Extraneural Metastasis
Metastasis of primary central nervous system (CNS) tumors to locations outside the craniospinal axis is uncommon. Although the true incidence in children and adults is not known, overall rates from 0.4% to 33% are documented in different published series.1–3 More recent data suggest that higher estimated incidences of 20 to 30% should be expected.
Pathophysiology
Several theories have been proposed as to why primary CNS tumors rarely metastasize outside of the CNS. The classic theory, introduced by Willis4 in 1952, postulated four basic premises: First, the CNS does not have a lymphatic system, and consequently there is no lymphatic pathway between the brain or spinal cord to the surrounding soft tissues or regional lymph nodes, thereby preventing local spread of primary CNS tumors. Second, as rapidly expanding neoplasms compress surrounding tissues, the small venous channels that normally carry hematogenous metastases to distant sites are compressed, subsequently preventing the initiation of systemic metastases from the CNS. Third, patients with malignant brain tumors usually have significantly decreased survival rates. Because patients do not survive longer than a few years following diagnosis, they rarely live long enough to develop visible or symptomatic metastases. Fourth, neural elements do not grow into the tissues outside of the CNS, which could prevent metastases from flourishing in extraneural environments. Willis′s original premises have been challenged and refuted. The existence of lymphatic drainage of cerebrospinal fluid (CSF) into the extracranial tissues has been demonstrated.5 The fact that malignant CNS tumors can invade veins and be recovered from the venous blood of patients during and after surgery has been demonstrated by Morley6 and Smith et al.3 Successful extracranial growth of brain tumor cells has been demonstrated in the tissue model after transplantation of glioma cells into the pleural and peritoneal cavities.7 Battista et al7 demonstrated that anaplastic astrocytomas can grow and develop in extraneural sites in humans.
Nevertheless, extraneural metastasis of CNS tumors does occur, and a significant majority of patients who develop metastasis have undergone previous surgery for treatment of the primary tumor. Consequently, surgery has been implicated as a mechanism by which the blood–brain barrier is bypassed by tumor cells.8 Several theories of how surgery allows for extra-neural metastasis have been proposed. The induction of negative atmosphere in the cerebral veins during surgery may possibly develop a suction effect, leading tumor cells to enter the systemic circulation2 as previously stated, as was demonstrated by Smith et al3 in 1969. Infiltration by tumor cells into glial scar vessels may also allow systemic dissemination. These vessels have been theorized to be less easily compressible than normal vessels and more patent, allowing easier infiltration by tumor cells.9 Another possible way for tumor cells to metastasize is by invading the dura′s vascular structures at the surgical site.10,11 Lastly, disruption of normal anatomic barriers associated with surgery may allow the tumor cells to migrate into the bone and scalp flaps, permitting access to the lymphatic and vascular systemic circulation.12
Another important and well-known mechanism for the spread of tumors outside of the CNS is via shunting of CSF to the peritoneum, atrium, or pleural cavity. Wolf et al13 in 1954 were the first to propose a causal relationship between extra-neural metastasis and CSF shunts. Since then, several authors have reported the association between shunting and extraneural metastasis. Kleinman et al14 reported on 103 patients with extracranial medulloblastoma metastasis and found that 22% had been shunted. In a series of patients shunted prior to craniotomy for removal of medulloblastomas, the extraneural metastatic incidence was 15%.15 An autopsy series of patients with ventriculoatrial shunts demonstrated a fourfold increase in extraneural metastasis to the lung.14 Mechanistically, shunts become open conduits for intracranial neoplasms that have seeded the CSF into the abdominal or pleural cavities or the vascular system via the atrium. Attempts have been made to decrease the risk of metastasis by placing filters in the shunts. However, these filters increase the rate of shunt obstruction by causing blockage of the shunt by tumor cells. The preoperative shunting of medulloblastomas or ependymomas is not currently recommended.
Another proposed cause of increased reports of extraneural metastasis is the successful treatment of these tumors and the concomitant prolongation of life with aggressive multimodality therapy.1,8 Theoretically, the concept of exponential tumor growth suggests that with tumor cells doubling in number, a predictable increase in tumor mass over time can be ascertained.16 After 20 doublings, the average cancer cell reaches a volume of 1 mm3. After 30 doublings, it reaches a diameter of 1 cm. The average glioma is diagnosed at four doublings and is fatal at eight doublings. If a CNS tumor metastasizes at surgery, it would take 30 doublings to reach 1 cm3, a size that could be diagnosed. By increasing the patient′s longevity with aggressive therapy, the necessary doubling time is achieved for the extra-neural metastasis to be detected and diagnosed ( Table 32.1 ).
Aside from postsurgical and shunt-induced metastases, a population still remains with spontaneous extraneural metastases. Several cases of gliomas metastatic to bone marrow and distant lymph nodes prior to any surgery have been reported.2,17,18 In another compelling discussion, the authors question why there is no difference in the sites of metastatic implant in pre-operative and postsurgical patients.2,17 These rare cases represent spontaneous metastases and warrant further investigation into the mechanisms of primary CNS tumor spread.
Prior surgery |
Shunting |
Increased long-term survival |
Incidence of Extraneural Metastases in Children
The reported literature of extraneural metastases is summarized in Table 32.2 .18–34 Hoffman and Duffner27 reported the known cases prior to 1985. Based on these data, the most common expected lesion is medulloblastoma, followed by astrocytic tumors and ependymoma. As expected, all listed tumors are poorly differentiated and aggressive ( Table 32.3 ).
Medulloblastomas
The true incidence of extraneural metastatic medulloblastoma is not known. Different reports estimate ranges from 2 to 20%.14,15,33,35–37 Although glioblastoma multiforme is the tumor most prone to extraneural metastasis in the adult population,8 medulloblastoma metastasizes more commonly in children. There is no age-related predilection toward extraneural metastasis of medulloblastoma.17
In one series, extraneural metastases were seen in patients age 9 months to 43 years; the average age was 13 years.14 Thirty percent of patients with medulloblastoma and extraneural metastases manifested their metastases by age 3 years. Seventy percent were diagnosed by age 15 years. Medulloblastomas were found to undergo extraneural metastasis twice as commonly in males than in females. This matches the sex-linked incidence of primary medulloblastoma.38 The most common sites of extraneural metastatic medulloblastoma are bone, bone marrow, and lymph nodes39 ( Table 32.4 ). In one autopsy series, 82% of metastases were to bone, 65% were to lymph nodes, and 40% were to viscera.14 Other commonly reported sites include lung, pleura, liver, breast, and peritoneum.40 Of bony metastases, the most common sites are pelvis, femur, and vertebrae.14,41 Other reported bony sites include rib, humerus, tibia, scapula, skull, mandible, clavicle, and sternum.14 See Figs. 32.1–4 .
Astrocytic Tumors
The astrocytic tumors of glioblastoma multiforme and anaplastic astrocytoma less commonly produce extraneural metastases in children. One series reports an incidence of 12.5% in the pediatric population.2 There is no increased incidence based on age or sex.17 Common sites of extraneural metastasis are lung, lymph nodes, bone, pleura, and liver.2 In one series involving children and adults, 60% of extraneural metastases were to lungs or pleura, 51% were to lymph nodes, 30% were to bone, and 22% were to liver.2 Other sites included heart, adrenal gland, kidney, diaphragm, mediastinum, pancreas, thyroid, and peritoneum. Of lymph node metastases, 62% were to cervical nodes and 32% were to hilar or mediastinal nodes. Of bony metastases, 73% were to vertebrae ( Table 32.5 ).
Ependymomas
Roughly parallel to the incidence in the astrocytic tumors, ependymoma accounts for approximately 10% of extraneural metastases in the pediatric population.27 Incidence matches the age and sex predilections of the primary tumor. Common sites of extraneural metastasis include lung, lymph nodes, bone, pleura, and liver.8 There have been reports of ependymomas metastasizing to the skin ( Fig. 32.5 ). Extraneural medulloblastoma metastases are less common than CNS metastases. Fifty-three percent of all medulloblastomas spread in the CSF pathways.14 Extraneural metastases may be associated with recurrent primary tumor. An autopsy series found 87% of patients with extraneural medulloblastoma metastases to have recurrent tumor in the posterior fossa.14 At least one case report discovered an extraneural medulloblastoma metastasis before the primary lesion was diagnosed.42 Two cases have been reported in which no primary tumor could be found.14
Chordomas
Chordomas are rare tumors, and less than 5% of all chordomas occur in children and adolescents ( Fig. 32.6 ). Chordomas in children tend to occur at the skull base, namely the clivus and parasellar areas, and have a more aggressive phenotype than do adult chordomas. In a review of 73 cases, the incidence in females (58%) was slightly greater than in males, with an age range from 1 to 18, and a mean age at diagnosis of 9.7 years. Unlike adult chordomas, many chordomas of childhood lack physaliferous cells and are composed of poorly differentiated cells that may have necrosis and nuclear atypia.43 This more aggressive histopathological subtype, often called atypical or poorly differentiated chordoma, is more likely to occur in children under 5 years of age.43–45 Extraneural metastasis tend to occur more often in this younger age group. A review of 74 cases of childhood chordoma found a metastatic rate of 57.9% in children under 5 years of age (n = 21) compared with 8.5% in children 5 years of age or older (n = 53). The most common sites reported are lungs, followed by lymph nodes (cervical), bone, liver, kidney, adrenal glands, and heart.45–48
Other Tumor Types
Less is known about other tumor types. One series of primary pineal tumors with extraneural metastases reported 93% of these to be germinomas.49 Patients with primary pineal tumors tended to manifest their extraneural metastases between the ages of 3 and 34 years. In this series, males were seven times more likely than females to suffer extraneural metastases. Table 32.6 lists the pineal tumor locations. Meningeal tumors tended to metastasize to lung, pleura, lymph nodes, liver, and bone.17 Pituitary tumors metastasized to lung, lymph nodes, bone, muscle, and viscera.49 The remaining tumor types with rare extraneural metastases include choroid plexus carcinoma, pinealoblastoma, choriocarcinoma, gliosarcoma, oligodendroglioma, primitive neuroectodermal tumor, and germ cell tumor.19,24,26,27,31,32,34
Medulloblastoma |
Glioma |
Ependymoma |
Clival chordoma |
Pineal germinoma |
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