We retrospectively reviewed neuroimaging examinations of 90 neuroblastoma patients whose cases were presented at neurooncology tumor board rounds over the previous 3 years at Memorial Sloan-Kettering Cancer Center (MSKCC). This series of patients does not represent the entire population of neuroblastoma patients treated at our institution, but represents a selected subset of patients with CNS manifestations. Most of these patients had primary or metastatic neuroblastoma confined to the spinal cord and paraspinal regions. These particular manifestations of the disease will not be emphasized in this review. Instead, this article will focus on the unusual manifestations of metastatic neuroblastoma involving the brain, skull, dura, and leptomeninges.

Skull—Metastatic involvement of the skull has been found in up to 25% of patients with neuroblastoma. Neuroblastoma is the most common malignant metastasis to the skull in children [3]. These calvarial lesions often extend to produce epidural deposits.

Metastatic involvement of the skull produces several possible radiographic findings: thickened bone, the so-called “hair-on-end” periosteal reaction, lytic defects, and separation of sutures. The differential diagnosis of multiple lytic skull lesions in a child includes Langerhans cell histiocytosis, leukemia, lymphoma, and sarcoma metastases [2, 4].

The sutural separation secondary to direct involvement of neuroblastoma is different from that found with generalized increased intracranial pressure. In neuroblastoma, the sutural separation is not uniform and the margins of the sutures are somewhat indistinct [3, 5] (Fig. 1). Extension of epidural deposits along the sutures produces erosion of the suture that then results in split sutures [4].

The hair-on-end appearance is a periosteal response to tumor cells extending from a calvarial metastasis (Fig. 2). The inner aspect of the periosteum is particularly resistant to penetration by tumor cells so the tumor, as it breaks out of the bone, lifts the periosteum, thereby producing plaquelike epidural deposits of tumor [2]. Skull metastases are often very subtle. Scalp lesions are a common accompaniment of calvarial metastases [4, 6] (Fig. 3).

Dura—Metastatic neuroblastoma has a predilection to metastasize to the dura (Fig. 4). Dural metastases tend to favor the external surface of the dura, spreading diffusely over both the convexities and base of the skull. The dura acts as a barrier to direct invasion, so involvement of the brain parenchyma is rarely seen [1]. Dural metastases are almost always associated with osseous metastases and can be hemorrhagic. Dural metastases may respond favorably to treatment (Fig. 5A, 5B).

Neuroblastoma commonly metastasizes to the base of the skull and orbits late in the disease. Both Langerhans cell histiocytosis and metastatic neuroblastoma characteristically involve the posterolateral part of the orbit where the frontal bone and greater wing of the sphenoid meet [7] (Fig. 6A, 6B).

Parenchymal metastases—Despite the high frequency of dissemination to the bone marrow, metastatic spread to the CNS, including involvement of either brain parenchyma or leptomeninges, has been rare. Like primary CNS neuroblastoma, which is even rarer, metastases are often hemorrhagic (Fig. 7A, 7B, 7C). Supratentorial lesions are more common than infratentorial lesions [8]. CNS involvement can be clinically occult and carries with it a poor prognosis.

Histologically, secondary forms of cerebral neuroblastoma are similar. They are highly cellular tumors. Grossly, they appear lobulated and well defined but frequently show cystic degeneration and blood staining of cysts and occasionally show extensive hemorrhages (Fig. 8A, 8B, 8C). Hemorrhage is uncommon in most other childhood cerebral neoplasms [2, 4].

Neuroblastoma should be considered in the differential diagnosis of a child with an intracranial mass. Some helpful distinguishing features, including frequent hemorrhage and calcification, have been reported.

Oligodendroglioma, astrocytoma, ependymoma, and other primitive neuroectodermal tumors must be included in the differential diagnosis [9].

Most CNS metastases are detected at the time of recurrence rather than diagnosis. The CNS is the sole site of recurrence in 64% of neuroblastoma patients. As the survival of children with metastatic neuroblastoma improves with recent advances in treatment, CNS involvement is being detected more frequently. The CNS can be a sanctuary site for cancer cells because the blood–brain barrier impedes penetration of most chemotherapeutic agents [10–12].

The MSKCC experience has confirmed the low but increasing incidence of CNS neuroblastoma as a complication of stage IV metastatic disease (Fig. 9A, 9B). Although the overall incidence rate for newly diagnosed patients is approximately 6.3%, among those who have recently been treated with intensive chemotherapy and immunotherapy, the incidence rate is 10% [13].

New regimens for the treatment of neuroblastoma have been developed including bone marrow transplantation and intensive chemotherapy and radiation, which may be changing the metastatic pattern of neuroblastoma. It is also possible that intensive chemotherapy leads to further genetic evolution of the tumors, with a change in metastatic potential [8].

Intraventricular and leptomeningeal metastases—An intraventricular location of metastasis appears to be exceptional: It was observed at diagnosis in only one patient in our series (Fig. 10A, 10B) and has not been reported previously to our knowledge.

Leptomeningeal metastasis is rare except in widely disseminated disease. In children, most leptomeningeal metastases are associated with medulloblastoma, ependymoma, and pineal gland tumors. Leptomeningeal metastases are very sensitive to radiation therapy [14]. The pathogenetic process leading to leptomeningeal involvement by extracranial neuroblastoma is uncertain. Neuroblastoma develops in the embryo from the neural crest, an ectodermal tissue with pluripotential differentiating capability. Investigators have postulated that leptomeningeal tissues, also derived from ectoderm, provide the appropriate “soil” to support metastasizing neuroectodermal tumors, such as neuroblastoma [15] (Fig. 11).

In one exceptional case in our series, progressive leptomeningeal metastases were detected in a 3-year-old girl over several months, with subsequent development of hemorrhagic transformation (Fig. 12A, 12B, 12C, 12D, 12E). To our knowledge, this is the first case of hemorrhagic leptomeningeal metastases reported in the literature.