I specialize in CNS disease (primary) and especially brain metastasis [see: Kaniklidis C [38], below], so I will here undertake to correct some common misunderstandings concerning extraneural metastases, rare but real, at 3% - 5% incidence (I have dealt with numerous cases over the last two decades, as have my colleagues here in in the European neuro-oncology community [EANO: European Association of Neuro-Oncology]), and will also sketch out some answers to why brain tumors are resistant, but not impervious, to distant extracranial metastasis, and how such resistance can and has been overcome.

EXTRANEURAL METASTASES

We now know that it is not the case that brain tumor don't engender distant metastases (on this see also Christopher Duntsch's shrewd observations and recognition of some extraneural metastases, above): although extraneural metastasis (ENM) is a rare complication of brain tumors, and although almost 90 years ago, Percival Bailey and Harvey Cushing [1] claimed - incorrectly - that certain brain tumors never metastasize outside of the nervous system, that claim was immediately disproved 2 years later when the first case of extraneural metastasis from a primary brain tumor was published, and in the intervening decades we now have documented, incontrovertible evidence [2-16] of true distal (non-shunted-related) metastases from medulloblastomas, germinomas and non-germinomatous germ cell, glioblastomas (GBM), ependymomas, pilocytic astrocytomas, pinealomas, sympathoblastomas, reti-noblastomas, meningiomas and sarcomas (particularly monstrocellular) [17], and numerous pediatric brain tumors [18], with distant metastasis to visceral sites of pleura/lungs which are the most common metastatic sites [19, 12] and liver, bone [20], heart, adrenal gland, kidneys, diaphragm and mediastinum, pancreas, thyroid, and the peritoneum [20,21,12,] besides locoregional lymph nodes, among others of lesser incidence (such as head and neck [22]), and ranging from a low of 0.02% (in most GBMs [23]) to 5% (the high end especially in medulloblastoma [24]). Furthermore, given that one reason for the low incidence is the high early mortality [25] associated with most CNS tumors, then as survival is improved, which we are seeing currently, I would expect that the incidence rate will rise to threaten 10% approximately within the next decade as we have larger pools of survivors living long enough for extraneural metastatic migration and colonization to emerge more frequently.

CNS RESISTANCE TO METASTATIC MIGRATION

As to why brain and other CNS tumor rarely show distant metastases is still not wholly settled, but some hypotheses have been proposed:

1. Compressed survival (short life span of involved patients) due to aggressive disease, where such poor prognosis intrinsically eliminates or radically reduces the opportunity of detectable metastases [as per recent review of GBM [26]; and remember, distant extraneural metastases are usually asymptomatic and found only at autopsy [27].

2. Basement membrane barrier effect: the capillary basement membrane can act as a physical barrier against migration of the glioma cells into the blood stream in the brain [28].

3. The cellular CNS environment, because the CNS lacks ECM (extracellular matrix) components like collagen and fibronectin overexpressed only in hyperplastic blood vessels; since extracellular spaces have hyaluronic acid and other glycosaminoglycans are their major components, active tumor cells can migrate into the surrounding tissue, but being missing in the CNS extracellular substrate environment makes hematogenous metastasis to distant organs and viscera rare [29,30,31]. In addition, the CNS lacks a connective stroma, but since metastasization is largely based on the ability to invade the connective stroma, this limits opportunity for stromal-based spread [30].

MECHANSIMS ENABLING EXTRANEURAL METASTASES

Based on documented cases and review and critical appraisal I conducted of the best evidenced, I would posit five potential mechanisms that enabled extraneural spread and metastasis:

1) lymphatic cerebrospinal fluid drainage into the extraneural tissue (active even in the absence of an identifiable lymphatic system in the CNS);

2) venous invasion, via either the leptomeningeal sinuses or via the intracerebral vein;

3) direct invasion through the dura and bone or through tumor cell migration along the ventriculoperitoneal shunts.

These three - lymphatic drainage, the venous system and the adjacent dura and bone, have been evidenced as the three possible routes of extraneural spread [32], along with:

4) surgical damage to the blood–brain barrier (BBB), which has been described as allowing extraneural spread after neurosurgical operation [33] which can allow tumor cells may access to the lymphatic or blood circulation through the surgically compromised blood-brain barrier (BBB); and craniotomy with tumor resection also being associated with opening of brain vessels and consequent spread of tumor cells[34].

5) immunosuppression by repeated irradiation or chemotherapy [35,36].

And one final note: GBM cells in particular may have special propensity for extraneural spread, because of their high levels of proteases such as uKA (urokinase type plasminogen activator) and lower levels of their inhibitors (PAI-I) [37].

These five mechanisms therefore can overcome CNS resistance to extracranial spread and hence enable rare but now well-evidenced extraneural metastatic capabilities, showing finally that primary brain tumors do indeed possess the sufficient ability to grow outside the CNS. And as I predicted above, we are seeing more cases of extraneural metastases as we advance against CNS malignancies.

METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) and SCIRUS databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using SCIRUS (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Bailey P, Cushing HA: A Classification of Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis. 1926, p. 175.

2. Anzil AP: Glioblastoma multiforme with extracranial metastases in the absence of previous craniotomy. Case report. J Neurosurg 33(1): 88–94, 1970.

3. Awad I, Bay JW, Rogers L: Leptomeningeal metastasis from supratentorial malignant gliomas. Neurosurgery 19(2): 247– 251, 1986.

4. Dietz R, Burger L, Merkel K, Schimrigk K: Malignant gliomas-glioblastoma multiforme and astrocytoma III-IV with extracranial metastases. Report of two cases: Acta Neurochir (Wien) 57(1–2): 99–105, 1981.

5. Duffner PK, Cohen ME: Extraneural metastases in childhood brain tumors. Ann Neurol 10(3): 261–265, 1981.

6. el-Gindi S, Salama M, el-Henawy M, Farag S: Metastases of glioblastoma multiforme to cervical lymph nodes. Report of two cases. J Neurosurg 38(5): 631–634, 1973.

7. Glasauer FE, Yuan RHP: Intracranial tumors with extracranial metastases. J Neurosurg 20: 474–493, 1963.

8. Hoffman HJ, Becker EL, Jenkin D, Chuang SH, Munro IR: Extraneural metastases of a cerebral astrocytoma. Can J Neurol Sci 8(2): 115–119, 1981.

9. Hulbanni S, Goodman PA: Glioblastoma multiforme with extraneural metastases in the absence of previous surgery. Cancer 37(3): 1577–1583, 1976.

10. Leifer D, Moore T, Ukena T, Wilner D, Thor A, Hedley-Whyte ET: Multifocal glioblastoma with liver metastases in the absence of surgery. Case report. J Neurosurg 71(5 Pt 1): 772–776, 1989.

11. Pasquier B, Pasquier D, Lachard A, N’Golet A, Panh MH, Couderc P: Extraneural metastasis of central nervous system tumours (author’s transl). Bull Cancer 66(1): 25–28, 1979.

12. Pasquier B, Pasquier D, N’Golet A, Panh MH, Couderc P: Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer 45(1): 112–125, 1980.

13. Pasquier B, Keddari E, Pasquier D, Morens A, Courel MN, Girard N, Delpech B, Couderc P: Spontaneous bone marrow micrometastasis of a cerebral glioma Immunohistochemical diagnosis in a biopsy sample and review of the literature. Ann Pathol 6(2): 130–136, 1986.

14. Smith DR, Hardman JM, Earle KM: Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31(1): 50–58, 1969.

15. Yung WK, Tepper SJ, Young DF: Diffuse bone marrow metastasis by glioblastoma: premortem diagnosis by peroxidase–antiperoxidase staining for glial fibrillary acidic protein. Ann Neurol 14(5): 581–585, 1983.

16. Hoffman HJ, Duffner PK: Extraneural Metastases of Central Nervous System Tumors. Cancer 56: 1778–1782, 1985.

17. Zülch KJ. Spontaneous Intra- and Extracranial Metastases of Brain Tumors in Man — Artificial Seeding. Brain Tumors 1986; 183-189.

18. Rickert CH. Extraneural metastases of paediatric brain tumours. Acta Neuropathol 2003; 105(4):309-27.

19. Pasquier B, Lachard A, Pasquier D, Muller F, Couderc P, Courel-Vidard MN, et al. Costal micrometastasis from a cerebral astrocytoma. Immunohistochemical detection (author's transl)] Arch Anat Cytol Pathol. 1982;30:50–55.

20. Rajagopalan V, El Kamar FG, Thayaparan R, Grossbard ML. Bone marrow metastases from glioblastoma multiforme--A case report and review of the literature. J Neurooncol 2005; 72(2):157-61.

21. Moon KS, Jung S, Lee MC, Kim IY, Kim HW, Lee JK, et al. Metastatic glioblastoma in cervical lymph node after repeated craniotomies : report of a case with diagnosis by fine needle aspiration. J Korean Med Sci. 2004;19:911–914.

22. Seo YJ, Cho WH, Kang DW, Cha SH. Extraneural metastasis of glioblastoma multiforme presenting as an unusual neck mass. J Korean Neurosurg Soc 2012; 51(3):147-50.

23. Hsu E, Keene D, Ventureyra E, Matzinger MA, Jimenez C, Wang HS, et al. Bone marrow metastasis in astrocytic gliomata. J Neurooncol. 1998;37:285–293.

24. Thapa A. Pathology Of Brain Tumors. Presentation to the All India Institute of Medical Sciences. New Delhi, India. 2005.

25. Alvord EC Jr.: Why do gliomas not metastasize. Arch Neurol 33: 73–75, 1976.

26. Mentrikoski M, Johnson MD, Korones DN, Scott GA. Glioblastoma multiforme in skin : a report of 2 cases and review of the literature. Am J Dermatopathol. 2008;30:381–384.

27. Frappaz D, Jouvet A, Pierre GS, Giammarile F, Guyotat J, Deruty R, Jouanneau E, Ranchere-Vince D: Lack of evidence of osteo-medullary metastases at diagnosis in patients with high grade gliomas. J Neurooncol 52: 249–252, 2001.

28. Bernstein JJ, Woodard CA. Glioblastoma cells do not intravasate into blood vessels. Neurosurgery. 1995;36:124–132. discussion 132.

29. Giese A, Loo MA, Rief MD, Tran N, Berens ME. Substrates for astrocytoma invasion. Neurosurgery. 1995;37:294–301. discussion 301-302.

30. Pansera F, Pansera E. An explanation for the rarity of extraaxial metastases in brain tumors. Med Hypotheses. 1992;39:88–89.

31. Subramanian A, Harris A, Piggott K, Shieff C, Bradford R. Metastasis to and from the central nervous system--the 'relatively protected site'. Lancet Oncol. 2002;3:498–507.

32. Cervio A, Piedimonte F, Salaberry J, Alcorta SC, Salvat J, Diez B, et al. Bone metastases from secondary glioblastoma multiforme : a case report. J Neurooncol. 2001;52:141–148.

33. Huang P, Allam A, Taghian A, Freeman J, Duffy M, Suit HD. Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. J Neurosurg. 1995;83:308–315.

34. Wallace CJ, Forsyth PA, Edwards DR. Lymph node metastases from glioblastoma multiforme. AJNR Am J Neuroradiol. 1996;17:1929–1931.

35. Itoyama Y, Kouchi M, Yamashiro S, Yoshizato K, Kuratsu J, Ushio Y (1993) Combination chemotherapy with cisplatin and etoposide for hematogenous spinal metastasis of intracranial germinoma—case report. Neurol Med Chir (Tokyo) 33:28–31.

36. Asanuma M, Aoyama T, Sakai K, Asano K, Uehara T, Hongo K. Hematogenous extraneural metastasis of the germinomatous component of a pineal mixed germ cell tumor. Brain Tumor Pathol 2012; 29(4):245-50.

37. Bindal AK, Hammoud M, Shi WM, Wu SZ, Sawaya R, Rao JS: Prognostic significance of proteolytic enzymes in human brain tumors. J Neurooncol 22: 101–110, 1994.

38. Kaniklidis, C. CNS Metastasis from Breast Cancer – New Promise: A Review. [pending publication; available on ResearchGate profile].

I think its called brain tumour simply because of the location. A brain tumour can arise from a number of different cells, glial cells, astrocytes and so on.

In fact, ependimomas, astrocytomas, medullo- and glioblastomas are able to spread in spinal cord along the liquor pathways (spinal metastases).

Eventually, brain tumors are not able to metastase out of CNS neither lymphogenically, because of the lack of lymphatic drainage, nor hematogenically, because of the BBB peculiarities (tight junctions between endothelial cells and thick basement membrane)

I am not sure but metastasis can be blocking by blood-brain barrier?

According to the text book: A tumor consists of a mass of rapidly dividing cells. Mature neurons, however, have little or no capacity for mitosis and seldom form tumors. Some brain tumors arise from the meninges (protective membranes of the CNS) or arise by metastasis from tumors elsewhere, such as malignant melanoma and colon cancer. Most adult brain tumors, however, are composed of glial cells, which are mitotically active throughout life. Such tumors are called gliomas.Gliomas usually grow rapidly and are highly malignant. Because of the blood–brain barrier, brain tumors usually do not yield to chemotherapy and must be treated with radiation or surgery.

Gliomas are named according to the specific type of cell they share histological features with, but not necessarily originate from. The main types of gliomas are:

Ependymomas – ependymal cells.

Astrocytomas - astrocytes

Oligodendroglyomas - oligodendrocytes

Brainstem glioma — develop in the brain stem

Optic nerve glioma — develop in or around the optic nerve

Mixed gliomas, such as oligoastocytomas, contain cells from different types of glia.

High-grade gliomas are highly- vascular tumors, and have a tendency to infiltrate. They have extensive areas of necrosis and hypoxia of surrounding tissue. Often tumor growth causes a breakdown of the blood – brain barrier in the vicinity of the tumor. As a rule, high-grade gliomas almost always grow back even after complete surgical excision, and so are commonly called recurrent cancer of the brain.

On the other hand, low-grade gliomas grow slowly, often over many years, and can be followed without treatment unless they grow and cause symptoms.

Partly, but also we need to keep in mind the patient death before systemic manifestation. Occasionally, systemic metastases of some gliomas were reported.

I think ,Due to blood brain barrier malignant cells are not able to cross this barrier and metastases to other part of the body.

Interestingly, other malignancies with neuroectoderm origin localized out of neuraxis, for instance, esthesioneuroblastomas, malignant schwannomas, neuroendocrine tumors, not to mention about melanomas, are metastasizing quite well. On the other hand, primary CNS tumors with different origin from neuroectoectodermal (like PCNSLs or already mentioned meningiomas) are confined to the neuraxis as well as gliomas.

I specialize in CNS disease (primary) and especially brain metastasis [see: Kaniklidis C [38], below], so I will here undertake to correct some common misunderstandings concerning extraneural metastases, rare but real, at 3% - 5% incidence (I have dealt with numerous cases over the last two decades, as have my colleagues here in in the European neuro-oncology community [EANO: European Association of Neuro-Oncology]), and will also sketch out some answers to why brain tumors are resistant, but not impervious, to distant extracranial metastasis, and how such resistance can and has been overcome.

EXTRANEURAL METASTASES

We now know that it is not the case that brain tumor don't engender distant metastases (on this see also Christopher Duntsch's shrewd observations and recognition of some extraneural metastases, above): although extraneural metastasis (ENM) is a rare complication of brain tumors, and although almost 90 years ago, Percival Bailey and Harvey Cushing [1] claimed - incorrectly - that certain brain tumors never metastasize outside of the nervous system, that claim was immediately disproved 2 years later when the first case of extraneural metastasis from a primary brain tumor was published, and in the intervening decades we now have documented, incontrovertible evidence [2-16] of true distal (non-shunted-related) metastases from medulloblastomas, germinomas and non-germinomatous germ cell, glioblastomas (GBM), ependymomas, pilocytic astrocytomas, pinealomas, sympathoblastomas, reti-noblastomas, meningiomas and sarcomas (particularly monstrocellular) [17], and numerous pediatric brain tumors [18], with distant metastasis to visceral sites of pleura/lungs which are the most common metastatic sites [19, 12] and liver, bone [20], heart, adrenal gland, kidneys, diaphragm and mediastinum, pancreas, thyroid, and the peritoneum [20,21,12,] besides locoregional lymph nodes, among others of lesser incidence (such as head and neck [22]), and ranging from a low of 0.02% (in most GBMs [23]) to 5% (the high end especially in medulloblastoma [24]). Furthermore, given that one reason for the low incidence is the high early mortality [25] associated with most CNS tumors, then as survival is improved, which we are seeing currently, I would expect that the incidence rate will rise to threaten 10% approximately within the next decade as we have larger pools of survivors living long enough for extraneural metastatic migration and colonization to emerge more frequently.

CNS RESISTANCE TO METASTATIC MIGRATION

As to why brain and other CNS tumor rarely show distant metastases is still not wholly settled, but some hypotheses have been proposed:

1. Compressed survival (short life span of involved patients) due to aggressive disease, where such poor prognosis intrinsically eliminates or radically reduces the opportunity of detectable metastases [as per recent review of GBM [26]; and remember, distant extraneural metastases are usually asymptomatic and found only at autopsy [27].

2. Basement membrane barrier effect: the capillary basement membrane can act as a physical barrier against migration of the glioma cells into the blood stream in the brain [28].

3. The cellular CNS environment, because the CNS lacks ECM (extracellular matrix) components like collagen and fibronectin overexpressed only in hyperplastic blood vessels; since extracellular spaces have hyaluronic acid and other glycosaminoglycans are their major components, active tumor cells can migrate into the surrounding tissue, but being missing in the CNS extracellular substrate environment makes hematogenous metastasis to distant organs and viscera rare [29,30,31]. In addition, the CNS lacks a connective stroma, but since metastasization is largely based on the ability to invade the connective stroma, this limits opportunity for stromal-based spread [30].

MECHANSIMS ENABLING EXTRANEURAL METASTASES

Based on documented cases and review and critical appraisal I conducted of the best evidenced, I would posit five potential mechanisms that enabled extraneural spread and metastasis:

1) lymphatic cerebrospinal fluid drainage into the extraneural tissue (active even in the absence of an identifiable lymphatic system in the CNS);

2) venous invasion, via either the leptomeningeal sinuses or via the intracerebral vein;

3) direct invasion through the dura and bone or through tumor cell migration along the ventriculoperitoneal shunts.

These three - lymphatic drainage, the venous system and the adjacent dura and bone, have been evidenced as the three possible routes of extraneural spread [32], along with:

4) surgical damage to the blood–brain barrier (BBB), which has been described as allowing extraneural spread after neurosurgical operation [33] which can allow tumor cells may access to the lymphatic or blood circulation through the surgically compromised blood-brain barrier (BBB); and craniotomy with tumor resection also being associated with opening of brain vessels and consequent spread of tumor cells[34].

5) immunosuppression by repeated irradiation or chemotherapy [35,36].

And one final note: GBM cells in particular may have special propensity for extraneural spread, because of their high levels of proteases such as uKA (urokinase type plasminogen activator) and lower levels of their inhibitors (PAI-I) [37].

These five mechanisms therefore can overcome CNS resistance to extracranial spread and hence enable rare but now well-evidenced extraneural metastatic capabilities, showing finally that primary brain tumors do indeed possess the sufficient ability to grow outside the CNS. And as I predicted above, we are seeing more cases of extraneural metastases as we advance against CNS malignancies.

METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) and SCIRUS databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using SCIRUS (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Bailey P, Cushing HA: A Classification of Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis. 1926, p. 175.

2. Anzil AP: Glioblastoma multiforme with extracranial metastases in the absence of previous craniotomy. Case report. J Neurosurg 33(1): 88–94, 1970.

3. Awad I, Bay JW, Rogers L: Leptomeningeal metastasis from supratentorial malignant gliomas. Neurosurgery 19(2): 247– 251, 1986.

4. Dietz R, Burger L, Merkel K, Schimrigk K: Malignant gliomas-glioblastoma multiforme and astrocytoma III-IV with extracranial metastases. Report of two cases: Acta Neurochir (Wien) 57(1–2): 99–105, 1981.

5. Duffner PK, Cohen ME: Extraneural metastases in childhood brain tumors. Ann Neurol 10(3): 261–265, 1981.

6. el-Gindi S, Salama M, el-Henawy M, Farag S: Metastases of glioblastoma multiforme to cervical lymph nodes. Report of two cases. J Neurosurg 38(5): 631–634, 1973.

7. Glasauer FE, Yuan RHP: Intracranial tumors with extracranial metastases. J Neurosurg 20: 474–493, 1963.

8. Hoffman HJ, Becker EL, Jenkin D, Chuang SH, Munro IR: Extraneural metastases of a cerebral astrocytoma. Can J Neurol Sci 8(2): 115–119, 1981.

9. Hulbanni S, Goodman PA: Glioblastoma multiforme with extraneural metastases in the absence of previous surgery. Cancer 37(3): 1577–1583, 1976.

10. Leifer D, Moore T, Ukena T, Wilner D, Thor A, Hedley-Whyte ET: Multifocal glioblastoma with liver metastases in the absence of surgery. Case report. J Neurosurg 71(5 Pt 1): 772–776, 1989.

11. Pasquier B, Pasquier D, Lachard A, N’Golet A, Panh MH, Couderc P: Extraneural metastasis of central nervous system tumours (author’s transl). Bull Cancer 66(1): 25–28, 1979.

12. Pasquier B, Pasquier D, N’Golet A, Panh MH, Couderc P: Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer 45(1): 112–125, 1980.

13. Pasquier B, Keddari E, Pasquier D, Morens A, Courel MN, Girard N, Delpech B, Couderc P: Spontaneous bone marrow micrometastasis of a cerebral glioma Immunohistochemical diagnosis in a biopsy sample and review of the literature. Ann Pathol 6(2): 130–136, 1986.

14. Smith DR, Hardman JM, Earle KM: Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31(1): 50–58, 1969.

15. Yung WK, Tepper SJ, Young DF: Diffuse bone marrow metastasis by glioblastoma: premortem diagnosis by peroxidase–antiperoxidase staining for glial fibrillary acidic protein. Ann Neurol 14(5): 581–585, 1983.

16. Hoffman HJ, Duffner PK: Extraneural Metastases of Central Nervous System Tumors. Cancer 56: 1778–1782, 1985.

17. Zülch KJ. Spontaneous Intra- and Extracranial Metastases of Brain Tumors in Man — Artificial Seeding. Brain Tumors 1986; 183-189.

18. Rickert CH. Extraneural metastases of paediatric brain tumours. Acta Neuropathol 2003; 105(4):309-27.

19. Pasquier B, Lachard A, Pasquier D, Muller F, Couderc P, Courel-Vidard MN, et al. Costal micrometastasis from a cerebral astrocytoma. Immunohistochemical detection (author's transl)] Arch Anat Cytol Pathol. 1982;30:50–55.

20. Rajagopalan V, El Kamar FG, Thayaparan R, Grossbard ML. Bone marrow metastases from glioblastoma multiforme--A case report and review of the literature. J Neurooncol 2005; 72(2):157-61.

21. Moon KS, Jung S, Lee MC, Kim IY, Kim HW, Lee JK, et al. Metastatic glioblastoma in cervical lymph node after repeated craniotomies : report of a case with diagnosis by fine needle aspiration. J Korean Med Sci. 2004;19:911–914.

22. Seo YJ, Cho WH, Kang DW, Cha SH. Extraneural metastasis of glioblastoma multiforme presenting as an unusual neck mass. J Korean Neurosurg Soc 2012; 51(3):147-50.

23. Hsu E, Keene D, Ventureyra E, Matzinger MA, Jimenez C, Wang HS, et al. Bone marrow metastasis in astrocytic gliomata. J Neurooncol. 1998;37:285–293.

24. Thapa A. Pathology Of Brain Tumors. Presentation to the All India Institute of Medical Sciences. New Delhi, India. 2005.

25. Alvord EC Jr.: Why do gliomas not metastasize. Arch Neurol 33: 73–75, 1976.

26. Mentrikoski M, Johnson MD, Korones DN, Scott GA. Glioblastoma multiforme in skin : a report of 2 cases and review of the literature. Am J Dermatopathol. 2008;30:381–384.

27. Frappaz D, Jouvet A, Pierre GS, Giammarile F, Guyotat J, Deruty R, Jouanneau E, Ranchere-Vince D: Lack of evidence of osteo-medullary metastases at diagnosis in patients with high grade gliomas. J Neurooncol 52: 249–252, 2001.

28. Bernstein JJ, Woodard CA. Glioblastoma cells do not intravasate into blood vessels. Neurosurgery. 1995;36:124–132. discussion 132.

29. Giese A, Loo MA, Rief MD, Tran N, Berens ME. Substrates for astrocytoma invasion. Neurosurgery. 1995;37:294–301. discussion 301-302.

30. Pansera F, Pansera E. An explanation for the rarity of extraaxial metastases in brain tumors. Med Hypotheses. 1992;39:88–89.

31. Subramanian A, Harris A, Piggott K, Shieff C, Bradford R. Metastasis to and from the central nervous system--the 'relatively protected site'. Lancet Oncol. 2002;3:498–507.

32. Cervio A, Piedimonte F, Salaberry J, Alcorta SC, Salvat J, Diez B, et al. Bone metastases from secondary glioblastoma multiforme : a case report. J Neurooncol. 2001;52:141–148.

33. Huang P, Allam A, Taghian A, Freeman J, Duffy M, Suit HD. Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. J Neurosurg. 1995;83:308–315.

34. Wallace CJ, Forsyth PA, Edwards DR. Lymph node metastases from glioblastoma multiforme. AJNR Am J Neuroradiol. 1996;17:1929–1931.

35. Itoyama Y, Kouchi M, Yamashiro S, Yoshizato K, Kuratsu J, Ushio Y (1993) Combination chemotherapy with cisplatin and etoposide for hematogenous spinal metastasis of intracranial germinoma—case report. Neurol Med Chir (Tokyo) 33:28–31.

36. Asanuma M, Aoyama T, Sakai K, Asano K, Uehara T, Hongo K. Hematogenous extraneural metastasis of the germinomatous component of a pineal mixed germ cell tumor. Brain Tumor Pathol 2012; 29(4):245-50.

37. Bindal AK, Hammoud M, Shi WM, Wu SZ, Sawaya R, Rao JS: Prognostic significance of proteolytic enzymes in human brain tumors. J Neurooncol 22: 101–110, 1994.

38. Kaniklidis, C. CNS Metastasis from Breast Cancer – New Promise: A Review. [pending publication; available on ResearchGate profile].

It needs more attention, If BBB is able to inhibit brain tumor to be metastatic why this barrier couldn't stop metastasis of tumor cells from other organs to brain?

Mohammad:

That is a very insightful point you raise (and why I did not find the BBB to a major factor in the egress/outbound migration of brain tumor cells to colonize distant organs and viscera).

In fact, despite it commonly stated as a given, there is substantial controversy as to the role of the BBB even in resistance to chemotherapy of intracranial tumors [1], since we know now several vital facts that are contradictive of this facile assumption:

(1) that a non-trivial number of chemotherapeutic agents do in fact (confirmed by imaging and permeability studies) achieve concentrations in malignant brain tumors quite comparable to those in extracranial tumors, and

(2) that even therapeutic agents that only cross the intact BBB poorly may still be active against intracranial tumors at a clinically relevant level;

(3) that the observed uptake limitation of drugs into brain tumors may at least be partially secondary to blood flow dynamics, specifically increased tissue pressure within tumors, rather than being due to BBB crossover resistance phenomena.

In addition, many mechanisms underlie and can engender blood–brain barrier dysfunction [2], such as physical endothelial damage resulting from traumatic brain injury, or degradation of ECM (extracellular matrix) proteins via MMP (matrix metalloproteinases) as part of an inflammatory response, and such BBB dysfunction which allows enhance cross-BBB migration in both directions - outbound and inbound - is in fact observed in a large variety of brain conditions and diseases that include stroke, traumatic brain injury (TBI), malignancy (as you mentioned, and especially from breast cancer [triple negative and HER2+ in particular], melanoma, and lung cancer], multiple sclerosis (MS), epilepsy, Alzheimer’s disease, vascular cognitive impairment, and even physiological aging, as well as almost any inflammatory condition that can dysregulate the BBB.

And it's been demonstrated by electron microscopic studies the blood brain barrier is not intact in tumor tissue, and furthermore also demonstrated in these same and related morphology and pathology studies that the blood-brain barrier (BBB) does not appear to represent a barrier to aggressive migrating tumor cells [3].

It has therefore been increasingly demonstrated that the BBB is more traversable, and more prone to underlying dysfunction, and in addition may be only one of several limiting factors in intracerebral accessibility which appears to include blood flow dynamics and pressure mechanisms, than most observers have acknowledged to date, helping in part to account for the substantial incidence (up to 5%) of outbound extraneural metastatic migration, and as you indicated, also for the phenomenon of inbound tumor traversal from external primaries that leads to not uncommon CNS metastasis.

References

1. Stewart DJ. A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J Neurooncol 1994; 20(2):121-39.

2. Schoknecht K, Shalev H. Blood-brain barrier dysfunction in brain diseases: clinical experience. Epilepsia 2012; 53 Suppl 6:7-13.

3. Kung PC, Bechstein WO, Bakay L: Vascular invasion by glioma cells in man: an electron microscopic study. J Neurosurg 31: 339–345, 1969.

Hi Arvind, 

Simply, this question is not answered yet, there are many things we do not know about metastasis mechanism in the CNS. However, metastasis from the brain is reported in many types of CNS neoplasms such as, metastasis of medulloblastoma cells to the spinal cord.