Pathophysiology, Incidence, Epidemiology, and Natural History of Thalamic Tumors

The vast majority of primary thalamic tumors are glial in origin. ¹ In adults, high-grade astrocytic tumors represent nearly one-half of thalamic gliomas, with a large case series demonstrating roughly similar proportions of anaplastic astrocytoma and glioblastoma. ² It was previously believed that high-grade tumors were much less common among children (comprising only 10% of all pediatric tumors); reexamination has suggested that high-grade tumors may be just as prevalent in the pediatric population. ³ Thalamic tumors in children have been categorized into three growth patterns: unilateral tumors, which have their epicenter within the thalamus; thalamopeduncular tumors, which originate from the interface between the thalamus and cerebral peduncle; and bilateral tumors, which are distinct from infiltrative unilateral tumors and are associated with a poor prognosis. ^{4 , 5} Of tumors with these three growth patterns, unilateral tumors are the most common and have been reported to comprise approximately 80% of all thalamic tumors. ^{4 , 6}

In terms of molecular pathology, immunohistochemistry procedures performed on thalamic gliomas have been demonstrated to be positive for the presence of the following proteins: p53, O-6-methylguanine-DNA methyltransferase (MGMT), phosphatase and tensin homolog (PTEN), epidermal growth factor receptor (EGFR), and oligodendrocyte lineage transcription factor 2 (Oligo2). ⁷ Indeed, changes have been made in the classification of central nervous system tumors with the 2016 publication of the World Health Organization update on central nervous system tumors. ⁸ This release marks a shift toward incorporating insights gained in molecular biology into the classification of central nervous system tumors. One particular change in diagnosis pertinent to thalamic gliomas is the use of the his-tone H3 lysine 27-to-methionine (K27M) mutation, which characterizes a new entity known as diffuse midline glioma, an H3 K27M-mutant. ⁸ This mutation has been associated with midline tumors, including both thalamic and brainstem gliomas, and it has not been associated with a worse prognosis for patients with tumors of the thalamus than for patients with tumors in the brainstem. ⁹ Less than 20% of primary thalamic tumors are germinomas, gangliogliomas, oligodendrogliomas, dysembryoplastic neuroepithelial tumors, and neurocytomas. ¹⁰

Thalamic tumors are a relatively rare subset of central nervous system tumors more commonly found in the pediatric population. They comprise approximately 4% of the central nervous system tumors found in children and approximately 1% of those found in adults. ^{1 , 6 , 11 , 12} Epidemiologic data are scarce, given the rarity of these tumors and their tendency to be categorized along with other “central” tumors, such as those in the brain-stem, hypothalamus, and corpus callosum.

Patients with untreated thalamic tumors generally die as a result of tumor progression or complications from obstructive hydrocephalus, whereas patients with thalamic tumors who undergo ventriculoperitoneal cerebrospinal fluid diversion procedures have been shown to have longer survival. ⁷ Patients with tumor progression can have local extension into the brainstem, basal ganglia, internal capsule, or contralateral thalamus, in addition to distant progression elsewhere. ⁷ Factors associated with a poorer prognosis include short symptom duration, high-grade histologic features, tumor volume greater than 30 mL, and limited extent of resection. ⁴

Clinical Presentation

The mean age of adult patients who presented with thalamic tumors in one series was 30 to 33 years, whereas in an exclusively pediatric series, the mean age at presentation was 8 to 10 years. ^{2 , 10 , 13} Patients with thalamic tumors can present with symptoms of short duration and a wide variety of manifestations, given the diverse functions of the thalamus and its close proximity to nearby structures in the diencephalon. ¹⁴ In one series of 57 patients who received a diagnosis of infiltrative thalamic astrocytoma, 34 (60%) presented with headache, 30 (53%) with hemiparesis or hemiplegia, 22 (39%) with papilledema, and 17 (30%) each with mental status changes and abnormal reflexes. ¹⁵

The most common clinical features of thalamic tumors include symptoms related to increased intracranial pressure (ICP) (e.g., frontal headache, lethargy, and vomiting) and signs of papilledema on fundoscopic examination; in infants, bulging fontanelles and split sutures are common. Elevated ICP can be caused by the presence of a space-occupying lesion or by obstructive hydrocephalus from intraventricular tumor extension. A tumor of the dorsomedial thalamus often results in noncommunicating hydrocephalus because of its proximity to the ventricles. In contrast, tumors of the ventrolateral thalamus, which includes afferent sensory tracts, can lead to contralateral sensory deficits and to hemiparesis when nearby capsular fibers of the corticospinal tract are affected. ³ Similarly, inferior compression of the pyramidal tracts of the midbrain can also produce motor deficits. ¹⁰

Several other less common signs have also been associated with the onset of thalamic tumors. Ocular manifestations can include visual loss, palsies of the oculomotor nerve (cranial nerve [CN] III) and the trochlear nerve (CN IV), mydriasis, convergence impairment, and hemianopia due to optic tract compression. ^{3 , 11} In light of the role of the thalamus in motor control, movement disorders such as dystonia and spasticity are surprisingly rare. ¹ Seizures can occur with wide variability, affecting 7 to 35% of patients who have thalamic tumors. ^{7 , 10} Thalamic tumors that extend into the hypothalamus can lead to menstrual irregularities in addition to other endocrinopathies. ³ The classic thalamic pain syndrome (Dejerine–Roussy syndrome), which includes contralateral motor and sensory losses, ataxia, and pain, is quite rare as a presenting set of symptoms for patients with these tumors. However, when the symptoms do occur, they are believed to be caused by involvement of thalamocortical fibers within the lateral nuclei. ^{10 , 13}

Perioperative Evaluation

As stated previously, the most common presentations for patients with thalamic tumors are symptoms of increased ICP and motor and sensory deficits. ⁷ Thus, it is imperative to obtain a comprehensive history from patients who may have a thalamic tumor and to conduct a comprehensive physical examination. Pertinent medical history includes any history of headaches, nausea, or vomiting. It is also important to ask for any family history of brain tumors, as patients with familial diseases, such as neurofibromatosis 1, have been shown to have a predilection for midline tumors involving the basal ganglia and thalamus. ^{16 , 17} The physical examination should include a careful examination of the CNs, noting any false localizing signs such as dysfunction of the abducens nerve (CN VI), which is a well-known sign of increased ICP. Ophthalmologic evaluation is also crucial for patients who are thought to have increased ICP. Patients with evidence of increased ICP and ventriculomegaly require cerebrospinal fluid shunting. For most unilateral thalamic tumors, shunt placement should be done on the contralateral side of the tumor to avoid hemorrhages. ⁷ The endoscopic biopsy of lesions, combined with endoscopic third ventriculostomy, may be a good method to temporize while obtaining tissue specimens in cases in which the diagnosis is not clear. ^{18 , 19} Also, one must take note of any motor or sensory dysfunction, as either can be an indication of the proximity of the tumor to the corticospinal pathway or an indication of the infiltrative nature of the tumor.

Detailed intracranial imaging is required in the work-up of patients who may have thalamic tumors. Because many of these patients present with symptoms of increased ICP, imaging of the ventricular system can be just as important as imaging of the tumor to assess for hydrocephalus. Magnetic resonance imaging (MRI) is the modality of choice for imaging thalamic tumors. The use of contrast is necessary, as enhancement can indicate the type of pathology and, for glial tumors, can provide a possible initial indication of the histopathologic grade. ^{20 , 21} In their series of 33 adult patients with unilateral thalamic gliomas, Zhang et al ⁷ found that more than 90% of tumors had enhancement with contrast. For those tumors that do not enhance with contrast, evidence exists that fluid-attenuated inversion recovery (FLAIR) MRI may be useful in determining the extent of a tumor. ²² Kurian et al ²³ report that neuroradiologic imaging may result in an underestimation of the grade found on histopathologic assessment of thalamic gliomas. Furthermore, interest in using diffusion tensor imaging has increased for the purpose of understanding the relationship between the corticospinal pathway and thalamic tumors, especially those tumors of the thalamopeduncular type. ^{24 , 25} In addition to focusing on ventricular anatomy and tumor margins, one should assess the vascular anatomy when possible. For interhemispheric approaches, one must be cognizant of the bilateral anterior cerebral arteries. The thalamus receives most of its vascular supply from the posterior cerebral arteries. ²⁶ This blood supply requires the thalamus to be approached from above to limit having to deal with en passage vessels. The venous drainage is also important. During inter-hemispheric approaches, one must take note of superficial veins that drain into the superior sagittal sinus. Taking note of the deep drainage is particularly important in posterior approaches. Most of this information can be gleaned from the T2-weighted MRI. It has not been our practice to acquire specific vascular imaging, such as computed tomography angiograms of thalamic tumors, unless imaging shows the presence of multiple large vessels in the tumors, which is indicative of arterial or venous structures feeding the tumors or passing through them.

Finally, it is important to consider the patient’s appropriateness for surgery. This process includes understanding coexisting comorbidities and other medical or surgical issues that may affect the outcomes of surgery. Our group has published quality measures on platelets, body mass index, and anticoagulation that are appropriate for surgery and how these may generally affect outcomes in patients with brain tumors. ^{27 , 28 , 29}

Surgical and Chemoradiotherapy Approaches

Controversy exists regarding the optimal treatment approaches for thalamic tumors. Past reports have advocated a conservative approach, usually involving biopsy or partial resection followed by chemoradiotherapy, because of the challenging anatomy and the morbidity and mortality associated with more invasive techniques. ³⁰ However, improvements in surgical technique, coupled with advances in multimodal treatment options, have led to lower rates of morbidity and mortality and to a more aggressive surgical stance toward these tumors. Patients with circumscribed tumors without tumor infiltration, as seen on radiographic imaging, are the best candidates for total resection. Patients with these low-grade lesions are often among the youngest patients to receive a thalamic tumor diagnosis, and their neurologic deficits result from mass effect.

The thalamus can be thought of as a tetrahedron with three free surfaces in contact with the ventricular system and a fourth inferior surface interfacing with critical neurovascular structures. In addition to stereotactic and endoscopic approaches, numerous surgical approaches have been described, including an anterior interhemispheric transcallosal approach, a transcortical transventricular approach, a contralateral infratentorial supra-cerebellar approach, a posterior interhemispheric parasplenial approach, and a transsylvian transinsular approach. ^{2 , 31 , 32 , 33} Choosing the proper approach depends on the origin and growth pattern of the tumor in relation to normal structures. Importantly, the surgeon’s level of comfort and experience with the chosen approach is a driving factor, because the location of a thalamic tumor will often allow the use of any one of several approaches. Other considerations include the presence of hydrocephalus, the proximity of the tumor to critical neurovascular structures, and the location of important white matter structures (e.g., the corticospinal tracts) identified on diffusion tensor imaging. ²⁴ Regardless of the approach, the surgeon should have a thorough understanding of the surgical anatomy that will be encountered and should pay particular attention to the vascular structures encountered in each approach.

The anterior interhemispheric transcallosal approach is the most appropriate for resecting thalamic tumors with most of their mass protruding into the lateral ventricle ³⁴ or for resecting large tumors in the dominant hemisphere where speech is lateralized. ³⁵ The medial approach avoids the need for a cortical incision and reduces the potential for neurologic deficit caused by damage to eloquent cortex (e.g., visual field cut or speech deficit). However, as with any interhemispheric approach, care is required in planning the craniotomy because draining veins to the superior sagittal sinus can be troublesome. During surgery, image guidance can be of particular help in planning a trajectory that avoids a difficult configuration. After lateral mobilization of the pericallosal arteries, a small callosal incision can be used to gain access to the lateral ventricle. However, special care must be taken not to overstretch the pericallosal arteries, which would limit a lateral exposure. In addition, care should be taken in manipulating the fornices, as patients can experience transient memory deficits after this approach.

The transcortical transventricular approaches provide straightforward access to thalamic tumors. Various approaches through frontal, parieto-occipital, and temporal trajectories have been described, including a middle frontal gyrus approach for thalamic tumors that displace the posterior limb of the internal capsule in an anterolateral direction. ³² Compared with interhemispheric approaches, all these approaches involve cortical incisions and carry an increased risk of postoperative seizure. In addition, in patients without hydrocephalus, the amount of cortex and the amount of white matter that must be traversed are increased, as are potential difficulties with retraction. However, compared with interhemispheric approaches, these approaches minimize the possibility of injuring a draining vein to the sagittal sinus. Like image guidance, B-mode ultrasound can be a useful intraoperative aid to help locate the tumor and plan a corticectomy with the shortest route to the tumor. It also allows dynamic assessment of the extent of resection, whereas most image-guided approaches do not show real-time brain shift during tumor removal.

Several approaches have been described for posterior thalamic tumors situated in the pulvinar region, including the posterior interhemispheric parasplenial approach described by Yaşargil, ³⁶ the occipital and parieto-occipital transventricular approaches, and an infratentorial supracerebellar approach. While the interhemispheric parasplenial approach allows wider access to the parapineal region and pulvinar thalami, the infratentorial supracerebellar approach allows the possibility of remaining extra-axial and thus incurring a smaller risk of damage to the optic radiation. However, this approach has a limited window between the veins of Rosenthal, and tumors situated more than 1 cm lateral from midline are harder to excise.

For ventral posterior thalamic tumors, including those in close proximity to the insula, Yaşargil ³⁶ described a pterional transsylvian transinsular approach. This approach involves a full sylvian fissure opening and a small incision in the postcentral sulcus of the insular cortex. Thalamic tumors in this region often displace the internal capsule and basal ganglia anteriorly, thereby minimizing any damage to these delicate structures. Two other options for reaching these tumors are the transcortical transtemporal approach described by Villarejo et al ³⁷ and the inferior temporo-occipital junction approach advocated by Kelly. ³⁸ However, these latter approaches necessitate a larger cortical incision. Thus, for tumors situated near the insula, Ozek et al ³¹ have advocated for the transinsular approach, which they believe is less invasive.

When a total resection is not feasible or is ill advised, such as in a patient with bilateral thalamic gliomas, stereotactic biopsy or endoscopic approaches for cerebrospinal fluid diversion may be preferable. Even for unilateral thalamic tumors, the initial use of stereotactic biopsy for tumor diagnosis can help surgeons to counsel their patients on whether total resection is warranted. With the incorporation of new technologies such as robot-assisted stereotactic biopsy, patients can undergo precisely targeted brain biopsy through a minimal incision. ³⁹ Another novel technique involves the use of microelectrode recordings to augment stereotactic biopsy. ⁴⁰ Preliminary work by Ohye et al ⁴¹ showed an absence of electrical activity when the microelectrode penetrated the tumor, in contrast to the presence of electrical activity outside the tumor. In a series of 12 patients who underwent deep-seated biopsy (including 7 with thalamic lesions), 100% of the patients received a diagnosis after the use of microelectrode recordings as an adjunct to image guidance. ⁴⁰ Another alternative approach is endoscopic biopsy, which can often be helpful for patients who also require treatment for hydrocephalus. ⁴² For patients with posterior thalamic tumors causing compression of the posterior third ventricle or aqueduct that results in obstructive hydrocephalus, an endoscopic third ventriculostomy combined with endoscopic biopsy is a viable option if resection is not undertaken first. When thalamic tumors distort the normal ventricular anatomy, resulting in obstructive hydrocephalus, another option might be an endoscopic septum pellucidotomy. If these endoscopic mechanisms fail to divert cerebrospinal fluid, or if anatomical distortion is too great, surgeons can resort to traditional shunting.

The need for adjuvant chemoradiotherapy is dictated by histologic analysis of the tumor tissue. Surgery remains the mainstay of treatment for low-grade tumors, and surveillance imaging can often be used to monitor residual tumors in many cases of focal masses with near-complete resection. In addition, surgery for select tumors such as pilocytic astrocytoma often results in long-term control or cure ( Fig. 15.1 ). Indications for adjuvant chemoradiotherapy often parallel those for lobar astrocytomas, and additional treatment is reserved for recurrent or progressive inoperable disease. Chemotherapy is often used before conventional radiotherapy, particularly among children, for low-grade gliomas because of the unique location of thalamic tumors and their close association with vascular structures, the optic apparatus, and the hypothalamus ( Fig. 15.2 ). When total resection is not possible for a pilocytic astrocytoma, stereotactic radiotherapy or stereotactic radiosurgery can be administered if progression occurs. In their series of 12 patients with progressive pilocytic astrocytomas, Lizarraga et al ⁴³ noted that 2 patients with thalamic tumors had no further progression after treatment at 36 months of follow-up.

High-grade gliomas are treated with surgery followed by radiotherapy ( Fig. 15.3 ). The typical regimen for adults with high-grade gliomas is fractionated focal therapy up to 60 Gy and concomitant temozolomide. ⁴⁴ For children older than 3 years, surgery followed by focal irradiation of the tumor bed (54–60 Gy delivered in daily fractions of 1.8–2.0 Gy) is also standard practice for supratentorial high-grade gliomas. ⁴⁵ Although chemotherapy is often used as an adjuvant treatment in pediatric patients, no consensus exists on a standard regimen. However, most patients are enrolled in a clinical trial, and new drug targets are being identified as a result of advances in molecular biology.