The annual incidence of cancer in children who live in developed countries is between 105 and 150 cases per 1 million children,¹ making it the second leading cause of childhood mortality after injury.² The distribution of the various types of childhood cancer is shown in Table 1.^2–6 To avoid missing the early diagnosis of childhood malignancies, primary care physicians should have a high index of suspicion along with excellent physical examination skills.

In studies of children with malignant tumors, the median delay in diagnosis was nine weeks for brain tumors, three weeks for leukemia, and 11.6 weeks for solid tumors.^7,8 The parental delay in seeking care was considerably shorter than the physician delay in making the diagnosis,⁹ emphasizing that parents are usually the best observers of their children, and that physicians should listen to the parents' concerns. In this review, we present common and less common early presenting signs and symptoms of childhood cancer, with an emphasis on red flag symptoms that should prompt evaluation.

Initial Assessment and Clinical Examination

Cancer diagnosis in children is often delayed because the presenting symptoms tend to be nonspecific and resemble those of benign conditions. In children who exhibit red flag symptoms for malignancy, a complete history, including personal and family history, is fundamental. Preliminary symptoms may have started abruptly (e.g., bone pain after minor trauma) or developed insidiously over a few weeks to several months (e.g., intermittent headaches). They may also be constitutional and nonspecific (e.g., fatigue, pallor, fever, anorexia) or localized (e.g., a palpable mass). A focused physical examination, including funduscopy, should follow.

Symptoms suggestive of specific malignancies in adults (such as rectal bleeding, which could indicate colon cancer, or breast lumps, which are suggestive of breast cancer) are rare in childhood, in which leukemia, brain tumors, and lymphoma account for more than 67% of all neoplasms.² The typical clinical characteristics of childhood cancer appear in Table 1.^2–6 Symptoms that should raise suspicion for cancer are discussed below.

Clinical Red Flags for Malignancy

Most red flags (e.g., fever, lymphadenopathy, vomiting, pallor) are also present in common and benign ailments and rarely result from a malignancy. It is important to interpret the red flag finding in combination with other findings from the history and physical examination, especially if the patient presents repeatedly with the same symptom or if the symptom persists. The most common nonspecific signs and symptoms associated with an underlying malignancy are listed in Table 2.^{4–6,10–25}

CONSTITUTIONAL SYMPTOMS

Prolonged fever with no identifiable cause is a common symptom of cancer in children, and is associated mainly with leukemia or lymphoma.¹¹ Symptoms such as pallor, fatigue, malaise, and reduced level of activity that are not associated with an acute infection may be caused by several types of cancer. Anorexia is common in many childhood illnesses. It could indicate a malignant cause if it persists, cannot be explained, results in failure to thrive or weight loss (defined as 10% loss of body weight in six months), or is associated with other suspicious findings.^4,13 “B symptoms” are the combination of prolonged drenching night sweats, fever, and significant weight loss; together with lymphadenitis, they are typical of Hodgkin lymphoma.⁴ Hemorrhagic diathesis (characterized by petechiae, ecchymoses, recurrent epistaxis, and bleeding gums) merits further investigation because it may indicate that malignant cells have infiltrated the bone marrow. The differential diagnosis includes idiopathic thrombocytopenic purpura, clotting factor deficiencies, and platelet dysfunction. In conclusion, any combination of persistent or unexplained fever, recurrent or persistent infection, pallor, malaise, hemorrhagic manifestations, hepatosplenomegaly, or lymphadenopathy should be evaluated with complete blood count and blood smear.^10–12

LYMPHADENOPATHY

Localized or generalized lymphadenopathy is a common complaint in children. Most cases of lymphadenopathy are benign and related to infections or collagen vascular diseases.¹⁴ Initial management (depending on the location) involves watchful waiting for up to four weeks; other options include a 10-day course of oral antibiotics (although evidence to support this practice is lacking and should be reserved for patients who show evidence of local inflammation).^12,26,27 If lymphadenopathy persists or other symptoms such as fever, night sweats, weight loss, hepatosplenomegaly, or orthopnea exist, malignancy should be excluded, and evaluation with complete blood count, blood smear, erythrocyte sedimentation rate, and chest radiography is needed.^10,12,14 Enlarged supraclavicular and epitrochlear lymph nodes have a higher risk of malignancy than other sites.¹⁴ The most common malignant causes of lymphadenopathy are shown in Table 2.^{4–6,10–25}

NEUROLOGIC SYMPTOMS

Neurologic symptoms occur in many malignancies and are present in 88% of patients with central nervous system tumors at diagnosis.^15,16 In children younger than two years, common neurologic symptoms are nonspecific and include unexplained irritability or lethargy, developmental delay or regression, and increasing head circumference. Headaches are also reported by 40% to 50% of elementary school–aged children and by 60% to 80% of high school–aged children.¹⁷ Headaches should be considered suspicious if they have started recently; occur in the morning or at night and awaken the child (46% to 76% of central nervous system tumors present with morning headaches); and are accompanied by vomiting.^15,16,18 Occipital location is also suspicious.¹⁹

A neurologic examination and funduscopy should be performed to help distinguish a brain tumor from conditions such as migraine, sinusitis, tension headache, and ocular abnormalities. Abnormalities of gait (ataxia) and coordination increase suspicion for brain tumor, especially of the posterior fossa.¹⁶ Seizures are the initial presentation in approximately 10% of central nervous system tumors.¹⁵ Seizures that are focal, without fever or a history of epilepsy or trauma, or that are associated with other neurologic symptoms or signs warrant investigation with neuroimaging.¹⁵ Neurologic deficits (e.g., cranial nerve palsies, motor and sensory problems such as leg weakness) can be the presenting features of several malignant conditions such as leukemia, neuroblastoma, and lymphoma, and occasionally Ewing sarcoma, rhabdomyosarcoma, and nasopharyngeal carcinoma.²⁰ Unexplained deteriorating school performance and personality changes may also be caused by brain tumors.^12,19,28 It is important to balance concerns about malignancy with appropriate caution regarding overuse of computed tomography, because imaging exposes children to significant doses of radiation, increasing their long-term risk of malignancy.

GASTROINTESTINAL SYMPTOMS

Any abdominal mass should be treated with a high degree of suspicion. In neonates, abdominal masses are usually of benign genitourinary origin.²¹ In children younger than five years, the most common malignant causes are neuroblastoma and nephroblastoma. The differential diagnosis also includes cysts and benign tumors of the kidneys, ovaries, or soft tissues. Abdominal masses, as well as any degree of hepatosplenomegaly, call for further investigation with ultrasonography, especially if they are associated with anorexia, vomiting, fever, pain, or a child who appears ill.^5,12 Persistent vomiting also requires further investigation, especially if it accompanies headaches or neurologic deficits and occurs mainly in the morning.¹⁵

Recent onset constipation that persists and does not respond to conservative treatment should be evaluated for abdominal masses that may cause bowel obstruction or spinal cord lesions that affect sphincters.^5,6 In children older than six years with intussusception, abdominal lymphoma must be ruled out.⁴ Diarrhea may be a symptom of leukemia or lymphoma, but when it is intractable and watery, it may be caused by a vasoactive intestinal-peptide–secreting neuroblastoma.⁴

MUSCULOSKELETAL SYMPTOMS

Bone pain that occurs at night, awakens the child, and is persistent or intermittent can be a first sign of malignancy. Localized pain associated with swelling or deformity may indicate a bone tumor.²² Before attributing the symptom to benign causes (e.g., “growing pains”)²³ or recent trauma,⁴ the examining physician should evaluate the patient with two-view radiography of the specific site, C-reactive protein measurement, complete blood count, and blood smear.^12,22,23

Generalized bone pain may indicate leukemia or neuroblastoma.¹⁹ Joint pain or arthritis usually ascribed to rheumatoid disorders (especially if accompanied by fever or rash) may also be caused by leukemia,¹⁹ whereas disruption of normal gait or refusal to walk can be caused by pain or reduced motor function associated with several malignancies.²⁴ Back pain, lordosis, kyphoscoliosis, and torticollis of sudden onset are rare symptoms of cancer. Back pain merits further investigation with CBC, blood smear, C-reactive protein level, and two-view radiography of the spine if the child is younger than four years, if the pain worsens at night, or if there are concurrent symptoms.^12,16,19 Pathologic fractures occurring at areas of osteolytic lesions may be caused not only by osteoporosis or cerebral palsy, but also by malignancies such as osteosarcoma, Ewing sarcoma, or histiocytosis.¹⁹ Finally, any palpable mass of the soft tissues that has recently appeared on the extremities, head, neck, or trunk warrants further investigation with ultrasonography or magnetic resonance imaging.¹²

GENITOURINARY SYMPTOMS

Hematuria is a frequent finding in urinary tract infections, trauma, or lithiasis. If common causes have been excluded, renal tumor or soft tissue sarcoma should be considered. Urine retention or enuresis of recent origin may result from spinal or pelvic tumors.⁴ Vaginal bleeding in prepubertal girls may be associated with vaginal rhabdomyosarcoma⁶ or with a hormone–secreting germ cell tumor. Every scrotal mass should be investigated, because it may be caused by a soft tissue or germ cell tumor, or even leukemia.⁶ Finally, an isolated right-sided varicocele is a red flag for a right kidney or other tumor and priapism of leukemia.

CARDIORESPIRATORY SYMPTOMS

Rarely, cardiorespiratory symptoms may be associated with malignancy. Nonproductive cough, dyspnea, or orthopnea with no obvious cause that persists for more than two to three weeks and does not respond to treatment, or that is associated with other disturbing findings (lymphadenopathy, weight loss, fever, pallor, facial swelling or plethora) may result from a mediastinal mass or a pleural effusion caused by lymphoma or leukemia.¹⁹ Hypertension is rare in children, and may be associated with Wilms tumor, neuroblastoma, and pheochromocytoma.

EAR, NOSE, AND THROAT SYMPTOMS

Gingival swelling or bleeding may result from gum infiltration in leukemia or histiocytosis.^6,19 Chronic otorrhea may be caused by middle ear histiocytosis, rhabdomyosarcoma, or nasopharyngeal carcinoma.^6,19 Nasal obstruction, epistaxis, and dysphagia may be signs of nasopharyngeal carcinoma or other tumors of the area.¹³

DERMATOLOGIC SYMPTOMS

Dermatologic manifestations provide information on bone marrow function through clinical signs such as pallor and bruising or petechiae. Additionally, subcutaneous nodules with bluish (“blueberry muffin”) or normal skin appearance may be caused by leukemia, neuroblastoma, or histiocytosis.²⁵ Pruritus is a rare manifestation of Hodgkin lymphoma.⁴ A scaly, seborrheic, eczematoid rash involving the scalp, ear canals, abdomen, and intertriginous areas of the neck and face that does not respond to treatment with topical corticosteroids may be a sign of histiocytosis.⁶

OCULAR SYMPTOMS

Several ocular symptoms warrant immediate attention because malignancy should be excluded before other diagnoses are considered. Squinting and diplopia are red flags for tumors of the eye and brain. Leukokoria (cat's eye reflex) is a red flag for retinoblastoma. Proptosis is a red flag for space-occupying lesions of the orbit (rhabdomyosarcoma, leukemia, optic glioma, histiocytosis). Neuroblastoma may manifest with periorbital ecchymoses (“raccoon eyes”) and, rarely, opsoclonus-myoclonus syndrome, Horner syndrome,²⁹ or acquired heterochromia of the iris. Aniridia may be associated with Wilms tumor.⁴

ENDOCRINE SYMPTOMS

The most common endocrine symptoms associated with childhood malignancies are described in Table 3.^25,30–32 They include diabetes insipidus (polyuria, polydipsia), growth arrest, precocious puberty, and pubertal delay. They may be caused by endocranial tumors (causing hypopituitarism) or by hormone-secreting germ cell tumors.^31,32 Concomitant headaches or visual disturbances should alert the physician.¹³ Diencephalic syndrome is a rare cause of failure to thrive in early childhood associated with neoplasms of the hypothalamic–optic chiasmatic region.^4,6

Paraneoplastic Syndromes and Symptoms

Paraneoplastic syndromes and symptoms are more common in adults than in children.³³ The most common paraneoplastic syndromes and symptoms associated with childhood malignancies are shown in Table 4^4,33,34 and are most often caused by neuroblastoma⁴ or Wilms tumor.³³ Rare paraneoplastic manifestations include osteoporosis and symptoms suggestive of rheumatic diseases.³⁴

Medical Conditions and Syndromes Associated with Childhood Cancer

Certain conditions predispose children to the development of cancer. These include genetically inherited disorders and syndromes, immunodeficiency disorders, and familial cancer syndromes. Siblings of children with a malignancy (especially twins) and survivors of childhood cancer are also at increased risk.³⁵ The most common conditions and syndromes associated with increased likelihood of a childhood malignancy are presented in Table 5.^36,37

Data Sources: We searched PubMed, the Cochrane Database of Systematic Reviews, Essential Evidence Plus, Clinical Evidence, the National Guideline Clearinghouse, the Institute for Clinical Systems Improvement, UpToDate, and the National Institute for Health and Clinical Excellence. Google Scholar was used to access full-text articles when not available through the publisher's site. Key words included childhood cancer or pediatric malignancies, and early diagnosis or delayed diagnosis or suspected cancer in children or symptoms or signs. A subsequent search was performed to identify usual and unusual presentations of specific types of cancer (e.g., neuroblastoma, leukemia). The identified articles were read initially by title, the relative abstracts were read in full, and then searches were done for the full articles. Certain pediatric oncology textbooks also were used to confirm that all aspects of the subject were adequately covered. Search dates: May 2011 and December 2011.