Treatment
Medical Therapy
Radiation therapy
Current treatment protocols for patients older than 3 years who have malignant pineal region tumors include radiotherapy. Early clinical trials of patients treated with radiotherapy reported significant mortality. Even low doses of radiation can have significant long-term effects upon a child's cognitive development. Radiation-induced deficits are an important consideration because many children with pineal region tumors enjoy prolonged survival.
Potential complications include hypothalamic and endocrine dysfunction, cerebral necrosis, secondary tumorigenesis, and progression of disease. 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 to 2500-3000 cGy. An additional dose directed at the tumor bed can be administered subsequently.
Several studies demonstrate 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 is focal radiotherapy followed by radiation to the ventricular field. The application of radiotherapy depends upon the histology of the tumor being treated.
Germinomas are among the most radiosensitive tumors, with patient response rates and long-term tumor-free survival rates greater than 90% in most published series. Nongerminomatous malignant germ cell tumors are significantly less responsive to radiation, with a 5-year survival rate of 30-40% using this treatment alone. Patients with low-grade pineocytomas can be observed cautiously after complete surgical resection without adjuvant radiation because no clear evidence shows that radiotherapy is beneficial. These patients' cases should be followed carefully with serial MRIs to assess tumor recurrence or progression.
The use of prophylactic spinal irradiation is controversial. Early recommendations for postoperative spinal irradiation have been preempted by reports showing the incidence of drop metastasis into the spine to be relatively low. The propensity of a pineal region tumor to metastasize to the spine varies with tumor histology. Estimates of the incidence of spinal seeding with pineal cell tumors are in the range of 10-20%, with significantly higher rates noted for pineoblastoma as compared with pineocytoma.
The incidence of spinal metastasis for germinomas has been reported to be as high as 11%, and, for endodermal sinus tumors, the incidence is as high as 23%. Craniospinal radiotherapy for nongerminomatous germ cell tumors is controversial but used routinely in some countries. For patients with pineoblastomas, some authors suggest the use of preemptive spinal radiation therapy even if the results of the postoperative surveillance MRI are negative. As modern improvements in surgical and adjuvant therapy are reflected in long-term survival, the rates of spinal metastasis will likely drop significantly, making the need for spinal irradiation obsolete. Currently, a reasonable approach is to administer spinal irradiation only for documented seeding.
Chemotherapy
Chemotherapy has evolved as an attractive means of minimizing the amount of radiation needed to effectively treat children with pineal region tumors. As with radiotherapy, the response to chemotherapy for patients with pineal region tumors varies according to tumor histology. Germ cell tumors historically have been more sensitive to chemotherapy than pineal cell tumors. Germinomas and nongerminomatous germ cell tumors have shown response rates ranging from 80-100% with platinum-based regimens. Patients with extracranial nongerminomatous germ cell tumors respond well to treatment with a wide array of chemotherapeutic agents.
Patients with intracranial nongerminomatous germ cell tumors have demonstrated response rates as high as 78% with some regimens. The Einhorn regimen, which includes cisplatin, vinblastine, and bleomycin, and later substituted VP-16 for vinblastine and bleomycin, has been used with some success.
Several ongoing studies are aimed at determining the optimal sequence of adjuvant therapy for children with nongerminomatous germ cell tumors. Presently, these children undergo treatment with a course of chemotherapy prior to radiation.
The dramatic success of radiotherapy in treating children with germinomas has precluded extensive consideration of chemotherapy as a first-line treatment in older children. Chemotherapy should be considered a first-line treatment only in very young children. Some authors advocate treating children with chemotherapy prior to radiation in an effort to reduce radiation exposure and its associated morbidity.
Most clinicians currently advocate a derivative of the Einhorn regimen as an alternative treatment for patients with recurrent or metastatic germinomas. Some clinicians advocate the use of chemotherapy as well as radiotherapy after diagnosis of nongerminomatous germ cell tumors. The impetus for adding chemotherapy initially in these patients comes from the 5-year survival rate of 30-65% in children with nongerminomatous germ cell tumors treated with radiotherapy alone.
The reported effectiveness of chemotherapeutic regimens for children with pineal cell tumors is limited to anecdotal case reports and reported series involving small numbers of patients. No dominant agent has evolved as the drug of choice, and treatment regimens have included various combinations of vincristine, lomustine, cisplatin, etoposide, cyclophosphamide, actinomycin D, and methotrexate.
Recently, high-dose cyclophosphamide has been advocated as a single-agent protocol in the treatment of children with pineoblastomas. In their 1996 study, Ashley and colleagues demonstrated that children treated with high-dose cyclophosphamide had stable or diminishing disease while on the protocol.5 Impaired pulmonary function and thrombocytopenia were notable adverse effects.
Radiosurgery
Stereotactic radiation or radiosurgery is increasingly being applied to patients with central nervous system disease. Currently, experience with radiosurgery in patients with pineal region tumors is limited; however, several small studies have shown safety and some efficacy in treating pineal region tumors over a range of histologies.6,7 The number of patients treated in the literature are too few to draw any far-reaching conclusions. Review of these studies shows that radiosurgery is not a magic bullet for all pineal lesions because treatment failures have occurred in all series but one with more malignant lesions; some treatment failures have also been reported for pineocytoma. This demonstrates the importance of obtaining a histological diagnosis before embarking on a treatment plan and highlights the risk of treating a tumor of unknown histology with radiosurgery alone.
In the pediatric population, radiosurgery is an attractive potential first-line treatment that merits further investigation. Some authors have proposed using radiosurgery in place of conventional radiotherapy in an effort to reduce or eliminate the long-term sequelae of radiotherapy in children. Radiosurgery is optimized for targets 3 cm or less, which precludes treatment of some patients with larger pineal region tumors.
Surgical Therapy
The decision to perform a biopsy versus an open procedure for the pineal region tumor has been debated extensively in the literature. While the ultimate choice of procedure is based to some extent upon the surgeon's personal bias and experience, some distinct advantages and disadvantages exist for each of these procedures.
Stereotactic biopsy has been described as the procedure of choice for obtaining a tissue diagnosis in certain 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 periventricular structures adjacent to the deep venous system. More recent studies, however, have shown stereotactic biopsy to be a safe and efficient means of obtaining a tissue diagnosis.
In their 1996 series, Regis and colleagues revealed a mortality rate of 1.3% and a morbidity rate of less than 1.0% in 370 patients with stereotactic biopsies of pineal region tumors.8 The study included data from 15 French neurosurgical centers and documented statistical homogeneity among the different centers.
In a similar study, Kreth and colleagues (1996) retrospectively evaluated the risk profile, diagnostic accuracy, and the therapeutic relevance of the stereotactic approach in 106 patients.9 They showed a morbidity rate of 2 out of 106 patients, a mortality rate of 9 out of 106 patients, and a definitive tissue diagnostic rate of 103 out of 106 patients. Although stereotactic biopsy can clearly be performed safely and effectively at centers familiar with the technique, it is disadvantageous to patients who would benefit from complete or near-complete resection of tumor.
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.10,11,12,13 Problems with the endoscopic technique are its limited ability to control bleeding and limited tissue sampling. Some series have reported up to 94% yield, although many patients require a second procedure.11 Performing an endoscopic third ventriculostomy and an endoscopic biopsy of the pineal region with one burr hole is usually not possible because of anatomical considerations.
Open resection carries the obvious advantage of complete tumor resection. The long-term benefits of complete tumor resection are best surmised by tumor type and histology. For patients with benign lesions, the surgical resection can be curative. In patients with malignant tumor components, evidence suggests that surgical debulking may improve the response to postoperative adjuvant therapy. Gross total tumor resection also provides ample tissue specimen to the neuropathologist for diagnosis. This circumvents the potential problems of sampling error and erroneous diagnosis associated with the small volume of tissue provided by stereotactic biopsy.
The bulk of information about surgical intervention in the current literature is derived from retrospective analyses that often include cases performed a decade ago. Several advances have been made over the past decade that will likely lower the morbidity and mortality associated with open procedures as well as stereotactic biopsy in future studies.
Tissue diagnosis is a vital part of management in most patients with pineal region tumors. However, nonoperative management of patients with positive tumor markers is a reasonable option for some patients. A markedly elevated level of AFP and bhCG is pathognomonic for germ cell tumors with malignant components. New strategies currently under study have been aimed at minimizing surgical intervention prior to ascertaining whether a tumor is responsive to radiation and/or chemotherapy.
In their 1998 retrospective study, Choi et al described the treatment of 107 patients with primary intracranial germ cell tumors.14 This included 60 patients with tumors in the pineal region. Thirty of these patients were treated without surgery based on radiological findings and tumor markers.
Univariant analysis of a response to trial radiation and chemotherapy was shown to be correlative with outcome, justifying the administration of trial chemotherapy or radiotherapy without tissue biopsy in the subgroup of patients with positive germ cell markers. These findings corroborate the results of a 1997 study by Sawamura and colleagues evaluating the necessity of radical resection in patients with intracranial germinomas.15
Twenty-nine patients treated with radiation and/or chemotherapy were studied retrospectively, including 10 with solitary pineal region masses. The results showed no significant difference in outcome related to extent of surgical resection and an overall tumor-free survival rate of 100% over a follow-up period of 42 months. This retrospective evidence is quite compelling in favor of withholding surgical treatment of children with pineal region tumors and positive serum or CSF markers.
Surgery in such cases is now reserved for a clean-up role for persistent or growing tumor on MRI after chemotherapy and radiation. Often benign, teratomatous elements are found at surgery, indicating the original tumor was in fact of mixed histology.
Preoperative Details
Patients presenting with hydrocephalus and radiographic evidence of a malignant pineal region tumor may have their hydrocephalus treated with third ventriculostomy or ventriculoperitoneal (VP) shunt prior to biopsy or resection. The staged procedure allows for definitive control of the hydrocephalus prior to surgical resection of lesions suspicious for being malignant.
A similar strategy may be used for patients with marked symptomatic hydrocephalus and benign-appearing lesions. The timing of the second procedure can vary according to the surgeon's preference. Peritoneal seeding with shunting is a rare but well-documented complication in these patients. However, the use of a filter to decrease the incidence of seeding has been associated with frequent shunt malfunctions and generally is not recommended, particularly because third ventriculostomy is a better option.
Improved endoscopic techniques have made third ventriculostomy an easy and reliable method to divert CSF. Third ventriculostomy is performed stereotactically with an endoscope passed via a burr hole into the right lateral ventricle and through the foramen of Monro. The floor of the third ventricle is then fenestrated to provide an alternate route for CSF flow.
As with all CSF diversion procedures, CSF may be acquired and sent for cytologic and biochemical analysis during the case. Third ventriculostomy has the added advantage of potentially allowing for a biopsy during the procedure by endoscopic guidance. This provides the opportunity to make an intraoperative diagnosis with subsequent tailoring of further therapy.
Intraoperative Details
Improvements in surgical techniques and neuroanesthesia have significantly lowered the morbidity and mortality rates associated with pineal region surgery. For those patients for whom primary surgical resection is the best therapeutic and diagnostic option, several well-described approaches currently are in use.
In general, surgical approaches to the pineal region can be divided into supratentorial, infratentorial, and (most recently) a combined supratentorial-infratentorial approach. Supratentorial approaches include the parietal-interhemispheric approach described by Dandy (1936) and the occipital-transtentorial approach originally described by Horrax, later modified by Poppen.16
Supratentorial approach
The 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 transcallosal interhemispheric approach uses a paramedian trajectory between the falx and the right parietal lobe, with partial resection of the corpus callosum. The occipital-transtentorial approach requires retraction of the occipital lobe and division of the tentorium for adequate exposure.
The main disadvantage of supratentorial approaches is the difficulty associated with removing a tumor that lies below the convergence of the deep venous system. Complications of the transcallosal interhemispheric approach may result from excessive retraction on the parietal lobe. The occipital transtentorial approach can result in visual defects secondary to occipital lobe retraction and associated damage to the calcarine cortex.
Infratentorial approach
The infratentorial approach is a direct midline approach, originally described by Krause and popularized by Stein, which provides an easily recognized orientation for the surgeon.17 A midline trajectory between the tentorium and the cerebellum allows the tumor to be encountered below the deep venous system. When performed in the sitting position, the cerebellum tends to fall away, exposing the pineal region while minimizing pooling of venous blood in the operative field.
The main disadvantage associated with this approach is the limited access to tumors that extend above the deep venous complex and anteriorly into the third ventricle. Lateral exposure also is restricted when using this approach.
Several different positions have been described for supratentorial and infratentorial approaches to the pineal region.
- The sitting slouch position is generally used for the infratentorial-supracerebellar and transcallosal-interhemispheric approaches. The main complications of this position include subdural and epidural hematoma secondary to ventricular and cortical collapse, pneumocephalus, and air embolus.
- The three-quarter prone lateral position is used for the occipital-transtentorial approach and avoids many of the complications associated with the sitting slouch position.
- A prone position with elevation of the patient's shoulders and the head tilted to the right combines the advantages of the sitting slouch and three-quarter prone lateral positions.
- The Concorde position was described by Kobayashi, and later modified by Bloomfield and colleagues, for patients with pineal region tumors. The Concorde position is more comfortable for the surgeon and reduces the risk of air embolism, but it can be more cumbersome in larger patients. It often is desirable for preadolescent patients.
Postoperative Details
Once the physician makes a diagnosis of malignant tumor from tissue acquired intraoperatively, the surgeon is obligated to evaluate the patient for spinal metastasis. Prior to widespread use of the MRI, patients' disease was staged postoperatively with CT myelogram.
Currently, the most sensitive radiographic modality for screening is a 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 1-2 weeks. Radiographic artifacts secondary to surgery regress while drop metastasis remain stable or increase 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 due to spillage during surgery.
The timing for follow-up cranial MRI varies depending upon tumor histology and degree of resection. In order to estimate the amount of tumor removed, acquiring a postoperative brain MRI within 48 hours of performing surgery is advantageous.
Postoperative enhancement unrelated to residual tumor may be observed on scans performed later. The significance of residual tumor depends upon tumor histology and the efficacy of available adjuvant therapy. The radioresponsive germinoma is a good example of this phenomenon. Series of patients treated with adjuvant radiation are reported to have a 100% tumor-free survival rate as long as 4 years after diagnosis. This survival rate has been demonstrated to be unrelated to the extent of tumor resection. In contrast, much of the literature evaluating tumor resection and malignant pineal cell tumors and nongerminomatous germ cell tumors suggests that larger resections facilitate adjuvant therapy and long-term survival.
Regardless of tumor histology, long-term follow-up is required for all patients with pineal region tumors because recurrences several years after remission are possible.
Follow-up
Life-long follow-up of children with pineal region tumors is required. These tumors can recur locally or appear distally as late as 5 years 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 original diagnosis, extent of resection, and presence of metastasis at time of diagnosis.
Tumor marker studies for patients with germ cell tumors should be performed also on a periodic basis, even if markers were not abnormal at diagnosis.
Complications
The most common complications following pineal region surgery, regardless of the approach, are extraocular movement dysfunction, ataxia, and altered mental status. Many of these neurological findings, such as extraocular movement dysfunction and ataxia, are present preoperatively and become transiently worse postoperatively before significantly improving or resolving completely. Some factors that correlate with an increased incidence of surgical complications include prior radiation treatment, severe preoperative neurological 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. The 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 third ventriculostomy following fenestration of the floor of the third ventricle, ventriculostomy closure, and aseptic meningitis. In addition, supratentorial approaches can result in seizures, hemianopsia, or hemiparesis.
When considering all published series reporting 20 or more patients in the microsurgical era, pineal region tumor surgery has an overall mortality rate of 0-8% and morbidity rate of 0-12%. This is in stark contrast to the mortality rate of 90% reported during the early part of the 20th century.
Long-term outcome after surgical resection depends largely upon tumor histology, as well as evolving modalities of adjuvant therapy. For patients with malignant tumors, gross total resection, in some cases, may be associated with a more favorable prognosis. In other patients, such as those with germinomas, initial surgical intervention may become obsolete as preemptive adjuvant therapy becomes more effective.
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Further Reading
Keywords
pineal, tumors, pineal tumor, pineal tumors, pineal gland, pineal gland tumors, pineal gland tumor, pineal region tumors, pineoblastomas, pineocytomas, pineal germ cell tumors, germinomas, pineal gliomas, pineal metastasis, obstructive hydrocephalus, vertical gaze palsy, astrocytomas, meningiomas, teratomas, pineal cyst, pineal cysts
