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Metastatic Tumors

Metastatic carcinoma. A cohesive growth pattern and clearly delimited tumor–CNS interface are hallmarks of neoplasms metastatic to the brain. The adenocarcinoma (right), derived from a primary in the left lung, ‘pushes’ against adjacent cerebral white matter.

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Definition

Discontinuous spread of a to the CNS, from a primary systemic tumor.

Clinical Features

Edematous expansion of neighboring white matter:
- may account for much of mass effect
- usually more pronounced than edema accompanying primary brain tumors
- often disproportionate to small size
Seizures due to involvement of cerebral cortex
Intralesional hemorrhage:
- occasionally leads to diagnosis
- especially common with:
  - germ cell neoplasia
  - melanoma1
Epidural spinal cord compression:
- most frequently caused by carcinomas that spread to vertebrae, such as:
  - pulmonary carcinoma
  - prostatic carcinoma
  - mammary carcinoma
Carcinoma of lung:
- systemic cancer most likely to present initially as intracerebral tumor
- accounts for:
  - ≈50% of all such cases2
  - up to 85% of lesions with adenocarcinomatous histology3

Unusual Presentations

Diffuse seeding of periventricular tissues by metastatic small cell carcinomas of lung:4
- a pattern of spread mimicking some primary CNS lymphomas
Miliary or ‘encephalitic’ cerebral carcinomatosis or melanomatosis:
- with widespread vascular cuffing by tumor cells but no conspicuous mass lesions5,6
Occlusion of major cerebral vessels by neoplastic emboli:
- resulting in ischemic stroke 7
- causes:
  - most often, intracardiac tumors such as myxomas
  - carcinomas of:
    - head and neck
    - lungs
    - colon
    - other visceral sites
Occult atrial myxomas:
- responsible for most neoplastic cerebrovascular aneurysms8,9
Subdural hemorrhage secondary to dura-based lesions 10

Useful Topographic Generalizations

Blood-borne tumor emboli may lodge at any level of central neuraxis
Intramedullary metastases (i.e. involving spinal cord parenchyma) are rare11,12
Most are in supratentorial or infratentorial compartments:
- distribution conforms to relative volumes and blood supply12,13
  - most within frontoparietal cerebral tissues subtended by middle cerebral artery (dominant tributary of circle of Willis)
  - often lodge within ‘watershed’ zone representing terminus of this vascular territory
- not clear why colorectal, uterine, and renocortical carcinomas are overrepresented among cancers seeding cerebellum 13
- prostatic adenocarcinoma intracranial metastases also show predilection for cerebellum, but:
  - more typically dura-based
  - only exceptionally involve neural parenchyma proper10,14
Dural metastases in women most often from mammary carcinomas 10,12,15
Generally metastases are:
- multiple if CNS frequently involved by tumor, e.g.:
  - malignant melanoma
  - carcinoma of lung
- solitary if CNS only occasionally involved by tumor, e.g.:
  - gastrointestinal adenocarcinoma

Pathogenesis

Secondary infiltration after metastasizing to juxtaneural structures (e.g. vertebral column)
Epidural spinal cord compression:
- neoplastic cells commonly enter spinal canal via bony foramina traversed by vertebral veins 16
Diffuse leptomeningeal carcinomatosis:
- principally complication of adenocarcinomas from lung and breast
- high incidence of vertebral and paravertebral metastases17
Blood-borne neuraxial metastases:
- more common than secondary CNS infiltration by contiguous malignant tumors
- most often from in order:
  - carcinomas of lung and breast
  - malignant melanomas, renocortical carcinomas, and adenocarcinomas of colorectal origin12
Intracranial deposits from ovarian carcinomas18 and osseous or soft tissue sarcomas:19,20
- increasingly effective management of systemic disease may account for perceived rises in incidence
- rare as neurosurgical specimens
Sarcomas:
- may give rise to isolated cerebral or dura-based metastases:
  - exceptionally herald discovery of primary tumor 20
Alveolar soft part sarcoma:
- one of rarest tumor types
- in some series prominent among mesenchymal neoplasms giving rise to intracranial metastases20,21
Intracranial HIV-1-associated Kaposi's sarcoma:22
- rare even in presence of widespread cutaneous and visceral involvement

Gross Pathology

Usually:
- relatively superficial
- straddling gray–white junction to involve:
  - cerebral cortex
  - digitate white matter

Histopathology

Tend to be sharply circumscribed with ‘pushing’ margins (Fig. 1
Fig. 1: Metastatic carcinoma. A cohesive growth pattern and clearly delimited tumor–CNS interface are hallmarks of neoplasms metastatic to the brain. The adenocarcinoma (right), derived from a primary in the left lung, ‘pushes’ against adjacent cerebral white matter.
)
Most:
- conform to histology of donor tumors
- readily distinguished from primary neoplasms of brain or meninges on casual inspection

Special Stains and Immunohistochemistry

Nuclear labeling for thyroid transcription factor-1:
- seems nearly restricted to metastatic deposits from differentiated carcinomas of:
  - thyroid gland
  - nonsquamous carcinomas of lung23

Diagnosis

Often made at surgery by examination of smear or crush preparations:
- cellular cohesion of most epithelial neoplasms is preserved (Fig. 2
  Fig. 2: Metastatic carcinoma. The cellular cohesion characteristic of most epithelial neoplasms and foreign to gliomas and lymphomas is generally maintained in cytology preparations, facilitating rapid intraoperative diagnosis. Note also the absence of cytoplasmic processes and presence of conspicuous nucleoli, the latter also alien to most neuroepithelial tumors, in this smear preparation of a poorly differentiated pulmonary adenocarcinoma that presented as a solitary, right frontal lobe brain mass.
  )
Diffuse leptomeningeal carcinomatosis:
- usually established by demonstration of malignant cells in CSF

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Metastatic Tumors

Depending on histologic findings may include:
- epithelioid or sarcomatoid glioblastoma
- capillary hemangioblastoma
- papillary ependymoma
- choroid plexus tumor
- meningioma
Occult atrial myxoma:
- may be misdiagnosed as cerebral epithelioid hemangioendothelioma24

Glial Neoplasms of Varied Type

Including fibrillary astrocytomas
May be labeled by:
- antibodies to cytokeratins (particularly AE1/3 ‘cocktail’)25–27
- on occasion, EMA 28
CAM 5.2, CK7, CK20, and Ber EP4 are more discriminating epithelial markers27,29
GFAP labeling of metastatic carcinomas exceptional 27,29,30

Anaplastic Gliomas

Unlike anaplastic gliomas, poorly differentiated carcinomas have:
- cohesive architecture
- abrupt interface with adjacent neural tissue
- ‘peritheliomatous’ pattern of tumor cell preservation about stromal blood vessels in cases with coagulative necrosis
- absence of complex microvascular hyperplasia (except some metastatic small cell carcinomas from lung)

Management

≈50% of brain metastases are unifocal:13
- a compelling case for neurosurgical intervention because:
  - usually compact growth patterns
  - lend themselves to excision12,31

References

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2 Le Chevalier T, Smith FP, Caille P, Constans JP, Rouesse JG. Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases. Cancer. 1985;56:880–882.

3 Mrak RE. Origins of adenocarcinomas presenting as intracranial metastases. An ultrastructural study. Arch Pathol Lab Med. 1993;117:1165–1169.

4 Vannier A, Gray F, Gherardi R, Marsault C, Degos JD, Poirier J. Diffuse subependymal periventricular metastases. Report of three cases. Cancer. 1986;58:2720–2725.

5 Floeter MK, So YT, Ross DA, Greenberg D. Miliary metastasis to the brain. Clinical and radiologic features. Neurology. 1987;37:1817–1818.

6 Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 28-1992. A 45-year-old man with confusion, seizures, and few focal findings. N Engl J Med. 1992;327:107–116.

7 O'Neill BP, Dinapoli RP, Okazaki H. Cerebral infarction as a result of tumor emboli. Cancer. 1987;60:90–95.

8 Furuya K, Sasaki T, Yoshimoto Y, Okada Y, Fujimaki T, Kirino T. Histologically verified cerebral aneurysm formation secondary to embolism from cardiac myxoma. Case report. J Neurosurg. 1995;83:170–173.

9 Ho KL. Neoplastic aneurysm and intracranial hemorrhage. Cancer. 1982;50:2935–2940.

10 Kleinschmidt-DeMasters BK. Dural metastases. A retrospective surgical and autopsy series. Arch Pathol Lab Med. 2001;125:880–887.

11 Costigan DA, Winkelman MD. Intramedullary spinal cord metastasis. A clinicopathological study of 13 cases. J Neurosurg. 1985;62:227–233.

12 Posner JB. Neurologic complications of cancer. Philadelphia: FA Davis; 1995;.

13 Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol. 1988;45:741–744.

14 Castaldo JE, Bernat JL, Meier FA, Schned AR. Intracranial metastases due to prostatic carcinoma. Cancer. 1983;52:1739–1747.

15 Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer. 1983;52:2349–2354.

16 Byrne TN. Spinal cord compression from epidural metastases. N Engl J Med. 1992;327:614–619.

17 Kokkoris CP. Leptomeningeal carcinomatosis. How does cancer reach the pia-arachnoid? Cancer. 1983;51:154–160.

18 LeRoux PD, Berger MS, Elliott JP, Tamimi HK. Cerebral metastases from ovarian carcinoma. Cancer. 1991;67:2194–2199.

19 Espat NJ, Bilsky M, Lewis JJ, Leung D, Brennan MF. Soft tissue sarcoma brain metastases. Cancer. 2002;94:2706–2711.

20 Lewis AJ. Sarcoma metastatic to the brain. Cancer. 1988;61:593–601.

21 Perry JR, Bilbao JM. Metastatic alveolar soft part sarcoma presenting as a dural-based cerebral mass. Neurosurgery. 1994;34:168–170.

22 Ariza A, Kim JH. Kaposi's sarcoma of the dura mater. Hum Pathol. 1988;19:1461–1463.

23 Srodon M, Westra WH. Immunohistochemical staining for thyroid transcription factor-1. A helpful aid in discerning primary site of tumor origin in patients with brain metastases. Hum Pathol. 2002;33:642–645.

24 Samaratunga H, Searle J, Cominos D, Le Fevre I. Cerebral metastasis of an atrial myxoma mimicking an epithelioid hemangioendothelioma. Am J Surg Pathol. 1994;18:107–111.

25 Cosgrove M, Fitzgibbons PL, Sherrod A, Chandrasoma PT, Martin SE. Intermediate filament expression in astrocytic neoplasms. Am J Surg Pathol. 1989;13:141–145.

26 Cosgrove MM, Rich KA, Kunin SA, Sherrod AE, Martin SE. Keratin intermediate filament expression in astrocytic neoplasms. analysis by immunocytochemistry, western blot, and northern hybridization. Mod Pathol. 1993;6:342–347.

27 Oh D, Prayson RA. Evaluation of epithelial and keratin markers in glioblastoma multiforme. An immunohistochemical study. Arch Pathol Lab Med. 1999;123:917–920.

28 Hitchcock E, Morris CS. Cross reactivity of anti-epithelial membrane antigen monoclonal for reactive and neoplastic glial cells. J Neurooncol. 1987;4:345–352.

29 Perry A, Parisi JE, Kurtin PJ. Metastatic adenocarcinoma to the brain. An immunohistochemical approach. Hum Pathol. 1997;28:938–943.

30 Budka H. Nonglial specificities of immunocytochemistry for the glial fibrillary acidic protein (GFAP). Triple expression of GFAP, vimentin and cytokeratins in papillary meningioma and metastasizing renal carcinoma. Acta Neuropathol (Berl). 1986;72:43–54.

31 Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494–500.

Last updated: 19 Feb 2006