Common Oncologic Disorders
Leukemia
The leukemias, which result from malignant transformation of early hematopoietic stem cells, are some of the most common malignancies of childhood ( Table 8.1 ). Acute lymphoblastic leukemia (ALL) accounts for 75% of all childhood acute leukemia, acute myelogenous leukemia (AML) accounts for 20%, and chronic myelogenous leukemias (CML) accounts for the other 5% of childhood leukemias.
| TYPE OF CANCER | INCIDENCE PER 1,000,000 |
|---|---|
| CNS (Central Nervous System) | 42.2 |
| ALL (Acute Lymphocytic Leukemia) | 39.9 |
| Neuroblastoma | 10.1 |
| Non-Hodgkin Lymphoma | 10.1 |
| AML (Acute Myelogenous Leukemia) | 7.7 |
| Wilms Tumor | 7.5 |
| Hodgkin Lymphoma | 6.4 |
| Rhabdomyosarcoma | 5.3 |
| Osteosarcoma | 4.2 |
| Retinoblastoma | 4.1 |
| Ewing Sarcoma | 2.4 |
| 1.5 |
Clinical manifestations of the leukemias are similar and consist primarily of lethargy, malaise, fever, and signs of bone marrow failure such as pallor, ecchymoses, or petechiae. Bone pain related to marrow infiltration from tumor cells is also a common presenting symptom. Infiltration by leukemic blasts can also cause lymphadenopathy, hepatosplenomegaly, testicular enlargement, and respiratory symptoms from a mediastinal mass or leukostasis. Initial laboratory findings usually include signs related to bone marrow failure, such as anemia, neutropenia, and thrombocytopenia. A white blood cell (WBC) count greater than 50,000 uL/mL is also highly suspicious for leukemia.
The treatment strategy for a newly diagnosed patient with leukemia is to stabilize the patient acutely (i.e., transfusions, antibiotics) and begin definitive treatment as soon as the diagnosis has been made. Delay in treatment initiation can lead to disease progression and critical complications including respiratory failure and stroke from leukostasis.
Patients with ALL are risk-stratified based upon age and WBC at presentation, pre-B versus T-ALL subtype, cytogenetics, and minimal residual disease response testing that can identify 1 in 100,000 leukemia cells. ALL therapy has several distinct phases, each with specific objectives. These phases are as following:
Induction : Four weeks of chemotherapy to induce a morphologic remission. Leukemia cell killing is highest in this month and patients are at very high risk for developing tumor lysis syndrome (see TLS section).
Consolidation : The goal in this 8-week period is to consolidate the remission but also to provide prophylaxis or treat the CNS, a common sight of recurrence.
Interim Maintenance : An 8-week cycle of intensified methotrexate, sometimes requiring inpatient admission.
Delayed Intensification : A reinduction and reconsolidation to intensify therapy one more time before moving to maintenance therapy.
Maintenance : Low-dose chemotherapy for 2–3 years, primarily taken orally at home to maintain a remission and eradicate any remaining leukemia cells.
Approximately 85% of pediatric patients with ALL are cured with the above therapy.
Chemotherapy for AML is more intensive than for ALL and results in significant myelosuppression. The prognosis for AML is worse than that for ALL, although subtypes of AML have been associated with better (NPM + and CEBPα +) and worse (FLT3-ITD) outcomes. Children with the best prognosis get four of five cycles of intensive chemotherapy. Those with a worse prognosis move to allogeneic bone marrow transplant after three cycles of intensive chemotherapy. Current cure rates for pediatric AML patients are 55% to 60%. CML is treated with an oral tyrosine kinase inhibitors (e.g., imatinib or dasatinib), possibly for life.
Lymphoma
Lymphomas are the third-most common malignancy of childhood. Approximately 60% of pediatric lymphomas consist of non-Hodgkin lymphoma (NHL), and the remainder is Hodgkin disease ( Table 8.2 ).
| NON-HODGKIN LYMPHOMA (60%) |
|---|
|
| HODGKIN LYMPHOMA (40%) |
Non-Hodgkin Lymphoma
NHL encompasses a heterogeneous group of diseases caused by neoplastic proliferation of immature lymphoid cells, which, unlike the malignant lymphoid cells of ALL, accumulate outside the bone marrow. Unlike adults, most cases of NHL in children are highly malignant and proliferate rapidly. The most common subtypes of NHL in children and adolescents are lymphoblastic lymphoma (30%); the mature B-cell lymphomas, including Burkitt’s and diffuse large B-cell lymphoma (50%); and the mature T-cell lymphomas, including anaplastic large cell lymphoma (20%). Distant noncontiguous metastases to the CNS and bone marrow are common.
Initial clinical manifestations may include fever, weight loss, prominent lymphadenopathy, and other nonspecific constitutional symptoms. Anterior mediastinal masses are associated with cough, wheeze, airway compromise, pleural and pericardial effusions, and superior vena cava syndrome (see anterior mediastinal mass, below). Gastrointestinal involvement, especially in Burkitt’s lymphomas, can result in rapid abdominal enlargement, pain, or ascites; intestinal obstruction occurs when the lymphoma serves as the lead point for an intussusception.
Each NHL subtype is treated differently but all involve aggressive multidrug chemotherapy. Radiation is avoided unless needed emergently or with recurrence. The therapy for lymphoblastic lymphoma is similar to that used for ALL. Therapy for Burkitt’s and diffuse large B-cell lymphoma is more intensive but of shorter duration.
Hodgkin Disease
Hodgkin disease accounts for 4% of all childhood cancer. Histopathologic subtypes are similar to those in adults: 40% to 60% nodular sclerosis, 10% to 20% lymphocyte predominance, 20% to 40% mixed cellularity, and 10% lymphocyte depleted. Its incidence has a bimodal distribution with peaks occurring at 15 to 30 years of age and after the age of 50 years. The most common presentation is painless firm lymphadenopathy involving either the supraclavicular or cervical nodes. Two-thirds of patients will also have mediastinal lymphadenopathy. Fever, night sweats, and weight loss, also termed “B” symptoms, occur in 30% of children. Staging and therapy is based upon histologic subtype, localized versus diffuse disease, presence of B symptoms, bulk of disease, and rapidity of response to initial therapy.
Most pediatric treatment protocols consist of multiagent chemotherapy, which may be combined with low-dose radiation therapy. The addition of radiation improves disease-free survival in children with bulk disease, those who present with B symptoms, and slow responders to inital chemotherapy but is avoided in females because of the risk for secondary breast cancer. Prognosis varies from a 90% to 95% cure of stage I disease to a 70% cure of stage IV disease.
Central Nervous System Tumors
Central nervous system (CNS) tumors are the most common solid tumors in children and are second to leukemia in overall incidence of malignant diseases. In contrast to adults, brain tumors in children are located predominantly infratentorial in the cerebellum and brainstem but can occur anywhere in the brain and spinal cord. Childhood brain tumors are usually low-grade astrocytomas or malignant neoplasms such as medulloblastoma. Infratentorial tumors may present with signs of increased intracranial pressure (ICP) (headache, nausea, emesis, lethargy, impaired upward gaze), nystagmus, ataxia, or cranial nerve deficits. Children with supratentorial tumors commonly present with signs of ICP, seizures, hemiparesis, or visual-field deficits. The treatment regimen depends on the histology, location, and staging of the tumor and the age of the patient. Surgery is undertaken to establish a diagnosis (biopsy), attempt maximal safe resection, and treat obstructive hydrocephalus. Radiation dose and volume (e.g., focal to the tumor bed, craniospinal, etc.) depend on tumor type and age (e.g., whole brain radiation is avoided in children less than 3 years of age). Many brain tumors are responsive to chemotherapy, which may even obviate the need for radiotherapy. Inhibitors of angiogenesis, molecularly targeted therapies, and immune-based therapeutics are being increasingly used and evaluated.
Neuroblastoma
Neuroblastoma accounts for 6% of all childhood cancers and in children is the most common solid tumor outside the central nervous system. Neuroblastoma is a malignancy of the primitive neural crest cells that form the adrenal medulla and the paraspinal sympathetic ganglia. Abdominal tumors account for 70% of cases, one-third of which arise from the retroperitoneal sympathetic ganglia and two-thirds from the adrenal medulla itself. Thoracic masses, accounting for 20% of the tumors, tend to arise from paraspinal ganglia in the posterior mediastinum. Neuroblastoma of the neck occurs in 5% of cases and often involves the cervical sympathetic ganglion.
Neuroblastoma represents a broad spectrum of disease. Although low-risk patients are often incidentally diagnosed, patients with high-risk disease are often ill, appearing with bone and bone marrow involvement. Symptoms depend on the location and spread of the tumor. Hypertension can result from compression of the renal vasculature by a large calcified abdominal mass or from tumor secretion of catecholamines. Thoracic or abdominal tumors may invade the epidural space posteriorly in a dumbbell fashion and cause back pain and symptoms of spinal cord compression. Children with neuroblastoma may be volume depleted secondary to chronic hypertension or diarrhea resulting from tumor production of vasoactive intestinal peptides.
The treatment of high-risk neuroblastoma is among the most intensive in pediatric oncology. The multidisciplinary approach includes chemotherapy, surgery, radiation therapy, stem cell transplant, and immunotherapy. Patients with low and intermediate risk disease may be treated with less intensive chemotherapy, surgery alone, or simply observation. Prognosis is dependent on age, stage, and histologic and molecular characteristics.
Wilms Tumor
Wilms tumor, a cancer of embryonal renal cells, accounts for 5% of all childhood cancers and predominantly occurs in the first 5 years of life. Wilms tumor occurs frequently in the setting of additional genitourinary tract anomalies. Most children are diagnosed after incidental detection of an asymptomatic abdominal mass. Associated findings include microscopic or gross hematuria, and hypertension. Hypertension may occur from renin secretion by tumor cells or compression of the renal vasculature by the tumor. Local extension of the tumor often involves the renal vein and inferior vena cava, with occasional extension to the level of the right atrium. The lung is the most common site of distant metastases.
Unilateral Wilms tumors are treated, when possible, with surgical resection of the affected kidney followed by chemotherapy. Unresectable tumors are treated with neoadjuvant chemotherapy. Radiotherapy may also be added for patients with higher stage disease. When the tumor is bilateral, presurgical chemotherapy is performed to shrink the tumors in an attempt to salvage some renal function, after which local tumor excision is attempted. Tumors with favorable histology, such as classic nephroblastoma, have a better than 90% overall survival rate. Tumors with unfavorable histology, such as anaplastic or sarcomatous variants, have a much lower survival rate.
Bone Tumors
Primary malignant bone tumors account for 4% of childhood cancer and consist primarily of Ewing sarcoma and osteogenic sarcoma.
Ewing Sarcoma
Ewing sarcoma, an undifferentiated sarcoma that arises primarily in bone, occurs mostly in adolescents. The most common presenting symptoms include pain and swelling at the site of the tumor. The most commonly involved sites are the femur (20%), pelvis (20%), fibula (12%), humerus (10%), and tibia (10%). Systemic manifestations are more common with metastases and include fever, weight loss, and fatigue.
Treatment consists of chemotherapy, surgery, and/or radiation therapy to provide local control of the primary tumor. If the tumor affects an expendable bone (proximal fibula, rib, or clavicle), complete surgical excision may be indicated. Patients with Ewing sarcoma are presumed to have micrometastatic disease at the time of diagnosis. As a result, chemotherapy is used not only to reduce the size of the primary tumor, but also to eradicate micrometastases. The prognosis is generally good (~75% survival) for patients with distal-extremity nonmetastatic tumors. Children with metastatic disease at diagnosis or tumors of the pelvic bones or proximal femur have less favorable outcomes.
Osteogenic Sarcoma
Osteogenic sarcoma (or osteosarcoma), a malignant tumor of the bone-producing osteoblasts, arises in the medullary cavity or the periosteum. The primary tumor is usually located at the metaphyseal portion of bones associated with maximum growth velocity (e.g., distal femur, proximal tibia, and proximal humerus) and occurs mostly during early adolescence. Similar to Ewing sarcoma, pain and localized swelling are the most common presenting complaints; but in contrast to Ewing’s sarcoma, systemic manifestations are rare. At diagnosis, 20% of patients have clinically detectable metastatic disease and most of the remaining patients have microscopic metastatic disease. Neoadjuvant and postoperative chemotherapy increases disease-free survival to greater than 70%. Osteogenic sarcomas are not radiation sensitive tumors, so complete resection of all known sites of disease is critical for cure. When feasible, limb-salvage surgical procedures are performed to limit resection to the tumor-bearing portion of the bone.
Chemotherapeutic Agents
A variety of classes of chemotherapeutic agents are used in children, depending on the particular type of malignancy and its progression. All chemotherapeutic agents have adverse effects. In particular, the anthracyclines—doxorubicin and daunorubicin—are associated with cardiac toxic effects. Atrial and ventricular conduction disturbances may occur acutely, and left ventricular failure may occur in chronically treated children. Heart failure is associated with a cumulative dose in excess of 300 mg/m 2 , age less than 4 years, the use of additional chemotherapeutic agents, and mediastinal irradiation. Children who receive these drugs are assessed by echocardiography before initiation of treatment and at regular intervals during treatment. Other significant chemotherapy toxicities include pulmonary toxicity with bleomycin and renal toxicity with cisplatin. Methotrexate when given in high doses can lead to neurotoxicity, and acute liver or renal failure. Intrathecal chemotherapy can cause seizures and neurotoxicity. Antiangiogenic agents (e.g. bevacizumab) increase the risk for bleeding and delay wound healing; therefore, such agents should be discontinued for an appropriate interval before any major surgical procedure. The preanesthetic evaluation should include a review of all chemotherapeutic agents used, as well as the results of toxicity studies, such as echocardiograms.
Miscellaneous Problems in Children With Cancer
Bone Marrow Dysfunction
Bone marrow dysfunction is a common occurrence in children with cancer as a result of the tumor’s effect on the bone marrow or as an effect of chemotherapeutic agents. Most children’s hospitals have prophylactic transfusion guidelines for patients receiving chemotherapy, often permitting the hemoglobin level to fall to 7 to 8 g/dL and the platelet count to about 10,000/µL. Although well-tolerated by patients for daily activities, these guidelines are not appropriate for invasive procedures. The presence of mild to moderate anemia is not normally hazardous to otherwise healthy children, but it may pose a threat to oxygen delivery when chemotherapy-induced cardiac toxicity is also present. Clinically significant thrombocytopenia is usually considered to be a platelet count <50,000/µL and should be corrected before major surgery. Many oncologists perform routine minor procedures such as bone marrow aspirates with platelet counts as low as 20 to 30,000/µL. Thrombocytopenia is considered a contraindication to central regional anesthesia or peripheral nerve blocks in the area of large blood vessels.
Neutropenic children are at increased risk for serious infections. Anesthesiologists should take extreme care to perform procedures and handle intravenous lines with meticulous sterile technique in these children. All members of the anesthesia team should rigorously follow central line care-and-use standards for their institution.
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