Pineal Tumors 

Updated: Aug 08, 2022
Author: Jeffrey N Bruce, MD; Chief Editor: Brian H Kopell, MD 

Overview

Practice Essentials

Anatomy and pathophysiology

The pineal gland develops during the second month of gestation as a diverticulum in the diencephalic roof of the third ventricle. It is flanked by the posterior and habenular commissures in the rostral portion of the midbrain directly below the splenium of the corpus callosum. The velum interpositum is found rostral and dorsal to the pineal gland and contains the internal cerebral veins, which join to form the vein of Galen.[1]

In their 1954 pineal tumor study, Ringertz and colleagues defined the pineal region as bound by the splenium of the corpus callosum and the tela choroidea dorsally, the quadrigeminal plate and the midbrain tectum ventrally, the posterior aspect of the third ventricle rostrally, and the cerebellar vermis caudally.[2] Important anatomic considerations include the presence of deep venous structures.

The pineal gland is richly innervated with sympathetic noradrenergic input from a pathway that originates in the retina and courses through the suprachiasmatic nucleus of the hypothalamus and the superior cervical ganglion. Upon stimulation, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone and follicle-stimulating hormone.[1]

The pineal gland is a neuroendocrine transducer that synchronizes hormonal release with phases of the light-dark cycle by means of its sympathetic input. However, the exact relationship between the pineal gland and human circadian rhythm remains unclear and is an area of active investigation.

Pineal region tumors are derived from cells located in and around the pineal gland. The principal cell of the pineal gland is the pineal parenchymal cell, or the pinocyte. This cell is a specialized neuron related to retinal rods and cones. The pinocyte is surrounded by a stroma of fibrillary astrocytes, which interact with adjoining blood vessels to form part of the blood-pial barrier.

The pathophysiology of pineal region tumors is mostly the result of anatomic compression of adjacent structures, although local infiltration of neural structures can lead to symptoms in cases of highly invasive tumor. In some cases, neuroendocrine dysfunction is precipitated by specific factors secreted by the tumor.[3, 4]

Types and grades

Pineal tumors can be one or a mix of several different types. They can be slow growing or fast growing. The World Health Organization (WHO) has a grading system for brain tumors. They are grouped as grade I, II, III, or IV. Grade I is the slowest growing. Grade IV is the most aggressive and grows and spreads faster. Tumors of the pineal gland may be one of the following types[5, 6, 7, 8] : 

  • Pineocytomas are slow-growing (grade I or II) tumors that usually appear between ages 20 and 64, but they can appear at any age. People with pineocytomas tend to have a good outcome.  
  • Pineal parenchymal tumors are intermediate-grade (grade II or III) tumors. Pineal parenchymal tumors and papillary pineal tumors may occur at any age. 
  • Papillary pineal tumors are intermediate-grade (grade II or III) tumors. 
  • Pineoblastomas are very rare, aggressive, and fast-growing (grade IV) tumors. They are almost always cancerous. These tumors most often affect people younger than 20 years.  
  • Mixed pineal tumors are a combination of slow- and fast-growing cell types.

Signs and symptoms

Pineal tumors are not always cancerous, but they do cause problems as they grow because they press against other parts of the brain and can block the normal flow of cerebrospinal fluid (CSF), raising intracranial pressure (ICP) inside the skull. Researchers do not know the cause of pineal tumors. Genes and environment may play a role.[5]  

Tumors of the pineal region have varied histology that generally can be divided into germ cell and non–germ cell derivatives. Most tumors are the result of displaced embryonic tissue, malignant transformation of pineal parenchymal cells, or transformation of surrounding astroglia.[9, 10] No specific genetic mutations have been associated with sporadic pineal region tumors.

Fast-growing tumors may cause worse symptoms. Common signs and symptoms of a pineal tumor include headache, nausea and vomiting, vision changes, trouble with eye movements, tiredness, memory problems, and balance or coordination problems.[5]

(Pineal tumors are shown below.)

Gadolinium-enhanced MRI of a 33-year-old woman who 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).
Noncontrast MRI of a pineocytoma in a 40-year-old 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.
MRI of a 21-year-old man with a germinoma in the p 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.

Indications for neurosurgical intervention relate to the severity and the chronicity of clinical presentation. Symptoms of pineal region tumors can be as varied as their diverse histology. Prodromal periods can last from weeks to years. Therefore, a rigorous and uniform preoperative workup is a requisite for all patients thought to harbor a pineal region tumor.

Endocrine abnormalities should be investigated prior to surgery. Patients presenting with signs and symptoms of raised ICP must undergo head computed tomography (CT) scanning or magnetic resonance imaging (MRI) to assess the need for emergent management. Subsequent nonemergent workup of a patient with a pineal region tumor can be divided into radiologic and laboratory studies.[11, 12, 13]

Management

Initial management of patients with pineal region tumors should be directed at treating hydrocephalus and establishing a diagnosis. Preoperative evaluation should include (1) high-resolution MRI of the head with gadolinium; (2) measurement of serum and CSF markers, if available; (3) cytologic examination of CSF, if available; (4) evaluation of pituitary function, if endocrine abnormalities are suspected; and (5) visual field examination, if suprasellar extension of the tumor is noted on MRI. The ultimate management goal should be to refine adjuvant therapy based on tumor pathology.[11, 12, 13]

Relatively few contraindications specifically preclude surgical treatment of pineal region tumors. Medical clearance for general anesthesia is a requisite, as is preoperative evaluation of neck motion (ie, tolerance of flexion) before a supracerebellar/infratentorial approach is planned.

Treatment includes radiation, chemotherapy, and surgery.[14, 15, 16, 17, 18]

History of the Procedure

In the early part of the 20th century, pineal region surgery had poor outcomes, with operative mortality approaching 90%. From Horsley's initial attempt at removing a pineal mass in 1910 through development of the lateral transventricular approach in 1931 by Van Wagenan, primitive anesthetic technique and lack of an operating microscope hindered pineal region surgery.[19]

In 1948, Torkildsen argued for abandoning aggressive surgical resection in favor of CSF diversion followed by empiric radiotherapy.[20] If the patient did not respond to radiation, a surgical procedure to remove radioresistant tumor was performed. The algorithm of CSF diversion, radiation, and observation sometimes was successful; however, patients with benign lesions were exposed to unnecessary and ineffective radiation.

Modification of this treatment strategy led to the radiation test heralded by Japanese clinicians whose patient population consisted of an inordinately high percentage of radiosensitive germinomas. According to this protocol, patients were administered small doses of radiation and were followed radiologically. Pineal tumors that decreased in size were presumed to be radiosensitive, and a full course of radiation was instituted. Patients not responding to radiotherapy underwent surgical exploration. Despite the low dose of radiation initially used, significant long-term morbidity remained associated with this strategy, particularly in children.

The advent of microsurgical techniques and stereotactic procedures in the latter part of the 20th century obviated the need for empiric radiotherapy without tissue diagnosis. Therapeutic decision-making now is based on tumor histology rather than on radiation responsiveness. Currently, initial surgical management for tissue diagnosis and possible resection is the standard of care for most children with pineal region tumors.[21]

Epidemiology

Tumors of the pineal area are rare and account for only 1% of intracranial tumors in adults, but they do account for up to 8% of the intracranial tumors in children. However, because of the number of different types of of tumors in the pineal area, incidence and prevalence vary greatly. For example, pineocytomas mostly occur in adults aged 20-60 years, and papillary tumors of the pineal area can be seen in individuals between 1 and 70 years. Pioneoblastoma is the most aggressive of the pineal parenchymal tumors and is typically seen in young children. Germinomas account for up to 50% of pineal parenchymal tumors and are more common in males aged 20 years or younger.[6, 8, 1]

Prognosis

The relative 5-year survival rate for pineal region tumors in 2021 was 69.5%, but many factors can affect prognosis. These include tumor grade and type, cancer traits, patient age and health at the time of diagnosis, and patient response to treatment.[22]

Vuong and coworkers reported on prognostic factors and survival trends for pineal gland tumors and found that chemotherapy adversely affected patient outcomes and should be considered carefully in specific circumstances to avoid its harmful effects. Younger age at diagnosis, female gender, germ cell tumor histology, and no chemotherapy use were indicators for an improved prognosis. Advances in serology, imaging, and pathology enable earlier and more accurate diagnosis and tumor staging, while improvements in surgical techniques, radiation, and chemotherapy are key changes leading to more effective treatment and management of patients.[23]

 

Presentation

Complications

Clinical syndromes associated with pineal region tumors relate directly to normal pineal anatomy, as well as tumor histology.

Mass lesions in the pineal region that compress adjacent structures result in typical clinical syndromes. One of the most common presentations is headache, nausea, and vomiting caused by aqueductal compression and resultant obstructive hydrocephalus. If left untreated, hydrocephalus may lead progressively to lethargy, obtundation, and death.

Compromise of the superior colliculus, either through direct compression or through tumor invasion, results in a syndrome of vertical gaze palsy that can be associated with pupillary or oculomotor nerve paresis. This eponymic syndrome was first described by the French ophthalmologist Henri Parinaud in the late 1800s and has become virtually pathognomonic for lesions involving the quadrigeminal plate.

Further compression of the periaqueductal gray region may cause mydriasis, convergence spasm, pupillary inequality, and convergence or refractory nystagmus. Impairment of downgaze becomes more pronounced with tumors involving the ventral midbrain. Patients also can present with motor impairment such as ataxia and dysmetria resulting from compromise of cerebellar efferent fibers within the superior cerebellar peduncle.

Children with pineal region tumors can present with endocrine malfunction. Hydrocephalus or concurrent suprasellar tumors can cause diabetes insipidus. More specific endocrine syndromes can arise from secretion of hormones by germ cell tumors. Pseudoprecocious puberty caused by beta–human chorionic gonadotropin (beta-HCG) can be observed with germ cell tumors in either the pineal or suprasellar region. In a large series of patients with germ cell tumors and suprasellar involvement, 93% of girls older than 12 years had secondary amenorrhea and 33% of patients younger than 15 years had growth arrest.

Pineal apoplexy, defined as bleeding into the tumor area, has been described as a rare presenting feature of pineal region tumors. Hemorrhage into a vascular-rich pineal tumor can occur preoperatively and is a well-described postoperative complication.

 

Workup

Laboratory Studies

Measurements of serum and CSF tumor markers are valuable components of the preoperative evaluation. As with radiologic studies, these results can be suggestive of tumor type but only occasionally provide the physician with diagnostic information.

Markers have been most helpful in the workup of patients with germ cell tumors. In addition to their histologic characteristics, germ cell tumors retain molecular characteristics of their primordial lineage. Therefore, expression of embryonic proteins such as alpha-fetoprotein (AFP) and beta-HCG is indicative of malignant germ cell elements. Other biological markers for germ cell tumors include lactate dehydrogenase isoenzymes and placental alkaline phosphatase, although these are less specific. Serum and CSF measurements can be used for diagnostic purposes and for monitoring response to therapy. In general, CSF measurements are more sensitive than serum measurements, and a CSF-to-serum gradient may be consistent with an intracranial lesion. However, active debate continues in the literature regarding the diagnostic value of CSF and serum measurements.

AFP is a glycoprotein produced by fetal yolk sac elements and by a wide range of cancers, including gastric, liver, and colon adenocarcinoma, as well as extracranial germ cell tumors. Serum levels of AFP are greatest among newborns and decline thereafter. The biological half-life of AFP is approximately 5 days; levels should always be normalized to known age standards to prevent false-positive results. AFP is markedly elevated with endodermal sinus tumors and is elevated to a lesser degree with embryonal cell carcinomas. Although teratomas do not secrete AFP, less-differentiated immature teratomas can produce detectable amounts.

Beta-HCG, a glycoprotein with a half-life of 15-20 hours, is usually produced by placental trophoblastic cells. Choriocarcinomas secrete large amounts of beta-HCG; lesser elevations can occur in patients with embryonal cell carcinomas. The presence of syncytiotrophoblastic giant cells in mixed germinomas may result in detectable levels of beta-HCG, but most germinomas are nonsecretory.

Significant variability in expression of tumor markers is such that absence of AFP or beta-HCG does not rule out a mixed germ cell tumor. Although some studies suggest a less favorable prognosis for patients with germinomas secreting beta-HCG, no established prognostic significance has been established for tumor markers. Determination of AFP and beta-HCG levels prior to surgical resection is extremely important because it provides a reference point that can be used to assess recurrence during follow-up.

Pineal parenchymal cell tumor markers are less well characterized than their germ cell counterparts and include melatonin and the S antigen. Neither of these proteins has proved valuable in the diagnosis of pineal parenchymal cell tumors. Some authors have reported using melatonin levels in follow-up for patients with pineocytoma after surgical treatment.

Imaging Studies

High-resolution MRI with gadolinium is necessary for evaluation of pineal region lesions. Tumor characteristics such as size, vascularity, and homogeneity can be assessed, as can the anatomic relationship with surrounding structures. Irregular tumor borders can be suggestive of tumor invasiveness and associated histologic malignancy. Although the type of tumor cannot be determined reliably from radiographic characteristics alone, some patterns are associated with specific tumors.

Non–germ cell tumors can derive from pineal parenchymal cells, as well as from surrounding tissue. Pineocytomas and pineoblastomas typically are hypointense to isointense on T1-weighted images, have increased signal on T2, and show homogeneous enhancement after administration of gadolinium. Pineoblastomas can be distinguished by their irregular shape and their large size (ie, some >4.0 cm).

Astrocytomas, which can arise from the glial stroma of the pineal gland or surrounding tissue, are also hypointense on T1 and hyperintense on T2. However, astrocytomas have variable enhancement patterns. Calcium may be present in both pineal cell tumors and astrocytomas.

Meningiomas typically enhance homogeneously and have smooth, distinct borders. Tentorial meningiomas can have an enhancing dural tail of origin and are anatomically distinguished by their dorsal location relative to the deep venous system.

Germ cell tumors arise from the neoplastic transformation of residual primordial tissue derived from ectoderm, mesoderm, or endoderm. Each tumor subtype represents the malignant correlate of a distinct stage of embryonic development. In some cases, the stage of tissue development can be identified by distinct radiographic features. Germinomas are isointense on T1-weighted MRI studies, are slightly hyperintense on T2, and have strong homogeneous enhancement. Germinomas can have evidence of calcification, which surrounds the pineal gland as the germinoma grows. In contrast, pineocytomas commonly have intratumoral calcium. Intratumoral cysts can exist as well. Unlike germinomas, teratomas typically have heterogeneous MRI signals because they can contain tissue from all 3 germinal layers.

Teratomas are well-circumscribed benign tumors characterized by heterogeneity and by irregular enhancement. These tumors can also show ring enhancement. In some cases, a well-circumscribed teratoma has areas of low attenuation that correlate with adipose tissue, which serves to further distinguish it from other pineal region tumors. Malignant nongerminomatous germ cell tumors can also have a heterogeneous appearance due to a mixture of benign and malignant germ cell components. Areas of intratumoral hemorrhage may distinguish specific subtypes such as choriocarcinoma.

In a diffusion-weighted imaging study of 20 pediatric patients (< 18 yr) with pineal tumors, 7 had pineoblastoma, 4 had primitive neuroectodermal tumor (PNET), 2 had other pineal tumors, and 7 had germ cell tumors. Mean apparent diffusion coefficient (ADC) values were found to be lower in pineoblastoma (544 ± 65 × 10⁻⁶ mm²/s) and in pineoblastoma/PNET (595 ± 144 × 10⁻⁶ mm²/s) than in germ cell tumor (1284 ± 334 × 10⁻⁶ mm²/s).[24] Wu and associates found that preoperative MRI and diffusion-weighted MRI help to differentiate between intracranial germinomas and nongerminomatous germ cell tumors in children.[25]

(Images of pineal tumors on MRI are shown below.)

Gadolinium-enhanced MRI of a 33-year-old woman who 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).
Noncontrast MRI of a pineocytoma in a 40-year-old 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.
MRI of a 21-year-old man with a germinoma in the p 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.
MRI of a 21-year-old man with a germinoma in the p 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).
MRI of a 21-year-old man with a germinoma in the p 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.
Sagittal MRI of a heterogeneous mixed germ cell tu 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.
T1-weighted contrast-enhancing sagittal MRI from a 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.
MRI of a 44-year-old woman 10 years after resectio 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).

In addition to MRI, angiography is sometimes used in cases of suspected vascular anomalies. However, the anatomic and vascular information provided by MRI has largely circumvented the need for routine angiograms in the evaluation of pineal region neoplasms.

Nonneoplastic Lesions

Benign cysts of the pineal gland are diagnosed more frequently with increased use of MRI for standard workups unrelated to the pineal region. These incidental lesions appear radiographically as cystic structures with peripheral calcification and rimlike contrast enhancement. They are normal variants of pineal gland anatomy; once documented, they require no treatment unless they grow.

When these cysts cause obstructive hydrocephalus or show evidence of progression, surgical resection is indicated, with excellent results.

Pineal cysts may be difficult to distinguish from low-grade cystic astrocytomas based exclusively on radiographic criteria. Any doubts of diagnosis should be addressed by careful observation of the patient via serial MRI scans to ensure that the lesion is not growing.

Histologic Findings

Germ cell tumors are the most prevalent neoplasms of the pineal region in children and are histologically indistinguishable from those found at extracranial locations, including the mediastinum and gonads. These extracranial locations most commonly are midline. Intracranial germ cell tumors commonly are divided into 2 categories: germinomas and tumors derived from totipotential germ cells.

Germinomas make up 60-70% of all pediatric germ cell tumors. Nongerminomatous germ cell tumors fall along a spectrum of differentiation.[26] The least differentiated is embryonal cell carcinoma, with further differentiation described as either embryonic or extraembryonic. Immature and mature teratomas result from maturation along embryonic cell lines, whereas the endodermal sinus tumor or the yolk sac tumor and choriocarcinoma result from extraembryonic differentiation.

Description and classification of a given lesion sometimes are confounded when more than one type of germ cell component is found in a surgical specimen. Mixed germ cell tumors are the result of simultaneous differentiation along more than one pathway such that, at presentation, 2 or more characterized components are recognized. An example of this is teratocarcinoma—an embryonal carcinoma that contains elements of an immature teratoma.

The germinoma is most likely to occur in pure form and is characterized histologically by large, round tumor cells interspersed with lymphocytes and septae of fibrous tissue. At low-power magnification with hematoxylin and eosin staining, the contrast between smaller, darkly staining lymphocytes and the larger, pale-staining cytoplasm of neoplastic cells is virtually pathognomonic. At higher magnification, germinoma cells are characterized by a nucleus with an open chromatin structure and prominent nucleoli. The cytoplasm is glycogen-rich, making these cells periodic acid-Schiff (PAS)–positive and diastase-labile. Characteristic cytoarchitecture of these cells includes cellular junctions in the form of simplified desmosomes and focal microvilli within intercellular lumina. The presence of microvilli is one of the few histologic characteristics that distinguish the intracranial lesion from its extracranial correlate.

The pathologic diagnosis of a germinoma can be confounded when the examined specimen contains an infiltrating portion of the tumor or tumors amidst significant inflammation.

Infiltrating germinomas can elicit an atypical gliosis, which may be confused with malignant glial neoplasms. This is true particularly of specimens taken from the periphery of the germinoma.

Noncaseating granulomatous inflammation accompanied by multinucleated giant cells can be found in biopsy samples taken from the periphery of some germinomas. An important consideration is that the degree of inflammation can vary significantly among specimens, underscoring the need to obtain an adequate amount of diagnostic tissue during surgical intervention.

Nongerminomatous germ cell tumors are more likely to arise in the pineal region than in the suprasellar region.

An embryonal cell carcinoma tumor consists of cuboidal-to-columnar cells arranged in sheets and cords with large nuclei, prominent irregular nucleoli, and significant mitotic activity. Unlike in germinomas, little or no lymphocytic infiltrate is present. Signs of differentiation of embryonal cell carcinomas are observed in cases of mixed germ cell tumors and can proceed along the embryonal cell lineage toward teratoid cells, or along the extraembryonic cell lineage toward the yolk sac or placental elements.

Teratomas can be composed of a mixture of tissues derived from all 3 germinal layers, with varying degrees of differentiation. Structured variants of teratomas may resemble adult tissue histologically, whereas unstructured examples do not recapitulate known tissue.

Hosoi first used the term "teratoids" in 1930 to describe less-structured tumors in which derivatives of all 3 germinal layers could not be identified easily. Current classification of these tumors divides them into mature and immature teratomas. Mature teratomas contain fully differentiated ectodermal, mesodermal, and endodermal elements, whereas immature teratomas have more primitive elements that closely resemble embryonic histology.

The spectrum of differentiation that exists within the teratoma lineage precludes definitive descriptions of immature versus mature lesions. However, some general microscopic characteristics can help guide the physician in making the diagnosis. Mature lesions often contain solid or cystic foci of squamous epithelium, cartilage, or glandular elements embedded in tubular structures lined with mucin-secreting columnar epithelium. Mesenchymal stroma consisting of smooth muscle can be observed interspersed among these well-differentiated tissue elements. Immature teratomas usually are composed of primitive cells derived from 1 of the 3 germinal layers. The pattern of these small round cells when viewed at lower magnification can resemble the hypercellularity of a medulloblastoma. Lesions containing primitive cells from all 3 germinal layers have been described.

Extraembryonic differentiation of embryonal cell carcinoma results in either an endodermal sinus tumor or a choriocarcinoma. These 2 entities represent differentiation toward the yolk sac and the trophoblast, respectively, and as with teratomas, these tumors can be admixed with germinomas. The yolk sac carcinoma is derived from the endoderm; consequently, it contains endodermal sinuses or Schiller-Duval bodies. These pathognomonic glomeruloid structures contain a tumor cell–lined space with an invaginated vascular pedicle covered by a single layer of tumor cells. Other characteristic cytoarchitecture includes perivascular endodermal cells and thin-walled cystic spaces. At higher magnification, globules of PAS-positive and diastase-resistant proteins can be observed easily within endodermal sinus cells and the surrounding extracellular stromal matrix. These globules of protein correlate with the presence of AFP in CSF and blood—a marker associated with endodermal sinus tumors.

Trophoblastic differentiation can result in isolated syncytiotrophoblasts expressing gonadotropins or in bilaminar arrangements of syncytiotrophoblasts and cytotrophoblasts typified by the choriocarcinoma. Unlike other nongerminomatous germ cell tumors, the choriocarcinoma very rarely appears as an isolated lesion. At low magnification, bilaminar cytotrophoblastic and syncytiotrophoblastic cells can be identified by surrounding blood. Intratumoral hemorrhage is common in choriocarcinoma and correlates with these blood-filled sinuses.

Non–germ cell tumors of the pineal region arise from the pineal gland or from surrounding tissue. The rarity of pineal cell lesions and lack of an extracranial correlate have complicated the classification of these tumors. Currently, pineal parenchymal tumors are divided into high- and low-grade variants based on the extent of differentiation. The primitive pineoblastoma and the differentiated pineocytoma exist at opposite ends of the spectrum, with intermediate-grade variants in between.

Pineoblastomas include those without differentiation; those with pinocytic differentiation; and those with neuronal, glial, or retinoblastic differentiation.[27] Similarly, pineocytomas have been divided into types without further differentiation, with neuronal differentiation only, with astrocytic differentiation only, and with divergent neuronal and astrocytic differentiation (eg, the ganglioglioma). In general, pineoblastomas are found in younger patients and pineocytomas are found in adults. However, numerous clinical exceptions arise.

Pineoblastomas consist of dense populations of small primitive cells that can form neuroblastic rosettes or Homer Wright rosettes. Less-common examples of pineoblastoma cytoarchitecture include Flexner-Wintersteiner rosettes, which have a ciliary 9 + 0 configuration similar to that of the retinal photoreceptor. Further differentiation of the pineoblastoma can be observed in some cases of familial bilateral retinoblastoma in which a pineoblastoma with retinoblastic features is found.

This rare syndrome has been referred to as trilateral retinoblastoma. The pineoblastoma is an aggressive tumor that resembles the medulloblastoma with respect to age of presentation and propensity to seed the subarachnoid space. The pineocytoma is significantly less aggressive than the pineoblastoma. It usually presents during adolescence and rarely seeds the subarachnoid space. Pineocytomas consist of small cells similar to those of the pineoblastoma. However, they appear more spread out and more lobular and are further distinguished by large hypocellular zones containing fibrillary stroma. These fibrils contain microtubules and dense core granules at the ultrastructural level. Healthy pineal gland tissue contains lobular cells of uniform size with an easily identified astroglial stroma—2 features that can be used to distinguish healthy gland from pineocytoma.

Neoplasms derived from glial cells in children with pineal region tumors were exceeded only by germinomas in 2 large series that included children with pineal region tumors. Histologic and macroscopic appearances are similar to those of malignant glial neoplasms found in other areas of the central nervous system (CNS). Glial-derived neoplasms in the pineal region can include low-grade and high-grade lesions.

(Gross and microscopic histologic images are shown below.)

Gross tissue specimens were obtained from a 21-yea 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.
Micrograph from a mature teratoma of the pineal re 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.
This micrograph shows osteoid bone with surroundin This micrograph shows osteoid bone with surrounding periosteal tissue and mesenchymal stroma occurring within a mature teratoma of the pineal region.
This micrograph features cartilaginous tissue obse This micrograph features cartilaginous tissue observed within a mature teratoma of the pineal region.
Immature teratoma of the pineal region with highly Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.
Endodermal sinus tumor with a characteristic Schil Endodermal sinus tumor with a characteristic Schiller-Duval body.
Pineoblastoma composed of highly cellular, poorly Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.
Pineocytoma consisting of benign, well-differentia Pineocytoma consisting of benign, well-differentiated cells forming rosettes.
 

Treatment

Approach Considerations

The first treatment for pineal region tumors is surgery, if possible. The goals of surgery are to obtain tissue to determine tumor type and to remove as much tumor as possible without causing more symptoms. Treatments after surgery may include radiation and chemotherapy. Clinical trials, with investigative chemotherapeutic agents, targeted therapies, or immunotherapy drugs, may be available and represent a possible treatment option. Treatments are decided by the patient’s healthcare team based on patient age, tumor remaining after surgery, tumor type, and tumor location.[22, 1]

Treatment Options

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.[1]

Potential complications include hypothalamic and endocrine dysfunction, cerebral necrosis, secondary tumorigenesis, and disease progression. 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 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.

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% when this treatment is used 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 should be followed carefully with serial MRIs to assess tumor recurrence or progression.[5, 26, 28, 29, 30, 31]

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 than pineocytoma.[5, 26, 28, 29, 30, 31]

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 is used routinely in some countries. For patients with pineoblastoma, some authors suggest use of preemptive spinal radiation therapy, even if results of postoperative surveillance MRI are negative. As modern improvements in surgical and adjuvant therapy are reflected in long-term survival, 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.[5, 26, 28, 29, 30, 31]

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% to 100% with platinum-based regimens. Patients with extracranial nongerminomatous germ cell tumors respond well to treatment with a wide array of chemotherapeutic agents.[1, 5, 22, 32, 28]

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. 

Kurucu and associates evaluated clinical characteristics, treatment, and outcomes of 52 patients with intracranial germ cell tumors. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others. The primary site was the pineal region in 20 patients and the nonpineal region in 32, which included 6 bifocal involvements. Pineal location was more common in boys than in girls. The histopathologic diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumor in 14, and immature teratoma in 4. The mean age for germinomas was higher than that for nongerminomatous tumors. Patients were treated with surgery, radiotherapy, and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12 to 228 months. Relapsed/progressive disease was observed in 11 patients. Relapse and progression were more frequent with nongerminomatous tumors than with germinomas. Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates were better for germinoma  than for malignant nongerminomatous tumor.[32]

Satomi and colleagues analyed 82 cases of CNS germ cell tumors predominantly arising in pediatric and young adult populations. They noted that nongerminomatous germ cell tumors required more intensive treatment. These authors sought to determine whether a 12p gain (an additional 12p in the background of potential polyploidy or polysomy) could predict the prognosis of patients with CNS nongerminomatous germ cell tumors. Results showed that a 12p gain was found in 25 out of 82 cases (30%) and was more frequent in nongerminomatous germ cell tumors (12% for germinomas, 50% for nongerminomatous germ cell tumors), particularly in cases with malignant components such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS), even with histology and tumor markers incorporated into the multivariate analysis. The investigators concluded that 12p gain may predict the presence of malignant components of nongerminomatous germ cell tumors and poor prognosis and may be associated with early tumorigenesis of CNS germ cell tumors.[33]

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.

Most clinicians currently advocate a derivative of the Einhorn regimen as an alternative treatment for patients with recurrent or metastatic germinoma. Some clinicians advocate the use of chemotherapy as well as radiotherapy after nongerminomatous germ cell tumor has been diagnosed. The impetus for adding chemotherapy initially for these patients comes from the 5-year survival rate of 30-65% in children with nongerminomatous germ cell tumors treated with radiotherapy alone.[9, 22, 23]

The reported effectiveness of chemotherapeutic regimens for children with pineal cell tumor 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.

Radiosurgery

Stereotactic radiation or radiosurgery (SRS) is increasingly provided to patients with CNS disease. It is used as primary therapy for pineocytomas and papillary tumors of the pineal region, as an adjuvant radiation boost in combination with radiation or chemotherapy for pineoblastomas and germ cell tumors, or in the context of tumor recurrence. Reported morbidity is low, consisting of transient oculomotor disturbance in most cases. As a noninvasive alternative to microsurgical resection, SRS should always be considered when these challenging cases are presented.[1, 28]

SRS is not a magic bullet for all pineal lesions because treatment failures have occurred in all series; some treatment failures have also been reported for pineocytoma. This shows the importance of obtaining a histologic diagnosis before embarking on a treatment plan and highlights the risk of treating a tumor of unknown histology with SRS alone.

In the pediatric population, SRS is an attractive potential first-line treatment that merits further investigation. Some authors have proposed using SRS in place of conventional radiotherapy in an effort to reduce or eliminate the long-term sequelae of radiotherapy in children. SRS is optimized for targets measuring 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. Although the ultimate choice of procedure is based to some extent upon the surgeon's personal bias and experience, some distinct advantages and disadvantages are known for each of these procedures.[1]

(Operative approaches are depicted in the images below.)

The right side of this image shows 3 operative app 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.
The left drawing is a sagittal view of a patient w 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.

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 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, more recent studies have shown stereotactic biopsy to be a safe and efficient means of obtaining a tissue diagnosis.

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.[34, 35, 36, 37, 38] Problems with the endoscopic technique include limited ability to control bleeding and limited tissue sampling. Some series have reported up to 94% yield, although many patients require a second procedure.[35] Performing an endoscopic third ventriculostomy and an endoscopic biopsy of the pineal region with a single burr hole usually is not possible because of anatomic considerations.

Open resection carries the obvious advantage of complete tumor resection. Long-term benefits of complete tumor resection are best surmised by tumor type and histology. 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. This circumvents the potential problems of sampling error and erroneous diagnosis associated with the small volume of tissue provided by stereotactic biopsy.

Several advances have been made that will likely lower morbidity and mortality associated with open procedures as well as stereotactic biopsy.

Clinicians have held the belief that stereotactic biopsies of ventricular lesions may be less safe and less accurate than biopsies of superficial lesions. Accordingly, endoscopic biopsies have been increasingly used for these lesions. In 2020, Birski and coworkers compared endoscopic versus stereotactic biopsies of intracranial lesions involving the ventricles. They retrospectively assessed a total of 85 stereotactic and 38 endoscopic biopsies performed for 1581 adults undergoing brain tumor biopsy from 2007 to 2018 and found that in 9 cases (5 stereotactic, 4 endoscopic), biopsies were nondiagnostic. Three people died: 2 (1 stereotactic, 1 endoscopic) from delayed intraventricular bleeding and 1 (stereotactic) from brain edema. No permanent morbidity occurred. In 6 cases (all stereotactic), additional surgery was required for hydrocephalus within the first month post biopsy. Rates of nondiagnostic biopsies, serious complications, and additional operations were not significantly different between groups. Mortality was higher after biopsy of lesions involving the ventricles compared with intracranial lesions in any location (2.4% vs 0.3%; P  = 0.016). Rates of nondiagnostic biopsies and complications were similar after endoscopic or stereotactic biopsies. Ventricular area biopsies were associated with higher mortality than biopsies in any brain area.[39]

Due to pathologic diversity within the pineal region, tissue diagnosis in patients with a pineal region mass is essential to optimize further clinical management. Cho and associates in 2020 reported a case of a 75-year-old woman with a known pineal region mass for 18 years who presented with progressive classic signs and symptoms of obstructive hydrocephalus over the past 6 months. Upon the novel application of near-infrared fluorescence for tumor identification of pineal region tumors known as the second window indocyanine green (SWIG) technique, a high-dose infusion of indocyanine green given 24 hours before surgery revealed a WHO grade I pineocytoma.[40]

A retrospective cohort study published in 2022 examined a series of pediatric patients with pineal tumors who underwent surgery through a microsurgical occipital interhemispheric transtentorial approach (OITA) from January 2006 to January 2020; investigators sought to evaluate the extent of resection (EOR) obtained with this approach and to define preoperative radiologic factors predictive of the EOR. Cinalli and coworkers measured tumor volume preoperatively; then on sagittal midline cuts, they identified the most cranial point of the torcular Herophili (defined as the "Herophilus point") and the lowest point of the inferior profile of the vein of Galen (defined as the "Galen point"). Authors used the line joining these 2 points (defined as the "Herophilus-Galen line" [H-G line]) to identify the "Herophilus-Galen plane" (H-G plane) perpendicular to the sagittal plane. They measured tumor volumes located below and above this plane and evaluated EOR by measuring residual tumor volume visible on T1 volumetric injected sequences of immediate postoperative MRI. These authors concluded that the H-G line is an intuitive, easy-to-use, and reliable indicator of the superior anatomic limit of visibility during microsurgical OITA, and that this anatomic landmark may be useful as a predictor of EOR for pineal tumor surgery performed through this approach.[41]

Tissue diagnosis is a vital part of management for most patients with pineal region tumor. However, nonoperative management with positive tumor markers is a reasonable option for some patients. Markedly elevated levels of AFP and beta-HCG are 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.

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 shunt prior to biopsy or resection. The staged procedure allows for definitive control of 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. 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, 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 for diverting 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. Third ventriculostomy offers the added advantage of potentially allowing for biopsy during the procedure under 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 morbidity and mortality rates associated with pineal region surgery. For patients for whom primary surgical resection is the best therapeutic and diagnostic option, several well-described approaches are currently in use.

In general, surgical approaches to the pineal region can be divided into supratentorial, infratentorial, and a combined supratentorial-infratentorial approach. Supratentorial approaches include the parietal-interhemispheric approach described by Dandy and the occipital-transtentorial approach originally described by Horrax, later modified by Poppen.[42]

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.[43] The occipital-transtentorial approach requires retraction of the occipital lobe and division of the tentorium for adequate exposure.

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. 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.[44] A midline trajectory between the tentorium and the cerebellum allows the tumor to be encountered below the deep venous system. When this procedure is performed with the patient in the sitting position, the cerebellum tends to fall away, exposing the pineal region while minimizing pooling of venous blood in the operative field.[45]

The main disadvantage associated with this approach is limited access to tumors that extend above the deep venous complex and anteriorly into the third ventricle. Lateral exposure also is restricted when this approach is used.

Several different positions have been described for supratentorial and infratentorial approaches to the pineal region.

  • The sitting slouch position is generally used for 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 with the head tilted to the right combines advantages of the sitting slouch and three-quarter prone lateral positions.

  • The Concorde position was described by Kobayashi and was 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 is often desirable for use in preadolescent patients.

Combined supratentorial-infratentorial approach

This combined approach is used for large pineal region tumors. With the patient in the semiprone position, this technique achieves wide exposure laterally, superiorly (to posterior third ventricle), and inferiorly (to superior medullary velum), as well as safe visualization of venous structures and minimal retraction of the cerebellum and occipital lobe.[46]

Disadvantages of this approach include that it is very extensive and it requires sacrifice of the nondominant transverse sinus, making it suitable for use only in exceptional cases.[46]

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 MRI, patients' disease was staged postoperatively with CT myelography.

Currently, 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 due to spillage during surgery.

Timing for follow-up cranial MRI varies depending upon tumor histology and degree of resection. 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 shown 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

Lifelong follow-up of children with pineal region tumors is required. These tumors can recur locally or can appear distally as long 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 the original diagnosis, the extent of resection, and the presence of metastasis at the time of diagnosis.

Tumor marker studies for patients with germ cell tumors 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, regardless of the approach, include extraocular movement dysfunction, ataxia, and altered mental status.[47] Many neurologic findings such as extraocular movement dysfunction and ataxia are present preoperatively and become transiently worse postoperatively before showing significant improvement or complete resolution. Factors that correlate with an 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 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 all published series reporting 20 or more patients in the microsurgical era are considered, pineal region tumor surgery is seen to have overall mortality of 0 to 8% and morbidity of 0 to 12%. This is in stark contrast to mortality of 90% as reported during the early part of the 20th century.

Long-term outcomes after surgical resection depend largely upon tumor histology, as well as evolving modalities of adjuvant therapy. For patients with malignant tumor, gross total resection in some cases may be associated with a more favorable prognosis. For other patients such as those with germinoma, initial surgical intervention may become obsolete as preemptive adjuvant therapy becomes more effective.

Outcome and Prognosis

The prognosis for patients with pineal region tumors is dependent upon tumor histology and is subject to change as more effective adjuvant therapy is developed. In general, patients with intracranial germinoma have an excellent prognosis because of the radiosensitivity of this tumor.

Children with nongerminomatous germ cell tumors have a significantly worse prognosis than do children with germinomas or pineal cell tumors. No conventional approach is designed 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 germ cell tumors have been shown to respond to chemotherapy, as have some pineal cell tumors, although to a lesser degree. Radiosurgery may be a consideration for all recurrences measuring less than 3 cm in diameter.