Approach Considerations
Treatment of pineal region tumors is complex. Various strategies exist for managing associated signs and symptoms, such as hydrocephalus or local mass effect, and achieving cytoreduction/oncologic control. The choice of strategies depends on the clinical presentation, the presence of hydrocephalus, results of cerebrospinal fluid (CSF) and serum tumor marker studies, the presence of metastatic disease, and the patient's age and general medical status.
When a patient presents with manifestations of hydrocephalus, decompression of the ventricles is the first priority. [41] Treatment typically begins with endoscopic third ventriculostomy (ETV) for relief of the obstruction, followed by inspection of the CSF for dissemination, sampling of the CSF, and biopsy of the tumor. The tumor may be resected endoscopically if indicated. [75] If ETV is contraindicated or unavailable, a ventriculoperitoneal shunt could be placed, but this carries the risk of peritoneal dissemination. [76] If hydrocephalus is emergently life-threatening, an external ventricular drain may be placed at bedside.
For patients with positive tumor markers, treatment depends on tumor type. Treatment may include a combination of radiotherapy, chemotherapy, and resection. Most patients cannot be confidently diagnosed with tumor markers and therefore histological diagnosis via tissue biopsy is required. Surgical resection may be indicated depending on tumor type.
Below is an algorithm to aid in decision making.
Treatment Options
Germ Cell Tumors
Germinomas may be treated with radiation or a combination of radiation and chemotherapy. They are among the most radiosensitive tumors, with patients experiencing long-term tumor-free survival rates greater than 90% from radiation alone in most published series. However, radiation therapy poses risks of long-term adverse effects and current standard of care includes adjuvant chemotherapy to allow for reduced doses of radiation. Chemotherapy alone results in cure in less than 50% of cases and is not recommended. [14]
For localized germinomas, radiation is delivered to the tumor bed and the whole ventricle instead of the whole brain. Bifocal disease of pineal and suprasellar regions is treated as localized disease. [77] For disseminated or recurrent germinomas, more extensive craniospinal irradiation (CSI) is recommended. [78]
Non-germinomatous germ cell tumors (NGGCTs) are more aggressive and significantly less responsive to radiation, with a 5-year survival rate of 30-40% when this treatment is used alone. This category includes embryonal carcinoma, yolk sac tumor, and choriocarcinoma. For these patients, chemotherapy and CSI is recommended. [79]
Teratomas are less responsive to radiation alone and due to histologic heterogeneity, no standard radiation recommendations exist. Immature teratomas are generally treated with chemotherapy and CSI. Mature teratomas may require only resection, if the surgeon is able to achieve gross total resection. [17]
Some tumors may contain multiple germ cell types. Treatment of these mixed GCTs should be based on their most malignant component. [18]
Surgical safe maximal resection is recommended when chemotherapy and radiation fail to shrink the tumor. This may be referred to as “second-look surgery.” The stable mass may be the remaining original tumor, concurrent teratoma, or fibrosis. [80] Small residual tumor after otherwise good response to treatment generally does not require surgical intervention and can be monitored, though this is an area of debate. [81]
Rarely, GCTs will progress quickly during or after treatment with chemotherapy. This phenomenon is called "growing teratoma syndrome", and it is more common in NGGCTs and immature teratomas. Treatment includes complete resection followed by chemotherapy and radiation. [82]
Pineal Parenchymal Tumors
Pineocytomas are primarily treated surgically. Asymptomatic pineal parenchymal tumors can be managed conservatively, but if enlarged and symptomatic, gross total resection is generally curative. For those with subtotal resection, postoperative radiotherapy is administered. [19]
Pineoblastomas are highly aggressive tumors that requires surgical resection as well as combination CSI radiotherapy, tumor boost, and chemotherapy. [20]
For pineal parenchymal tumors of intermediate differentiation, treatment is dependent on degree of invasion. [21] Disease that is limited locally is treated with surgical resection alone. Locally invasive or disseminated disease is treated with resection, CSI and chemotherapy. [22]
Lastly, papillary tumors of the pineal region are typically treated with resection, CSI and chemotherapy. They frequently recur, but CSI has been shown to be effective both in initial management and at recurrence. [23]
Complications of Radiation and Chemotherapy
For almost all tumors, adjuvant chemotherapy plus radiotherapy is standard of care [24] . The exceptions include pineocytomas and mature teratomas. Specifically, radiotherapy is included in protocols as early as three years old. [24]
Radiation therapy is associated with significant toxicities to endocrine, bone and neurocognitive function. Before the use of chemotherapy, these feared radiation-associated toxicities challenged the field and dose of radiation used to treat pineal tumors. [83, 84] These toxicities eventually prompted the use of adjuvant chemotherapy to reduce exposure to irradiation. [84]
A long term study following children and adults with pineal parenchymal tumors found that there were no severe side effects from radiation treatment. Side effects included transient blindness and sepsis due to leukopenia. Neurotoxicity was not observed. However, growth and neurocognitive effects were difficult to assess given that many of the pineoblastoma patients died within 2 years of treatment. [85]
Since 1953, at least 35 cases of radiation-induced meningioma have been reported in children after radiotherapy for pineal region tumors. Standard radiotherapy protocols for children with malignant pineal cell tumors use 4000 cGy of whole brain radiation followed by 1500 cGy to the pineal region. The dose is administered in 180-cGy daily fractions.
Whole brain radiation can cause significant morbidity in prepubescent patients, limiting the recommended initial extended-field dose to 2500 to 3000 cGy. An additional dose directed at the tumor bed can be administered subsequently.
Several studies have shown that patients receiving less than 5000 cGy are at risk for recurrence, strongly suggesting that this is the optimal total dose of radiation. For children with malignant germ cell tumors, standard treatment consists of focal radiotherapy followed by radiation to the ventricular field. The application of radiotherapy depends on the histology of the tumor being treated.
The dramatic success of radiotherapy in treating children with germinoma has precluded extensive consideration of chemotherapy as a first-line treatment for older children. Chemotherapy should be considered as first-line treatment only for very young children. Some authors advocate treating children with chemotherapy prior to radiation in an effort to reduce radiation exposure and its associated morbidity.
Radiosurgery
Stereotactic radiosurgery (SRS) is a surgical intervention that relies on a coordinate system to deliver focused radiation at small targets in the body. In the treatment of pineal gland tumors, it is considered standard of care for pineocytomas. Further, for GCTs and pineoblastomas, it can be used in conjunction with chemotherapy and radiation. [24, 86]
Surgical Therapy
Approaches for Biopsy
When nonoperative diagnosis with tumor markers cannot be achieved, tissue diagnosis is vital for patients with pineal region tumors. There are multiple approaches to specimen collection with distinct advantages and disadvantages. [24]
Stereotactic biopsy has been described as the procedure of choice for obtaining a tissue diagnosis in situations such as widely disseminated disease, clearly invasive malignant tumor, or patients with multiple medical problems. Early experience with stereotactic biopsies resulted in morbidity and mortality specifically related to targeting of periventricular structures adjacent to the deep venous system. However, current studies show that stereotactic biopsy is a safe and efficient means of obtaining a tissue diagnosis. [87]
Endoscopic biopsy offers another means of obtaining tissue for diagnosis without open resection and can be used as an alternative to stereotactic biopsy, depending on the surgeon's judgment and experience. [88, 89, 90, 91, 92, 93] In recent years, techniques have been developed to perform endoscopic third ventriculostomy and an endoscopic biopsy of the pineal region with a single burr hole. [94, 95, 96] This dual approach is beneficial in addressing hydrocephalus as well as establishing a tissue diagnosis.
Patients may undergo open resection as a primary surgical treatment. While this carries the advantage of complete tumor resection and a decrease in tissue sampling error, not all tumor types require surgical removal and the patient may be subjected to undue risk from the procedure. For example, patients with germinomas are generally treated with radiation and chemotherapy alone. For patients with benign lesions, surgical resection can be curative. For patients with malignant tumor components, evidence suggests that surgical debulking may improve response to postoperative adjuvant therapy. Gross total tumor resection also provides ample tissue specimen to the neuropathologist for diagnosis.
Open versus Endoscopic Resection
Pineal tumors can be resected through open or endoscopic approaches. The open approach remains the standard of care. However, techniques in endoscopic surgery continue to improve. As endoscopic resection is shown to be a safe and effective method of gross total resection, it may be utilized more frequently. [97, 98, 99]
Intraoperative Details
Strategies for open resection of pineal region tumors are categorized as supratentorial or infratentorial. The infratentorial workhorse is the supracerebellar infratentorial approach (SCIT). Supratentorial approaches include occipital transtentorial (OTT), interhemispheric transcallosal (IHTC), and the rarely used transcortical transventricular (TTV) approach. The choice of approach depends on the surgeon’s experience and comfort. Many of these approaches are interchangeable, although there are several caveats. Improvements in surgical techniques and neuroanesthesia have significantly lowered morbidity and mortality rates associated with pineal region surgery.
Infratentorial supracerebellar approach
The infratentorial supracerebellar approach utilizes the natural corridor created between the tentorium and the cerebellum and is ideal for tumors inferior to deep cerebral veins. See the images below. The main disadvantage associated with this approach is limited access to tumors that extend above the deep venous complex, anteriorly into the third ventricle, or with extensive lateral growth.
View during a infratentorial supracerebellar approach from the operative microscope. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
Pre and postoperative MRI from a patient with a pineal tumor resected via supracerebellar infratentorial approach. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
Suboccipital exposure begins with linear midline incision from above the torcular and external occipital protuberance down to the level of C4. [76] Arachnoid adhesions and midline bridging veins between the dorsal surface of the cerebellum and tentorium are cauterized in order to open the infratentorial corridor. This allows for the cerebellum to separate easily from the tentorium with minimal retraction. Here, with retraction, the arachnoid covering the pineal region can be observed. Utilizing the surgical microscope, the tumor is then debulked with a variety of tools including suction, cautery, tumor forceps, and ultrasonic aspirator. If the tumor is completely removed, the surgeon should have a direct view into the third ventricle. [76]
The lateral suboccipital approach is a modification of the SCIT approach that utilizes a paramedian corridor to the pineal region. [100] This modification avoids the many medial vermian bridging veins, which would normally be sacrificed in the midline approach. A modified lateral decubitus position should be used. The approach begins with a lateral suboccipital craniotomy, which exposes the transverse sinus. Unilateral suboccipital craniotomy protects the cerebellum, torcula, and contralateral transverse sinus, reducing morbidity. Next, retraction sutures are placed to gently rotate and elevate the transverse sinus, expanding the lateral supracerebellar corridor. [100]
Previous reports have noted that this paramedian approach is insufficient in providing the necessary view for resecting large pineal region tumors. [101] However, a 2016 study reported that this approach was sufficient for resection of pineal region tumors > 3 cm. [100]
Occipital transtentorial approach
A supratentorial approach is best applied to patients with tumors extending supratentorially or laterally into the trigone of the lateral ventricle. The main advantage of the supratentorial approach relates to the wide exposure that can be obtained. The main disadvantage of the supratentorial approach is the difficulty associated with removing a tumor that lies below the convergence of the deep venous system. The occipital transtentorial approach can result in visual defects secondary to occipital lobe retraction and associated damage to the calcarine cortex.
A three-quarter prone position is ideal for the occipital transtentorial approach. This approach divides the tentorium, allowing for exposure of the quadrigeminal plate and access to tumors that extend inferiorly. The operating microscope helps to identify the straight sinus where it lies adjacent to the tentorium. The tentorium is divided and the falx is retracted for greater exposure. The arachnoid covering the tumor as well as the quadrigeminal plate can be seen. Tumor is then debulked and resected. [76]
Interhemispheric transcallosal approach
This is one of the oldest approaches that creates a corridor between the falx and the brain to the pineal region along the parieto-occipital junction and can reach tumors with anterior extension into the third ventricle. It requires a wide craniotomy, roughly 8 cm in length, to provide flexibility in avoiding bridging veins. A limitation of this approach is that it cannot be used for tumors that extend below the collicular plate. Complications of the transcallosal interhemispheric approach may result from excessive retraction on the parietal lobe.
Prone or sitting positions can be used. It begins with a wide U-shaped scalp flap extending across the midline and reflected laterally. This is followed by a wide craniotomy over the vertex. This creates flexibility for the corridor between the falx and hemisphere along the parieto-occipital junction. [76] The parietal lobe and falx are retracted. The corpus callosum is identified, by its white appearance, via the operating microscope, and its pericallosal arteries are retracted. The corpus callosum is then opened approximately 2 cm, which typically does not lead to postoperative impairment. [76] After an opening is created, the dorsal surface of the tumor as well as the deep venous system should be appreciated. Sacrifice of greater than one vein would have deleterious consequences. Here, the tumor can be debulked and dissected. [76]
Transcortical transventricular approach
This approach reaches the pineal region by transversing the right lateral ventricle. It is a historical approach that is now rarely used, as it requires a cortical incision and provides limited exposure. Patients may suffer visual field deficits. Stereotactic guidance is used as an aid, and eloquent cortex is avoided. [76]
Postoperative Details
If an intraoperative diagnosis of malignant tumor is made, the patient must be evaluated for spinal metastasis. The most sensitive radiographic modality for screening is complete spinal MRI with and without gadolinium. The first MRI scan should be timed at least 2 weeks after surgery because spinal canal enhancement can occur in the early postoperative period.
Equivocal findings on the initial postoperative scan warrant a repeat scan within 1 to 2 weeks. Radiographic artifacts secondary to surgery regress while drop metastasis remains stable or increases in size over time. The role for postoperative lumbar puncture and subsequent CSF analysis for cytology is questionable. The presence of abnormal cells postoperatively does not correlate well with spinal metastasis, as it may instead be due to spillage during surgery.
Timing for follow-up cranial MRI varies depending upon tumor histology and degree of resection. To estimate the extent of resection, MRI brain is acquired within 48 hours of surgery. Scans performed after this period may exhibit postoperative enhancement and cannot be reliably interpreted. The significance of residual tumor depends upon tumor histology. Regardless of tumor type, long-term follow-up is required for all patients with pineal region tumors to monitor for recurrence.
Follow-up
Lifelong follow-up of children with pineal region tumors is required. These tumors can recur locally or can appear distally long after diagnosis. In addition, patients can present later in life with new tumor formation (eg, meningioma).
MRI scans should be obtained on a periodic basis as determined by tumor histology of the original diagnosis, the extent of resection, and the presence of metastasis at the time of diagnosis.
Tumor marker studies for patients with GCTs should also be performed on a periodic basis, even if markers were not abnormal at the time of diagnosis.
Complications
The most common complications following pineal region surgery include extraocular movement dysfunction, ataxia, and altered mental status. [102] Many such neurologic findings are transient, with eventual significant improvement or complete resolution. Factors contributing to increased incidence of surgical complications include prior radiation treatment, severe preoperative neurologic deficit, malignant tumor pathology, and invasive tumor characteristics.
The most devastating complication of pineal region tumor surgery is postoperative hemorrhage into a subtotally resected tumor bed. Hemorrhage may be delayed for several days and is most commonly associated with vascular tumors such as pineal cell tumors. Venous infarction, with or without hemorrhage, is another grave complication. Less-common postoperative complications include shunt malfunction, hemorrhage during ETV and aseptic meningitis. In addition, supratentorial approaches can result in seizures, hemianopsia, or hemiparesis.
A 2022 study by Shepard et al reported outcomes of 68 patients following resection of pineal tumors. [103] Almost half the patients (45.6%) experienced at least one adverse outcome within 30 days after surgery. These included worsening hydrocephalus and focal motor deficits. Importantly, the mortality rate within 30 days of surgery was 5.9%, a stark contrast to the high mortality rates of a century prior. [35] Mortality was often due to intratumoral hemorrhage. Gross total resection, improved performance status, and low histopathologic grade were associated with improved survival. [103]
Outcome and Prognosis
The prognosis for patients with pineal region tumors depends on tumor histology and is subject to change as more effective adjuvant therapy is developed. In general, patients with intracranial germinomas have an excellent prognosis because of the radiosensitivity of this tumor.
Children with NGGCTs have a significantly worse prognosis than do children with germinomas, pineocytoma,s or pineoblastomas. There is no standard of care for managing recurrence. Chemotherapy, radiotherapy, or radiosurgery can be applied if maximal doses have not already been administered. A second surgical procedure is generally reserved for patients with benign lesions who demonstrate recurrence several years later.
Recurrent GCTs have been shown to respond to chemotherapy, as have some pineocytomas and pineoblastomas, although to a lesser degree. Radiosurgery may be a consideration for all recurrences measuring less than 3 cm in diameter.
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Gadolinium-enhanced MRI of a 33-year-old woman who presented with visual loss, amenorrhea, and diabetes insipidus. MRI shows germinomatous invasion of the pineal gland (large arrowhead), optic chiasm (long arrow), pituitary stalk (small arrowhead), and the floor of the third ventricle (short arrow).
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Noncontrast MRI of a pineocytoma in a 40-year-old man presenting with acute hydrocephalus. At surgery, the high signal area (arrow) turned out to be acute hemorrhage.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T1-weighted noncontrast sagittal scan shows isointense tumor, which has obstructed the aqueduct of Sylvius (arrow) to cause hydrocephalus.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T2-weighted noncontrast axial scan shows the tumor as hyperintense to brain matter but hypointense to cerebrospinal fluid (CSF).
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MRI of a 21-year-old man with a germinoma in the pineal region. Homogenous gadolinium enhancement of the tumor is shown on this T1-weighted contrast-enhancing sagittal scan.
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Sagittal MRI of a heterogeneous mixed germ cell tumor of the pineal region in a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma.
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Gross tissue specimens were obtained from a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma. Gross tissue specimens reflect heterogeneity of various germ cell components.
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T1-weighted contrast-enhancing sagittal MRI from a 41-year-old man with a pineocytoma. The tumor enhances homogeneously with gadolinium, except for a cystic portion.
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Micrograph from a mature teratoma of the pineal region that consists of well-differentiated tissue from all 3 germinal layers. This image demonstrates nonkeratinizing squamous cell epithelium alternating with areas of ciliated columnar epithelium.
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This micrograph shows osteoid bone with surrounding periosteal tissue and mesenchymal stroma occurring within a mature teratoma of the pineal region.
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This micrograph features cartilaginous tissue observed within a mature teratoma of the pineal region.
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Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.
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Endodermal sinus tumor with a characteristic Schiller-Duval body.
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Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.
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Pineocytoma consisting of benign, well-differentiated cells forming rosettes.
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MRI of a 44-year-old woman 10 years after resection of a mixed pineal cell tumor. The tumor has recurred in the pineal region (arrow) and has seeded the fourth ventricle (arrowheads).
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The right side of this image shows 3 operative approaches to the pineal region. Appropriate patient positioning for each approach is on the left. Number 1 is the supracerebellar-infratentorial approach, number 2 is the occipital-transtentorial approach, and number 3 is the parietal-interhemispheric approach.
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The left drawing is a sagittal view of a patient with a pineal region tumor. The right drawing shows a sagittal view of the supracerebellar/infratentorial approach to the pineal region.
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Biopsy specimen from an intracranial germ cell tumor. arge tumor cells with large nuclei; prominent nucleoli; and abundant, clear cytoplasm (rich in glycogen) are noted among reactive inflammatory cells.
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View during a infratentorial supracerebellar approach from the operative microscope. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
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Pre and postoperative MRI from a patient with a pineal tumor resected via supracerebellar infratentorial approach. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
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Demographics and imaging findings of pineal tumors.
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Markers of pineal tumors.
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Management of pineal tumor.
