Management of Pineal Region Tumors

Pathology

Pineal parenchyma is comprised of lobules of pinealocytes surrounded by astrocytes with ependymal cells of the third ventricle lining the anterior border of the gland. The various cell types that comprise the mature pineal gland and surrounding region account for the diversity of histologic tumor subtypes that can occur in the pineal region. The term pinealoma was originally used by Krabbe to describe tumors arising within the pineal region and is a misnomer because it originally pertained to germ cell tumors. Eventually, the term was applied more generically to refer to any tumors of the pineal region. However, ultimately, the term became obsolete in favor of pineal region tumors for a general reference, or in favor of the individual tumor’s histology when specificity is preferred (e.g., astrocytoma of the pineal region). As such, pineal tumors are currently grouped into four main categories: germ cell tumors, pineal cell tumors, glial cell tumors, and miscellaneous tumors (covering a wide range of histology). Each category contains tumors existing along a continuum from benign to malignant and can include mixed tumors of more than one cell type.

Presentation

Regardless of their histology, tumors in the pineal region generally become symptomatic by three mechanisms:

• 1.

  Increased intracranial pressure from hydrocephalus

• 2.

  Direct cerebellar or brain stem compression

• 3.

  Endocrine dysfunction

Headache, the most common presenting symptom, occurs after obstruction of the third ventricle outflow at the sylvian aqueduct. More advanced hydrocephalus can result in nausea, vomiting, papilledema, obtundation, and other cognitive deficits.

Direct brain stem compression may lead to disturbances of extraocular movements, classically known as Parinaud syndrome. Involvement of the superior cerebellar peduncles can lead to ataxia and dysmetria. Hearing disturbances can occasionally occur, probably from compression of the inferior colliculi.

Endocrine dysfunction is rare and may be caused by direct tumor involvement in the hypothalamus or from secondary effects of hydrocephalus. Diabetes insipidus and other neuroendocrine disturbances are often indicative of hypothalamic infiltration by tumor, even when not radiographically visualized.

Laboratory Diagnosis

α-Fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG) are markers of germ cell malignancy and should be measured in serum and cerebrospinal fluid (CSF) if possible, as part of the preoperative workup in all pineal region tumor patients. ^{, ,} Elevation of germ cell markers is pathognomonic for the presence of malignant germ cell elements and may preclude surgical intervention for tumors with sensitivities to chemotherapy and radiation, saving resection for residual or recurrent tumors only. In patients with marker-positive germ cell tumors, measurement of marker levels can also be useful to monitor therapeutic response and as a sensitive early sign of tumor recurrence. ^, The absence of germ cell markers should be interpreted cautiously because malignant germ cell tumors such as germinomas and embryonal cell carcinomas cannot be ruled out.

Specifically, AFP is associated with fetal yolk sac elements and is markedly elevated with endodermal sinus tumors, whereas smaller elevations occur with embryonal-cell carcinomas and immature teratomas. Notably, elevations in AFP in the presence of a germinoma suggest a mixed tumor with embryonal-cell or endodermal sinus tumor components. β-hCG is normally secreted by placental trophoblastic tissue and indicates the presence of choriocarcinoma, with smaller elevations associated with embryonal cell carcinomas and those occasional germinomas containing syncytiotrophoblastic giant cells. Importantly, most germinomas are nonsecretory and carry a better prognosis than β-hCG positive germinomas.

Imaging

The standard diagnostic workup includes magnetic resonance imaging (MRI), with and without contrast. MRI provides information on type, size, and extent of the tumor, anatomic features such as degree of invasion, vascularity, and the anatomic relationships of the tumor with its surroundings, as well as permits the evaluation of associated hydrocephalus ( Fig. 21.1 ). Some tumors can be suspected from the appearance of the scans, particularly teratomas, which contain multiple germ layers ( Fig. 21.2 ). Angiography is only performed if the MRI suggests a vascular lesion such as a vein of Galen aneurysm or arteriovenous malformation. Despite this broad diagnostic armamentarium, the exact histologic nature of the tumor cannot be reliably determined without surgery.

The increasing use of MRI has revealed a large number of patients with lesions of the pineal gland that are mostly cystic but contain a small amount of solid tissue ( Fig. 21.3 ). ^, Initially, these lesions were considered to be low-grade cystic astrocytomas. However, after surgical removal, most were found to be composed of normal astrocytes and normal pineal cells. Histologically, pineal cysts are now considered normal anatomic variations of the pineal gland, and as experience with pineal cysts has increased, it has become clear that they should be managed conservatively with serial MRI scans and without surgery. In most cases of pineal cysts, the aqueduct is not compromised and patients are otherwise asymptomatic. As a result, surgery is reserved for lesions that are symptomatic, progressing in size, or causing hydrocephalus.

Dedicated spinal column imaging is critical as many malignant pineal region tumors may seed the spinal canal. Preoperative imaging avoids the difficulties of interpretation of postintervention imaging studies.

Surgical Anatomy

Most pineal region tumors arise from or develop attachments to the undersurface of the velum interpositum and tela choroidea with rare superior extension. As a result, these lesions involve the choroid plexus, deep venous system, and posterior choroidal arteries, and these structures may be tightly adjacent to the tumor or intimately involved, depending on the degree of tumor invasion. Tumor blood supply frequently comes from within the velum interpositum, mainly through small-caliber posterior medial and lateral choroidal arteries with anastomoses to the pericallosal arteries and quadrigeminal arteries. ^, These vessels generally do not supply any clinically significant areas of the brain.

While some tumors extend ventrally to the foramen of Monro, most are centered at the pineal gland, extending to the midportion of the third ventricle and posteriorly to compress the anterior portion of the cerebellum. In rare instances, the internal cerebral veins are ventral to the tumor. More typically, however, the vein of Galen, internal cerebral veins, basal veins of Rosenthal, and precentral cerebellar vein surround or cap the periphery of these tumors. The quadrigeminal plate may give rise to an exophytic astrocytoma within the pineal region or be otherwise infiltrated by more malignant, diffusely infiltrative tumors of the pineal region, ultimately encompassing the aqueduct in the course of tumor growth.

The most important aspects of the anatomy, which can be gleaned by radiographic imaging, are the relationship of the tumor to the third ventricle and quadrigeminal cistern, and the lateral and superior extent of the tumor. These features determine the route of the operation and the degree of difficulty likely to be encountered during surgery.

Hydrocephalus

Tumor-associated compression of the cerebral aqueduct or the posterior third ventricle results in obstructive hydrocephalus in most patients and may be managed in several ways. Preoperative CSF diversion treats symptomatic hydrocephalus and offers an opportunity to identify the presence of tumor markers. If urgent, bedside placement of an external ventricular drain (EVD) can be performed. This strategy may also be utilized when a complete tumor removal is anticipated and a permanent ventriculoperitoneal shunt may not be necessary. Ventricular drains can be removed or converted to a permanent shunt on postoperative day 2 or 3, conditional with patient dependence on permanent CSF diversion. Occasionally, in mildly symptomatic patients, no preoperative or permanent CSF diversion is necessary, and the hydrocephalus resolves after complete tumor removal as there is a reduction of mass effect on the cerebral aqueduct and communication of the third ventricle with the quadrigeminal cistern through the operative corridor.

Patients with more advanced symptomatology should be managed with an image-guided stereotactic endoscopic third ventriculostomy (ETV) to allow a gradual reduction in intracranial pressure and resolution of symptoms. This method is preferable to ventriculoperitoneal shunting as it eliminates potential complications such as infection, overshunting, subdural hematoma, and peritoneal seeding of malignant cells classically associated with ventriculoperitoneal shunt insertion. Contraindications to ETV include the presence of tumor occupying the floor of the third ventricle or an unfavorable relationship between the floor of the third ventricle and the basilar artery. ETV also permits endoscopically assisted biopsy of pineal region tumors through the posterior ventricle during the same procedure in some situations.

Biopsy Versus Resection

Tumor histology is critical for making decisions concerning adjuvant therapy, metastatic workup, prognosis, and long-term follow-up for pineal region lesions. The wide diversity of pathology that can occur makes histologic diagnosis a necessity to optimize patient management decisions. This diversity remains problematic for even experienced neuropathologists, who can best resolve the subtleties of histologic diagnosis when free from the constraints of limited tissue sampling. As a result, the most reliable strategy to ensure accurate diagnosis is to ensure adequate tissue sampling.

Strategies for tissue sampling include stereotactic and endoscopic biopsies or open surgical procedures. Passionate advocates for either approach can be found. However, it is important to recognize the relative advantages and disadvantages of each and use them in a complementary fashion for appropriate patients rather than having an inflexible dedication to one. Ultimately, the radiographic and clinical features of the tumor and the surgeon’s experience will influence procedural decisions.

Experienced neurosurgeons using current microsurgical techniques can expect favorable results with open surgery. Open procedures have the advantage of providing more extensive tissue sampling. This is particularly important for pineal region tumors where heterogeneity and mixed cell populations are common. Additionally, open procedures provide a clinical advantage by facilitating tumor removal. ^{, ,} This is particularly important for the one third of patients with benign pineal tumors, in whom resection is usually complete but can also be useful for patients with malignant tumors in whom debulking may provide a more favorable response to adjuvant therapy and a better long-term prognosis. Additional advantages of aggressive tumor debulking include the ability to reduce mass effect on critical neural structures, the potential to relieve hydrocephalus without additional procedures, and the ability to control the risks of postoperative hemorrhage into an incompletely resected tumor bed. A disadvantage of open procedures is the relatively higher surgical morbidity compared with that of stereotactic biopsy, at least in the short term. This short-term disadvantage, however, may be a reasonable concession for the long-term advantage of better tumor control. Any discussion about the relative risks and benefits of open procedures must recognize that the highly favorable outcome for patients with pineal tumors assumes an advanced level of experience, judgment, and expertise. Stereotactic procedures, in contrast, can be appealing because of their ease of performance. Biopsy may be preferred in patients with known primary systemic tumors, multiple lesions, or other comorbidities that may increase surgical risk. Biopsy may also be preferable for tumors that are clearly invading the brain stem. However, the degree of invasion is not always easily discernible, and tumors may have a surgically dissectible capsule that is not predicted on preoperative imaging studies. It is critical to understand that the pineal region is among the most hazardous areas in the brain to safely biopsy, and careful forethought must be given to planning the target and trajectory to minimize hemorrhagic risks. The potential for hemorrhage is increased because of several mechanisms including: bleeding from any of several pial surfaces that must be traversed, bleeding from highly vascular tumors, damage to the deep venous system, and bleeding into the ventricle, where the tissue turgor is insufficient to tamponade minor bleeding. ^, Both techniques have been associated with risks of postoperative hemorrhage and obstructive hydrocephalus. Furthermore, tissue sampling is limited with either stereotactic or endoscopic biopsy and may result in inaccurate diagnosis due to sampling error. Despite these risks, several series have validated the effectiveness of stereotactic biopsy for these tumors. ^,

The exception to mandatory histologic diagnosis occurs in patients with elevated germ cell markers who can be treated with chemotherapy and radiation without a biopsy. ^, A minority of these patients who undergo treatment for germ cell tumors based on presumptive CSF markers will ultimately require a delayed surgical resection to remove residual radiographic abnormalities that may represent residual tumor or recurrence. In all other situations, CSF cytology and radiographic examination are considered insufficiently consistent to supplant the need for a tissue diagnosis.

Stereotactic Biopsy

Advances in radiographic imaging and software planning provide several alternatives for safely planning biopsy trajectories. Stereotactically guided procedures are acceptable because of their high degree of accuracy and common availability. Although nearly any stereotactic frame system is sufficient, target-centered stereotactic frame systems such as the Cosman-Roberts-Wells (CRW) have the versatility to facilitate even complex biopsies. Recent advances in frameless stereotactic guidance systems also provide a variety of accurate methodologies for accurate and safe stereotactic biopsy. Local anesthesia with mild sedation is safe and usually sufficient to perform biopsies.

The most common surgical trajectory to the pineal region is via an anterolaterosuperior approach anterior to the coronal suture and lateral to the midpupillary line. This trajectory passes through the frontal lobe and the internal capsule. The ependyma of the lateral ventricle and the internal cerebral veins should be avoided. An alternative approach is a posterolaterosuperior approach through the parieto-occipital junction, which is best suited for large tumors that have a lateral extension.

Whenever possible, multiple serial biopsy specimens should be obtained. Obviously, the risks of bleeding for each additional specimen must be considered, taking into account the size of the mass. A frozen section intraoperatively may be useful in verifying pathologic tissue. However, the high diversity of tissue types reduces the accuracy of a frozen tissue diagnosis.