Intracerebral metastases pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Pathophysiology

Pathogenesis

• The ability of cancer cells to sever their link to the primary tumor site and commence the metastatic process, once specific functions have been acquired by an appropriate subset of cancer cells. The multistep cascade can be grouped into two stages: migration (intravasation, dissemination, and extravasation) and colonization.

Migration	Colonization
Cellular heterogeneity and proliferation Epithelial-mesenchymal transition (EMT) Interactions with tumor stroma Local Invasion E-cadherin-catenin complex (ECCC), integrins, and other molecules Genetic alterations Dissemination	Organ-Specific Infiltration The blood brain barrier, function of the brain microenvironment, and brain metastasis Neoangiogenesis and proliferation Cascade-nonspecific contributors to metastasis Overview of microRNAs (miRNAs) and their emerging role in oncogenesis

Gallery

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  _{(a) Formation of metastatic tumor cell lines at primary sites like breast, lung, and skin (melanoma) seen as the red nodes. Metastasis from these primary sites then spreads to the brain via the circulatory system (red arrows) and also to adjacent sites like the liver, bone, lung, and lymph nodes (black arrows). The inset shows the primary site of melanoma cells proliferating and migrating towards the vasculature, subsequently disseminating to secondary organ sites.}

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  _{(b) The metastatic tumor cells detach from the primary site and penetrate the adjacent parenchyma to reach the blood vessels. On reaching the vessels, the cells invade and enter the circulation (intravasation) and then disseminate within the vascular system (left half of figure). These cells eventually adhere to secondary sites “soil” to then extravasate out of the blood vessels and for colonies of metastatic cells (right half of figure).}

Genetics

Genes involved in the pathogenesis of intracerebral metastases are tabulated below:

Gene	Cancer site (primary)	Role and implications	Chromosome location
RHoC	Melanoma	Regulates remodeling of actin cytoskeleton during morphogenesis and motility Important in tumor cell invasion	1p21-p13
LOX	Breast Head and neck cancer	Increases invasiveness of hypoxic human cancer cells through cell matrix adhesion and focal adhesion kinase activity	5q23.1-q23.2
VEGF	Lung Breast Melanoma Colon	Angiogenic growth factor Inhibition decreases brain metastasis formation; reduces blood vessel formation and cell proliferation; increases apoptosis	6p21.1
CSF1	Breast Lung	Stimulate macrophage proliferation and subsequent release of growth factors	1p13.3
ID1	Breast Lung	Involved in matrix remodeling, intracellular signaling, and angiogenesis	20q11.21
TWIST1	Breast Gastric Rhabdomyosarcoma Melanoma Hepatocellular	Causes loss of E-cadherin mediated cell-cell adhesion, activates mesenchymal markers, and induces cell motility by promoting epithelial-mesenchymal transition	7p21.1
MET	Renal cell cancer	Affects a wide range of biological activity depending on the cell target, varying from mitogenesis, morphogenesis, and motogenesis	7q31.2
MMP-9	Colorectal Breast Melanoma Chondrosarcoma	Extracellular matrix degradation, tissue remodeling	20q13.12
NEDD9	Melanoma	Acquisition of a metastatic potential	6p24.2
LEF1	Lung	Transcriptional effecter—WNT pathway; predilection for brain metastasis Knockdown inhibits brain metastasis, decreases colony formation; in vitro decreases invasion	4q25
HOXB9	Lung Breast	Homeobox gene family; critical for embryonic segmentation and patterning. Also a TCF4 target Knockdown in vitro decreased invasion and colony formation; in vivo appears to inhibit brain metastasis	17q21.32
BMP4	Lung Colorectal	Plays an essential role in embryonic development and may be an essential component of the epithelial-mesenchymal transition	14q22.2
STAT3	Melanoma	Cell signaling transcription factor Reduction suppresses brain metastasis; decreases angiogenesis in vivo and cellular invasion in vitro	17q21.2

Gross Pathology

• Typically metastases are sharply demarcated from the surrounding parenchyme and usually there is a zone of peritumoral edema out of proportion with the tumor size.
• Common intracranial sites associated with subependymal giant cell astrocytoma include:

• Cerebrum (80%)
• Cerebellum (15%)
• Brain stem (5% )

Gallery

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  _{This solitary brain metastasis from thyroid papillary carcinoma resulted in neurological symptoms. The thyroid primary was clinically occult. (Courtesy of Dr. Nikola Kostich, Minneapolis, MN.).}

Microscopic Pathology

The histopathological appearance of intracerebral metastases may vary with the type of primary tumor. Common findings are listed below:

• Tubule formation/glands
• Well-circumscribed and sharply demarcated from surrounding tissue (with the exception of melanoma metastasis)
• Mitoses
• Nuclear atypia

• Nuclear hyperchromasia
• Variation of nuclear size
• Variation of nuclear shape

Gallery

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  _{Very low magnification micrograph demonstrating metastatic adenocarcinoma that from a colorectal primary, i.e. colorectal carcinoma, by immunostains on HPS stain. The cerebellum seen on the image has Bergmann gliosis and Purkinje cell loss.}

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  _{High magnification micrograph demonstrating metastatic adenocarcinoma that is from a colorectal primary, i.e. colorectal carcinoma, by immunostains on HPS stain. The cerebellum has Bergmann gliosis and Purkinje cell loss.}

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  _{High magnification micrograph of a brain metastasis on HPS stain demonstrating normal brain tissue on the left and tumor cells on the right. The sharp demarcation between tumor and normal is typical of brain metastases.}

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  _{Adenocarcinoma infiltrating the brain in a case of lung cancer on H&E stain.}

Immunohistochemistry

• The immunohistochemistry profile of intracerebral metastases may vary with the type of the primary tumor.
• Intracerebral metastases are demonstrated by positivity to tumor markers such as:

• General brain metastases: Pankeratin +ve, GFAP -ve
• Lung adenocarcinoma and small cell lung carcinoma: TTF-1 +ve, CK7 +ve, CK20 -ve
• Breast carcinoma: CK7 +ve, ER +ve, PR +ve, BRST2 +ve/-ve
• Colorectal carcinoma: CK20 +ve, CDX2 +ve, TTF-1 -ve, CK7 -ve
• Clear cell renal cell carcinoma: PAX8 +ve, vimentin +ve, CD10 +ve, CK7 -ve, CK20 -ve
• Melanoma: S-100 +ve, HMB-45 +ve, melan-A +ve.

Gallery

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  _{Immunohistochemistry profile of intracerebral metastases from an adenocarcinoma of lung (primary) demonstrating positivity to CK7, CK20, and TTF1.}

References

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