Leukemia

The leukemias of infancy, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and juvenile myelomonocytic leukemia (JMML) occur at a rate of 51.7 per 1 000 000 infants [1], and account for only 2 percent of childhood leukemias. They are a disease in which a stem cell gives rise to an unregulated proliferation of cells termed “blasts.” The abnormal cells have an increased rate of proliferation and a decreased rate of spontaneous apoptosis which ultimately results in bone marrow failure.

Neonates with leukemia usually present with hyperleukocytosis and extensive tissue infiltration. Central nervous system (CNS) disease may be present, along with hepatosplenomegaly. Diffuse pulmonary infiltrates may cause tachypnea, and infants with AML may have subcutaneous nodules called leukemia cutis [6]. Older infants may present with nonspecific anorexia, fatigue, irritability, fevers, and bony pain. Bone marrow failure often results in bruising, bleeding, and pallor. Lymphadenopathy and hepatosplenomegaly may be noted. Compression of the airways by mediastinal lymph nodes can contribute to respiratory distress.

Genetic conditions that predispose to acute leukemia include Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Li–Fraumeni syndrome, and neurofibromatosis type 1.

Neonatal leukemia has a guarded prognosis despite aggressive chemotherapy. Acute lymphoid leukemia and AML have a five-year relative survival of 56.5 percent and 65 percent respectively in this age group; however, patients can experience late-effects from treatment, including neurologic and cardiac sequelae.

Neonatal or infant ALL may respond well to oral steroids alone, but typically multiple chemotherapeutic agents including vincristine, L-asparaginase, and daunomycin are used for induction. Consolidation involves agents (e.g., cytarabine) more typically used in patients with AML with an intensive schedule.

Acute myeloid leukemia is as common as ALL in neonates [1]. The presentation is similar in terms of bone marrow failure, but can also include “blueberry muffin” lesions which are subcutaneous nodules, gingival infiltrates, disseminated intravascular coagulation, and chloromas or granulocytic sarcomas [3].

Up to 10 percent of patients with Down syndrome develop transient myeloproliferative disease (TMD), which is a transient clonal myeloproliferation [6]. It may be associated with hepatomegaly and liver fibrosis. Clinically symptomatic patients are treated with low-dose cytarabine. Patients will need careful follow-up as 20 percent will develop AML within the first four years of life [3].

Juvenile myelomonocytic leukemia is a rare leukemia that affects children less than two years of age. It consists of a clonal proliferation of hematopoietic stem cells. Patients may have rashes, lymphadenopathy, splenomegaly and hemorrhage [6]. While most cases resolve spontaneously, monocytosis and splenomegaly may persist for several years and approximately 10 percent of patients have a fatal progressive disease [1].

Patients with leukemia may present for anesthesia for diagnostic and treatment purposes. Newly diagnosed patients may receive general anesthesia for central line placement and associated procedures, and it is important to avoid administering dexamethasone to minimize the risk of tumor lysis syndrome or chemotherapy protocol violation. It is also important to avoid placing rectal thermometers in infants that are immunocompromised.

CNS and Miscellaneous Intracranial and Intraspinal Neoplasms

Central nervous system, intracranial, and intraspinal neoplasms occur at a rate of 48.8 per 1 000 000 infants and have a five-year relative survival of 56.6 percent [1]. According to the World Health Organization (WHO), more than 100 categories and subtypes of primary CNS tumors occur in children [7]. Tumors of the CNS may be located in the supratentorial space, posterior fossa, parasellar region, or in the spinal cord. Infants are more likely than older children to present with tumors in the supratentorial space and the predominant tumor types are choroid plexus tumors and teratomas. There are several syndromes associated with pediatric brain tumors, including neurofibromatosis types 1 and 2 (NF-1/2), von Hippel–Lindau, tuberous sclerosis, Li–Fraumeni, Cowden, Turçot, and nevoid basal cell carcinoma [7].

The presenting symptoms for infants with CNS lesions vary depending on the location. Symptoms are usually due to increased intracranial pressure (ICP), are often nonspecific in infants, and may include vomiting, lethargy, irritability, and increasing head circumference. Infratentorial tumors may present with irritability due to headache pain, vomiting, papilledema, and nystagmus. Symptoms of brainstem tumors can include cranial nerve palsies and abnormal eye movements, weakness of an extremity, and upper motor neuron deficits. Supratentorial tumors present more commonly with focal neurologic deficits as well as a bulging fontanelle and the onset of seizures. Tumors of the parasellar may result in neuroendocrine abnormalities, failure to thrive, and visual abnormalities due to the proximity to the pituitary gland, optic pathways, and hypothalamus. Spinal cord tumors may present with crying and irritability due to pain and motor deficits as the tumor expands, causing compression within the spinal cord [7].

The evaluation of CNS tumors generally involves magnetic resonance imaging (MRI), which in most infants requires the administration of a general anesthetic to keep the child quiet during the imaging. In very young infants, swaddling and feeding the child just before the imaging has been successful. Tumors in the midline or suprasellar region should prompt an evaluation for neuroendocrine dysfunction. A lumbar puncture is indicated for tumors that are known to spread to the meninges, such as medulloblastoma/primitive neuroectodermal tumor (PNET), ependymoma, and germ cell tumors, but should be delayed until hydrocephalus and supratentorial midline shift is ruled out due to the potential for brain herniation and death [8].

Astrocytoma is the most common CNS malignancy of infancy and occurs at a rate of 15.5 per 1 000 000 infants and has a five-year relative survival of 76.5 percent [7]. It is most likely to occur in the cerebellum. Other locations include the hypothalamic/third ventricular region and the optic nerve and chiasmal region [7]. Astrocytoma tumors are graded I–IV according to their histological features as well as their clinicopathological characteristics. Pilocytic astrocytoma (PA) is a WHO grade I tumor because it has a low metastatic potential and rarely metastasizes [7]. There is a 15 percent incidence of PA of the optic nerve and chiasmal region in patients with NF-1. Fibrillary infiltrating astrocytoma is a WHO grade II tumor, which is still considered low grade. High-grade astrocytomas include anaplastic astrocytoma (WHO grade III) and glioblastoma multiforme (WHO grade IV), both of which have high malignant potential [7].

Treatment for astrocytomas in newborns and infants includes surgery and chemotherapy. Chemotherapeutic agents include carboplatin, vincristine, temozolomide, vinblastine, lomustine, and procarbazine [7]. Radiation is avoided for as long as possible because of potential long-term negative effects on brain development.

Ependymomas are tumors derived from the ependymal lining of the ventricular system. They are most likely to be in the posterior fossa. They are usually noninvasive, expanding in the ventricular system and eventually displacing normal structures, leading to obstructive hydrocephalus. Primary treatment is surgery, although chemotherapy and radiation are also indicated [7].

Choroid plexus tumors are rare, representing only 3 percent of all childhood brain tumors; however, most present within the first year of life. They are intraventricular epithelial neoplasms that arise from the choroid plexus. Tumors may be papillomas, which are considered low-grade tumors or carcinomas which are malignant tumors with the potential to metastasize to the CSF pathways [7]. The tumor is most likely to be supratentorial in the lateral ventricles. Choroid plexus papillomas have an excellent five-year survival rate of 95 percent, whereas choroid plexus carcinomas have a much poorer prognosis [7].

Primitive neuroectodermal tumors are malignant embryonal tumors. They can metastasize to the CNS and beyond and are classified as WHO grade IV tumors. Included in this group of tumors are medulloblastoma, supratentorial PNET, ependymoblastoma, medulloepithelioblastoma, and atypical teratoid/rhabdoid tumor (ATRT). Treatment can include surgery, chemotherapy, and radiation.

Craniopharyngioma is a rare pediatric tumor that is derived from ectodermal remnants, Rathke cleft, or other embryonal epithelium in the sellar or parasellar region [9]. The tumor usually arises in the region of the pituitary gland and endocrine abnormalities may be the presenting feature. Craniopharyngiomas are minimally invasive [7], but surgical resection can result in significant morbidity such as panhypopituitarism, growth failure, and visual loss due to the tumor location [7]. Life-threatening obesity in older children and adults can result from tumor resection due to damage to the hypothalamus [9]. Incomplete resection with less morbidity augmented by radiation to prevent local recurrence is one treatment approach.

There is significant morbidity associated with patients who survive neonatal brain tumors, including chronic neurologic deficits, seizure disorders, neurocognitive deficits, and neuroendocrine deficiencies [7]. Survivors are also at risk of secondary malignancies [7].

Infants with brain tumors undergo anesthesia for diagnostic neuroimaging, ventricular shunt placement, and surgical tumor resection. The preoperative assessment should include a thorough neurologic exam for signs of increased ICP. Typically premedication is not indicated. Anesthetic induction can be either intravenous or inhalational, depending on clinical symptoms. Intraoperative bleeding can be significant in tumor resections, and arterial line and large-bore intravenous catheters are essential. Blood should be immediately available. Positioning of the infant during tumor resection depends on the location of the tumor. In most cases, access to the airway will be limited; therefore careful attention should be made to securing the endotracheal tube (ETT) and to ETT positioning, especially if the infant is in the prone position with neck flexion. Intraoperative arterial blood gases, core temperature, urine output, and hemoglobin should be closely monitored. The operating room should be warmed and a forced-air warming blanket used to prevent hypothermia.

Neuroblastoma

Neuroblastoma is a malignancy that arises from primordial neural crest cells which usually develop into sympathetic ganglia and the adrenal medulla. Pathologically, neuroblastoma is a small, round, blue cell tumor. Neuroblastoma and neuroganglioblastoma occur at a rate of 51 per 1 000 000 infants, with a five-year relative survival rate of 92 percent [1]. These tumors are by far the most common malignancy of infancy, followed by retinoblastoma and lymphoid leukemia [1].

Familial neuroblastoma accounts for approximately 1–2 percent of all cases and is associated with a younger age at diagnosis. The tumor is also associated with Hirschsprung disease, central hypoventilation syndrome, NF-1, Beckwith–Wiedemann syndrome, and hemihypertrophy [10].

Approximately half of neuroblastoma tumors arise in the adrenal glands [10]. Prenatal diagnosis is possible, but the tumor is difficult to distinguish from other adrenal pathology such as hemorrhage [11]. Metastatic spread is uncommon in infants and neonates, and likely contributes to the favorable prognosis for this age group.

Presentation of neuroblastoma is dependent on the location of the tumor. Localized disease may present as an asymptomatic abdominal mass. Larger masses may present with symptoms of respiratory distress, dysphagia, or vocal cord paralysis. There may be symptoms of spinal cord compression, bowel or bladder dysfunction, and superior vena cava syndrome. Alternatively, patients may be asymptomatic with an incidental finding on chest X-ray [12]. Spinal cord and nerve root compression result from invasion of the neural foramina by paraspinal neuroblastoma.

There are a number of clinical syndromes associated with neuroblastoma [10]. The opsoclonus myoclonus ataxia syndrome is a paraneoplastic syndrome of autoimmune origin and is characterized by myoclonic jerking, random eye movements, and cerebellar ataxia. While tumors that present this way tend to have a good outcome, the syndrome does not necessarily improve with tumor removal. Pepper syndrome refers to disease with massive liver metastases which may cause respiratory distress due to hepatomegaly. Horner syndrome occurs with a thoracic or cervical primary tumor but does not resolve with tumor resection. Kerner–Morrison syndrome is intractable secretory diarrhea due to secretion of vasoactive intestinal peptides. Neurocristopathy syndrome occurs when neuroblastoma is associated with other neural crest disorders [10].

Prenatal suspicion of neuroblastoma is followed by measurement of tumor markers, including catecholamine metabolites homovanillic acid and vanillylmandelic acid in urine. Tumor biopsy confirms the diagnosis. Workup for metastatic disease includes CAT scan (CT) or MRI of the chest and abdomen, bone scans, and bone marrow aspirates and biopsies. MIBG (iodine-123 meta-iodobenzylguanidine) scans may be used to define metastatic disease.

Treatment for neuroblastoma varies depending on the patient’s age, tumor, and tumor biology. Patients who present with spinal cord compression may require urgent surgical intervention or chemotherapy. Low-risk tumors are treated with surgery. Intermediate-risk tumors are treated with surgery and chemotherapy. Patients with high-risk neuroblastoma undergo aggressive treatment with chemotherapy, autologous stem cell transplantation, surgery, radiation and immune modulation with 13-cis-retinoic acid, and monoclonal therapy. Chemotherapeutic agents used include cyclophosphamide, topotecan, doxorubicin, vincristine, cisplatin, and etoposide.

Infants and neonates with neuroblastoma will potentially undergo anesthesia for biopsies, port placement, and ultimately tumor resection. If neoadjuvant chemotherapy has been administered, the medications and potential effects on cardiovascular function must be noted. The preoperative evaluation should include a detailed history and physical examination for signs of respiratory distress, hypertension, and superior vena cava syndrome. Infants should be evaluated for associated syndromes such as congenital hypoventilation syndrome or Beckwith–Weideman syndrome. Preoperative imaging and laboratory values should be carefully reviewed. Large, abdominal operations can be accompanied by extensive blood loss due to the proximity of blood vessels to the tumor. Large-bore intravenous access and arterial monitoring are indicated. Infants undergoing abdominal procedures are at risk for hypothermia and increased evaporative losses. Careful attention should be paid to volume status and hemodynamic changes. Core temperature should be monitored and methods to prevent hypothermia should be used such as forced-air warming blankets, warmed irrigation fluids, and a warmed operating room. Patients may benefit from regional analgesia. Patients are typically cared for in the intensive care unit postoperatively.

Retinoblastoma

The rate of retinoblastoma diagnosis in infants is 27.7 per 1 000 000, with a five-year relative survival rate of 98.1 percent [1]. It is the most common primary intraocular malignancy of childhood and there are approximately 300–350 new cases each year [13]. Children with hereditary retinoblastoma suffer from loss of the retinoblastoma gene (RB1) and generally present at a younger age with multifocal and bilateral disease [14]. The classical presentation is leukocoria, which is a white pupillary reflex as opposed to the normal red reflex. The diagnosis is confirmed by a dilated fundoscopic exam under anesthesia. An MRI may be required to evaluate the optic nerve and pineal region of the brain. Many neonates can undergo MRI scanning without anesthesia by using a feed-and-swaddle technique. However, it may be necessary to provide general anesthesia for extended scans or if other procedures are needed.

The treatment for retinoblastoma needs to be prompt, and early intervention is aimed at saving the globe if not vision. Treatment may be via laser, brachytherapy, local chemotherapy, systemic chemotherapy, and surgery [13]. Chemotherapeutic agents may include carboplatin and vincristine with or without etoposide. Each of 4–6 cycles of chemotherapy involves an exam under anesthesia [13]. External beam radiation is utilized only if absolutely necessary for infants due to the potential for significant orbital hypoplasia, cataract development, and increased incidence of secondary tumors later in life for patients with the retinoblastoma1 (RB1) gene [13].

The prognosis for children with retinoblastoma is excellent in this country, where most are diagnosed early, prior to metastatic spread of the tumor. However, children with the RB1 germ line mutation are at significant risk for development of second malignancies, especially if radiation therapy was used during infancy [14].

Renal Tumors

Renal tumors occur at a rate of 15.3 per 1 000 000 in the infant population [1]. Five-year survival rates are excellent at 90 percent [1]. Renal tumors in children include Wilms tumor, mesoblastic nephroma, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney or renal cell carcinoma. Syndromes associated with renal tumors include Beckwith–Wiedemann, Denys–Drash, Simpson–Golabi–Behmel, and WAGR syndrome (Wilms, Aniridia, Genitourinary anomalies and mental Retardation) [15].

In the neonatal population, the most likely diagnosis for a renal tumor is congenital mesoblastic nephroma [16]. The vast majority of mesoblastic nephromas present prior to six months of age [15]. Prenatal ultrasound findings may include polyhydramnios, hydrops, and premature delivery [16]. Most patients not diagnosed prenatally will present with an abdominal mass. Patients may also present with hematuria and hypertension, as well as failure to thrive. The treatment for congenital mesoblastic nephroma is radical nephrectomy. Partial resections and positive margins are associated with recurrence of the tumor. Generally, chemotherapy is not indicated unless a patient is considered to be at high risk of recurrence [15].

Wilms tumor is an embryonal malignancy of the kidney and comprises about 20 percent of neonatal renal tumors [17,18]. Between 1 and 2 percent of patients have a familial case of Wilms tumor which has autosomal dominant inheritance with variable penetrance, and is more likely to present at a younger age and with bilateral disease [17]. Treatment for Wilms tumor is radical nephrectomy unless the tumor is bilateral. While some patients with early-stage tumors undergo surgery alone, most patients will also have treatment with chemotherapy and possibly radiation therapy. Lower-risk tumors are treated with vincristine and actinomycin. Higher-risk tumors may also be treated with doxorubicin, cyclophosphamide, and/or etoposide. As with mesoblastic nephroma, the most likely presentation is a palpable abdominal mass with increasing abdominal girth. However, imaging is more likely to demonstrate tumor invasion or thrombus in the renal vein or inferior vena cava (IVC) [15]. Patients may also present with hypertension (25 percent), hematuria (~20 percent), anemia, polycythemia, elevated platelet count, factor VII deficiency, and an acquired deficiency of von Willebrand factor [17]. Risk factors for local recurrence include advanced local stage, unfavorable histology, and spillage of tumor at the time of primary resection [12].

Other renal tumors in neonates are less common. Rhabdoid tumor of the kidney comprises approximately 11 percent of neonatal renal tumors [16]. The tumor is very aggressive and prognosis is poor, with an overall survival in neonates of <10 percent [15]. Metastases to lung, abdomen, lymph nodes, liver, bone, skin, and brain can be seen in nearly 10 percent of cases. Clear cell sarcoma of the kidney is also an aggressive tumor, with approximately 30 percent metastatic at diagnosis [15]. Early-stage tumors have an excellent prognosis. Treatment is radical nephrectomy, chemotherapy, and radiation.

Preoperative workup for infants with renal tumors is focused on cardiopulmonary and gastrointestinal function. Large tumors may impair gastric emptying and full stomach precautions may be indicated. While renal dysfunction is unusual, electrolytes may be abnormal if the patient has been vomiting and resuscitation may be warranted. Toxicity of chemotherapeutic agents should be considered. Intraoperative positioning requires additional consideration as the surgery may be prolonged. Intravenous lines should be placed above the diaphragm when possible in case of severe bleeding requiring cross-clamping of the IVC [12]. Access should be adequate for substantial blood loss in case of vascular involvement or injury. Ventilation may be quite challenging if a laparoscopic approach is planned, and discussion with the surgical team can be helpful in guiding the operative plan. Adjunctive regional anesthesia can be beneficial for postoperative pain control.

Hepatic Tumors

Hepatic tumors that present in the first year of life can be malignant or benign. Malignant hepatic tumors occur at a rate of 10.1 per million children less than one year of age and the vast majority of these tumors are hepatoblastoma [1]. The five-year relative survival of infant hepatoblastoma is 83.7 percent [1]. Benign liver tumors include hamartomas and vascular lesions such as hemangiomas [15]. A final common pathway for liver tumors that are not treatable with medical management or surgical intervention can be liver transplantation.

Vascular lesions are the most common liver tumor in neonates. Many vascular liver lesions involute after about one year. They are frequently associated with hypothyroidism due to activity of type 3 iodothyronine deiodinase. Patients may present in high-output cardiac failure due to hemodynamic shunting. Symptomatic vascular lesions require surgical intervention only if medical intervention fails. Medical treatment includes propranolol, corticosteroids, and vincristine. For lesions not amenable to resection, hepatic artery ligation or arterial embolization are potential options. Ligation of the hepatic artery renders the lesion ischemic and controls the arteriovenous shunting. The liver maintains blood supply via the portal system [15].

Mesenchymal hamartoma is a benign liver tumor that generally presents as a palpable but asymptomatic abdominal mass. Prenatal diagnosis is possible; hydrops fetalis may occur and alpha-fetoprotein may be elevated. These tumors can be difficult to diagnose radiographically since they are composed of both solid and cystic components. The natural history of mesenchymal hamartomas ranges from possible spontaneous regression to malignant degeneration. Treatment is generally surgical resection for tumors that do not regress with efforts toward negative margins.

Hepatoblastoma also presents with an enlarging abdominal mass. It is the most common liver malignancy in children and most cases occur in infancy [15]. The risk of developing hepatoblastoma is increased in premature infants, especially those with birthweight <1500 g [15]. Development of hepatoblastoma has been associated with hemihypertophy, Beckwith–Wiedemann syndrome, polyposis coli, Wilms tumor, and fetal alcohol syndrome [12]. Patients may have anemia, jaundice, and ascites upon presentation, but liver function tests are likely to be normal [12]. The alpha-fetoprotein level is usually markedly elevated; however, normal alpha-fetoprotein levels do not rule-out the diagnosis. Radiologic features of hepatoblastoma include large tumors, multifocal tumors, calcifications, and vascular invasion. Metastatic spread may be present at diagnosis and is most likely to be in the lungs, brain, and bone [15]. Hepatoblastoma is derived from primitive epithelial parenchyma and there are four histological variants including fetal, embryonal, macrotrabecular, and anaplastic. The anaplastic, or small cell undifferentiated has a very poor prognosis. The highest survival rate is associated with fetal histology. Outcome is dependent upon complete resection. Eighty-five percent of the liver can be resected and there is hepatic regeneration postoperatively [18]. Chemotherapy includes cisplatin with vincristine and 5-fluorouracil or doxorubicin [18].

Anesthesia for liver surgery in neonates is a highly specialized endeavor. Patients may present with large tumors causing hemodynamic and respiratory compromise. Neoadjuvant chemotherapy can have significant repercussions for the cardiac and respiratory systems. Furthermore, massive blood volume replacement intraoperatively can result in coagulopathies, acid–base imbalance, electrolyte imbalance, hypothermia, and compromised oxygen delivery.