Persistent adenopathy is common in children. At least 70% of pediatric patients <7 years have enlarged anterior or posterior cervical nodes, or both.

Size and location are important in assessing children with lymphadenopathy. Lymph nodes are considered enlarged if their greatest diameter is >10 mm. The exception is that epitrochlear nodes are considered enlarged if the diameter is >5 mm. Inguinal nodes are not abnormal unless the diameter is >15 mm. In most children, the cervical, axillary, and inguinal nodes are palpable and small. Posterior auricular, epitrochlear, and supraclavicular adenopathy all warrant further investigation. Pathologic cervical adenopathy is usually indicated by a diameter of >15 to 20 mm. Enlargement of lymph nodes to a pathologic size (e.g., >2 cm in the head and neck), followed by a decrease to a nonpathologic or even imperceptible size, probably represents a reactive adenopathy. However, if the same nodes continue to increase and decrease in size over time, especially in a pathologic (e.g., supraclavicular) area, an investigation for malignancy should be undertaken. Within 2 to 3 weeks, most noncancerous nodes should return to normal size.

Infection is the most common cause of acute cervical adenopathy. In cases of localized cervical adenitis with moderate inflammation and fever, the child can be treated with an oral antibiotic empirically. The therapy should include both antistaphylococcal and antistreptococcal coverages, and also anaerobic coverage if a dental source is suspected. When a child does not respond to antibiotic therapy in 7 days, or has a node that is fluctuant or >2 cm, a more extensive workup is necessary. This includes chest radiography, a complete blood cell count, metabolic studies (lactate dehydrogenase, uric acid, phosphorus, calcium and other electrolytes, blood urea nitrogen, creatinine,
bilirubin, and liver enzymes), measurement of the sedimentation rate, and a tuberculin skin test. Viral, bacterial, and fungal serologies should be obtained only if indicated by the history and physical examination findings. Bone marrow biopsy and aspiration may be indicated if the blood cell counts are abnormal or a mediastinal mass or hepatosplenomegaly is detected.

In chronic lymphadenopathy of the head and neck, malignancy becomes a consideration. Lymph nodes with malignant involvement are usually firm, rubbery, and matted. They are generally nontender, and when observed over time, they increase in size.

The following malignancies are associated with generalized adenopathy:

Patients with these conditions usually have other evidence of systemic disease, such as fever, night sweats, bone pain, arthralgias, easy bruising, petechiae, and peripheral blood changes. A mediastinal mass (see subsequent section) can be found in ALL (usually T-cell ALL) and the lymphomas (Hodgkin and non-Hodgkin).

A lymph node biopsy is suggested for any of the following:

A number of benign and malignant tumors are found in the thorax. The mediastinum is the site of most intrathoracic masses in children. The location of a mass in one of the three anatomic areas of the mediastinum is a clue to the diagnosis (Table 56.2).

Patients with mediastinal tumors can be asymptomatic; however, with close questioning, more than half are found to have unreported symptoms, such as cough, dyspnea, orthopnea, or stridor caused by the compression or erosion of adjacent structures, such as the respiratory tract or superior vena cava. These patients can present with superior mediastinal syndrome, the most common symptom of which is shortness of breath or dyspnea that develops when the patient is in a supine position. It should be considered a medical emergency, and a workup should be undertaken immediately in the hospital.

Frequently, a mass is discovered on routine chest radiography, leading to computed tomography (CT) scan as the next diagnostic maneuver, which frequently requires
sedation in children. It is imperative to note that children with a mediastinal mass resulting in orthopnea or tracheal caliber <50% of normal cannot tolerate sedation or general anesthesia. Specialists in pediatric anesthesia, oncology, and surgery should be consulted together immediately to plan a safe evaluation, which will involve unsedated scans and biopsies.

The most common histologic diagnosis of a mediastinal tumor in children is a “small, blue, round cell tumor,” which is one of the following: lymphoma, leukemia (lymphoid), neuroblastoma, rhabdomyosarcoma, or primitive neuroectodermal tumor (PNET/Ewing sarcoma family). An anterior mediastinal mass is leukemia (usually T-cell ALL) or lymphoma (Hodgkin or non-Hodgkin) until proved otherwise. A posterior mediastinal mass is a neurogenic tumor such as neuroblastoma or PNET until proved otherwise. If a posterior mediastinal mass is present, magnetic resonance imaging (MRI) of the thoracic spine should be performed, ideally before surgery, to rule out extension of tumor into the spinal canal, which can cause spinal cord compression.

Headache is one of the most common symptoms seen in pediatric practice. Although very few headaches are associated with an intracranial tumor, it is important to consider this diagnosis when a patient has recurrent headaches.

Brain tumors are the solid tumors most frequently encountered in pediatrics. The diagnosis of brain tumor is initially suspected on the basis of a symptom complex that most often depends on the site of the tumor. Because most brain tumors are so situated that they interfere with the circulation of cerebrospinal fluid, increased intracranial pressure (ICP) is a common problem. Early symptoms may be nonlocalizing. Supratentorial lesions typically present with signs of high ICP (headache and vomiting) and focal neurologic deficits; infants may have an enlarging head size. Infratentorial lesions tend to present with ataxia or other gait disturbances, signs of high ICP if there is aqueduct compression, and cranial nerve abnormalities if the brain stem is involved. Spinal tumors present with back pain and signs of cord compression (weakness of extremities, and loss of bladder and bowel function).

MRI or CT scan of the brain is indicated in patients who have:

Most of the pain associated with cancer is the consequence of bone, nerve, or hollow viscus involvement. Childhood cancers rarely present with pain except for bone cancers and leukemia. The differential diagnosis includes malignancy if pain awakens the child from sleep, function is compromised in the absence of trauma, no cause for the pain is apparent within 2 weeks, or there is an associated mass with or without fracture. The pain associated with bone cancer (Ewing sarcoma and osteosarcoma) tends to be intermittent at first and increases in severity with time. In both Ewing sarcoma and osteosarcoma, the time between the onset of symptoms and the diagnosis can be as long as 6 to 12 months.

Bone pain as a presenting complaint or resulting in a limp (or refusal to bear weight or walk in toddlers) has been reported in 27% to 33% of cases of acute leukemia. This is more common in ALL than in acute myeloid leukemia (AML). Patients who are being evaluated for acute rheumatoid arthritis may need to undergo a bone marrow examination to rule out acute leukemia, as leukemic arthritis may be mistaken for various rheumatic diseases.

Bone pain may also be a presenting complaint in children with neuroblastoma. Some children who present with abnormal blood cell counts and bone pain and who are evaluated for leukemia may have stage 4 neuroblastoma. If neuroblastoma is suspected, abdominal ultrasonography should be performed to search for an adrenal mass. If an abdominal mass is present, abdominal CT scan may reveal a calcified mass consistent with neuroblastoma. Further workup would include urine collection for catecholamine metabolites (vanillylmandelic and homovanillic acids) and bone marrow examination.

Rarely, children present with metastatic lesions to the bone from other types of tumors, such as rhabdomyosarcoma, other soft-tissue sarcomas, lymphoma, brain tumors (e.g., PNET, or medulloblastoma), and liver cancer (hepatocellular carcinoma).

If a child has persistent or chronic intermittent pain of bone/extremity, a plain film should be obtained and bone scan/MRI considered, especially if the pain is associated with a swelling, mass, or limited motion. If a destructive lesion is seen or the periosteum is disrupted, further workup is indicated. Patients who have persistent bone pain associated with fever should be evaluated for infection, such as osteomyelitis, in addition to malignancy.
Before biopsy, simultaneous input from pediatric oncology and orthopaedic oncology is essential.

A palpable abdominal mass is the most common sign that should suggest a malignant solid tumor, although the mass is more likely to be benign or pseudotumor (e.g., feces, the abdominal aorta, a distended bladder, or hydronephrotic kidneys). Age is important when the differential diagnosis is considered (Table 56.3).

When the history is obtained and the physical examination performed, the presence of generalized adenopathy, pallor, bruising, petechiae, cachexia, gastrointestinal symptoms, genitourinary (GU) symptoms, jaundice, chest pain, dyspnea, shoulder pain, and pain on palpation of the mass should be noted.

Abdominal ultrasonography is the most common initial radiologic study performed to characterize an abdominal mass. CT scan of the chest, abdomen, and pelvis may also be indicated. If a renal mass is present, ultrasonography of the inferior vena cava and the heart is also indicated to rule out a tumor thrombus extending into the inferior vena cava and possibly into the heart. If a neuroblastoma is suspected, a scan with metaiodobenzylguanidine (MIBG) should be performed because this radioactively labeled compound is taken up by catecholaminergic cells, which are found in most neuroblastomas. In cases of neuroblastoma and paraspinal PNET, MRI of the spine should be performed to rule out an extension of the tumor into the spinal canal.

Anemia, leukopenia, or thrombocytopenia frequently occur alone as a presenting sign of acute leukemia, or all three may develop. Pancytopenia is primarily a consequence of replacement of the bone marrow by tumor cells. Anemia is also associated with malignancy for other reasons. Anemia of chronic disease or hemolytic anemia can develop as a paraneoplastic manifestation of lymphomas (autoimmune hemolytic anemia). Except when the marrow is involved, leukopenia is rarely a manifestation of extramedullary malignancies. The same is true of thrombocytopenia, except for the rare association of immune thrombocytopenic purpura with Hodgkin lymphoma or thrombocytopenia with disseminated intravascular coagulation (DIC), which may occur in widely disseminated tumors such as AML, rhabdomyosarcoma, and neuroblastoma. Any other malignancy that involves the bone marrow can also produce a pancytopenia or depression of any of the cell lines. Pediatric solid tumors that can involve the bone marrow include neuroblastoma, lymphoma, rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma.

An elevated white blood cell count is common in acute leukemia. A peripheral white blood cell count >100,000/mm³ is almost always a manifestation of acute or chronic leukemia. Leukemoid reactions with white blood cell count >50,000/mm³ are seen in children with septicemia. Lymphoid leukemoid reactions have been seen in infectious lymphocytosis, mumps, varicella, pertussis, and infections with adenovirus and cytomegalovirus. Myeloid leukemoid reactions with cell count >100,000/mm³ have been reported in premature infants whose mothers received corticosteroids during pregnancy.

Approximately 10% of neonates with Down syndrome may develop a transient leukemia or myeloproliferative syndrome characterized by high leukocyte counts, blast cells in their peripheral blood, and associated anemia, thrombocytopenia, and hepatosplenomegaly. This usually resolves spontaneously within days to weeks after onset, although some very ill children (respiratory compromise caused by massive organomegaly) require a short course of chemotherapy. These infants require close follow-up, as 20% to 30% develop leukemia by age 3 years (median age: 16 months). The most common type of leukemia following TMD (transient myeloproliferative disorder) in a child with Down syndrome is acute megakaryocytic leukemia. TMD may occur in infants who do not have phenotypic features of Down syndrome. Blasts from these patients may show trisomy 21, suggesting a mosaic state. GATA1 mutations (a transcription factor that controls megakaryopoiesis) are present in the blasts from patients with Down syndrome who have TMD and also in those with leukemia.

Leukocytosis secondary to an exaggerated eosinophilia with white blood cell counts in the range of 20,000 to 100,000/mm³ is often seen in parasitic infections, especially visceral larval migrans. Other causes of eosinophilia include hypereosinophilic syndrome, periarteritis nodosa, and allergic
and hypersensitivity reactions. The malignant causes of eosinophilia are eosinophilic leukemia, Hodgkin lymphoma (20% of patients), and acute lymphoid leukemia. Eosinophilia is also seen in sarcoidosis. The absolute eosinophil count is used to quantitate eosinophilia. Many diseases are associated with moderate (1500-5000 cells/μL) or severe (>5000 cells/μL) eosinophilia. Patients with sustained blood eosinophilia may develop organ damage, especially cardiac, as found in HES (hypereosinophilic syndrome). These patients need to be monitored closely for evidence of cardiac disease. Eosinophilia is observed in many patients with primary immunodeficiency syndromes, especially hyper IgE syndrome and Wiskott-Aldrich syndrome. Eosinophilia is also seen in syndromes of thrombocytopenia with absent radii (TAR syndrome) and familial reticuloendotheliosis with eosinophilia. Wiskott-Aldrich syndrome may evolve into leukemia or lymphoma. Reticuloendotheliosis, class III, is associated with acute monocytic leukemia and true malignant histiocytosis.

Bleeding is an uncommon initial sign of malignancy in children. When it occurs, it is usually related to thrombocytopenia secondary to primary bone marrow involvement of leukemia or infiltrative marrow disease (e.g., lymphoma, rhabdomyosarcoma). It can represent a systemic consumptive process: disseminated intravascular coagulopathy (DIC) secondary to leukemia. In newly diagnosed acute leukemia, bleeding can also be related to the use of nonsteroidal antiinflammatory drugs, such as ibuprofen. The use of aspirin in the treatment of bone pain can induce bleeding. High doses of antibiotics such as penicillin and ticarcillin can cause bleeding. This bleeding caused by nonsteroidal anti-inflammatory medications, aspirin, and penicillin is caused by platelet dysfunction. Coagulation abnormalities are also seen in disseminated malignancies. They rarely give rise to signs or symptoms unless DIC develops or there is significant bone marrow involvement causing thrombocytopenia. DIC is a prominent feature of acute promyelocytic leukemia (APL), especially after the institution of chemotherapy. DIC can occur in any type of leukemia presenting with hyperleukocytosis (WBC >100,000). DIC also occurs in sepsis syndromes, such as gram-negative sepsis. These infections can be the presenting features in severely neutropenic or immunocompromised patients with undiagnosed acute leukemia and lymphomas.

Brain tumors are the second most common cancer, and the most common solid tumor seen in pediatrics.