Taken together, this illustrates that gliomas besides brain metastases are the most challenging entities in adult neurooncology.

Another important point is the differentiation of extraand intracerebral localization of brain tumors. This usually allows an early distinction between meningiomas and gliomas or brain metastasis. As the clinical management differs substantially, this radiological differentiation is important. Small meningiomas in uncomplicated locations might not need an early histological diagnosis and can be followed by MRI scans. On the other hand, gliomas or brain metastasis usually need an immediate histological diagnosis. Further, the early radiological differentiation between gliomas, metastasis, and lymphomas is equally essential as the clinical management differs. For primary CNS lymphomas, steroids should be avoided before histological diagnostics and have traditionally been preferred over resection (Weller et al. 2012a). If brain metastases are suspected, systemic diagnostics are essential, and brain surgery may not always be necessary.

The current WHO classification from 2007 tries to indicate the prognosis of primary brain tumors by grading tumors from I° (benign) to IV° (malignant) primarily based on morphology (Louis et al. 2007). However, it is clear that the progress in molecular analyses will profoundly alter and refine this classification. In the future, prognostic and predictive markers and profiles will have practical importance for the vast majority of patients. Accordingly, a number of established molecular markers will be integrated in the upcoming WHO classification (Louis et al. 2014; Weller et al. 2012b, 2013; Wick et al. 2014).

In this chapter, we will focus on glioma, lymphoma, and brain metastasis.

2Clinical Management

As the location of brain tumors is variable, the clinical presentation can be heterogeneous. Neurological or neuropsychological deficits, epileptic seizures, and symptoms of increased intracranial pressure are guiding symptoms. Symptomatic treatment includes, but is not limited to, anticonvulsive drugs for symptomatic epilepsy and dexamethasone for the treatment of symptomatic peritumoral edema (Soffietti et al. 2010; Weller et al. 2012c, 2014).

After medical history taking and the neurological examination, MRI of the brain with contrast-enhancing agent is the most important diagnostic procedure. Lumbar puncture to allow the evaluation of the cerebrospinal fluid (CSF) can be helpful in primary CNS lymphoma where tumor cells or tumor-specific molecular alterations can be detected in CSF or in germ cell tumors where elevated amounts of AFP or β-HCG can be found. In almost all other cases, the diagnosis

should be confirmed via a stereotactic biopsy or, when appropriate, via resection. Despite all innovative imaging, the procurement of tumor tissue has gained particular relevance in the era of molecular diagnostic (Weller et al. 2014).

Nonetheless, innovative imaging has gained a lot of attention in the last decade. Before confirmation of the diagnosis via tissue analysis, MR spectroscopy, MR perfusion, and positron emission tomography (PET) imaging can be helpful for specific topics (Suchorska et al. 2014, 2015). Spectroscopy and perfusion can be helpful to distinguish between neoplastic lesions and other possible diagnoses. Some of the most important differential diagnoses are infectious or inflammatory causes and postischemic lesions. Moreover, metabolic imaging might show “hot spots” inside a tumor mass that can be targeted by stereotactic biopsy, thereby increasing the chance to get the most accurate diagnosis (Hermann et al. 2008). PET imaging using amino acid tracers also supports the diagnostic workup or can guide stereotactic biopsy to hot spots.

After the diagnosis has been confirmed pathologically, these innovative imaging modalities can be even more valuable. In particular, they may be useful for planning of radiotherapy (Revannasiddaiah et al. 2014). The irradiated field can be tailored to include areas with elevated PET tracer uptake, and radiation dose may be increased at hot spots seen on MR spectroscopy/perfusion or on amino acid PET.

Even more established in clinical practice is the use of innovative imaging for the monitoring during therapy and follow-up. MRI and PET can both be useful to distinguish between progressive tumor and pseudoprogression (Hutterer et al. 2014).

Functional MRI and fiber tracking using diffusion tensor imaging (DTI) might help to identify eloquent areas and improve results of surgery. Intraoperative brain mapping and awake surgery can be of further benefit. This may help to increase the extent of resection and improve progression-free survival (PFS) and overall survival (OS) while reducing perioperative morbidity.

3Glial Tumors

3.1Focal Glial and Glioneuronal Tumors Versus Diffuse Gliomas

Compared to focal glial tumors like pilocytic astrocytomas of the WHO grade I, grade II gliomas show diffuse infiltrative growth patterns and a propensity to evolve into grade III or grade IV gliomas. Therefore, and in contrast to pilocytic astrocytomas, a surgical cure is not possible in these (Louis et al. 2007).

Like pilocytic astrocytomas, glioneuronal tumors like dysembryoplasticneuroepithelialtumors(DNET)organglioglioma

show a benign course. If clinically necessary, these glioneuronal tumors can usually be resected completely.

(“honeycomb”). Microcalcifications, mucoid/cystic degenerations, and a dense network of branching capillaries (chicken wire) are frequently observed. Again, the presence of microvascular proliferation or necrosis is not compatible

Neuropathological analyses of diffuse astrocytomas (WHO grade II) reveal well-differentiated fibrillary or gemistocytic neoplastic astrocytes on a loosely structured and often microcystic tumor matrix. Cellularity is only moderately increased. There is no mitotic activity, and proliferation rate determined by Ki-67/ MIB-1 labeling index is usually below 4 % (Louis et al. 2007).

Histopathology of anaplastic astrocytomas shows the same features as those for diffuse astrocytoma. In addition, anaplastic astrocytoma shows increased cellularity, distinct nuclear atypia, and mitotic activity. Proliferation rate ranges from 5 to 10 %, but might overlap with low-grade gliomas and glioblastomas. Microvascular proliferation and necrosis are still absent (Louis et al. 2007).

Glioblastomas show a remarkable regional heterogeneity with anaplastic, poorly differentiated pleomorphic astrocytic tumor cells. Nuclear atypia is common, and mitotic activity is high. Proliferation rates range between 10 and 20 %, again with high regional heterogeneity. Microvascular proliferation and/or necrosis is essential for the diagnosis of glioblastoma (Louis et al. 2007).

Regarding prognosis, the WHO classification has obvious limitations. First, oligodendroglial tumors, anaplastic or not, have a similar clinical course that is superior to that of astrocytoma of the corresponding WHO grade. Molecular markers like 1p/19q deletions, IDH1/2 mutations, and MGMT promotor methylation are of prognostic value as they define subgroups of favorable survival. In addition, they are of predictive value and necessary for therapy decisions. It is now clear that true oligodendroglial tumors are characterized by 1p/19q codeletions and uniformly carry IDH1/2 mutations (Weller et al. 2012b, 2013; Reuss et al. 2015).

Moreover, anaplastic gliomas with favorable clinical and molecular markers can show superior survival compared to low-grade gliomas with unfavorable markers. On the other hand, anaplastic glioma with unfavorable constellation can have a prognosis inferior to that of patients with glioblastoma and favorable markers. This elucidates that molecular markers should be incorporated into an upcoming WHO classification (Louis et al. 2014; Reuss et al. 2015; Hartmann et al. 2010).

3.3Astrocytomas Versus Oligodendroglial Tumors

In contrast to astrocytomas (see above), oligodendroglial tumor cells are monomorphic cells that show uniform round nuclei and perinuclear halos on paraffin sections

Compared to the corresponding low-grade gliomas, mitotic activity, microvascular proliferation, and areas of necrosis are frequent in anaplastic oligodendroglial tumors. A diagnosis of so-called mixed oligoastrocytoma has been established for tumors with both morphological features of oligodendroglioma and astrocytoma (Louis et al. 2007). However, the definition of oligoastrocytoma, low grade or anaplastic, is under heavy debate, and molecular markers are likely to lead to the omission of this diagnosis (Louis et al. 2007).

The mentioned calcifications in histology of oligodendroglial tumors are relevant for clinical management as they often can be detected on CT and MRI scans.

As shown by the NOA-04 trial, anaplastic oligodendroglioma and anaplastic oligoastrocytoma display a favorable outcome compared to anaplastic astrocytoma (Wick et al. 2009). This is also true for low-grade gliomas. As response rates to radiotherapy or chemotherapy in oligodendroglial tumors are higher than in astrocytic tumors, the avoidance of perioperative morbidity has even higher importance.

3.4Low-Grade Glioma (WHO Grade II)

The absence of neurological symptoms and the presence of younger age or oligodendroglial histology are favorable clinical prognostic factors (Pignatti et al. 2002). However, even when short-term MRI scans (e.g., 3 months) suggest stable tumor size, all low-grade gliomas constantly grow in the long run (Mandonnet et al. 2003). Consequently, adjuvant treatment will be necessary at a certain time point in the course of the disease for all patients. Resection improves seizure control and may reduce the risk of malignant transformation (Soffietti et al. 2010).

3.4.1Diffuse Astrocytoma (WHO Grade II)

After gross total resection, adjuvant treatment can be postponed at least in patients younger than 40 years of age with no neurological symptoms and a favorable location of the tumor (Pignatti et al. 2002). Regarding all other patients, there is an ongoing debate on which patients to treat and on the best time point of treatment. Radiotherapy prolongs PFS but not OS (van den Bent et al. 2005). Therefore, the EORTC defined five prognostic factors useful to identify low-risk and high-risk patients, the latter being treated with early radiotherapy (Pignatti et al. 2002). Prognostic favorable factors are age < 40 years, largest tumor diameter < 6 cm, tumor not crossing the midline, oligodendroglial or oligoastrocytic