Overview of Pediatric Cancers

Introduction

The incidence of childhood cancer has been steadily increasing over the last few decades, from approximately 13 per 100,000 in 1975 to over 17 per 100,000 in 2005. While pediatric malignancies account for only 1% of all cancers diagnosed each year, cancer is the leading cause of death by disease in children aged 1–19 years. In the United States alone, each year an estimated 15,780 children and adolescents are diagnosed with cancer, and more than 40,000 children require cancer treatment. Despite the improvement in the cure rate, approximately 12% of children diagnosed with cancer do not survive, and cancer remains responsible for more deaths (57%) than all other diseases combined in children.

The incidence rate of cancer in children varies between races, with Caucasians followed by Hispanics having the highest incidence, while African Americans have the lowest incidence. Incidence rates also vary between high- and low-income countries. Countries with the lowest income have fewer medical resources, lack advanced diagnostic tools, and have limited access to cancer therapy. In addition, these countries have higher environmental exposures such as secondhand tobacco exposure, carcinogens in air pollution such as asbestos and silica dust, and unpurified water containing traces of carcinogens. The incidence of cancer in children also varies according to age and sex. Overall, leukemia is the most common cancer among children and adolescents, while neuroblastoma, Wilms tumor, and retinoblastoma predominate in infancy. Pediatric cancers, except for Wilms tumor, are slightly predominant in males. Fig. 45.1 shows rhe common pediatric malignancies and their incidence.

The majority of pediatric cancers have no known cause or risk factor, and only 10% can be linked to a familial or genetic factor. Specific prenatal and postnatal exposures have also been implicated in some childhood cancers. While a wide range of environmental agents has been thought to be oncogenic, thus far, only prior chemotherapy and high-dose radiation have been proven to be causal. Certain genetic and inherited conditions, such as Downs syndrome, Li Fraumeni syndrome, Beckwith-Wiedmann syndrome, neurofibromatosis, and cancer predisposition syndromes, have a higher risk of particular malignancies, requiring these patients to be screened for these malignancies periodically ( Fig. 45.1 ).

The survival rates of pediatric malignancies have improved significantly over the past 50 years, from less than 40% to as high as 80%. The mainstay of treatment for pediatric solid tumors (neural or nonneural) is chemotherapy for the overall reduction in tumor burden, along with a modality of local control. Local control is often achieved by surgical resection, radiation therapy, or a combination of both. The primary survival contributors have been early diagnosis and significant discoveries of new chemotherapeutic agents, which now constitute the standards of care for most of these malignancies.

Tables 45.1 and 45.2 summarize the classes of chemotherapy and radiotherapy for cancer treatment modalities, respectively.

Table 45.1

Classes of Chemotherapy Agents Used in Treatment of Childhood Cancers and Mechanisms of Action

Chemotherapy Class	Drug	Mechanism of Action
Antimetabolites
Antifolates	Methotrexate	Inhibition of dihydrofolate reductase (DHFR)
Purine antagonists	Cytarabine, 5-fluorouracil, gemcitabine	Addition of faulty purine analogs between DNA base pairs
Pyrimidine antagonists	Fludarabine	Addition of faulty pyrimidine analogs between DNA base pairs
Purine analog	6-Mercaptopurine	Inhibition of DNA polymerase leading to DNA breaks
Tubular interactive agents
Vinca alkaloids	Vincristine, vinblastine	Destruction of tubulin in microtubules leading to mitotic arrest
Alkylating agents
Oxazaphosphorines	Cyclophosphamide, ifosfamide	Intercalate DNA double strand
Nitrogen mustards	Busulfan, melphalan	Intercalate DNA double strand
Platinum complexes	Cisplatin, carboplatin	Intercalate DNA double strand
Topoisomerase inhibitors
Topoisomerase I inhibitors	Topotecan, irinotecan	Single-strand DNA breaks from inhibition of topoisomerase I
Topoisomerase II inhibitors	Etoposide	Double-strand DNA breaks from inhibition of topoisomerase II
Anthracyclines	Doxorubicin, daunorubicin	Formation of free radicals that lead to DNA breaks
Antibiotics	Bleomycin, actinomycin
Enzymes	l-Asparaginase	Cleavage of amino acid l-asparagine
Tyrosine kinase inhibitors	Imatinib, dasatinib	Prevent activation and phosphorylation of tyrosine kinase

Table 45.2

Type of Radiation Therapy Used in Pediatric Cancers and Their Characteristics

Photon Therapy	Proton Therapy
X-ray, a source of energy without mass	Heavy part of the atom
Higher entrance and exit dose	Relatively low entrance dose, no exit dose
Scattered spillage beyond the tissue/region of interest	Ability to tailor peak intensity in target tissue, and minimal spillage beyond tissue of interest
Higher dose and gradual dose gradient in tissue	Lower dose and steep dose gradient in tissue
Heterogeneous dose within the tumor	Homogeneous dose within the tumor
Increased risk of second malignancies and late effect	Very sensitive to tumor motion regression
Lower cost	Much higher cost

The field of surgical oncology has also undergone significant advances over the last few decades, with a shift in focus to finding surgical procedures with maximal therapeutic impact while limiting late effects on quality of life, which has improved outcomes. Unfortunately, many children who survive cancer still suffer from long-term sequelae of cancer treatments, with conditions such as mental disabilities, organ dysfunction, and secondary cancers. Developing more innovative and less damaging therapies is therefore crucial for pediatric malignancies. Cancers that are metastatic at diagnosis, those that do not respond to standard treatment, or progress/relapse despite appropriate treatment have poor survival rates (<20%).

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosis in children. It accounts for 20% of all cancers diagnosed in children and young adults. An estimated 3000 new cases of childhood ALL are diagnosed each year in the United States. After a peak incidence of 90 cases per million per year at the age of 2–3 years, ALL incidence rates decrease steadily into adolescence. Initial complete remission rates are achieved in 95% of patients. Survival in childhood ALL is approaching 90% through the application of reliable prognostic factors permitting risk-stratification-based treatment protocols. Unfortunately, relapse occurs in approximately 20% of cases, with higher relapse rates in older patients and infants less than 1 year of age. The standard of care therapy for ALL is based on different phases and spans a total duration of 2–3 years of chemotherapeutic regimens. Traditionally, risk stratification is based on patient age, leukemic blast count at diagnosis, and high-risk genetic markers (e.g., BCR-ABL fusion or MLL rearrangement). Despite excellent outcomes overall, patients with relapsed ALL outnumber nearly all other childhood malignancies. With traditional intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation, 30%–40% of all children with relapsed ALL can be cured.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the second most common type of leukemia in children, accounting for 15% of cases. It has a bimodal pattern of incidence, with most patients either being diagnosed in the first 2 years of life or during teenage years. Unfortunately, survival is poorer than that for ALL, with approximately two-thirds of patients surviving for at least 5 years. AML is associated with chromosomal abnormalities, including translocations (e.g., PML-RARA t15;17), gain or loss of chromosomes (chromosome 16), and other abnormalities (FLT3, MLL). The disease is characterized by leukemic cells proliferating in the bone marrow, which then interferes with the production of normal blood cells, leading to infections, bleeding, and other symptoms and complications. Similar to ALL, treatment risk grouping is based on molecular findings and the response to induction treatment. The relapse rate is high, with approximately 30% of children relapsing in the first 5 years. Treatment depends on the subtype and usually has a shorter duration but higher intensity than that of ALL. Most patients with relapsed disease are considered for stem cell transplantation.

Pediatric Lymphomas

Lymphomas are the third most common cancers in children. Hodgkin’s lymphoma and non-Hodgkin’s lymphoma are the main types of lymphoma in this age group. The most common presentation is painless lymphadenopathy with or without other symptoms such as fever, night sweats, and weight loss (known as B symptoms).

Hodgkin’s lymphoma is the most common type of lymphoma in children and is the most common malignancy that affects adolescents between 15 and 19 years of age. Non-Hodgkin’s lymphoma in children is usually of high-grade nature, with Burkitt’s lymphoma being an aggressive subtype. Both Hodgkin’s lymphoma and non-Hodgkin’s lymphoma can present as mediastinal masses. Lymphomas in the anterior mediastinum may risk significant respiratory or cardiovascular embarrassment (see Chapter 47 ). The role of surgery in the management of mediastinal masses depends on the primary diagnosis, the need for immediate decompression of vital organs, and the sensitivity of the tumor to chemotherapy or radiotherapy.

Bone Sarcomas

Osteosarcoma and Ewing sarcoma are the two most common malignant bone tumors in children and adolescents, with osteosarcoma being the most common. The peak incidence of osteosarcoma is around the growth spurt during adolescence and is rare before 5 years of age. Ewing sarcoma has a peak incidence in the preadolescent years. Both bone tumors present with pain and swelling. Diagnosis is usually delayed by 2–3 months, secondary to confusing it with sports-related injuries. The most common location for osteosarcoma is the metaphyseal region of the long bones, most commonly the femur. While the majority of Ewing sarcomas also arise from long bones, they mainly involve the diaphysis. Ewing sarcoma may also develop from the axial skeleton-like pelvis and chest wall, and very rarely from soft tissue.

Both tumors have different risk factors. Osteosarcoma is strongly associated with specific genetic syndromes, such as Li-Fraumeni syndrome, NF1, and Bloom syndrome. Ewing sarcoma has a strong racial predilection and is primarily seen in Caucasians, with almost none in children of African descent.

Bone cancer is diagnosed by biopsy. Open biopsy is preferred over core biopsy to obtain the highest chance of an accurate diagnosis. Magnetic resonance imaging (MRI) of the affected area may help determine the tumor size, the extent of local invasion into the soft tissue and neurovascular bed, and guide the surgeon during biopsy. Computed tomography (CT) of the chest is required to rule out metastatic pulmonary disease, and positron emission tomography (PET) helps diagnose distant metastasis. Ewing sarcoma can metastasize to the bone marrow; therefore bone marrow aspiration and biopsy are required for staging.

The treatment of these sarcomas includes neoadjuvant chemotherapy followed by resection of the primary tumor and adjuvant chemotherapy, with or without radiation. Ewing sarcoma is more sensitive to radiation than osteosarcoma.

Historically, local control of bone cancer has been attempted by amputation of the affected extremities. However, with advancements in surgical approaches, innovation in prostheses, and better disease control with chemotherapy, the management of bone tumors has changed dramatically. Limb salvage surgery is the procedure of choice for most patients, along with endoprosthetic reconstructive surgery with allograft or autograft. For adolescents who have not reached or are in their growth spurt, expandable prostheses are now available to avoid leg length discrepancy. Rotation-plasty is another recent surgical technique for patients with above-the-knee amputation. It is an excellent option for patients aspiring to return to sports. In rotation-plasty, after above-the-knee amputation, the ankle joint is rotated 180 degrees and attached to function as a knee joint. A below-the-knee prosthesis is then applied to complete the restoration.

For Ewing sarcoma of the axial skeleton, the surgical approach for local control depends on the location, extent of disease, and presence of metastatic disease. Hemipelvectomy for pelvic tumors and rib resection for chest wall tumors are the standard therapeutic options. In patients with nonresectable tumors, radiation therapy is an effective option for Ewing sarcoma but is not indicated for osteosarcoma. Radiotherapy is only used for emergent situations such as cord compression or palliative treatment in patients with intractable pain.

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric population, with a slight male predominance; it occurs more commonly in the first decade of life. Rhabdomyosarcoma accounts for 4.5% of all pediatric malignancies. Rhabdomyosarcoma is a heterogeneous tumor with distinct histologic subtypes that affects the prognosis of patients. Approximately half of rhabdomyosarcomas arise from skeletal muscle.

Any part of the body can be affected by rhabdomyosarcoma, including the orbit, head, neck, parameningeal space, and extremities. For extensive disease or metastatic spread at presentation, it is essential to discern the primary disease site to inform treatment decisions and prognosis. Patients are stratified into low, intermediate, and high risk based on histology, location of the primary tumor, extent of the disease, nodal involvement, and metastatic spread. In addition, four groups are formed based on how resectable the cancer is and the resection status of the tumor (residual disease postsurgical).

The overall survival rate for nonmetastatic disease is close to 70%. The treatment involves a combination of systemic chemotherapy and surgery, with or without radiation, for local control. For tumors that are considered resectable with negative margins, surgery is preferred before chemotherapy. For large tumors surrounding vital or neurovascular structures, chemotherapy is preferred before surgery to reduce the disease mass and make it surgically resectable. After resection, all patients with any residual tumor, positive margins on resection, or suspicious lymph node involvement receive adjuvant radiation. For patients in whom complete resection was not achieved during the first surgery and radiation is not an option due to age or site of disease, a second-look surgery can be considered to achieve cure.

Solid-Organ Tumors: Wilms Tumor and Hepatoblastoma

Wilms tumor is the most common primary malignant tumor of the kidney in children. The mean age at diagnosis is3 years, and the prognosis is generally very good with current treatment modalities. The most common presentation is a painless abdominal mass palpated by a caregiver during bathing. Uncommonly, it also presents with hematuria and hypertension. The diagnosis is based on abdominal MRI, which provides information regarding tumor size, extent, proximity to surrounding structures, and the contralateral kidney’s involvement.

Surgery is the mainstay of treatment. Biopsy of the tumor without resection is not recommended because of the upstaging of cancer secondary to local spread from capsule break. The most common surgical procedure performed for a unilateral Wilms tumor is radical nephrectomy, which includes the whole kidney, ureter, fatty pad around the kidney, and lymph node sampling. Postsurgical chemotherapy is administered to the majority of patients to reduce the risk of recurrence.

In cases where the tumor has spilled from the renal capsule or the tumor is believed to be unresectable, preoperative chemotherapy is administered to control the local spread or shrinking the mass to improve resectability. Preoperative chemotherapy is used in bilateral Wilms tumors to salvage any functional kidney. When such a salvage procedure is not possible or fails, bilateral radical nephrectomy with renal transplant is the only option available.

Hepatoblastoma is the most common liver malignancy in pediatric patients. This rare tumor is a disease of early childhood. Like Wilms tumor, hepatoblastoma has been associated with overgrowth syndromes such as Beckwith-Weidemann syndrome and familial adenomatous polyposis. Most patients present with an asymptomatic abdominal mass. However, in some patients, anorexia and weight loss might be seen due to the mass effect of an enlarging tumor. Although hepatoblastoma arises from the liver, elevated liver enzymes and liver dysfunction are rarely seen. Alpha-fetoprotein, a tumor marker, is elevated in most patients and can serve as a marker for disease persistence and treatment monitoring. The use of imaging is standard for diagnosis; MRI of the abdomen is helpful to evaluate the disease extension, and CT of the chest is helpful to assess for metastatic pulmonary disease. Biopsy is usually indicated for diagnosis. If the tumor is thought to be resectable, attempts are made for complete resection. Historically, surgery with resection alone was the treatment for these tumors, but we now know that chemotherapy plays a significant role in curing hepatoblastoma, along with surgery. For most tumors, a course of preoperative and postoperative chemotherapy is indicated.

Central Nervous System Tumors

Central nervous system tumors are the most common solid tumors in children. There have been significant advances in managing children with central nervous system tumors in the past few decades, but these are still associated with high morbidity and mortality rates. It is estimated that in the United States, 4700 new patients are diagnosed with central nervous system tumors annually, with the majority being malignant. Juvenile pilocytic astrocytoma is the most common central nervous system neoplasm, while medulloblastoma is the most common central nervous system malignant tumor. The most common presentation is increased intracranial pressure, manifested by headache, vomiting, and altered mental status. Depending on the tumor location, patients may have motor weakness, sensory changes, seizures, or cranial nerve neuropathies. The incidence varies with age, with younger patients mostly having tumors of embryonal origin and older children having tumors of glial origin. However, overall survival has improved in the last few decades due to advances in chemotherapy, radiation therapy, and surgical techniques.

A gross total resection is performed whenever safe and feasible. Chemotherapy and radiation therapy are typically administered following surgery for malignant tumors, except for chemoresistant tumors such as ependymoma. Local spread, such as leptomeningeal disease, is seen in some tumors such as embryonal neoplasms (medulloblastoma), while metastatic spread outside the neuraxis is uncommon. For benign tumors such as low-grade gliomas, surgery is the standard of care if feasible, and chemotherapy is reserved for nonresectable or progressive tumors. Radiation therapy is an effective adjuvant therapy for malignant central nervous system tumors and refractory central nervous system neoplasms. Some malignant central nervous system neoplasms with high neuraxis metastatic predilection also receive craniospinal radiation and focal radiation. The favored treatment modality is proton radiation, which is associated with fewer late effects in children younger than 10 years of age.

Preoperative Care for the Pediatric Patient With Cancer

The advancement of new oncologic treatments, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy, has brought more children to the operating/procedure room than ever before. Numerous procedures are performed in the operating/procedure room, including the following:

•

Primary tumor resection of solid tumors.
•

Secondary tumor resection (e.g., lung metastasis in Ewing sarcoma).
•

Gastrostomy tube placement to facilitate enteral nutrition.
•

Ventriculoperitoneal shunt placement for hydrocephalus in patients with central nervous system tumors.
•

Central line placement for chemotherapy.
•

Ommaya placement for interventricular chemotherapy delivery for central nervous system tumors and leukemia.
•

Palliative procedures such as chordotomy in patients with severe pain related to their tumor or chest tube placement for malignant pleural effusion.

Prior to any procedure, the surgeon and the anesthesiologist need to be familiar with the pathophysiologic effects of cancer, side effects of chemotherapy, radiotherapy, immunotherapy, and their interactions with anesthetics. Chemotherapeutic agents affect every organ system but affect the gastrointestinal tract, bone marrow, and lymphoreticular system most severely. The most common side effects of chemotherapeutic agents are nausea, vomiting, mucosal irritation, and bone marrow suppression ( Table 45.1 ). The team involved in the care of these patients needs to understand the previous chemotherapeutic agents and doses administered to plan for any expected toxicity or side effect. Radiation therapy also produces skin reactions that include inflammation, necrosis, and fibrosis that can compromise wound healing.

Every cancer patient should undergo a thorough assessment with a detailed medical history and a physical examination, emphasizing the patient’s functional status before any procedure. The medical history should include the type and location of the cancer, prior medical treatment, total doses received, date of previous therapy, a list of all medications taken within the last 6 months, a history of glucocorticoid administration, and a history of all allergies. This assessment should have all the elements considered essential to ensure safety, as outlined by the American Society of Anesthesiologists (ASA) guidelines of preanesthetic evaluation of patients. All patients should have basic laboratory testing. Patients with complex preexisting conditions should have a thorough preoperative laboratory workup and blood cross-matched. A complete blood count should ideally have a platelet count of more than 50,000/mm³ to prevent excessive bleeding and a hemoglobin concentration of more than 8.5 g/dL. The indication for transfusions should be based on expected surgical bleeding and patients’ cardiorespiratory function. Coagulation studies should be performed as part of the screening for bleeding diathesis before invasive procedures. A full electrolyte panel should be obtained because electrolyte abnormalities and kidney dysfunction are common in pediatric oncology patients secondary to chemotherapy administration and dehydration. Patients who have received anthracyclines require a preoperative electrocardiogram (ECG) to rule out cardiac toxicity. Patients with ST-wave changes, decreased QRS voltage, or arrhythmias on their ECG should have an echocardiogram. Chest radiographs should be obtained, especially in patients with symptoms of cough, dyspnea, orthopnea, respiratory distress, and any patient with an abnormal physical examination and history of lung exposure to toxic chemotherapy such as bleomycin has a high likelihood of producing respiratory side effects.

The fasting (nil per os, NPO) guidelines for pediatric patients with cancer are the same as those for healthy pediatric patients ( Table 45.3 ). However, investigators have found that 1 h of fasting for clear liquids is sufficient for elective pediatric general anesthesia on the premise of no increased risk for pulmonary aspiration. ^, Most orally or intravenously administered medications are continued on the day of surgery, especially anticonvulsants, gastrointestinal reflux prophylaxis, and asthma medications. Anticoagulants should be withheld according to recommended guidelines before any procedure. Age of the patient, grade ≥III ASA, history of prematurity, and break in fasting guidelines are independent risk factors to predict extended postoperative ICU admission and risk of mortality in pediatric patients.

Table 45.3

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