Pathophysiology

Pineal region tumors arise from a remarkable number of different cell types, rendering it one of the most pathologically diverse, and therefore complex, areas of the brain. Germ cell, pineal parenchymal cell, and glial cell tumors are the three most common tumor types found in the pineal region; in addition, a variety of miscellaneous tumors may occur, including meningiomas, melanomas, metastases, lymphomas, and cysts. ^{1 , 2} Mixed tumors that contain more than one cell type can also occur. Tumors within each of these groups range from benign to malignant. ³ Vascular pathologies, such as cavernous malformations, arteriovenous malformations, and vein of Galen malformations, may also occur in this region. ⁴

Germ cell tumors are pluripotent tumors of germ cell origin that span a wide range of histologic and malignant characteristics. Teratomas, dermoid tumors, and epidermoid tumors are benign, whereas endodermal sinus tumors, embryonal cell tumors, and choriocarcinomas are malignant. Germinomas and immature teratomas fall somewhere between these two extremes. Pineal cell tumors, also referred to as pineal parenchymal tumors, originate from pineal parenchymal cells within the pineal gland. They can be subdivided into pineocytomas, pineoblastomas, and mixed forms known as pineal parenchymal tumors of intermediate differentiation.

Incidence and Prevalence

Pineal region tumors are rare, accounting for only 1.2% of all central nervous system tumors according to the 2012 report from CBTRUS (Central Brain Tumor Registry of the United States). ⁵ Historically, reported incidence has been approximately 1.0%, with the exception of several series reporting rates of up to 6.2% in Japanese populations. ⁶ These reports have given rise to the traditional teaching that pineal region tumors are more common in Japan, but some authors suggest that these findings may be due to selection bias. Prospective studies of population-based incidence have failed to demonstrate any marked increase in Japan over other countries. ^{7 , 8 , 9 , 10} However, it is of particular importance to consider the incidence of different tumor subtypes, given the histologic diversity of this region of the brain.

Germ cell tumors, cysts, and heterotopias account for 0.5% of all intracranial neoplasms seen in the United States according to the CBTRUS report, with an incidence of 0.10 per 100,000 person-years among the U.S. population. ⁵ Germinomas comprise the majority of germ cell tumors, with teratomas, endodermal sinus tumors, embryonal cell tumors, and choriocarcinomas correspondingly less frequent. ¹¹ Moreover, large series have shown that mixed germ cell tumors account for 25% of germ cell tumors. ^{12 , 13 , 14}

Pineal cell tumors are less common, accounting for only 0.2% of all central nervous system tumors, with an incidence estimated at 0.01 per 100,000 persons per year in the United States. ^{5 , 15} The distribution of subtypes within this classification is mixed among prior reports, but aggregating cases from U.S. institutional reports yields 42% pineocytomas, 32% pineoblastomas, and 26% mixed-cell types. ^{14 , 15 , 16} Notably, pineal cell tumors are less common in Japan, making up only 11% of tumors in the pineal region, compared with 30% of tumors in the pineal region in the United States. However, given Japan’s overall higher incidence of tumors in this region, the incidence of pineal cell tumors is about the same in both countries. ⁶

Epidemiology

Clinical Presentation

Patients with pineal region tumors present most commonly with symptoms of obstructive hydrocephalus, brainstem or cerebellar compression, or endocrine dysfunction. Tumor-induced obstruction of the aqueduct of Sylvius often leads to the gradual onset of increased intracranial pressure ( Fig. 19.1 ). Brainstem or cerebellar compression is usually a direct, local effect of tumor growth and often leads to visual disturbances given the proximity of the tumor to the superior colliculus. Endocrine dysfunction is rare by comparison, but it can arise secondary to obstructive hydrocephalus or direct tumor infiltration of the hypothalamus.

Headache is the most common initial complaint suggestive of hydrocephalus. The patient’s history often indicates a sub-acute course. Without treatment, aqueductal obstructions can progress, causing nausea, vomiting, ataxia, papilledema, and cognitive impairment. Patients can also present acutely with symptoms in the setting of pineal apoplexy. ²⁰ Pineal cell tumors and, less commonly, choriocarcinomas have a greater predisposition to hemorrhage due to their increased vascularity ( Fig. 19.2 ).

Extraocular movement disorders are a frequent sign of mid-brain compression. Parinaud syndrome, consisting of upgaze paralysis, convergence or retraction nystagmus, and light-near pupillary dissociation, is caused by compression at the level of the superior colliculus and is particularly common. Sylvian aqueduct syndrome, which includes paralysis of downgaze or horizontal gaze, can occur in conjunction with Parinaud syndrome when additional midbrain compression is present. Other signs of dorsal midbrain compression include lid retraction (Collier sign) or ptosis. Less commonly, fourth nerve palsies may give rise to diplopia, and head tilt may occur. Of note, both hydrocephalus and direct brain compression can prompt these visual disturbances. Symptomatic relief after cerebrospinal fluid (CSF) diversion is confirmatory for hydrocephalus as the inciting cause. Brainstem or cerebellar involvement can manifest in other ways, including ataxia and dysmetria from disturbance of the superior cerebellar peduncles or, rarely, hearing dysfunction or tinnitus, presumably due to interference with structures associated with the inferior colliculi. ²¹

Germinomas that spread along the floor of the third ventricle can induce diabetes insipidus early in their course, even when radiographically occult. Pineal region lesions have also been linked to precocious puberty in the past, although there are few actual documented cases. ²² This syndrome is more accurately described as precocious pseudopuberty, given the immaturity of the hypothalamic-gonadal axis. This syndrome is specific to male patients with choriocarcinoma or germinoma whose syncytiotrophoblastic cells ectopically produce β-human chorionic gonadotropin (β-hCG). In turn, β-hCG stimulates the Leydig cells of the testes to secrete androgens and cause premature sexual maturation characteristics. ^{11 , 22}

Preoperative Evaluation

The preoperative evaluation for patients with pineal region tumors consists of imaging, neurologic examination, and laboratory tests for tumor markers. Gadolinium-enhanced magnetic resonance imaging (MRI) is necessary to determine the relationship of the tumor to relevant neighboring structures, such as the third ventricle, quadrigeminal plate, deep cerebral veins, and tentorium. The degree of local tumor invasion is of particular importance, although it is often exaggerated by MRI. Attention should be paid to the potential presence of separate lesions of the suprasellar region, pituitary stalk, and third ventricle, as these can be seen with germ cell tumors. Spinal MRI is useful in identifying disseminated leptomeningeal disease or drop metastases ( Fig. 19.3 ), which would confer a poor prognosis and warrant a more conservative, nonsurgical treatment.

Themeasurementofα-fetoprotein(AFP)andβ-hCGisrequired prior to any surgical intervention, as positivity for either is pathognomonic for malignant germ cell elements ( Table 19.1 ²³ )., ^{24 , 26} Serum levels are less sensitive than CSF levels, but measurement of both is recommended. ^{24 , 25} Elevated AFP levels are diagnostic of fetal yolk sac elements, with higher levels associated with endodermal sinus tumors and lower levels indicating embryonal cell carcinoma or immature teratoma. ^{11 , 24 , 25 , 26} Similarly, elevated β-hCG levels indicate the presence of trophoblastic elements. Substantial elevations in β-hCG levels can be associated with choriocarcinoma, whereas lower levels are more suggestive of embryonal cell carcinoma and germinoma. ^{11 , 24 , 25 , 26} Although the presence of germ cell markers is specific for a malignant germ cell tumor, the absence of such markers should be interpreted cautiously. A germinoma or embryonal cell carcinoma may still be present even if both germ cell markers are absent. ² However, the specificity of these markers allows patients with positive assay results to forgo tissue diagnosis and instead be managed adequately with radiotherapy and chemotherapy.

The presence or absence of obstructive hydrocephalus dictates the CSF sampling strategy ( Fig. 19.4 ² ). Intracranial pressure can be reduced gradually to resolve symptoms before a craniotomy using stereotactic-guided endoscopic third ventriculostomy to manage symptomatic patients. This method is preferable to ventriculoperitoneal shunting because it minimizes infection risk and negates the risk of shunt failure, overs-hunting, or peritoneal seeding. Placement of a ventricular drain at the time of surgery is a reasonable alternative for mildly symptomatic patients. ²⁷ Advantages of a ventricular drain are its ease of removal or conversion to a shunt as postoperative circumstances dictate. Mild or asymptomatic hydrocephalus often resolves after resection of the mass and does not require preoperative treatment.

Surgical Considerations: Biopsy versus Resection

Either biopsy or open resection can provide a tissue diagnosis, which is fundamental in guiding treatment decisions of patients with pineal region tumors and negative germ cell marker assays. The histologic subtype strongly influences postoperative management (i.e., determining the utility of a metastatic evaluation, estimating prognosis, and developing a long-term follow-up plan). Although MRI findings and CSF studies may, in combination, suggest a particular subtype, they are not an adequate alternative to tissue diagnosis. ²⁸

Strict dedication to either biopsy or resection is not appropriate, although some scenarios strongly favor one over the other. Stereotactic biopsy is appropriate for patients who have known primary systemic tumors, multiple lesions, or medical contraindications to safe open resection. ^{24 , 27} Biopsy would seemingly be favored when there is evidence of brainstem invasion on MRI, but such evidence often does not correspond to intraoperative findings.

Generally, open resection is favored over biopsy because of its provision of larger amounts of tissue for diagnostic evaluation, clinical advantage from tumor debulking, and probable cure in the case of benign lesions ( Table 19.2 ²³ ). ^{13 , 16} Because of the histologic diversity and frequency of mixed-cell populations in these tumors, the histologic features of small specimens cannot readily be extrapolated to the entirety of the tumor. ^{27 , 29}

In contrast, stereotactic biopsy offers relative ease of performance, often requiring only local anesthesia and resulting in reduced complications. ³⁰ Even so, some associated risks remain. The most concerning among these is the risk of hemorrhage. During biopsy, bleeding may occur when the tumors are highly vascular or when there is deep venous system damage. A particular concern is bleeding into the ventricle, as tissue turgor is insufficient to tamponade the bleeding. ^{27 , 29 , 31} One isolated report of a patient with a pineoblastoma has described metastatic seeding along the biopsy tract. ³² Endoscopic biopsy has become increasingly popular in recent years. Its principal advantage stems from the use of flexible endoscopes, which allows a single bur hole to be used simultaneously for third ventriculostomy and biopsy. Notably, the risks and limitations of this approach are similar to those of stereotactic biopsy, including risks such as bleeding and limitations such as sampling bias.

Biopsy

Stereotactic Biopsy

Stereotactic biopsy of pineal region lesions should be approached cautiously in spite of the relative technical ease of stereotactic biopsy procedures in most other regions. In particular, a thorough anatomical understanding of the planned trajectory to the biopsy site is critical.

Most of the target-centered stereotactic frame systems that are available can be used, and both computed tomography and MRI are sufficiently accurate for targeting and tracking trajectories. A precoronal entry point, which provides an anterolateral superior approach to the tumor, avoids the lateral ventricle and internal cerebral veins ( Fig. 19.5 ³³ ). ^{24 , 30} A posterolateral superior approach near the parieto-occipital junction is used less commonly; however, this approach can be useful for tumors extending laterally or superiorly. ³³ Serial biopsies should be taken when possible because of the aforementioned issues with tissue sampling error, but the often small size of these lesions frequently limits serial sampling. During this procedure, a side-cutting cannula biopsy needle is preferable to a cup forceps, which has a higher risk of tearing a blood vessel. In the event of bleeding, irrigation with continuous suction may become necessary. When intraventricular bleeding is suspected, imaging should be obtained immediately and the degree of bleeding and hydrocephalus should be used to determine whether a ventricular drain is required.

Related posts:

15 Tumors of the Thalamus 14 Pediatric Brainstem Tumors 13 Adult Brainstem Gliomas 21 Radiotherapy for Pineal, Thalamic, and Brainstem Tumors 20 Stereotactic Radiosurgery for Tumors of the Brainstem, Thalamus, and Pineal Region 22 Neuro-oncologic Considerations for Pineal, Thalamic, and Brainstem Tumors

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