The first step in the diagnosis of a metastatic brain lesion is to exclude a primary CNS tumor. Knowledge of a systemic malignancy, especially one with tissue diagnosis is extremely helpful. However, even among the patients with known cancer, 11% of the single brain lesions represent something other than metastasis, the majority of which turn out to be high-grade gliomas.[45
] The microscopic features of the metastatic tumors are usually similar to their primary, and when the metastatic tumor is well differentiated, diagnosis is rarely a problem. However, poorly differentiated neoplasms in the brain parenchyma, especially when solitary, almost always trigger a differential diagnosis with high-grade gliomas, such as glioblastoma.
In contrast to metastases, high-grade gliomas typically feature an invasive border with surrounding brain parenchyma. However, limited and mostly perivascular brain invasion can also be seen in some metastases, especially those from small cell lung carcinoma, melanoma, and lymphoma. In metastatic lesions, surrounding brain parenchyma shows reactive astrocytosis, proliferation of microglia, and vascular proliferation, all of which might be misinterpreted as glioblastoma in a small biopsy from this region. This is an especially difficult pitfall for solitary brain metastases in patients with an absence of known systemic malignancy. In a similar vein, predominantly epithelioid or rhabdoid glioblastoma may resemble metastatic carcinomas or melanomas. While negative stains for melanoma and carcinoma may suggest glioma, addition of glial markers, such as glial fibrillary acidic protein (GFAP), OLIG2, and SOX2 resolves this dilemma in nearly all cases.
Another primary CNS tumor that may enter in the differential diagnosis, especially for metastatic RCC is hemangioblastoma. Hemangioblastomas have foamier cytoplasm and darker nuclei with degenerative atypia. Metastatic RCC, clear cell type often has clear (but not typically foamy) cytoplasm, vesicular nuclei with prominent nucleoli, and shows high grade features including mitoses and necrosis. RCCs are generally positive for epithelial membrane antigen (EMA), CD10, and RCC protein, whereas hemangioblastomas are positive for inhibin A, D2-40, neuron-specific esterase (NSE) and S-100 protein.[50
] Hemangioblastomas are also negative for transcription factors expressed by the cells of nephric and mullerian duct origin such as PAX2 and PAX8.[5
True epithelial differentiation is rare in the CNS but such tumors may enter into the differential diagnosis of a metastatic carcinoma. For instance, choroid plexus tumors are variably positive for GFAP, S100, and transthyretin, unlike the most common metastatic carcinomas that enter in the differential such as breast, lung, ovary, and biliary tract.[14
] Unfortunately, both choroid plexus tumors and these carcinomas are usually CK7-positive, CK20-negative, and therefore, other organ-specific markers are necessary to exclude a metastasis. Fortunately, the great majority of choroid plexus carcinomas occur in infants, where metastatic carcinoma is not a realistic differential diagnostic consideration, but rare examples have also been reported in adults; in these rare cases, newly identified choroid plexus markers, such as Kir7.1 and stanniocalcin-1 may be of additional aid.[17
] Carcinomas metastatic to the sellar region may similarly require exclusion from primary epithelial neoplasms, such as pituitary adenoma and craniopharyngioma, especially the papillary variant.
Dural and intraventricular metastases often raise the alternate possibility of anaplastic meningioma. When there is a component of classical meningioma present, diagnosis is straightforward, except in rare cases of metastasis to a meningioma. Unfortunately there are no absolutely specific markers for meningiomas. Although most are positive for EMA, this marker is also expressed in almost all carcinomas. Moreover, high-grade meningiomas may show positivity for various cytokeratins, further complicating the diagnostic workup. Another marker that may potentially help is vimentin since it is strongly positive in meningiomas and negative in the majority of carcinomas. However, more specific makers are required when metastatic neoplasm is suspected to be RCC or melanoma, which are also commonly positive for vimentin. Fortunately, most melanomas will express at least one of several specific markers, such as HMB-45, Melan A (melanoma antigen recognized by T-cells-1, or MART-1), tyrosinase, and microphthalmia-associated transcription factor (MITF).[39
] Organ specific markers for kidney such as the RCC antibody and PAX8 may be similarly useful in the differential of metastatic RCCs and clear cell meningiomas.[48
Germ cell neoplasms, primary or metastatic, are more commonly seen in children and young adults. Although considerably rarer, this category is particularly important to consider given its much greater likelihood of response to radiation and chemotherapy. Metastatic carcinoma is rarely a consideration in this age group; however, immunohistochemical (IHC) studies may help since germ cell tumors stain with various specific markers, such as CD117 (c-kit), OCT4, alpha fetoprotein (AFP), beta human chorionic gonadotropin (β-HCG), and CD30 . The majority of primary CNS germ cell tumors are located in the midline, unlike metastatic germ cell tumors that are predominantly seen in cerebral hemispheres. However, there is extensive overlap and knowledge of a prior or synchronous systemic neoplasm is therefore critical.
Figure 6 Metastatic choriocarcinoma. (a) Gross pathology reveals a hemorrhagic, well-demarcated mass involving basal ganglia and internal capsule. (b) Histology shows mononucleated epithelioid cells consistent with cytotrophoblast, covered by larger multinucleated (more ...)
The second step in the diagnosis of metastatic brain tumors is to either verify or identify the primary tumor and the site. When the microscopic features of the metastatic tumors are similar to the known primary tumor, the diagnosis is straightforward. However, the grade and degree of differentiation may vary, with more anaplastic tumors often requiring ancillary IHC studies for confirmation. Ancillary studies become even more important in the evaluation of a metastatic neoplasm of unknown primary (NUP).
There is an extensive literature on the evaluation of NUPs, including antibody sensitivities and specificities, diagnostic staining patterns, cross-reactivity patterns, and potential pitfalls for each stain.[40
] Positive stains supporting a diagnosis are generally more reliable than the negative stains excluding a diagnosis. Also as a general principle, more than one stain should be evaluated to control for aberrant expression patterns, technical artifacts, and spurious findings. The general goal is to subtype the tumor, so that the site of origin is established and tumor specific therapy may be initiated. Although the main principles are same, there are slight variations in the approach to the NUP in the CNS versus other regions.