Melanoma Metastases Are Underrepresented in Cerebellum Compared with Metastases from Colorectal Cancers

Epidemiology

Brain metastases are estimated to be the most common intracranial malignancy in adults ( ). However, the exact incidence is unknown as epidemiological, clinical, neurosurgical, and autopsy series present different incidence rates due to different patient selections. Autopsy series report the highest incidence rates, as they include asymptomatic metastases in patients with advanced disseminated cancer disease. Autopsy series from the 1970s and 1980s reported that 1/6 to 1/4 of patients with cancer harbored brain metastases at autopsy, and about one-third of these metastases were estimated to be asymptomatic during the patient’s lifetime ( ). As fewer patients undergo autopsy today, similar autopsy series with updated data are not available. Population-based series suggest that 8–10% of adults with cancer will experience symptomatic metastases during their lifetime ( ). The incidence rate of brain metastases in population-based series is reported in the range of 8.3–14.3 per 100,000 population ( ). However, most of these series are old and outdated.

Incidence rates from epidemiological and clinical series are likely to underestimate the true incidence as a consequence of inadequate reporting ( ). In contrary to primary cancers, which are systematically and compulsorily registered in cancer registries in many western countries, brain metastases are not necessarily registered and may even be omitted from discharge diagnosis code. Furthermore, asymptomatic metastases are not accounted for in most of these series.

Neurosurgical series report incidence rates that are depended upon referral patterns and management strategies of the department. At our department, intracranial metastases constituted 16% of all intracranial tumor surgeries in adults (unpublished results). In Norway, about 30,000 patients develop cancer annually and the age-standardized incidence rate of all primary cancers is 367 and 296 per 100,000 person-years for men and women, respectively (The Cancer Registry of Norway, http://www.kreftregisteret.no/en/ ). We have estimated the annual annual incidence of first-time craniotomy for a brain metastasis to be 2.6 per 100,000 people in the south-eastern population of Norway ( ). The average annual risk of having a craniotomy for a brain metastasis in cancer patients was 0.48% ( ).

The increased incidence of intracranial metastases observed over the last decades has been attributed improved diagnostic imaging, prolonged survival of cancer patients as a result of better systemic treatment and an altered treatment approach toward an increasingly elderly population ( ). Many chemotherapeutic agents used for cancer treatment do not cross the blood–brain-barrier, which may leave the brain parenchyma as a sanctuary for growth of metastases ( ). As cancer patients live longer due to improved therapy, brain metastases are, for certain cancer types, a common first sign of relapse ( ).

The Pathogenesis of Brain Metastasis

The process of metastasis from a primary tumor to the brain parenchyma consists of a series of complex, interactive steps including; genetic alterations, proliferation, transformation, angiogenesis, invasion, spread, tumor cell arrest, and growth in brain microenvironment ( ). Metastatic cells most commonly reach the brain parenchyma by hematogenous spread ( ). Local extension from adjacent cranium metastases is a less common alternative route for central nervous system involvement. Intracranial metastases may be located in intra-axial parenchyma and/or may involve the leptomeninges.

Parenchymal metastases are often located in the gray-white matter interfaces and the watershed areas. These are areas where the arterioles narrow and may mechanically arrest embolic tumor cells ( ). Generally, parenchymal metastases are located in cerebral hemispheres in 80%, cerebellum in 15%, and brain stem in 5%, a distribution that closely parallels the regional blood flows and blood volumes of the respective regions. These observations support Ewing’s mechanical hypothesis from 1928, that is, that the pattern of metastasis is sufficiently explained by a mechanical entrapment of tumor cells defined by the vascular anatomy and blood flow between primary tumor and receptive organs ( ). Other observations supporting this hypothesis are the high occurrence of lung as primary tumor site, and the high occurrence of lung metastases among patients with brain metastases. Primary lung tumors may disseminate in the arterial circulation and thus directly reach the brain parenchyma, whereas metastatic cells from other primary sites might be arrested in the capillary bed of the lung parenchyma before reaching the brain ( ). However, the mechanical hypothesis fails to fully explain why small cell lung cancer (SCLC) has much higher propensity for brain metastasis than squamous cell carcinoma ( ). Furthermore, vascular anatomy, blood flow, volume, and number of tumor cells in circulation in clinical and observational series have not been sufficient to explain the variable pattern of brain metastasis from different primary cancers ( ).

Over a century ago, Paget introduced the hypothesis that a metastasis was the result of an interaction between the metastatic tumor cells (“seed”) and the host organ microenvironment (“soil”) ( ). The current conception of this “seed and soil hypothesis” has three defined core principles ( ). First, primary tumors in general and metastatic lesions in particular, are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis is highly selective for cells that can complete all of the steps in the process. Metastases can have a clonal origin, and different metastases can originate from the proliferation of different single cells. Third, the outcome of a metastasis depends on multiple interactions between the metastatic cells and the host’s homeostatic mechanisms that include the organ microenvironment which tumor cells exploit for their own gain ( ). A newer hypothesis is that primary tumor cells can take with them their own soil to secondary organs ( ). However, a detailed review of all molecular steps lies beyond the scope of this chapter.

Histology of Primary Cancer

Histology of primary tumor is an important predictor of the incidence and pattern of intracranial metastasis ( ). Intracranial metastases can originate from virtually any primary cancer, but different primary tumors may have a variable propensity to metastasize to the brain. In absolute numbers, the most common primary tumor origins are lung, breast, melanoma, kidney, and colorectal cancer, in that respective order ( ). However, when taking the relative incidence of primary tumor into account, melanomas have the greatest propensity to disseminate to the brain ( ).

Malignant melanomas represent only 4% of all cancers, but have the highest propensity for brain metastasis of all primary cancers. Melanoma patients are in clinical series diagnosed with intracranial metastases in 6–43% and in autopsy series in up to 90% ( ).

Colorectal cancer only metastasize to brain parenchyma in 1–3% ( ), but as the incidence of colorectal is high, colorectal brain metastases are seen quite often in clinical series. Upper GI cancers, especially gastric cancer, very rarely metastasize to the brain ( ).

Cerebellar Metastases

The scientific literature review provides only few studies addressing the outcome of cerebellar metastases separate from the more common supratentorial lesions ( ). However, different primary cancers are seen to even have different propensity to spread to specific regions within the brain. For instance, leptomeningeal metastases often originate from lung cancers and melanomas, whereas colorectal cancers commonly metastasize to the cerebellum ( ).

A metastasis located in the cerebellum has been perceived as an isolated negative prognostic marker for survival ( ). In general, infratentorial tumors are considered more life-threatening than supratentorial ones, as tumors in the confined space of the posterior fossa can result in hydrocephalus, brainstem compression, and tonsillar herniation ( ). Gradual onset headache, nausea, and gait instability are the most common presenting symptoms, but some patients might deteriorate rapidly, requiring immediate neurosurgery to prevent a neurological cause of death ( ).