Signs and Symptoms of Childhood Cancer: A Guide for Early Recognition IOANNA FRAGKANDREA, MD, PhD, The Royal Marsden Hospital, Sutton, London, United Kingdom JOHN ALEXANDER NIXON, MD, Epsom and St. Helier NHS University Hospital, Sutton, London, United Kingdom PARASKEVI PANAGOPOULOU, MD, MPH, PhD, Panagiotis and Aglaia Kyriakou Children’s Hospital, Athens, Greece Although cancer in children is rare, it is the second most common cause of childhood mortality in developed coun- tries. It often presents with nonspecific symptoms similar to those of benign conditions, leading to delays in the diagnosis and initiation of appropriate treatment. Primary care physicians should have a raised index of suspicion and explore the possibility of cancer in children who have worrisome or persisting signs and symptoms. Red flag signs for leukemia or lymphoma include unexplained and protracted pallor, malaise, fever, anorexia, weight loss, lymphadenopathy, hemorrhagic diathesis, and hepatosplenomegaly. New onset or persistent morning headaches asso- ciated with vomiting, neurologic symptoms, or back pain should raise concern for tumors of the central nervous system. Palpable masses in the abdomen or soft tissues, and persistent bone pain that awakens the child are red flags for abdominal, soft tissue, and bone tumors. Leukokoria is a red flag for retinoblastoma. Endocrine symptoms such as growth arrest, diabetes insipidus, and precocious or delayed puberty may be signs of endocranial or germ cell tumors. Paraneoplastic manifestations such as opsoclonus-myoclonus syndrome, rheumatic symptoms, or hyperten- sion are rare and may be related to neuroblastoma, leukemia, or Wilms tumor, respectively. Increased suspicion is also warranted for conditions associated with a higher risk of childhood cancer, including immunodeficiency syndromes and previous malignancies, as well as with certain genetic conditions and familial cancer syndromes such as Down syndrome, Li-Fraumeni syndrome, hemihypertrophy, neurofibromatosis, and retinoblastoma. Am( Fam Physician. 2013;88(3):185-192. Copyright © 2013 American Academy of Family Physicians.) CME This clinical content he annual incidence of cancer in cancer, with an emphasis on red flag symp- conforms to AAFP criteria children who live in developed toms that should prompt evaluation. for continuing medical education (CME). See CME countries is between 105 and 150 Quiz on page 162. cases per 1 million children,1 Initial Assessment and Clinical Tmaking it the second leading cause of child- Examination Author disclosure: No rel- 2 evant financial affiliations. hood mortality after injury. The distribu- Cancer diagnosis in children is often delayed tion of the various types of childhood cancer because the presenting symptoms tend to be is shown in Table 1.2-6 To avoid missing the nonspecific and resemble those of benign early diagnosis of childhood malignancies, conditions. In children who exhibit red flag primary care physicians should have a high symptoms for malignancy, a complete his- index of suspicion along with excellent phys- tory, including personal and family history, ical examination skills. is fundamental. Preliminary symptoms may In studies of children with malignant have started abruptly (e.g., bone pain after tumors, the median delay in diagnosis was minor trauma) or developed insidiously over nine weeks for brain tumors, three weeks for a few weeks to several months (e.g., intermit- leukemia, and 11.6 weeks for solid tumors.7,8 tent headaches). They may also be constitu- The parental delay in seeking care was con- tional and nonspecific (e.g., fatigue, pallor, siderably shorter than the physician delay fever, anorexia) or localized (e.g., a palpable in making the diagnosis,9 emphasizing that mass). A focused physical examination, parents are usually the best observers of their including funduscopy, should follow. children, and that physicians should listen Symptoms suggestive of specific malig- to the parents’ concerns. In this review, we nancies in adults (such as rectal bleeding, present common and less common early pre- which could indicate colon cancer, or breast senting signs and symptoms of childhood lumps, which are suggestive of breast cancer) Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2013 American Academy of Family Physicians. For the private, Augustnoncommercial 1, 2013 use ◆ ofVolume one individual 88, Number user of the 3 Web site. All other rights reserved.www.aafp.org/afp Contact [email protected] for copyright questionsAmerican and/or Family permission Physician requests. 185 SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Any combination of persistent or unexplained fever, recurrent or persistent infection, pallor, malaise, C 10-12 hemorrhagic manifestations, hepatosplenomegaly, or lymphadenopathy should be evaluated with CBC and blood smear. Enlarged lymph nodes—especially those larger than 2 cm that persist for more than four to six weeks or C 10, 12, 14 that are associated with fever, night sweats, weight loss, hepatosplenomegaly, or orthopnea—should be evaluated with CBC, blood smear, erythrocyte sedimentation rate, and chest radiography. Headaches of new onset and with certain features (persistent, occipital, awakening the child or occurring in C 12, 19, 28 the morning, associated with nausea and vomiting or neurologic deficits) may indicate a brain tumor when other causes such as migraine, sinusitis, tension headache, and ocular abnormalities are excluded. Taking a history and performing a neurologic examination are essential before neuroimaging is requested. Any abdominal mass or hepatosplenomegaly, especially if associated with anorexia, vomiting, fever, or pain, C 5, 12 or in a child who appears ill, requires further evaluation with ultrasonography. Bone pain that persists, awakens the child, does not respond to nonsteroidal anti-inflammatory drugs, or is C 12, 22, 23 associated with swelling should be evaluated with two-view radiography, C-reactive protein measurement, CBC, and blood smear. Persistent back pain that appeared recently in a child younger than four years requires further investigation C 12, 19 with CBC, blood smear, C-reactive protein measurement, and radiography of the spine. Any palpable, recent, nontender soft tissue mass, especially if larger than 2 cm, should be examined with C 12 ultrasonography or magnetic resonance imaging. CBC = complete blood count. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp. org/afpsort. are rare in childhood, in which leukemia, brain tumors, drenching night sweats, fever, and significant weight and lymphoma account for more than 67% of all neo- loss; together with lymphadenitis, they are typical of plasms.2 The typical clinical characteristics of childhood Hodgkin lymphoma.4 Hemorrhagic diathesis (charac- cancer appear in Table 1.2-6 Symptoms that should raise terized by petechiae, ecchymoses, recurrent epistaxis, suspicion for cancer are discussed below. and bleeding gums) merits further investigation because it may indicate that malignant cells have infiltrated the Clinical Red Flags for Malignancy bone marrow. The differential diagnosis includes idio- Most red flags (e.g., fever, lymphadenopathy, vomiting, pathic thrombocytopenic purpura, clotting factor defi- pallor) are also present in common and benign ailments ciencies, and platelet dysfunction. In conclusion, any and rarely result from a malignancy. It is important to combination of persistent or unexplained fever, recur- interpret the red flag finding in combination with other rent or persistent infection, pallor, malaise, hemorrhagic findings from the history and physical examination, manifestations, hepatosplenomegaly, or lymphadenopa- especially if the patient presents repeatedly with the same thy should be evaluated with complete blood count and symptom or if the symptom persists. The most com- blood smear.10-12 mon nonspecific signs and symptoms associated with an underlying malignancy are listed in Table 2.4-6,10-25 LYMPHADENOPATHY Localized or generalized lymphadenopathy is a com- CONSTITUTIONAL SYMPTOMS mon complaint in children. Most cases of lymphade- Prolonged fever with no identifiable cause is a common nopathy are benign and related to infections or collagen symptom of cancer in children, and is associated mainly vascular diseases.14 Initial management (depending on with leukemia or lymphoma.11 Symptoms such as pallor, the location) involves watchful waiting for up to four fatigue, malaise, and reduced level of activity that are not weeks; other options include a 10-day course of oral associated with an acute infection may be caused by sev- antibiotics (although evidence to support this practice eral types of cancer. Anorexia is common in many child- is lacking and should be reserved for patients who show hood illnesses. It could indicate a malignant cause if it evidence of local inflammation).12,26,27 If lymphade- persists, cannot be explained, results in failure to thrive nopathy persists or other symptoms such as fever, night or weight loss (defined as 10% loss of body weight in six sweats, weight loss, hepatosplenomegaly, or orthopnea months), or is associated with other suspicious find- exist, malignancy should be excluded,