Congenital Malignant Disorders

Genetic Predisposition Syndromes and Congenital Defects

The cause of cancer in children is multifactorial, involving both genetic and environmental factors. However, in neonates, predisposing genetic factors more often play an important role. An acquired or inherited abnormality of a cancer-predisposing gene that is critical during embryogenesis underlies some cases of neonatal cancer, and the malignant transformation of normal cells results from the activation or suppression of these cancer-predisposing genes. The retinoblastoma gene at 13q is an example of a constitutional chromosomal abnormality that results in a high risk of malignancy.

A number of defined hereditary conditions and genetic defects are associated with an increased incidence of specific neoplasms; these are listed in Table 73.3 . Except for retinoblastoma, hepatoblastoma, and Wilms tumor, the neoplasms associated with these syndromes seldom manifest themselves in the neonatal period, but the associated abnormalities may be recognized early, allowing regular screening. A lack of a family history should not dissuade the clinician from investigating these syndromes, as both spontaneous germline mutations and parental mosaicism occur. The genetic defect in many of these neoplasms has been identified. For example, the NF1 gene, located at 17q11.2, encodes a protein, neurofibromin, that normally acts as a guanosine triphosphatase–activating protein that downregulates the Ras signaling pathway. Children with neurofibromatosis 1 (NF1) are at increased risk of developing juvenile myelomonocytic leukemia (JMML), a rare but aggressive myeloproliferative neoplasm that is treated with hematopoietic stem transplant but has also been seen to spontaneously regress. In children with NF1 and JMML, the hematopoietic cells display loss of the wild-type NF1 gene and duplication of the mutant allele, thus resulting in the complete loss of the normal neurofibromin protein in the leukemia cells. This promotes cell growth because there is no functional “off” switch.

A large number of childhood tumors occur in association with congenital defects. For instance, Down syndrome has an increased association with both leukemia and transient myeloproliferative disorders (TMDs). Children with congenital aniridia have an increased incidence of Wilms tumor. Although aniridia is found in only 1 in 75,000 persons, it is found in as many as 1 in 75 children with Wilms tumor. Children with abnormalities of the Wilms tumor 1 gene (WT1) , located at chromosome band 11p13, also have an increased risk of developing Wilms tumor. Most individuals with constitutional WT1 defects have associated phenotypic syndromes that include combinations of genitourinary abnormalities, renal dysfunction, and mental retardation. Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy syndromes are associated with several neoplasms. This syndrome is typified by macroglossia, gigantism, and abdominal wall defects; patients may also have visceromegaly, flame nevus, neonatal hypoglycemia, microcephaly, and retardation. Approximately 8% of infants with either the complete syndrome or the partial syndrome develop neoplasms, including Wilms tumor, adrenal cortical carcinoma, and hepatoblastoma—tumors of the same organs in which visceromegaly develops. Also reported are RMS, neuroblastoma, ganglioneuroma, and adenomas and hamartomas. BWS is linked with abnormalities of 11p15; this is the location of the insulin-like growth factor II gene (IGF2) and the tumor suppressor gene H19 .

Transplacental Tumor Passage

An exceedingly rare cause of cancer in neonates and infants is the transplacental passage of tumor cells from the mother. Rare cases of transplacentally transmitted cancer have been reported. The malignancies transmitted include leukemia, melanoma, lymphoma, hepatic carcinoma, and lung cancer. The diagnosis of transplacentally acquired neoplasm usually occurs at birth but has been reported as late as age 8 months. The frequency of concurrent maternal malignancy in pregnant women is estimated at 1 per 1000 pregnancies, and alternative treatment plans or delays in treatment are options for pregnant women. That transplacental transmission is so rare is attributed to the protective function of the placenta.

Twin-to-Twin Transmission

The risk of development of leukemia is increased in a monozygotic twin. If one monozygotic twin has leukemia, the cotwin has an approximately 25% chance of developing leukemia, usually within weeks or months of the diagnosis in the sibling. In contrast, a dizygotic twin has only a slightly increased risk of developing leukemia. This increased incidence is likely due to in utero twin-to-twin transmission of a preleukemic clone rather than the simultaneous development of a shared germline mutation facilitating the later development of leukemia.

Environmental Factors

Environmental factors are probably less important in the development of neonatal cancer compared with their role in the development of cancer in older children and adults. Nonetheless, there is evidence that environmental influences, including radiation exposure, maternal medication use, and various environmental exposures, may affect the incidence of neonatal cancer.

Exposure to ionizing radiation during pregnancy is known to increase the risk of a number of tumors, including acute leukemia, in exposed offspring. There appears to be a dose-response relationship between the dose of ionizing radiation received by the fetus in utero and the subsequent development of cancer in childhood, with doses on the order of 10 milliGray sufficient to produce an increase in risk. Mixed evidence comes from atomic bomb survivors who were exposed to radiation in utero. Maternal exposure to ionizing radiation should be used sparingly and only for diagnostic purposes if required.

Maternal exposure to some drugs during pregnancy has been associated with the subsequent development of cancer in offspring. Maternal use of diethylstilbestrol has been strongly associated with the development of clear cell adenocarcinoma of the vagina and cervix in daughters born from those pregnancies. Some substances and exposures known to be teratogenic may also be carcinogenic to offspring. Excessive maternal alcohol consumption may be linked to an increased risk of developing cancer in the newborn period, particularly acute myeloid leukemia (AML). The use of fertility drugs does not appear to increase the risk of cancer in the exposed offspring.

Environmental exposures of the mother or father to hydrocarbons, dyes, and other chemicals and solvents may be related to the development of neonatal tumors, but there is only a weak association for most of the risk factors identified. The association of neoplasms with other environmental factors, such as maternal use of tobacco, has not been conclusively proven.

Overview

Neuroblastoma is the most common malignant tumor of infancy. It is of embryonal origin, derived from neural crest cells that have committed to the sympathoadrenal lines. The tumor can present in utero, in infancy, and in childhood; the age of presentation significantly affects the prognosis and treatment plans. Because, in part, of improvements in prenatal ultrasonography, neonatal neuroblastoma is now diagnosed in more children; neuroblastoma is diagnosed in approximately 100 children per year in North America prenatally or at age less than 3 months. Neonatal neuroblastoma (defined as age younger than 28 days) represents 5% of neuroblastoma cases.

Etiology

Neuroblastoma can be associated with genetic disorders but does not have a single cause. The incidence is increased in patients with Turner syndrome, Noonan syndrome (in 50% of Noonan syndrome patients the PTPN11 gene is mutated, which is associated with an increased risk of leukemia and neuroblastoma), and Costello syndrome. While NF1 mutations have been detected in neuroblastoma cell lines, patients with germline NF1 mutations do not have a predisposition to neuroblastoma. Neuroblastoma is seen in BWS and other overgrowth disorders; abdominal ultrasonography is recommended quarterly until age 8 years for early detection. Congenital central hypoventilation syndrome (specifically the PHOX2B mutation) and Hirschsprung disease are associated with increased risk of neuroblastoma and ganglioneuroblastoma. There are cases of familial neuroblastoma; in 80% of these cases the anaplastic lymphoma kinase (ALK) receptor has been found to be mutated, although there are no phenotypic abnormalities. In addition to germline mutations in the familial cases, somatic ALK mutations are found in up to 12% of sporadic neuroblastoma tumors.

Presentation

In children, symptoms of neuroblastoma are often due to a mass effect in the compartment of tumor origin. Among all pediatric neuroblastoma cases, two-thirds of cases occur within the abdominal cavity; most of these occur in the adrenal glands. Abdominal distention is a common initial presentation. However, neuroblastoma can occur anywhere along the sympathetic chain and is sometimes incidentally found on chest x-rays. Neuroblastoma in the posterior mediastinum can present as bronchial obstruction. Neuroblastoma arising in the sympathetic paraspinal ganglia may invade the neural foramina, causing spinal cord compression with associated neurologic symptoms. Tumor cells can also rarely be found circulating on review of the peripheral blood smear ( Fig. 73.1 ).

In the newborn, neuroblastoma presents commonly as an asymptomatic adrenal mass found on routine ultrasonography in the third trimester, but it most often manifests as stage 4 S (now referred to as stage MS and inclusive of patients up to 18 months of age) neuroblastoma with hepatomegaly, seen in 65% of cases, followed by subcutaneous metastases, seen in 32% of cases. This metastatic pattern is different from that seen in older infants and children. Metastases to the lungs, bones, skull, and orbit are rare in the newborn, although clumps of tumor cells are often found in the bone marrow. In the newborn the primary site of disease often cannot be identified or may be a small adrenal primary tumor. Liver involvement can cause massive hepatomegaly, which can be a cause of dystocia during vaginal delivery. This massive involvement can also cause abdominal distention, coagulopathy, heart failure, and life-threatening respiratory distress ( Fig. 73.2 ), necessitating immediate chemotherapy. Subcutaneous skin nodules can be present; these are typically bluish, and palpation of the nodules leads to transient erythema followed by blanching, presumably because of the vasoconstriction caused by the release of catecholamines from the tumor cell.

The neoplasm may also arise in the neck or pelvis. Involvement of the stellate ganglion may result in Horner syndrome, which includes ptosis of the upper eyelid, slight elevation of the lower eyelid, meiosis, narrowing of the palpebral fissure, anhidrosis, and enophthalmos ( Fig. 73.3 ). Neuroblastoma arising from the paravertebral sympathetic ganglion has a tendency to grow into the intervertebral foramina, causing spinal cord compression and resultant paralysis. Careful periodic neurologic evaluation should be performed in a child with neuroblastoma in this region to evaluate the child for the onset of cord compression, which may necessitate emergency intervention with chemotherapy, surgery, or irradiation.

Unusual Presentations

Intractable diarrhea can be the sole presenting manifestation of neuroblastoma. Secretion of vasoactive intestinal peptide by the tumor has been postulated to be the cause of the diarrhea, which resolves following surgical removal of the tumor.

Opsoclonus and myoclonus (“dancing eyes, dancing feet”) are associated with neuroblastoma, although this presentation is only rarely seen in the neonatal period. Patients have rapid multidirectional eye movements (opsoclonus), myoclonus, and truncal ataxia (OMA) in the absence of increased intracranial pressure (ICP). The condition may be due to an autoimmune reaction, as the presence of antineuronal antibodies has been shown to be significantly more common in children with neuroblastoma and OMA than in case-controlled neuroblastoma patients. Removal of the tumor usually results in a decrease in neurologic signs and symptoms, but the use of steroids, intravenous (IV) gammaglobulin, and other immunosuppressive therapy such as cyclophosphamide or rituximab is frequently required for complete resolution. In general, the prognosis for survival of children with OMA is excellent, although long-term neurologic deficits and learning delays are common and can be quite debilitating.

Catecholamine Secretion

A hallmark of neuroblastoma cells is the ability to store and secrete catecholamines. Patients with neuroblastoma usually have elevated urinary levels of norepinephrine as well as its biochemical precursors and their metabolites. More than 90% of patients have an elevated urinary excretion of vanillylmandelic acid (VMA) or homovanillic acid (HVA) or both. VMA and HVA determinations can be made on random urine samples when values are normalized for creatinine concentration. In the occasional case with no elevation of catecholamine levels, a 24-hour urine collection is necessary. Catecholamine secretion can be used not only as a diagnostic aid but also as a means to assess the response to therapy and to detect tumor recurrence. Thus urine catecholamine levels should be measured before surgical removal of the tumor or before initiation of therapy.

Diagnosis

Clinical evaluation should include a physical examination with particular attention paid to detecting an abdominal mass, hepatomegaly, lymphadenopathy, Horner syndrome, and skin lesions; a baseline neurologic examination is also performed. Laboratory evaluation should include a CBC, tests for urine levels of VMA and HVA, and tests for serum ferritin and lactate dehydrogenase. While the initial imaging study in an infant is often abdominal ultrasonography, additional imaging to better delineate the tumor and to evaluate the infant for metastatic disease is needed; this should include computed tomography (CT) or MRI of the primary lesion. MRI of the spine should be performed for paraspinal and posterior mediastinal lesions. An [ ¹²³ I]metaiodobenzylguanidine (MIBG) scan is particularly important for diagnosis and follow-up. MIBG, a norepinephrine analogue specifically taken up by neuroblastoma in bone and soft tissue, serves as a sensitive modality (90% sensitive) for disease localization. Bilateral bone marrow aspiration (along with bilateral bone marrow biopsy in patients older than 6 months) is also part of the initial evaluation.

Histologic evidence provides confirmation of the diagnosis of neuroblastoma. Tissue may be obtained from a primary lesion or a metastatic site. Because tumor-specific biologic information plays a critical role in risk classification and treatment recommendations, obtaining adequate tissue for biologic studies is essential.

Pathologic Classification

Neuroblastoma is made up of small round blue cells that are uniformly sized and contain dense, hyperchromatic nuclei and scattered cytoplasm with stroma around it. Immunohistochemistry is positive for neurofilament protein, synaptophysin, neuron-specific enolase, ganglioside GD2, and chromogranin A, which distinguishes it from the other small round blue cell tumors of childhood. The histopathologic appearance of neuroblastoma ranges from undifferentiated neuroblasts, to more mature ganglioneuroblastoma, to fully differentiated and benign ganglioneuroma. The most widely used morphologic classification system is based on the system proposed by Shimada et al. in which tumors are classified as favorable or unfavorable. It is based on age, the amount of stroma, degree of neuroblastic differentiation, and the mitosis-karyorrhexis index. Further clarification with international agreement followed with the International Neuroblastoma Pathology Classification, which separates neuroblastoma into four categories: (1) neuroblastoma that is undifferentiated, poorly differentiated (<>5%); (2) ganglioneuroblastoma, intermixed; (3) ganglioneuroblastoma, nodular; and (4) ganglioneuroma.

Genetic Prognostic Factors: Tumor Biology

In addition to clinical factors and histology, a number of biologic factors have been shown to correlate with prognosis ( Table 73.6 ). Genomic data currently used in risk classification schemes include the status of the MYCN oncogene, tumor cell DNA content (ploidy), and the allelic status of chromosome arms 1p, 11q, 14q, and 17q. More recently, it has been found that any segmental chromosomal abnormality indicates a less favorable outcome.

Amplification of the MYCN oncogene is present in 16% to 25% of primary neuroblastomas and has been shown to correlate with poor prognosis independent of age, stage, and other genetic alterations. Patients with stage 1, 2, or 4 S disease demonstrate MYCN amplification only rarely; when present, it has been associated with rapid disease progression in these normally favorable stages. In a Children's Cancer Group study of stage 4 neuroblastoma in infants, the progression-free survival rate after 3 years was less than 10% in infants with tumors that demonstrated MYCN amplification, compared with 93% for those with single-copy tumors.

Total cellular DNA content also predicts response to therapy in infants with neuroblastoma. Diploid DNA content is an unfavorable prognostic factor, particularly in infants younger than 12 months. Infants with hyperdiploid tumors have a significantly better response to therapy than those with diploid tumors. Diploidy often correlates with tumor MYCN amplification, although in rare cases of hyperdiploidy with MYCN amplification, the MYCN amplification portends an unfavorable outcome.

Tumor karyotype also influences outcome. Loss of heterozygosity (LOH) of 1p occurs in up to 36% of primary tumors, and LOH at 11q23 is seen in 44% of primary neuroblastomas. Both are associated with poor outcomes, older age at presentation, and advanced-stage disease. Gain of 17q occurs in 60% of neuroblastomas and is associated with metastatic disease and unfavorable prognosis. Comprehensive genome-wide approaches such as comparative genomic hybridization are becoming increasingly useful in refining the prognostic accuracy of chromosomal alterations.

Staging

Neuroblastoma has traditionally been staged according to the International Neuroblastoma Staging System (INSS). Staging is based on age, disease site(s), and degree of surgical resection. New guidelines for a pretreatment risk classification system have been developed by the International Neuroblastoma Risk Group (INRG) Task Force and are being used in addition to the INSS summarized in Table 73.7 ; this system is undergoing evaluation in risk-based clinical trials. INRG stages include L1, localized tumor not involving vital structures (corresponds to INSS stages 1 and 2); L2, locoregional tumor with one or more image-defined risk factors (corresponds to INSS stage 3); M, metastatic disease (corresponds to INSS stage 4); and MS, metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow (corresponds to INSS stage 4 S). Two important differences in the INRG system compared with the INSS are that it is a radiologic rather than a surgical staging system and that the upper age limit for stage MS has been extended from 12 to 18 months.

Stage 4 <15% of marrow replacement by tumor), without radiographic evidence of skeletal metastases. There is lack of MYCN oncogene amplification in most INSS stage 4 S tumors, in contrast to INSS stage 4 tumors. Infants with INSS stage 4 >90%); spontaneous regression occurs without cytotoxic therapy in approximately 50% of cases.

Treatment

Treatment modalities for neuroblastoma include observation alone, surgery, chemotherapy, and radiation therapy or a combination of these. Patients with INSS stage 1 and INSS stage 2 neuroblastoma have a 96% to 100% survival rate with surgery alone. Isolated adrenal masses, the more common presentation among infants with neuroblastoma diagnosed prenatally, can be monitored closely for spontaneous regression if a tumor diameter meets the size criteria and if urine VMA and HVA levels are decreasing. Infants with INSS stage 3 and INSS stage 4 disease have a poorer survival, even with aggressive chemotherapy, although the outcome, with better than 70% surviving overall, is far better than the survival rate of 10% to 20% reported for older children with disease of these stages.

The unpredictable course of neuroblastoma, with its occasional spontaneous maturation or regression, not only makes this tumor unusual but also requires careful assessment of clinical and biologic risk factors in planning therapy. The type and intensity of treatment are determined by identification of infants with relatively good, intermediate, and poor prognoses on the basis of stage, international pathology classification, ploidy, segmental chromosomal abnormalities, and MYCN amplification. Patients who have localized disease (L1 or L2) without amplification of MYCN have an excellent prognosis, and such patients should undergo surgical resection or partial resection, but they likely will not derive any additional benefit from postoperative chemotherapy or radiation therapy. An exception to this is in the case of spinal cord compression, in which prompt decompression with chemotherapy (preferred), laminectomy, or local irradiation may be used to preserve function. The combination of extensive laminectomy with postoperative irradiation should be avoided because later spinal deformity is almost inevitable. Infants with stage 3 and stage 4 disease are usually treated with a combination of chemotherapy and local surgery, with radiation therapy given only as necessary to eradicate residual disease. The active drugs that are most commonly used include cisplatin or carboplatin, etoposide, doxorubicin, cyclophosphamide, and vincristine. Infants with stage 4 disease with amplification of the MYCN oncogene have a very unfavorable prognosis; standard chemotherapy regimens are not sufficient for cure. In these high-risk patients, intensive chemotherapy followed by myeloablative therapy with stem cell support may offer additional benefit. In addition, the use of the differentiation agent isotretinoin and the anti-GD2 antibody ch14.18 has been shown to improve outcome in patients with advanced-stage, high-risk neuroblastoma.

Infants with INSS stage 4 S disease have a highly favorable prognosis and may require minimal or no therapy. Because many patients undergo spontaneous regression, therapy should be directed toward supportive care, with use of chemotherapy and surgery restricted to relieving symptoms. The main cause of death in these patients is massive hepatic involvement resulting in respiratory insufficiency or compromise of renal or gastrointestinal function. Symptomatic patients are treated with chemotherapy. When there is a risk of organ impairment due to tumor bulk not responding to initial chemotherapy, low-dose radiotherapy can be considered (450 centiGray given in three fractions; in some cases not all three fractions are needed).

Prenatal Diagnosis

Neuroblastoma is increasingly being detected prenatally by screening ultrasonography. Newborns with adrenal or other mass lesions detected prenatally should be evaluated by urine catecholamine levels (although this has a low specificity) and follow-up ultrasonography. Careful observation may be adequate for infants with localized tumors, which frequently regress.

Epidemiology

Although leukemia is the second most common malignancy in infants, congenital leukemia, defined as leukemia diagnosed in the first 4 weeks of life, is quite rare. The incidence of leukemia in the first 3 months is approximately five cases per million. Two-thirds of congenital leukemia cases are classified as AML, in contrast to older infants and children, in whom ALL predominates. Congenital leukemia is associated with a high mortality with an overall survival rate at 24 months of only 20%, which is due to the aggressive biology of these leukemias and age-related treatment complications.

The cause of leukemia is unclear. In infants and older children a number of factors are associated with the development of leukemia; these include genetic factors, environmental influences, and immunodeficiencies. Genetic epidemiologic studies of infant leukemia indicate that most, if not all, cases are initiated in utero and involve acquired, noninherited genetic rearrangements; chromosome band 11q23 ( KMT2A , previously known as MLL ) is frequently involved. Leukemia-associated gene rearrangements have been retrospectively identified in archived newborn screen blood spots of children who subsequently developed leukemia. The Children's Oncology Group has reported a trend toward higher incidence of AML, but not ALL, in infants of mothers who consumed larger amounts of naturally occurring topoisomerase 2 inhibitors, such as those in foods high in flavonoids and phytates.