Pineal Tumors 

Updated: Oct 19, 2017
Author: Jeffrey N Bruce, MD; Chief Editor: Brian H Kopell, MD 

Overview

Practice Essentials

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.

In their 1954 pineal tumor study, Ringertz and colleagues defined the pineal region as being bound by the splenium of the corpus callosum and tela choroidea dorsally, the quadrigeminal plate and midbrain tectum ventrally, the posterior aspect of the third ventricle rostrally, and the cerebellar vermis caudally.[1] 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 the sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone and follicle-stimulating hormone.

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 active area of 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 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 a result of anatomic compression of adjacent structures, although local infiltration of neural structures can lead to symptoms in cases of highly invasive tumors. In some cases, neuroendocrine dysfunction is precipitated by specific factors secreted by the tumor.[2, 3]

Tumors of the pineal region have a varied histology that generally can be divided into germ cell and non–germ cell derivatives. Most tumors are a result of displaced embryonic tissue, malignant transformation of pineal parenchymal cells, or transformation of surrounding astroglia.[4, 5] No specific genetic mutations have been associated with sporadic pineal region tumors.

Some images of pineal tumors are provided 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 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 chronicity of clinical presentation. The 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.

Any endocrine abnormalities should be investigated prior to surgery. Patients presenting with signs and symptoms of raised intracranial pressure must receive a head CT scan or an 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.[6, 7, 8]

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.[6, 7, 8]

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

Treatment includes radiation, chemotherapy, and surgery.[9, 10, 11, 12, 13]

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 the development of the lateral transventricular approach in 1931 by Van Wagenan, primitive anesthetic technique and the lack of an operating microscope hindered pineal region surgery.[14]

In 1948, Torkildsen argued for abandoning aggressive surgical resection in favor of cerebrospinal fluid (CSF) diversion followed by empiric radiotherapy.[15] 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 had an inordinately high percentage of radiosensitive germinomas. According to this protocol, patients were administered small doses of radiation, and their cases 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 later part of the 20th century has obviated the need for empiric radiotherapy without tissue diagnosis. Therapeutic decision-making now is based on tumor histology rather than radiation responsiveness. Currently, initial surgical management for tissue diagnosis, and possible resection, is the standard of care for most children with pineal region tumors.[16]

Epidemiology

Pineal region tumors make up 0.4-1.0% of intracranial tumors in adults and 3-8% of brain tumors in children. Most children are aged 10-20 years at presentation, with the average age at presentation being 13 years. Adults typically are older than 30 years at presentation. A complete differential diagnosis for masses in the pineal region also should include vascular anomalies, as well as metastatic tumor.

Prognosis

In a study of 35 consecutive patients from 7 academic centers of the Rare Cancer Network diagnosed between 1988 and 2006 (median age, 36 yr), median disease-free survival was 82 months. Age younger than 36 years was an unfavorable prognostic factor, and patients with metastases at diagnosis had poorer survival. Histologic subtypes were pineoblastoma in 21 patients, pineocytoma in 8 patients, and pineocytoma with intermediate differentiation in 6 patients.[17]

In a study of medical records of 31 patients with pineoblastoma (female, 67.7%; median age, 18.2 yr), median overall survival was found to be 8.7 years, with 2-, 5-, and 10- year actuarial rates of 89.5%, 69.4%, and 48.6%, respectively. Median disease-free survival was 10 years, with 2-, 5-, and 10- year actuarial rates of 84.3%, 62.6%, and 55.7%.[18]

In another study of patients with pineoblastoma, the overall survival rate was 54% (175 of 299 patients) at a mean follow-up of 31 ± 1.9 mo (range, 1-159 mo). A markedly worse prognosis was demonstrated for children aged 5 years or younger compared with older patients (5-year survival rate: 15% for children aged ≤5 yr vs 57% for children aged ≥5 yr). A failure to achieve gross total resection markedly worsened patient survival.[19]

 

Presentation

Complications

The 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, 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 a valuable component of the preoperative evaluation. As with radiologic studies, these results can be suggestive of tumor type but only occasionally provide the physician 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, the expression of embryonic proteins, such as alpha-fetoprotein (AFP) and beta-HCG, are 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 a 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 is produced 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 in newborns and decline thereafter. The biological half-life of AFP is approximately 5 days, and levels always should be normalized to known age standards to prevent false-positive results. AFP is markedly elevated with endodermal sinus tumors and elevated to a lesser degree with embryonal cell carcinomas. Although teratomas do not secrete AFP, the less-differentiated immature teratomas can produce detectable amounts.

Beta-HCG is a glycoprotein with a half-life of 15-20 hours and is usually produced by placental trophoblastic cells. Choriocarcinomas secrete large amounts of beta-HCG, and 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 the 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 of tumor markers exists. 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 proven 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 in the evaluation of pineal region lesions. Tumor characteristics, such as size, vascularity, and homogeneity, can be assessed, as well as 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 the 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 demonstrate homogeneous enhancement after administration of gadolinium. Pineoblastomas can be distinguished by their irregular shape and 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 either pineal cell tumors or 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 have distinct radiographic features. Germinomas are isointense on T1-weighted MRI studies, are slightly hyperintense on T2, and have strong homogenous 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 their heterogeneity and irregular enhancement. These tumors can also demonstrate 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 (20 </ref>Wu et al found that preoperative MRI and diffusion-weighted MRI help differentiate between intracranial germinomas and nongerminomatous germ cell tumors in children.[21]

MRI images of 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 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 demonstrated 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 the 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, and once documented, they require no treatment unless they grow.

A study by Al-Holou et al indicated that follow-up imaging and neurosurgical evaluation are not mandatory for adults with asymptomatic pineal cysts. In this study, 151 patients with pineal cysts received a follow-up MRI at a mean interval of 3.4 years. Of these, 124 pineal cysts remained stable, 4 increased in size, and 23 decreased in size. Cysts that were larger at the time of initial diagnosis were more likely to decrease in size over the follow-up interval.[22]

When causing obstructive hydrocephalus or showing 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 carefully observing the patient via serial MRI scans to make sure 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.[23] The least differentiated is the 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 yolk sac tumor and the choriocarcinoma are a result of extraembryonic differentiation.

Description and classification of a given lesion sometimes is confounded when more than one type of germ cell component is found in a surgical specimen. Mixed germ cell tumors are a 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 the teratocarcinoma, an embryonal carcinoma containing 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 the 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 specimen examined 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 also 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.

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 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 embryonal cell lineage toward teratoid cells or along extraembryonic cell lineage toward 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 teratoid 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 also been described.

Extraembryonic differentiation of embryonal cell carcinoma results in either an endodermal sinus tumor or a choriocarcinoma. These 2 entities represent differentiation towards the yolk sac and trophoblast respectively, and as with the teratomas, these tumors can be admixed with germinomas. The yolk sac carcinoma is derived from the endoderm, and 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 easily can be observed within endodermal sinus cells and the surrounding extracellular stromal matrix. These globules of protein correlate with the presence of AFP in the CSF and blood, a marker associated with endodermal sinus tumors.

Trophoblastic differentiation can result in isolated syncytiotrophoblasts expressing gonadotropins or 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, the 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 its surrounding tissue. The rarity of pineal cell lesions and the 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.

Russell and Rubinstein have described a more specific classification such that pineoblastomas include types without differentiation; those with pinocytic differentiation; and those with neuronal, glial, or retinoblastic differentiation.[24] 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 are the 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 and resembles the medulloblastoma with respect to age of presentation and its 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. The 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 occur second most frequently in children with pineal region tumors, exceeded only by germinomas in 2 large series that include children with pineal region tumors. The histologic and macroscopic appearances are similar to malignant glial neoplasms found in other areas of the 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 demonstrates osteoid bone with sur This micrograph demonstrates 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-differentiat Pineocytoma consisting of benign well-differentiated cells forming rosettes.
 

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. Currently, 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.

High-dose cyclophosphamide has been advocated as a single-agent protocol in the treatment of children with pineoblastomas. Ashley and colleagues demonstrated that children treated with high-dose cyclophosphamide had stable or diminishing disease while on the protocol.[25] 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.[26, 27] 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 histologic 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 of 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. Operative approaches are depicted in the images below.

The right side of this image demonstrates 3 operat The right side of this image demonstrates 3 operative approaches to the pineal region. The 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 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.

Regis and colleagues revealed a mortality of 1.3% and a morbidity of less than 1.0% in 370 patients with stereotactic biopsies of pineal region tumors.[28] The study included data from 15 French neurosurgical centers and documented statistical homogeneity among the different centers.

In a similar study, Kreth and colleagues retrospectively evaluated the risk profile, diagnostic accuracy, and therapeutic relevance of the stereotactic approach in 106 patients.[29] They showed a morbidity of 2 out of 106 patients, a mortality 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.[30, 31, 32, 33, 34] 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.[31] Performing an endoscopic third ventriculostomy and an endoscopic biopsy of the pineal region with one burr hole is usually not possible because of anatomic 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 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 beta-HCG 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.

Choi et al described the treatment of 107 patients with primary intracranial germ cell tumors.[35] This included 60 patients with tumors in the pineal region. Thirty of these patients were treated without surgery based on radiologic 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 study by Sawamura and colleagues evaluating the necessity of radical resection in patients with intracranial germinomas.[36]

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 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 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.[37]

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.[38] 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.[39] 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.[40]

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

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

Complications

The most common complications following pineal region surgery, regardless of the approach, are extraocular movement dysfunction, ataxia, and altered mental status.[41] Many of these neurologic 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 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. 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 of 0-8% and morbidity of 0-12%. This is in stark contrast to the mortality 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.

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 germinomas have an excellent prognosis because of the radiosensitivity of these tumors.

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 less than 3 cm in diameter.