or inhibition of growth. Malignant cells have a genetic makeup that differs from the constitutional karyotype of the host. A series of mutations occurs in genes that regulate cell growth and differentiation, resulting in dysregulation of cell growth, differentiation, and death. Oncogenes promote cell growth and tumor suppressor genes inhibit cell division. With inappropriate overexpression of an oncogene or under-expression of a tumor-suppressor gene, inappropriate cell growth and division may occur, resulting in a malignant transformation.

Usually, multiple genetic aberrations are present that result in malignant transformation of a cell. One of the most important tumor suppressor genes is p53. The p53 gene encodes for a nuclear protein that is expressed in all cells of the body and serves to induce cell cycle arrest or apoptosis in response to DNA damage. Inactivation of p53 has been identified in numerous cancers. An initial event can alter or knock out 1 allele of a p53 gene pair, and a second event results in loss of heterozygosity for that genetic locus. An inherited abnormality of p53 (ie, Li-Fraumeni syndrome) or a serendipitous accident to p53 can cause heterozygosity for that gene. If a second event knocks out complete function of p53, a DNA-damaged cell can escape the signal to arrest its growth or undergo apoptosis. The result can be a malignant transformation that allows the abnormal cell to grow unchecked. The retinoblastoma gene is another classic and well-studied tumor suppressor, the loss of which results in malignant transformation of the cell.

The threat of cancer to a living organism lies in its uncontrolled growth. By growing unchecked and invading, compressing, and metastasizing to vital organs, malignant cells threaten normal life functions and cause symptoms specific to the affected area of the body.

Differential Diagnosis

Cancer is rare and often challenging to diagnose in children. Many of the presenting symptoms can be nonspecific and easily attributed to more common childhood conditions. To add to the difficulty, a pediatric practice will, on average, see a case every 5 to 7 years. Differential diagnoses for some common childhood symptoms that may suggest an underlying malignancy are discussed herein.

Lymphadenopathy is a common pediatric physical finding and is most frequently the result of infection (see Chapter 100). Acute bacterial adenitis, usually involving the head and neck region, is typically associated with local signs of inflammation, such as erythema, warmth, and tenderness. Cervical adenopathy resulting from viral illness is typically bilateral, and the lymph nodes are usually mobile, soft, and nontender. Generalized lymphadenopathy or regional lymphadenopathy characterized by firm, matted, rubbery lymph nodes should raise the suspicion for an underlying malignancy. Lymphadenopathy that is persistent or progressive, despite empiric antibiotic therapy or resolution of infectious symptoms, also merits further evaluation for malignancy. Leukemia often presents with generalized lymphadenopathy, usually in association with hepatosplenomegaly and abnormal laboratory findings. Lymphoma typically presents with regional lymphadenopathy, often in the cervical or mediastinal region, in conjunction with other signs of systemic illness. Metastatic disease (eg, neuroblastoma, rhabdomyosarcoma) may also present with regional lymphadenopathy. Nonmalignant causes of neck masses that can be mistaken for cervical lymphadenopathy include structural anomalies, such as branchial cleft cysts or cystic hygromas (see Chapter 94).

Bone and joint pain are common symptoms in children with acute leukemia because of bone marrow involvement and may be generalized. This presentation can be confused with various rheumatologic conditions. Localized bone pain is a common presentation for the child with primary bone cancer (eg, osteosarcoma, Ewing sarcoma) and often is attributed by the child or parent/guardian to some trauma. It is not unusual for the diagnosis to be delayed several months. Differential diagnosis includes infection (eg, osteomyelitis), trauma, musculoskeletal conditions, and benign bone lesions.

Headache is a common symptom encountered by the general pediatrician, and few of these headaches are caused by intracranial brain tumors (see Chapter 129). When evaluating a child with headaches, signs to raise the index of suspicion for a brain tumor include persistent vomiting, recurrent morning headaches or headaches that awaken the child, worsening headaches, associated neurologic abnormalities, and visual changes (eg, papilledema on examination). In infants, increasing head size, setting sun sign, and loss of acquired developmental milestones are red flags. The differential diagnosis for headaches in children is broad and includes infections (eg, meningitis, sinusitis), migraines, hydrocephalus, hemorrhage, and seizures.

An abdominal mass in an infant or child is always concerning and merits an evaluation. The most common malignant causes for an abdominal mass in this age range include neuroblastoma, nephroblastoma (ie, Wilms tumor), hepatoblastoma, non-Hodgkin lymphoma (ie, Burkitt lymphoma), sarcomas, and germ cell tumors. Massive hepatosplenomegaly resulting from leukemic or lymphomatous infiltration can also be palpated as an abdominal mass. Nonmalignant etiologies of an abdominal mass may include hepatomegaly or splenomegaly, renal cysts, hemangiomas, or constipation.

Pancytopenia or single cytopenias are always worrisome for a malignancy involving bone marrow. Acute leukemia is the most common malignancy involving bone marrow and can present with leukopenia, anemia, thrombocytopenia, or any combination of these. Any malignancy that can metastasize to the bone marrow (eg, neuroblastoma, lymphoma, Ewing sarcoma, rhabdomyosarcoma) can also produce pancytopenia or depression of 1 of the cell lines resulting from replacement of the bone marrow. Pancytopenia can also occur as a primary bone marrow failure syndrome, such as Fanconi anemia, or as an acquired aplastic anemia resulting from infections (eg, post-hepatitis), drugs (eg, chloramphenicol, anticonvulsant agents), radiation, or idiopathic causes. Transient mild depression of the cell lines (most often leukopenia or anemia) from infectious causes is quite common during childhood. Depression of more than 1 hematopoietic cell line merits a closer evaluation and consultation with a pediatric hematologist.

Evaluation

History

The history should focus on the duration and evolution of symptoms as well as the presence or absence of constitutional symptoms (eg, anorexia, fever, night sweats, weight loss). The effect of the symptoms on daily activities (eg, school attendance, sports) should be determined and will clue the physician to the scope of the illness. The presence of recent or persistent infections, medications (especially steroids), or unusual environmental exposures should also be ascertained (Box 152.1). Relevant medical history should be considered. A previous cancer diagnosis would raise the index of suspicion for relapse or a secondary malignancy. Certain immunodeficiencies and genetic syndromes are associated with an increased risk for malignancy (eg, trisomy 21 syndrome and leukemia) and should also be considered. A family history of childhood cancers or genetic syndromes is also important.

Physical Examination

A thorough physical examination is essential, with particular attention paid to symptomatic areas (Table 152.1). Generally, the lymph nodes should be carefully assessed for enlargement or malignant characteristics (ie, firm, fixed, rubbery nodes or nodular conglomerates) and the abdomen for organomegaly or masses. The skin should be evaluated for the presence of pallor, petechiae, or purpura that would suggest anemia or thrombocytopenia. A thorough search for signs of persistent infection should be performed and, if present, may reflect bone marrow disease with neutropenia. Neurologic symptoms, including headache, vomiting, or focal concerns, warrant a full neurologic examination. Increased ICP may manifest as papilledema or sixth nerve palsy. In the infant, increased ICP can manifest with a large head size, full fontanels, or setting sun sign. A report of back pain also merits a full neurologic examination with close attention to any sign of spinal cord compression that may be suggestive of a possible spinal or paraspinal mass.

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