Physical examination should include a detailed head and neck evaluation looking for fixed, hard cervical masses as well as common ocular presentations of the disease, including Horner’s syndrome, opsoclonus, proptosis, and periorbital ecchymoses. Skull based metastatic lesions may also be palpable. The abdominal exam should aim to assess for the presence of hepatomegaly and/or a fixed, hard abdominal mass, as primary tumors arising from the adrenal gland are most common. Lastly, a detailed neurologic exam specifically looking for an evolving paralysis is essential in all patients with NB until paraspinal masses have been ruled out.

The International Neuroblastoma Pathology Classification (INPC), established in 1999 and later revised in 2003, uses morphologic features including Schwannian stroma development, grade of neuroblastic differentiation, and mitosis-karyorrhexis index (MKI) to determine if neuroblastic tumors are of favorable or unfavorable histology (Table 31.2) [23, 24]. The INPC includes age at diagnosis as well, but the morphologic features alone have been found to be prognostic independent of age [25].

Undifferentiated and poorly differentiated NB are the most immature and aggressive of the neuroblastic tumors with no significant Schwannian stroma and composed of neuroblasts without or with neuropil, respectively (Fig. 31.3a). MKI can vary throughout the tumor cells. NB is one of the many small round blue cell tumors of childhood and when devoid of neuropil can be difficult to distinguish from other small round blue cell tumors such as lymphoma, osteosarcoma, rhabdomyosarcoma, and Ewing Sarcoma. Immunohistochemistry using antibodies that specifically interact with neural tissue such as synaptophysin and chromogranin, is often positive in NB. Ganglionic differentiation as well as the presence of significant Schwannian stroma in neuroblastic tumors are important in the histopathologic classification. In differentiating NB, more than 5 % of tumor cells show ganglionic differentiation (Fig. 31.3b). Ganglioneuroma is benign and composed entirely of mature ganglion cells (Fig. 31.3c; a variant of ganglioneuroma, the maturing ganglioneuroma is also benign but some ganglion cells are small and not fully developed). Ganglioneuroblastomas are composite tumors made of NB and ganglioneuroma . There are two variants: the intermixed ganglioneuroblastoma in which poorly differentiated neuroblasts are dispersed within the ganglioneuroma and the nodular ganglioneuroblastoma in which the NB component form separate grossly visible nodules.

Pathologic review of the bone marrow aspirate and biopsy from bilateral iliac crests as well as the primary mass should be performed in the evaluation of NB. Approximately ten core needle biopsies of the mass should be obtained for histopathologic diagnosis.

Current International Neuroblastoma Risk Group (INRG) pretreatment risk stratification takes into account disease stage, patient age, histopathology classification, MYCN amplification status, ploidy and allelic loss of heterozygosity at 1p or 11q. It is this risk stratification that determines the next steps in NB treatment (Table 31.3) [26].