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Overview of common presenting signs and symptoms of childhood cancer

Overview of common presenting signs and symptoms of childhood cancer
Literature review current through: Jan 2024.
This topic last updated: Feb 15, 2023.

INTRODUCTION — Childhood cancer often is difficult to detect in its early stages because the associated signs and symptoms are nonspecific, insidious in onset, and mimic other more common disorders.

The topic will provide an overview of common signs and symptoms that are suspicious for childhood cancer and outline the general principles of evaluation. The evaluation and diagnosis of specific pediatric malignancies are discussed separately:

Acute leukemias (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Acute myeloid leukemia in children and adolescents")

Central nervous system tumors (see "Clinical manifestations and diagnosis of central nervous system tumors in children")

Germ cell tumors (see "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis" and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors")

Lymphomas (see "Overview of Hodgkin lymphoma in children and adolescents" and "Overview of non-Hodgkin lymphoma in children and adolescents")

Neuroblastoma (see "Epidemiology, pathogenesis, and pathology of neuroblastoma")

Retinoblastoma (see "Retinoblastoma: Clinical presentation, evaluation, and diagnosis")

Sarcomas (Ewing sarcoma, osteosarcoma, rhabdomyosarcoma) (see "Epidemiology, pathology, and molecular genetics of Ewing sarcoma" and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis" and "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging")

Thyroid cancer (see "Thyroid nodules and cancer in children")

Wilms tumor (see "Presentation, diagnosis, and staging of Wilms tumor")

BACKGROUND — Optimal management of childhood cancer requires a high level of suspicion by the primary care practitioner and early referral to a pediatric oncologist. Early detection and treatment may reduce disease-related morbidity and complications.

The following facts about childhood cancer set the stage for a discussion of issues surrounding clinical assessment of the child with suspected cancer:

Although childhood cancers are rare, they are the leading cause of disease-related death in individuals between 1 and 19 years of age in the United States [1]. Mortality is higher among boys compared with girls and among adolescents compared with younger children [2,3].

At least 85 percent of pediatric cancers are associated with the presenting signs and symptoms discussed in this topic review; the remaining 10 to 15 percent of tumors are associated with unusual signs and symptoms and are more difficult to diagnose in the early stages [4].

Delays in diagnosis have been shown to be related to the child's age (older children are at a higher risk for delay), the specific type of cancer, presenting symptoms, tumor site, first medical specialty consulted, and access to health care [5-8]. The time from onset of symptoms to diagnosis of pediatric cancer is variable based on the type of malignancy. The reported average time to diagnosis ranges from 2 to 5 weeks for neuroblastoma, 3 to 5 weeks for acute leukemias, 7 to 10 weeks for lymphomas, 8 to 15 weeks for bone tumors, and 8 to >20 weeks for brain tumors [5].

Common sites of childhood malignancies include blood and bone marrow, brain and nervous system, lymph nodes, kidneys, bone, and soft tissues [2,9]. The frequency of a particular cancer depends upon the age of the child (table 1). For example, neuroblastoma and Wilms tumor occur most commonly in children between birth and four years of age; leukemia occurs most often in children <10 years old; and Ewing sarcoma, Hodgkin lymphoma, and thyroid cancer are more common in children >10 years of age [10].

Five-year survival rates vary by diagnosis but are approximately 80 to 85 percent when all cancer types are considered together [11,12]. Survival has improved considerably over the past several decades [12-14].

WARNING SIGNS — Obtaining a detailed history is the first step in evaluating the child with suspected cancer. Emphasis should be placed on the chief complaint. Early warning signs of childhood cancer include [15]:

Unexplained pallor and loss of energy

A new lump, mass, or swelling

Recent unexplained weight loss

Unexplained fever or persistent constitutional symptoms

Easy bruising or bleeding

Prolonged or ongoing pain in one or more areas of the body

Limping

Frequent headaches, particularly if occurring in the morning and associated with vomiting

Sudden eye or vision changes

PREDISPOSITION TO MALIGNANCY — Certain genetic conditions and immune deficiency syndromes are associated with an increased risk of developing cancer (table 2 and table 3) [16]. Survivors of certain types of childhood cancer (eg, retinoblastoma) are at risk for developing secondary malignancies [17,18]. The family history should include information about parents, siblings, and first cousins. Age, serious illnesses, congenital anomalies, and cause of death for deceased family members should also be elicited [4].

COMMON SIGNS AND SYMPTOMS — Childhood cancer may present with signs and symptoms that are shared by other childhood illnesses (table 4). Although a single finding in isolation does not always require evaluation for cancer, a combination of multiple findings (eg, weight loss, bone pain, and lymphadenopathy; easy bruising, abnormal blood counts, and hepatosplenomegaly) is worrisome and generally warrants evaluation for malignancy. In addition, certain findings are worrisome even as isolated findings (eg, abdominal or mediastinal masses, headaches associated with vomiting in the morning, blasts on the peripheral blood smear) and require prompt evaluation and consultation.

Constitutional symptoms — Nonspecific constitutional symptoms including fever, weight loss, and fatigue are common findings in children with cancer.

Fever — Fever is a common complaint in children and is rarely attributable to malignancy.

When to suspect malignancy – Suspicion for noninfectious causes should be raised when the febrile illness does not follow the usual course or fails to respond to seemingly appropriate therapy. However, even when fever is prolonged, infection remains the most common cause [19]. In published reports of children with prolonged fever, a small minority (approximately 5 percent) were found to have a malignancy, most commonly leukemia and lymphoma [19]. (See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation", section on 'Causes'.)

In the absence of infection, persistent or recurring fever may reflect an occult neoplasm, such as lymphoma; rarely, it may be secondary to tumor-related necrosis, such as with neuroblastoma or Wilms tumor. Persistent fever also may be the only complaint in children with leukemia, Ewing sarcoma, and Langerhans cell histiocytosis [4]. More than one-half of children with leukemia have fever at the time of presentation [20]. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical presentation, staging, and prognostic factors of Ewing sarcoma" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

A thorough physical examination may reveal additional worrisome findings such as lymphadenopathy or hepatosplenomegaly. (See 'Lymphadenopathy' below and "Approach to the child with an enlarged spleen".)

Evaluation – The initial diagnostic evaluation for a child with a fever that does not respond to seemingly appropriate therapy should include (but is not limited to) a complete blood count (CBC) with differential, examination of the peripheral blood smear, blood culture, and chest radiography. Additional studies may be indicated for fever of unknown origin, as discussed separately. (See "Fever of unknown origin in children: Evaluation", section on 'Overview of evaluation'.)

The white blood cell (WBC) differential and examination of the peripheral blood smear may help distinguish the underlying cause of fever. The presence of circulating blasts (picture 1A) or profound neutropenia or thrombocytopenia can suggest the diagnosis of leukemia, in which case, referral to a pediatric oncologist and bone marrow examination is generally warranted, particularly if two cell lines are affected (see 'Blood count abnormalities' below). On the other hand, the presence of atypical lymphocytes may suggest a nonmalignant etiology (eg, mononucleosis or other viral illnesses).

Chest radiography may reveal an intrathoracic mass. (See 'Mediastinal masses' below.)

Weight loss — Most children who present with isolated weight loss have nonmalignant etiologies (eg, dehydration, infection, malnutrition). However, patients with continued, unintentional weight loss in the setting of anemia, pallor, bruising, body pains, lymphadenopathy, hepatosplenomegaly, unexplained fevers, or fatigue may have an underlying malignancy. The evaluation of children with weight loss is discussed separately. (See "Evaluation of weight loss in infants over six months of age, children, and adolescents".)

Fatigue and pallor — Decreased energy, fatigue, and pallor can occur in a wide range of diseases. Pallor is most often due to anemia but may also occur in nonhematologic conditions such as chronic infection, rheumatologic disorders, heart failure, arrhythmia, or metabolic disorders. Fatigue and pallor are most commonly due to nonmalignant causes; however, concern for malignancy may be raised if there are other concerning accompanying findings (petechiae, bruising, lymphadenopathy, hepatosplenomegaly, bone pain). Initial laboratory testing in children with pallor generally includes a CBC with differential and reticulocyte count. This can help to identify if there are other concerning hematologic findings (eg, other cell lines affected, peripheral blasts (picture 1A)), which should prompt consideration of referral and bone marrow examination. (See 'Blood count abnormalities' below.)

The evaluation of pallor and anemia in children are discussed separately. (See "Evaluation of pallor in children" and "Approach to the child with anemia".)

Headache — Headache is another common symptom in general pediatric practice. Intracranial tumors are a rare cause of headache in children, but they must be considered when headaches are persistent or worsening in intensity, particularly if they are associated with vomiting, visual changes, asymmetric weakness, or coordination difficulties. (See "Headache in children: Approach to evaluation and general management strategies", section on 'Worrisome findings' and "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Common presenting signs and symptoms'.)

History and physical examination – The history of headache for a child, particularly a child who is <10 years old, is best obtained with input from the parents. Important aspects of the history and physical examination are summarized in the tables (table 5A-B). The approach to evaluating headache in childhood is discussed in detail separately. (See "Headache in children: Approach to evaluation and general management strategies", section on 'Physical examination'.)

Features of the history and physical examination that may raise concern for a brain tumor include (see "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Headache'):

Headaches that persist or recur frequently for more than three or four weeks

Headaches that occur in a young child (ie, <4 years of age)

Headaches that occur upon waking or that wake a child from sleep

Headaches associated with vomiting upon waking

Headaches associated with other concerning findings (eg, motor abnormalities, visual changes, papilledema, altered mental status, seizures)

Neuroimaging – Neuroimaging is the major diagnostic modality in the evaluation for a possible brain tumor. Indications for neuroimaging and the choice of imaging modality in children with suspected brain tumors are reviewed separately. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Neuroimaging'.)

Lymphadenopathy — Lymphadenopathy is another common finding in children. The size of normal lymph nodes in children varies widely as children are exposed to new viruses and bacteria. Most children have palpable small cervical, axillary, or inguinal lymph nodes at some time during childhood. The size of a lymph node that is considered abnormal varies depending upon the lymph node region and age of the child. The risk of malignancy is increased in lymph nodes that are >2 cm (0.8 inches) in diameter, although malignancy may occur in smaller nodes. This is discussed in greater detail separately. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Lymph nodes'.)

Most enlarged nodes are related to benign causes such as infection [21]. However, lymphadenopathy may be a presenting sign of leukemia, lymphoma and neuroblastoma. In contrast, lymphadenopathy is uncommon (although seen occasionally) with soft tissue, bone, and germ cell tumors. The site of the adenopathy and the child's age may help narrow the range of possible diagnoses. The most common cancers associated with lymphadenopathy of the head and neck are neuroblastoma, rhabdomyosarcoma, non-Hodgkin lymphoma, and leukemia in children <6 years old, whereas lymphomas (both Hodgkin and non-Hodgkin) predominate in children between 7 and 13 years of age; Hodgkin lymphoma is the most common histology in children older than 13 years.

Evaluation – Clinical features that are worrisome for malignancy in children with lymphadenopathy are summarized in the table and discussed in detail separately (table 6). (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Worrisome features'.)

The evaluation of unexplained lymphadenopathy in children depends in part upon whether it is generalized or localized and, if localized, which lymph node region is involved. Asymmetric lymph node enlargement may also warrant further evaluation. In addition, the evaluation may vary depending upon whether there are other associated signs or symptoms. The diagnostic approach is summarized in the tables and discussed in detail separately (see "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Diagnostic approach'):

Generalized lymphadenopathy (table 7) – (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Generalized lymphadenopathy'.)

Cervical lymphadenopathy (table 8) – (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Diagnostic approach'.)

Supraclavicular (or lower cervical) lymphadenopathy – (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Supraclavicular lymphadenopathy'.)

Axillary adenopathy (table 9) – (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Axillary lymphadenopathy'.)

Epitrochlear lymphadenopathy – (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Epitrochlear lymphadenopathy'.)

Inguinal lymphadenopathy (table 10) – (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Inguinal lymphadenopathy'.)

Lymph node biopsy – Excisional lymph node biopsy may be indicated in patients with worrisome features (table 6). This is discussed separately. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Lymph node biopsy'.)

Bone and joint pain — Bone and joint pain may be a presenting symptom for tumors that involve the bone or bone marrow (eg, primary or metastatic bone tumors, leukemias, neuroblastoma). (See "Evaluation of limp in children" and "Back pain in children and adolescents: Evaluation" and "Approach to hip pain in childhood", section on 'Other neoplasms'.)

Malignant bone tumors – Ewing sarcoma and osteosarcoma are the two most common malignant bone tumors in children. Most affected patients present with bone pain, typically for a duration of several weeks to months [22,23]. The pain associated with primary bone tumors typically begins as intermittent pain and increases in severity over time, though it may wax and wane [22,23]. An associated mass may be palpable on examination. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Clinical presentation' and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Clinical presentation'.)

Pathologic fractures occur in approximately 10 to 15 percent of cases of Ewing sarcoma or osteosarcoma [22]. Because fever may be present at diagnosis, particularly in patients with Ewing sarcoma, osteomyelitis must be considered in the differential diagnosis of such cases. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma" and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Acute leukemia – Bone pain is a presenting symptom in approximately 20 to 30 percent of children with acute leukemia, and other musculoskeletal symptoms (including hip pain, limb pain, joint pain, and limp) occur in approximately 60 to 70 percent [20]. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Presentation'.)

Differentiating leukemia from rheumatologic conditions – The musculoskeletal pain associated with acute leukemia, particularly if it occurs in the joints, may be mistaken for rheumatologic pain [24-27]. A combination of clinical and laboratory findings may be helpful in making the distinction. Nocturnal pain and nonarticular bony pain are more commonly associated with leukemia, whereas morning stiffness and rash occur more commonly in rheumatologic conditions [28]. In addition, children with leukemia often (but not always) display more significant abnormalities on CBC (ie, leukopenia, anemia, thrombocytopenia). (See 'Blood count abnormalities' below.)

Because the presenting features of childhood malignancy and rheumatologic disorders may overlap, bone marrow examination should be performed if there is uncertainty about the diagnosis, particularly if any of the following are present [4,25,26,28-30]:

Type and/or severity of pain are atypical for rheumatologic pain (table 11).

Patient refuses to bear weight or has new-onset limping.

Associated cytopenias (including mild leukopenia, anemia, or thrombocytopenia) (table 12 and table 13).

Elevated serum lactate dehydrogenase.

It is important to perform a bone marrow evaluation before beginning treatment with glucocorticoids because glucocorticoids can induce a transient tumor response in some children with leukemia or lymphoma, which may interfere with the subsequent diagnostic evaluation [31]. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Pretreatment evaluation'.)

Evaluation of bone and joint pain – Findings that may raise concern for malignancy in children with bone and joint pain include:

Inability or refusal to walk

Nighttime pain that wakens a child from sleep

Pain at rest

Bone or hip pain in a child ≤3 years of age

Persistent (ie, >2 weeks) or recurring pain or limp

Limitation of joint movement on examination

Palpable mass on examination

Patients with any of these findings should generally undergo evaluation including the following:

Plain radiographs

CBC with platelet count and differential

C-reactive protein and/or erythrocyte sedimentation rate

Alkaline phosphatase

Lactate dehydrogenase

Uric acid

Plain radiographs are typically obtained as the initial imaging study; however, magnetic resonance imaging (MRI) is generally the preferred modality for definitive evaluation of bone and soft tissue lesions.

The evaluation of children with bone pain or limp is discussed in greater detail separately. (See "Evaluation of limp in children" and "Approach to hip pain in childhood", section on 'Evaluation' and "Back pain in children and adolescents: Evaluation".)

Radiographic findings – Radiographic findings that are characteristic of malignant bone tumors include:

Onion skinning – "Onion skinning" is caused by repetitive periosteal reactions, each depositing a layer of calcium, as the tumor grows beyond the periosteum (image 1). The onion skin periosteal reaction is most common in Ewing sarcoma but may occur in other conditions and may be absent in Ewing sarcoma. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Radiographic studies'.)

Sunburst phenomenon – "Sunburst" phenomenon is a periosteal reaction that occurs when malignant osteoblasts deposit new bone and blood vessels that radiate perpendicularly from the tumor [32,33]. This phenomenon is most commonly (but not necessarily) seen in osteosarcoma (image 2A-B). (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Plain radiograph'.)

A pathologic fracture should also raise suspicion for a bone tumor. Other nonmalignant causes of pathologic fractures in children are discussed separately. (See "General principles of fracture management: Fracture patterns and description in children", section on 'Pathologic fracture'.)

Radiographic features that suggest leukemia include osteopenia, lytic lesions, metaphyseal bands, periosteal new bone, and sclerotic lesions [34].

Although abnormal findings on diagnostic imaging can raise suspicion for malignancy, they generally do not obviate the need for obtaining a tissue biopsy. (See 'Obtaining tissue samples' below.)

Mediastinal masses — Mediastinal tumors may be asymptomatic or may be associated with symptoms such as cough, shortness of breath (often positional), hoarseness, wheezing, or facial or neck swelling [35]. When symptoms are present, they usually result from extrinsic compression or involvement of adjacent structures, such as the recurrent laryngeal nerve. Mediastinal masses are often incidentally discovered on chest radiographs obtained for other reasons.

Types of tumors according to location – The mediastinum is divided into three anatomic compartments (figure 1). The compartment in which the mass is located can provide information about its likely etiology [36,37]:

Anterior – Masses commonly found in the anterior mediastinum include thymomas, teratomas, lymphomas, thyroid tumors, germ cell tumors, angiomas, and lipomas, [38]. The first four of these tumors are often referred to as the proverbial "four Ts": thymoma, teratoma, "terrible" (or T cell) lymphoma, and thyroid [39].

Middle – Masses commonly found in the middle mediastinum include lymphoma, metastatic cancer, infection-related lymphatic lesions, malignancies that extend directly from the abdomen, pericardial cysts, bronchogenic cysts, esophageal lesions, and hernias.

Posterior – Masses commonly found in the posterior mediastinum include neurogenic tumors such as neurofibromas; neuroblastomas; ganglioneuroblastomas; ganglioneuromas; enterogenous cysts; thoracic meningoceles; and malignancies such as Ewing sarcoma (either osseous or extraosseous), lymphoma, and rhabdomyosarcoma.

In one study, children with malignant mediastinal masses were more likely to have tumors in the anterior mediastinum compared with patients with benign mediastinal masses [40]. In addition, children with malignant tumors more commonly presented with malaise, neck swelling, abnormal extrathoracic lymphadenopathy, and lymphopenia.

Evaluation – Mediastinal masses that are discovered on chest radiography require further diagnostic imaging, which usually consists of contrast-enhanced computed tomography (CT). This helps to delineate the precise location of the mass and provides additional anatomic detail that can help narrow the diagnostic possibilities. Other advanced imaging modalities may also be required (eg, MRI or 18-fluoro-2-deoxyglucose [FDG]-positron emission tomography [PET] scan [either as an integrated PET/CT or as a separate PET study]) [37,41-43].

Children who are suspected to have malignancy based upon the imaging findings should be referred to pediatric oncology. Peripheral blood flow cytometry and/or bone marrow examination may be indicated. If these tests are nondiagnostic, it may be necessary to perform a more invasive procedure to obtain tissue from the mediastinal mass for definitive pathologic diagnosis. Patients with large anterior mediastinal masses are at increased risk of respiratory or cardiac arrest during general anesthesia or deep sedation. Therefore, this procedure should be undertaken with appropriate consideration of the potential risks of anesthesia. Many centers of excellence in pediatric oncology have "mediastinal mass" evaluation teams that include clinicians from the pediatric intensive care unit, anesthesiology, and cardiology to address the potential need for extracorporeal membrane oxygenation (ECMO). (See "Approach to the adult patient with a mediastinal mass" and "Overview of Hodgkin lymphoma in children and adolescents", section on 'Diagnosis'.)

Abdominal masses — A palpable abdominal mass, which often is detected by a family member or primary care provider, is one of the most common presenting signs of malignant solid tumors in children [4]. The presenting symptom may be pain, vomiting, constipation, or, less commonly, intestinal obstruction. Although some abdominal masses are benign, all require early, thorough workup. Timely referral to an oncologist is critical to ensure that the proper diagnosis is be made and treatment is initiated promptly.

Common intraabdominal tumors – Wilms tumor and neuroblastoma are the most common intraabdominal tumors; others include lymphoma, hepatic tumors, ovarian tumors, and soft tissue sarcomas. The age of the child helps in the differential diagnosis. Wilms tumor and neuroblastoma occur more commonly in infants and toddlers, whereas leukemic or lymphomatous involvement of the liver, spleen, or retroperitoneal lymph nodes occurs more commonly in older children [4]. (See "Presentation, diagnosis, and staging of Wilms tumor" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)

Evaluation – When obtaining the history, it is important to determine whether the child has symptoms related to the mass and, if so, their duration and intensity. These features may help to determine how rapidly the mass is growing and/or to distinguish malignancy from another more chronic condition. Abdominal masses in infants and young children often have a renal origin [4]. Thus, the history should include questions about genitourinary symptoms, including hematuria. Ovarian cysts and tumors are common causes of abdominal masses in girls. Thus, the history for adolescent females should include a menstrual and sexual history. (See "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Adnexal masses: Evaluation in infants, children, and adolescents".)

Physical examination should characterize the location and extent of the abdominal mass. Palpation is easier if the child is relaxed. The following structures are normally palpable in children and sometimes are mistaken for abdominal masses: liver edge, spleen, kidneys, aorta, sigmoid colon, and spine. (See "The pediatric physical examination: Chest and abdomen", section on 'Palpation'.)

If a mass is palpated on physical examination, the child should undergo additional evaluation including laboratory studies (a CBC, serum electrolytes, blood urea nitrogen, creatinine, and urinalysis) and abdominal imaging. Ultrasound is typically performed as the initial imaging study; however, depending on the findings, additional imaging with CT, PET scan, or MRI may be warranted. Details of the evaluation for common abdominal tumors in children are provided separately:

Wilms tumor (see "Presentation, diagnosis, and staging of Wilms tumor", section on 'Diagnostic evaluation')

Neuroblastoma (see "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Diagnostic and staging evaluation')

Ovarian tumors (see "Adnexal masses: Evaluation in infants, children, and adolescents")

Abdominal lymphomas (see "Overview of Hodgkin lymphoma in children and adolescents" and "Overview of non-Hodgkin lymphoma in children and adolescents")

Bleeding symptoms — When bleeding is the initial sign of childhood cancer, it is usually because of thrombocytopenia, which, in turn, is most often caused by neoplastic involvement of the bone marrow. This typically manifests as cutaneous bleeding (such as petechiae (picture 2) and ecchymoses) and/or mucosal bleeding (epistaxis, gingival bleeding, buccal bleeding). (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia".)

Coagulopathy is less common but can accompany acute promyelocytic leukemia, a rare form of acute myelogenous leukemia [44]. Coagulopathy also has been reported in patients with acute lymphoblastic leukemia (especially T cell acute lymphoblastic leukemia), lymphoma, and neuroblastoma [4]. Other disseminated malignancies may be associated with a coagulopathy, but signs or symptoms are rare findings unless disseminated intravascular coagulation supervenes. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Disseminated intravascular coagulation in infants and children".)

Evaluation – Important considerations in the differential diagnosis for a child presenting with bleeding symptoms and thrombocytopenia include malignancy (particularly acute leukemia), infection, and immune thrombocytopenia (ITP) (table 14). Initial testing includes a CBC with differential, platelet count, coagulation studies (prothrombin time and activated partial thromboplastin time), and examination of the peripheral blood smear. Peripheral blood flow cytometry and bone marrow examination may be performed if there are concerning findings on initial testing (eg, peripheral blasts, multiple cytopenias) or if there are clinical findings that are atypical for ITP (ie, if thrombocytopenia is associated with constitutional symptoms, bone pain, lymphadenopathy, or splenomegaly). The diagnostic approach is discussed in separate topics:

Diagnostic approach to unexplained thrombocytopenia (see "Approach to the child with unexplained thrombocytopenia")

Indications for bone marrow examination in children with suspected ITP (see "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Indications for bone marrow examination')

Diagnostic approach to the child with suspected acute leukemia (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Laboratory evaluation')

Blood count abnormalities — Abnormal blood counts are a common presenting feature in childhood malignancies. These findings may be noted on a CBC obtained for evaluation of other concerning findings (eg, pallor, petechiae, lymphadenopathy, bone pain) or a CBC obtained for other reasons (eg, routine screening or evaluation of febrile illness). If the CBC was performed in an otherwise healthy patient and the results do not match the clinical picture (eg, marked thrombocytopenia in a child without bleeding symptoms), it should be confirmed with repeat testing.

Cytopenias – Anemia, leukopenia, and thrombocytopenia often occur in combination or as isolated findings in acute leukemias and tumors that involve the bone marrow (eg, neuroblastoma, lymphoma, Ewing sarcoma, and rhabdomyosarcoma) [4]. Normal values for WBC counts and hemoglobin vary by age, as summarized in the tables (table 13 and table 12). Thrombocytopenia is generally defined as platelet count <150,000/microL. The approach to evaluating cytopenias in children is discussed in separate topic reviews. (See "Approach to the child with anemia" and "Overview of neutropenia in children and adolescents" and "Approach to the child with unexplained thrombocytopenia".)

Abnormal WBCs – Childhood leukemia can present with any of the following:

Leukopenia – Leukopenia, including neutropenia (absolute neutrophil count <1500/microL) and/or lymphopenia (absolute lymphocyte count <1500/microL), may be a presenting finding in childhood leukemia. Other causes include infections, drugs, primary immune disorders, hypersplenism, other bone marrow disorders (eg, aplastic anemia), and congenital neutropenias. (See "Overview of neutropenia in children and adolescents" and "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Lymphocytopenia'.)

Leukocytosis and lymphocytosis – Leukocytosis, particularly lymphocytosis, is a common presenting feature of acute leukemia. Peripheral WBC counts >100,000/microL are almost always indicative of leukemia. Other causes of leukocytosis and lymphocytosis include infections (eg, bacterial infections, mononucleosis, pertussis), drugs (eg, glucocorticoids), stress, and asplenia. Usually, by the time the child has evidence of significant malignant lymphocytosis, there are other abnormal findings in the blood count that suggest the diagnosis of leukemia (eg, anemia, neutropenia, thrombocytopenia, peripheral blasts). (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Evaluation of the child with lymphocytosis' and "Approach to the patient with neutrophilia".)

Leukemoid reaction – The term "leukemoid reaction" refers to the presence of a striking increase in leukocyte count (eg, >50,000 cells/microL) and/or immature cells (≥5 percent) in the peripheral blood. Immature WBCs, normally only present in the bone marrow, may be observed in the peripheral blood in a variety of disorders including septicemia, sudden erythropoietic stimulation caused by hemolysis or hemorrhage, bone marrow recovery phase after bone marrow depression, and rheumatoid arthritis [4,45]. In a study of 603 pediatric patients with isolated leukemoid reaction, only 4 percent were ultimately found to have leukemia [45].

Abnormal WBCs (blasts) – It is never normal to see blast forms (eg, lymphoblasts (picture 1A-B) or myeloblasts (picture 1C)) on the peripheral smear. Further evaluation of such patients (including hematology/oncology consultation, formal review of the peripheral smear, and bone marrow examination) is warranted. (See "Evaluation of the peripheral blood smear", section on 'Blasts or tumor cells' and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

Evaluation – The evaluation of a patient with abnormal peripheral blood counts generally includes investigation for infectious and malignant causes. Referral to a hematologist/oncologist for further evaluation including bone marrow examination and peripheral flow cytometry is warranted if any of the following are present [4]:

Finding of atypical or blast cells on peripheral blood smears

Significant depression of two or more cell lines without obvious explanation

Association with unexplained lymphadenopathy or hepatosplenomegaly

Association with an abdominal or mediastinal mass

Absence of other explanation (eg, infectious cause) for the blood abnormality

GENERAL PRINCIPLES OF EVALUATION

Referral — The treatment for malignancy can begin only after the tumor has been accurately diagnosed and the extent of disease defined precisely. Thus, once initial evaluation shows a high likelihood of cancer, the child should be referred to a pediatric oncology center for a complete diagnostic workup. The subsequent evaluation and management of childhood cancer should be carried out in a pediatric oncology center where the necessary subspecialists and tests required for timely diagnosis and/or treatment protocols are available.

The importance of establishing the correct diagnosis and accurately determining the extent of disease before therapy begins must be emphasized to the parents and child (if of appropriate age) at the initial evaluation. Such care helps to ensure appropriate therapy and prevents the need for performing repeat examinations and biopsies after the initiation of treatment [4].

Oncologic emergencies — In some cases, administration of emergency therapy is necessary at the time of presentation to stabilize the child's condition. Examples include:

Mediastinal masses causing airway, cardiac, or major blood vessel compression. (See "Overview of Hodgkin lymphoma in children and adolescents", section on 'Mediastinal mass' and "Overview of non-Hodgkin lymphoma in children and adolescents", section on 'Oncologic emergencies'.)

Brain tumors causing elevated intracranial pressure. (See "Overview of the management of central nervous system tumors in children", section on 'Elevated intracranial pressure'.)

Hyperleukocytosis due to acute leukemia, which can cause neurologic morbidity, including intracranial hemorrhage or ischemic stroke. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

Hyperuricemia, electrolyte derangements (hyperkalemia, hyperphosphatemia, hypocalcemia), and acute kidney injury due to tumor lysis syndrome (TLS). TLS usually occurs after the initiation of cytotoxic therapy. However, TLS can occur prior to therapy in malignancies that have a high proliferative rate, such as some forms of lymphoma (eg, Burkitt lymphoma, T cell lymphoma) and acute leukemia. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

In these cases, telephone consultation with a pediatric oncologist is critically important to ensure proper management and expedite the diagnostic workup. If the child is being evaluated in an outpatient clinic, appropriate arrangements should be made to transport the child to an emergency department.

Obtaining tissue samples — Noninvasive imaging techniques such as computed tomography (CT), diagnostic ultrasonography, magnetic resonance imaging (MRI), positron emission tomographic (PET) scans, and nuclear medicine scans have improved the assessment and staging for cancer. However, for most malignancies, the diagnosis is primarily established by tissue biopsy. Whenever possible, this should be performed at a pediatric oncology center with appropriate coordination among pediatric oncologists, surgeons, and pathologists. A pediatric oncologist should be consulted prior to any biopsy to ensure that an appropriate biopsy approach is requested.

General principles for obtaining a biopsy are as follows:

Enough tissue must be obtained so that additional biopsies are not necessary

Obtaining tissue for diagnosis should not compromise future therapy

Excisional biopsy is preferred when the malignancy involves an organ or lymph nodes

Proper timing and handling of the biopsy material is essential

The specific approach to obtaining tissue depends on the suspected type of tumor/malignancy:

Suspected leukemia – Bone marrow aspirate and biopsy are performed. This topic is discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Diagnosis of ALL/LBL' and "Acute myeloid leukemia in children and adolescents".)

Suspected lymphoma – The preferred approach is excisional biopsy of affected lymph node(s). Core needle biopsies are often not adequate for diagnostic studies, due to heterogeneity of the lymph nodes and rarity of cancer cells. This is discussed separately. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Lymph node biopsy' and "Overview of Hodgkin lymphoma in children and adolescents", section on 'Diagnosis' and "Overview of non-Hodgkin lymphoma in children and adolescents", section on 'Diagnosis'.)

Suspected Wilms tumor – Biopsies are not routinely performed unless the tumor is initially assessed to be inoperable. Surgical management varies. In some treatment protocols, surgical resection is performed prior to chemotherapy administration; other protocols use a primary chemotherapy approach followed by surgical resection and staging several weeks later. This is discussed separately. (See "Treatment and prognosis of Wilms tumor", section on 'Difference in approaches of COG and SIOP'.)

Suspected neuroblastoma – Tissue is usually obtained by incisional or image-guided core needle biopsy of the primary tumor, or evaluation of the bone marrow by biopsy/aspirate in patients who are suspected to have metastatic disease in the marrow. This is discussed separately. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Biopsy'.)

Suspected hepatoblastoma – The most common method of tissue sampling is image-guided percutaneous biopsy with fine-needle aspiration or core needle biopsy. This is discussed separately. (See "Overview of hepatoblastoma", section on 'Diagnosis and initial evaluation'.)

Bone and soft tissue tumors – Image-guided core needle biopsy is typically performed; however, an open biopsy may be required in some cases. Proper planning of the biopsy with careful consideration of the future definitive surgery is important so as not to jeopardize the subsequent treatment, particularly in the case of limb salvage procedure. This is discussed separately. (See "Bone tumors: Diagnosis and biopsy techniques" and "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Tumor biopsy' and "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging", section on 'Diagnostic biopsy' and "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Diagnostic biopsy'.)

Brain tumors – Histologic examination is necessary for diagnosis of brain tumors. The surgical procedure varies and may involve complete resection of the tumor, tumor reduction surgery, or tumor biopsy. This is discussed separately. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Diagnosis' and "Overview of the management of central nervous system tumors in children", section on 'Surgery'.)

Germ cell tumors – The approach varies. Details are provided separately. (See "Adnexal masses: Evaluation in infants, children, and adolescents", section on 'Indications for referral' and "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Staging and surgical treatment' and "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Diagnostic evaluation'.)

Thyroid nodules – Fine-needle aspiration is performed if the nodule meets size criteria or has other concerning features. This is discussed separately. (See "Thyroid nodules and cancer in children", section on 'Fine-needle aspiration'.)

Retinoblastoma – The diagnosis is made based upon the dilated retinal examination and imaging findings. There is no role for direct tumor biopsy for tissue diagnosis, given the risk of extraocular spread of disease. Tissue samples are obtained only if the child undergoes enucleation as part of treatment. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Diagnosis'.)

Proper timing and handling of tissue from biopsy or tumor resection is essential. Prior to biopsy, it is essential to involve a pathologist, ideally with pediatric oncology expertise, to ensure appropriate initial specimen processing. Biopsy specimens should be placed in normal saline and then transported immediately on ice to the surgical pathology laboratory. Gross examination of the tissue by the pathologist before processing helps to ensure that the specimen is adequate. Intraoperative frozen sections may be necessary to ensure diagnostic material, particularly if an immediate diagnosis will alter the planned operation. Definitive, specific diagnoses are rarely made from frozen sections, and it is critical to wait for final pathology results to ensure an accurate treatment plan. When appropriate, other procedures (eg, central venous catheter placement, bone marrow aspirate/biopsy) may be performed at the time of biopsy.

SUMMARY AND RECOMMENDATIONS

Importance of early diagnosis – Optimal management of childhood cancer requires a high level of suspicion by the primary care practitioner and early referral to a pediatric oncologist. Early detection and treatment may reduce disease-related morbidity and complications. (See 'General principles of evaluation' above.)

Common sites and types of cancer in childhood – Common sites of malignancies in childhood include blood and bone marrow, brain and nervous system, lymph nodes, kidneys, bone, and soft tissues. The frequency of particular types of cancer varies depending upon the age of the child (table 1). (See 'Background' above.)

Presenting signs and symptoms – Childhood cancer may present with signs and symptoms that are shared by other childhood illnesses (table 4).

Although a single finding in isolation does not always require an evaluation for cancer, a combination of multiple findings (eg, weight loss, bone pain, and lymphadenopathy; easy bruising, abnormal blood counts, and hepatosplenomegaly) is worrisome and warrants prompt referral to a pediatric oncologist and evaluation for malignancy. (See 'Common signs and symptoms' above.)

In addition, certain isolated findings are worrisome (eg, abdominal or mediastinal masses (figure 1), headaches associated with vomiting in the morning, blasts on the peripheral blood smear (picture 1A-C)). These symptoms also require prompt evaluation and consultation. (See 'Abdominal masses' above and 'Headache' above and 'Blood count abnormalities' above.)

Warning signs – Early warning signs of childhood cancer include (see 'Warning signs' above and 'Common signs and symptoms' above):

Unexplained pallor and loss of energy (see 'Fatigue and pallor' above and "Evaluation of pallor in children")

Unusual lump, mass, or swelling (see 'Lymphadenopathy' above and 'Abdominal masses' above)

Sudden unexplained weight loss (see 'Weight loss' above and "Evaluation of weight loss in infants over six months of age, children, and adolescents")

Unexplained persistent fever or illness (see 'Fever' above and "Fever of unknown origin in children: Etiology")

Easy bruising or bleeding (see 'Bleeding symptoms' above and "Approach to the child with bleeding symptoms")

Prolonged or ongoing pain in one or more areas of the body (see 'Bone and joint pain' above)

Limping (see 'Bone and joint pain' above and "Evaluation of limp in children")

Frequent headaches, particularly if occurring in the morning and associated with vomiting (see 'Headache' above and "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Headache')

Sudden eye or vision changes (see "Approach to the child with leukocoria" and "Diagnostic approach to acute vision loss in children")

Referral – If malignancy is suspected based upon initial clinical, laboratory, and imaging studies, the child should be referred to a pediatric oncology center. The subsequent diagnostic workup and management of childhood cancer should be carried out in a pediatric oncology center where the necessary subspecialists and tests required for diagnosis and/or treatment protocols are available. (See 'Referral' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kathleen A Neville, MD, MS, MBA, FAAP, FCCP, and C Philip Steuber, MD, who contributed to earlier versions of this topic review.

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