As a group, pineal region tumors are uncommon and account for 1% of adult tumors. Pineal tumors are diverse and are grouped together because of their location. Germ cell tumors predominate among older patients; pineal parenchymal tumors (pineocytoma, pineoblastoma) are occasionally seen. Pineal region tumors are more common in males than females (3:1). Pineal region tumors typically present within the second or third decade of life.

In the past, a reluctance to biopsy lesions in this area because of associated morbidity led to the empiric treatment of many lesions with radiation therapy. In modern series with routine biopsy, benign lesions account for up to 50% of pineal lesions, highlighting the need for histopathologic confirmation.

The WHO classification subdivides pineal tumors into pineocytomas, pineoblastomas, and germinomas. The first two tumors are rare, and the incidence of germinoma is less than 1% of all intracranial tumors.

Pineal germ cell tumors are identical histologically to their ovarian and testicular counterparts. When originating in the CNS, germinomas commonly present within the pineal or sellar regions, and multifocal presentation within these regions is not uncommon. Nongerminomatous germ cell tumors (NGGCTs) of the CNS are also seen and include embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, malignant teratoma, and mixed tumors. In North American series, germinomas account for about 30% to 40% of cases and NGGCT for 10% to 20%. Germ cell tumors may secrete markers (AFP, beta-HCG) into the serum or CSF. Radiographically, germ cell tumors are often hyperdense compared with normal brain, enhance uniformly, and are well circumscribed. Teratomas may contain mixed-density components and heterogeneous enhancement consistent with their variable composition. Neoplasms arising from pineal parenchymal cells account for 10% to 20% of pineal tumors. Pineocytomas are well-circumscribed, slowly growing lesions that compress adjacent structures and are composed of well-differentiated, mature-appearing pineal cells. Pineoblastomas are generally regarded as pineal PNETs and are very cellular tumors composed of small round blue cells with little cytoplasm. Like other PNETs, pineoblastomas have a propensity to spread to the CSF space. An association with bilateral retinoblastoma (trilateral retinoblastoma) is noted with pineoblastoma.

Tumors of the pineal and suprasellar region usually cause symptoms caused by local compression. Tumors with a higher risk of CSF dissemination (pineoblastoma, NGGCT) may present with signs or symptoms of CSF spread. Suprasellar tumors may cause endocrinopathies and visual symptoms. Tumors of the pineal region are in close proximity to the cerebral aqueduct and tectum of the mid-brain and commonly present with hydrocephalus and oculomotor symptoms. Parinaud's syndrome is common with pineal masses and comprises a constellation of symptoms including paralysis of upward gaze, convergence retraction nystagmus, and light near dissociation (pupils constrict to accommodation but not light).

CT or MRI frequently shows a mass within the suprasellar or pineal region. Occasionally a patient will present with a small lesion of the tectal plate that may mimic benign aqueduct stenosis. Simultaneous pineal and suprasellar tumors (multiple mid-line tumors) may be seen with germinomas. Baseline ophthalmologic assessment is necessary for patients presenting with visual disturbance.

All patients with pineal region masses should have serum and CSF, beta-HCG, and AFP markers measured. Neuraxis staging should be performed on all patients except those with biopsy-confirmed benign lesions and low-grade glial tumors.

Treatment

The treatment of pineal region tumors is controversial. Small numbers of patients, incomplete histologic information, nonuniform imaging of the primary tumor, variable staging of the CSF, and widely variable treatment using various combinations of surgery, radiation therapy, and chemotherapy make interpretation of results difficult.

In the past, many patients with pineal region masses had shunts placed to relieve symptoms of hydrocephalus followed by irradiation without biopsy; tumors with a good response to radiation therapy were presumed to be germinomas. Given the known incidence of benign tumors in 10% to 50% of patients, this policy will lead to the unnecessary treatment of a substantial proportion of patients. Response to radiation therapy does not always correlate with histology, and in the case of a partial response to radiation therapy, the situation is even less clear. Histologic information allows tailoring of the treatment regimen, and with improved neurosurgical technique, the mortality and morbidity rates of resection within the pineal region have decreased to 1% to 2%. Thus, the current recommendation is for histologic confirmation of all pineal and suprasellar masses if it can be performed safely.

As a group, pineal tumors are regarded as radiosensitive, but some controversy exists about how to treat them with radiation therapy, because of varying opinions regarding seeding incidence (8% to 37%).

Germinomas

Aggressive surgical resection is not generally indicated for these tumors; however, adequate sampling is essential because nongerminomatous elements may be present in 10% to 40% of cases. Correlation with serum and tumor markers is essential because germinomas may be associated with mildly elevated beta-HCG but not AFP.

Although radiation therapy is established as the current treatment of choice for intracranial germinomas, controversy exists as to the exact volume of the CNS to be irradiated, particularly the need to treat the entire neuraxis prophylactically. Most series indicating a benefit to prophylactic irradiation of the neuraxis have included tumors not\ examined via biopsy, many treated before contemporary CT or MRI imaging was available, and patients with incomplete neuraxis staging. Series with biopsy-proven germinomas and negative neuraxis staging treated to limited fields have demonstrated a low incidence of isolated spinal canal recurrence (less than 10%).

Currently, craniospinal irradiation is reserved for patients with neuraxis spread (positive imaging or CSF cytology), patients with subependymal spread, and possibly patients with multiple mid-line tumors. Craniospinal doses of 30 to 36 Gy with a local-field boost to the primary tumor to 50 Gy (1.8- to 2-Gy fractions) are recommended. For patients in whom craniospinal irradiation is not indicated, partial cranial fields are sufficient; whole ventricular irradiation to 30 Gy, followed by a local field boost with a 1- to 2-cm margin, to a total dose of 50 Gy is recommended. Response to cisplatin-based chemotherapy among patients with primary intracranial germinomas has been noted. Small pilot series have reported good results with neoadjuvant chemotherapy followed by reduced-dose radiation therapy or chemotherapy alone; however, the role of chemotherapy remains to be defined.

Nongerminomatous Germ Cell Tumors

NGGCTs should be suspected in patients with elevated serum or CSF AFP and those with marked elevation of beta-HCG. NGGCTs are less
radiosensitive than germinomas, and maximal safe resection is recommended for the majority of patients. For patients with elevated AFP and evidence of neuraxial spread, stereotactic biopsy only may be preferable because aggressive resection in these cases may not improve survival. It is not clear whether patients with NGGCT and negative neuraxis staging are at a higher risk of neuraxial failure than are those with germinomas. Poor survival among NGGCT patients has led some investigators to recommend routine craniospinal irradiation after surgery, although this may not be necessary in patients with negative neuraxial staging. More recently, neoadjuvant and/or adjuvant platinum-based chemotherapy has been used in an attempt to improve survival. Maximal surgical resection, followed by five or six courses of platinum-based chemotherapy similar to testis carcinoma regimens (i.e., cisplatin, etoposide, bleomycin), is typically used. Consolidative local field (negative neuraxis) or craniospinal radiation therapy (positive neuraxis) as described earlier should be added after chemotherapy.

Pineocytoma and Pineoblastoma

Pineocytomas are treated in a manner similar to low-grade gliomas. Patients with complete surgical resection may be observed. Patients with subtotal resection should receive postoperative radiation therapy. Local-field irradiation encompassing the preoperative tumor volume with a 2-cm margin to a dose of 50 to 55 Gy is recommended.

Pineoblastomas generally are regarded as a variant of PNET and are treated in a manner similar to medulloblastoma. Generally, patients should receive maximal safe resection, then be treated with craniospinal irradiation (35 to 40 Gy to the craniospinal axis, local boost to 54 Gy). Adjuvant chemotherapy is recommended for pineoblastomas, similar to that for high-risk medulloblastoma.

Other Histologies

Excellent results are achieved on benign tumors such as mature teratoma, hamartoma, and cysts treated with surgical intervention alone. Glial tumors (astrocytoma, ependymoma, oligodendroglioma) are treated in a conventional fashion as previously outlined according to histology and grade.

Results

For biopsy-proven germinomas, 5-year disease-specific survivals of 80% to 90% should be attainable with local field or craniospinal irradiation. Spinal relapse rates vary between series but are generally reported to be 10% to 20%. Five-year survival rates with lesions not examined via biopsy are somewhat less (average 70%), likely a consequence of the uneven mix of histologies treated in this category. NGGCTs have a worse outlook, with 5-year relapse-free survivals of 30% or less. The introduction of neoadjuvant and adjuvant chemotherapy will hopefully improve these results. Available reports suggest survival of patients with pineocytoma to be in the range of 60% to 70% with surgery followed by local field radiation therapy to more than 50 Gy. Patients with pineoblastomas have survival comparable to that of high-risk medulloblastoma patients. Chao and colleagues,  in 25 patients with primary pineal tumors treated with irradiation (median dose 36 Gy) to the primary tumor with an adequate margin or to the whole brain with or without a
cone-down boost of 10 to 20 Gy, reported 86% relapse-free survival at 5 years for pineal germinomas and 21% for pathology other than germinoma. A ventricular-peritoneal shunt was necessary in nine patients who were treated with irradiation without histologic verification; only one patient developed local recurrence, with 5-year relapse-free survival of 89%. Only two patients with pineal tumors who had surgical resection had positive CSF cytology and received craniospinal irradiation. Likewise, Linstadt and co-workers,  in a report of 33 patients with intracranial germinomas (13 biopsy-proven and 20 not examined via biopsy) treated with irradiation (40 to 55 Gy) to the tumor volume and only two treated prophylactically to the spinal axis, noted that none of the biopsy-proven tumor patients had a recurrence. Although only one patient received prophylactic spinal irradiation, no
spinal axis failures were noted. Six of the 20 patients with tumors not examined via biopsy died, two of recurrent primary tumor, one of peritoneal metastasis, two of complications of treatment, and one of intercurrent disease. The 5-year survival rate in this group was 72%. Nineteen tumors not examined via biopsy were treated without craniospinal irradiation, and only one patient developed spinal metastasis. These investigators recommended craniospinal irradiation only for patients with gross tumor spill causing CSF contamination, malignant cytology demonstrated on CSF, or documented subependymal or subarachnoid metastases. Shibamoto and associates [ref: 209] reported on 70 patients with confirmed or suspected intracranial germinoma (30 based on histology, 12 on CSF cytology, and 28 on clinical and radiologic findings) treated with irradiation. In 34 patients the primary tumor site was irradiated, in four the whole brain, in 22 the entire neuraxis, and in six the ventricle plus spine. Average tumor dose was 30 Gy to the
whole brain, 50 to 55 Gy to the tumor, and 24 Gy to the spinal axis. The 5- and 10-year survival rates in 68 primary cases on whom irradiation was completed were 86% and 79%, respectively. Relapse-free or overall survival for the four groups did not differ significantly. The investigators recommended irradiation of the primary tumor with a wide margin for cytology-negative patients. In patients with tumor extension into the ventricular walls or in both the pineal and suprasellar regions or with positive cytology, the craniospinal axis should be irradiated. Quality of life and sequelae were comparable in the various groups. One patient with intracellar germinoma failed after 56 Gy and was retreated with 43 Gy in 26 fractions; the two fields overlapped, and radiation necrosis in the hypothalamic region was confirmed at autopsy 8 years and 5 months after the second treatment.