Serum Biochemical Markers

••Ferritin Normal Elevated

••Lactate Dehydrogenase £1500 U/mL > 1500 U/mL

Trk-A, tyrosine kinase receptor A; MRP, multidrug resistance-associated protein.

*Corresponds to the most commonly used parameters in clinical practice for assessment of prognosis and risk stratification.

a It is not only the presence but also the amount of schwannian stroma that confers the designation of a favorable histology. At least 50% or more schwannian stroma is required before a

neoplasm can be classified as ganglioneuroblastoma or ganglioneuroma.

b Mitotic rate is classified as low (£10 mitoses/10 high power fields) or high (>10 mitoses/10 high power fields).

c Mitotic karyorrhexis index (MKI) is defined as the number of mitotic or karyorrhectic cells per 5000 tumor cells in random foci.

biologic characteristics (see below), while those with advanced stage disease have <20% 5-year survival, irrespective of other prognostic variables. In contrast, children older than age 5

years usually have extremely poor outcomes irrespective of stage.

Morphology is an independent prognostic variable in neuroblastic tumors.[112] An age-linked morphologic classification of neuroblastic tumors has recently been proposed that divides

them into favorable and unfavorable histologic subtypes. The specific morphologic features that bear in prognosis are listed in Table 10-11 .

Ploidy of the tumor cells correlates with outcome. In general, hyperdiploidy and near-triploidy have a correlation with young age, low stage, and a good prognosis, whereas diploidy, neardiploidy,

and near-tetraploidy are associated with an unfavorable outcome irrespective of age. For example, in infants and children younger than age 2 years who have advanced disease,

the presence of hyperdiploidy or near-triploidy correlates with response to chemotherapy and long-term disease-free survival, while corresponding diploid tumors have a significantly

worse prognosis (the beneficial prognostic effects of ploidy tend to be negated in older children with advanced disease).

Amplification of the N-myc oncogene in neuroblastomas is a molecular event that has possibly the most profound impact on prognosis. [116] N-myc is located on the distal short arm of

chromosome 2 (2p23-24). Amplification of N-myc does not karyotypically manifest at the resident 2p23-24 site, but rather as extrachromosomal double minute chromatin bodies or

homogeneously staining regions on other chromosomes ( Fig. 10-30 ). N-myc amplification is present in about 25% to 30% of primary tumors, most in advanced-stage disease. Up to 300

copies of N-myc have been observed in some tumors; the greater the number of copies, the worse the prognosis. N-myc amplification is currently the most important genetic abnormality

used in risk stratification of neuroblastic tumors (see below).

Partial gain of the distal long arm of chromosome 17 is the most common karyotypic abnormality in neuroblastomas, present in up to 50% of tumors.[117] The mechanism of 17q gain is

via an unbalanced translocation, where a portion of 17q is translocated to a partner chromosome (most commonly the distal short arm of chromosome 1, or the distal long arm of

chromosome 11). Partial gain of 17q demonstrates significant association with adverse outcome in neuroblastomas, independent of other prognostic variables.

Deletion of the distal short arm of chromosome 1 in the region of band p36 has been demonstrated in 25% to 35% of primary tumors.[118] In addition, constitutional deletions of 1p36 have

been demonstrated in a subset of patients with neuroblastomas. The loss of genetic material implies that one or more putative tumor suppressor genes in this region may be important in the

pathogenesis of neuroblastomas, but their identity remains elusive. At least two distinct loci of deletions on 1p36 have been identified. The first, more distal region appears to demonstrate

preferential loss of the maternal allele in tumors,

Figure 10-30Fluorescence in situ hybridization using a fluorescein-labeled cosmid probe for N-myc on a tissue section. Note the neuroblastoma cells on the upper half of the photo with

large areas of staining (yellow-green); this corresponds to amplified N-myc in the form of homogeneously staining regions. Renal tubular epithelial cells in the lower half of the photograph

show no nuclear staining and background (green) cytoplasmic staining. (Courtesy of Dr. Timothy Triche, Children's Hospital, Los Angeles, CA.)

Figure 10-31Wilms tumor in the lower pole of the kidney with the characteristic tan-to-gray color and well-circumscribed margins.

Figure 10-32Triphasic histology of Wilms' tumor: the stromal component is comprised of spindle-shaped cells in the less cellular area on the left; the immature tubule in the center is an

example of the epithelial component and the tightly packed blue cells, of the blastemal elements. (Courtesy of Dr. Charles Timmons, Department of Pathology, University of Texas

Southwestern Medical School, Dallas, TX.) Anaplasia in Wilms' tumor is characterized by cells with large, hyperchromatic, pleomorphic nuclei and abnormal mitoses (inset).

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