Pineal gland masses

INTRODUCTION — Tumors involving the pineal gland or body are uncommon (figure 1). The classification, presentation, and general approach to lesions involving the pineal gland will be presented here, focusing on the management of pineal parenchymal tumors.

Germ cell tumors (GCTs), the most frequent tumor type found in the pineal region, are discussed elsewhere. (See "Intracranial germ cell tumors".)

EPIDEMIOLOGY — In Europe and North America, pineal tumors account for less than 1 percent of all primary brain tumors [1]. Pineal tumors are more common in children aged 1 to 12 years where these constitute approximately 3 percent of brain tumors [2].

Worldwide, pineal tumors are most common in Asian countries, for reasons that are not known [3,4]. This increased frequency is due largely to an increase in germ cell tumors (GCTs), which compose 70 to 80 percent of all pineal region tumors in Japan and Korea, for example. In the United States, the incidence of intracranial GCTs is highest in individuals with Asian/Pacific Island ancestry in the 10- to 29-year age group, suggesting that underlying genetic susceptibility may play a role in the etiology of these tumors [5].

Pineal tumors are substantially more common in males. In an analysis of 633 cases from the Surveillance, Epidemiology, and End Results (SEER) database over a 32-year period, pineal tumors were three times more common in males than females [6]. In those with GCTs, the male predominance was approximately 12:1.

CLASSIFICATION — The three histologic tumors that account for most neoplasms arising within the pineal gland are germ cell tumors (GCTs), pineal parenchymal tumors, and gliomas. In a series of 633 cases from the Surveillance, Epidemiology, and End Results (SEER) database, these comprised 59, 30, and 5 percent of patients, respectively [6]. Other pineal tumors reported included meningiomas, gangliogliomas, ependymomas, lipomas, trilateral retinoblastomas, and metastases [7]. Benign lesions arising within the pineal gland that can be confused with neoplasms include pineal cysts, vascular malformations, and vein of Galen aneurysms. There have been rare reports of choroid plexus papilloma in the pineal region, pineal epidermoid tumors, and primary malignant melanomas of the pineal region [8-13]. Other rare tumors of the pineal region are neuroendocrine carcinoma of the pineal parenchyma, schwannomas arising from the trochlear nerve, and gliosarcoma [14-16].

GCTs include germinomas and six nongerminomatous GCTs (NGGCTs) (table 1) [17]. The NGGCTs include embryonal carcinoma, yolk sac tumor (previously known as endodermal sinus tumor), choriocarcinoma, teratoma (immature and mature), teratoma with somatic-type malignancy, and mixed GCTs with more than one element. Germinomas comprise approximately three-quarters of all GCTs in the SEER series and approximately 45 to 50 percent of all pineal tumors [6,18]. Germinomas and teratomas are frequently encountered as pure tumors, whereas the other types are mostly part of mixed GCTs [19]. (See "Intracranial germ cell tumors", section on 'Pathology'.)

The World Health Organization (WHO) classification of central nervous system (CNS) tumors recognizes five types of pineal tumors [17]:

●Pineocytoma (grade 1)

●Pineal parenchymal tumors of intermediate differentiation (grade 2 or 3)

●Papillary tumor of the pineal region (grade 2 or 3)

●Pineoblastoma (grade 4)

●Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant (provisional)

Tumors that contain areas histopathologically like both pineocytoma and pineoblastoma (mixed pineocytoma/pineoblastoma) are often included within the intermediate differentiation group.

The relative prevalence of histologic types depends on the age of the patient population under study. As an example, among patients with a pineal GCT, germinoma is most frequent among those between 10 and 19 years of age, and there are some patients aged >30 years. Choriocarcinoma, embryonal carcinoma, and yolk sac tumor are rare in those over age 30 years. Pineoblastoma is most frequent among patients under five years of age, while pineocytoma is evenly distributed in patients between 10 and 60 years of age [18]. Astrocytomas tend to occur in two separate age groups: 2- to 6-year-olds, and 12- to 18-year-olds.

PRESENTING FEATURES — Pineal gland tumors share some common clinical and radiographic features based upon their anatomic location. The initial diagnostic approach is similar, and the treatment and prognosis depend upon establishing a histologic diagnosis. (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

Clinical signs and symptoms — Pineal tumors may cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. The rate of tumor growth determines the rapidity of symptom onset and progression and is an important prognostic factor.

Common signs and symptoms are summarized in the following table (table 2). Hydrocephalus is common, manifested by headaches, lethargy, and signs of increased intracranial pressure. Up to 75 percent of patients with pineal tumors have Parinaud syndrome, a constellation of neuro-ocular symptoms that result from pressure on the pretectal region (the dorsal aspect of the rostral or upper midbrain) (table 3). (See "Ocular gaze disorders", section on 'Parinaud syndrome'.)

Progressive local tumor growth may result in cranial neuropathies or hypothalamic dysfunction. While extracranial metastases are rare, patients may have symptoms of leptomeningeal dissemination, which is present at diagnosis in up to 19 percent of pineoblastomas and approximately 12 percent of germ cell tumors (GCTs) [20,21]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

Rare cases of precocious puberty caused by a pineal mass have been reported, particularly in females [22,23]. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Central nervous system lesions'.)

Neuroimaging — Magnetic resonance imaging (MRI) is the most useful initial study to identify the tumor and delineate its relationship to adjacent structures. As an example, obstructive hydrocephalus from aqueductal stenosis is common; in the majority of cases, this is due to the tumor extending into the third ventricle (figure 1 and image 1 and image 2).

In some cases, the imaging findings may suggest certain tumor types. While GCTs and malignant gliomas characteristically "invade" through the wall of the third ventricle, expansive compression is more common with pineal parenchymal tumors, low-grade astrocytomas, and meningiomas. However, imaging alone is generally not reliable enough to establish a histologic diagnosis [24]. Descriptions of typical imaging characteristics for each tumor type are provided below.

While quantitative imaging using computed tomography (CT), MRI, and 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) cannot differentiate between pineal parenchymal tumors and germinomas, careful attention to clinical characteristics (eg, age, sex), calcification patterns, and thalamic involvement can improve the accuracy of preoperative differential diagnosis [25,26]:

●Localized calcification is seen in more than 70 percent of GCTs, while it is scattered in more than half of pineal parenchymal tumors

●Cystic components in tumors are most frequent in nongerminomatous GCTs (NGGCTs)

●Multiplicity is characteristic of GCTs and is rare in other tumor types

●Thick peritumoral edema is more frequent in germinoma than in NGGCT

●Bithalamic extension of tumor is seen in up to 80 percent of germinomas, while it is significantly rare in other groups of tumors

Germ cell tumors — GCTs typically are seen as a homogeneous hyperdense mass. By contrast, teratomas are multilocular heterogeneous masses containing lipid areas [27].

Pineal calcification on skull radiographs, uncommon in children younger than 10 years, is a useful clue to the diagnosis of a GCT because approximately 70 percent of patients with GCTs have calcifications that are seen within the mass rather than calcifications "exploding" to the periphery [27].

Intracranial GCTs typically appear hypointense or isointense on T1-weighted imaging and hyperintense on T2-weighted imaging; their contrast enhancement pattern can be homogeneous or heterogeneous. Cystic areas are common and may be multiple. (See "Intracranial germ cell tumors", section on 'Neuroimaging'.)

Pineal parenchymal tumors — Pineal parenchymal tumors include pineocytomas, pineoblastomas, pineal parenchymal tumors of intermediate differentiation, and papillary tumor of the pineal region.

On CT, pineocytomas are typically isodense and enhance homogeneously with contrast. Cysts and calcifications are present in up to one-half of cases; peripheral calcifications are more suggestive of pineocytoma than germinoma, as pineal parenchymal tumors classically result in preexisting pineal calcifications dispersing to the periphery of the lesions (image 1) [24,27,28]. Benign pineal cysts may present similarly. (See 'Pineal cysts' below.)

On MRI, pineocytomas are typically ≤3 cm, sharply demarcated lesions with a high degree of cytoplasm that are hypointense on T1-weighted images and hyperintense on T2-weighted images [29,30]. They enhance homogeneously with contrast, and only one-third have associated hydrocephalus (image 1).

Pineoblastomas are hyperdense and have no associated calcifications [24]. They tend to be larger than 3 cm, lobulated, and poorly demarcated on MRI, and they are essentially isointense to gray matter on T2-weighted images, possibly related to the known paucity of cytoplasm in these tumor cells and overall dense cellularity seen in these lesions [30-32]. These tumors enhance heterogeneously with contrast, and 90 percent have associated hydrocephalus (image 2).

Glial tumors — Pineal glial tumors typically arise from the neighboring tectal plate and have a similar appearance on CT and MRI as when encountered elsewhere in the brain. Given their location of origin, pineal calcifications are displaced superiorly [27]. Calcifications can be identified in approximately two-thirds of pineal gliomas [24,29]. Pilocytic astrocytomas may be cystic, and unlike other low-grade gliomas, they enhance with contrast.

The typical appearance of high-grade gliomas (eg, glioblastoma) is a multilobular solid tumor with indistinct margins and heterogeneous contrast enhancement. Enhancing tumor can be distinguished from the surrounding hypointense signal of edema on T1-weighted images. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

Other tumors — A number of other tumors may be suspected based upon neuroimaging results:

●Meningiomas – Pineal meningiomas are small tumors (<2 cm) that have well-defined margins. Attachments to the falx often can be identified on sagittal images. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Diagnostic evaluation'.)

●Lipomas – Lipomas have low attenuation on CT, have increased signal on T1-weighted images, and lack contrast enhancement.

●Pineal metastases – The MRI features of metastases to the pineal gland are nonspecific. As in other areas of the brain, metastases are accompanied by more edema than would be expected based upon lesion size. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Imaging studies'.)

Nonneoplastic lesions — Nonneoplastic pineal lesions in the differential diagnosis of pineal masses include vascular malformations, arachnoid cysts, and pineal cysts, which must commonly be distinguished from cystic GCTs, pineal parenchymal tumors, or gliomas. (See 'Pineal cysts' below.)

INITIAL APPROACH — Pineal tumors are a challenge to the neurosurgeon because the pineal gland is a deep structure, surrounded by important vascular and neural structures. However, advances in microsurgery and neuroanesthesia have improved accessibility to the pineal region, and there is less hesitancy to approach this region surgically [33-35].

Staging work-up — The staging work-up for patients with suspected pineal tumors must include contrast-enhanced MRI of the brain and the entire spine. The cerebrospinal fluid (CSF) should be examined cytologically only if the patient is considered safe for a lumbar puncture. If CSF cannot be obtained by lumbar puncture then CSF can be obtained at the time of surgery and sent for the appropriate studies.

Both serum and CSF should be assayed for alpha-fetoprotein and beta-human chorionic gonadotropin (beta-hCG) to help diagnose a germ cell tumor (GCT). Once tissue is obtained, immunohistochemistry (IHC) may be of additional value in detecting these markers or placental alkaline phosphatase. There are no serum markers for other pineal tumors.

Tissue diagnosis — A tissue diagnosis is generally needed prior to therapy, since treatment is histology dependent. In very select cases of suspected GCTs, empiric therapy may be considered. This is discussed separately. (See "Intracranial germ cell tumors", section on 'Evaluation and diagnosis'.)

Stereotactic biopsy — A direct, visually guided biopsy of the pineal gland mass with open or neuroendoscopic surgery has been preferred due to concerns about injury to the deep cerebral veins. An open procedure also allows CSF to be obtained for tumor marker studies, permits direct visualization of the third ventricle for staging purposes, and allows a third ventriculostomy to be performed for CSF diversion if needed [36].

Despite these concerns, contemporary series suggest that stereotactic biopsy is reasonably safe and well tolerated, provided a low frontal approach is used to access the tumor below the level of the internal cerebral veins [37-40]. CSF sampling is possible because the biopsy trajectory often traverses the lateral ventricle.

The diagnostic yield of stereotactic biopsy ranges from 94 to 100 percent when multiple target biopsies are obtained, but sampling error may be an issue due to the heterogeneity of some pineal tumors (particularly mixed GCTs) [35]. Procedure-related morbidity is generally limited to transient worsening of ocular symptoms, although fatal complications have been reported [38]. A frameless stereotactic robot has been successfully used for brain biopsies over the past few years [41].

If the biopsy is nondiagnostic, equivocal, or suggests a benign tumor such as mature teratoma or meningioma, surgery is recommended to establish a definitive diagnosis or to identify focal areas of malignant disease [42,43].

Open surgery — Open surgery, including an attempt at gross total resection, is favored by some as the initial approach to patients with pineal tumors, rather than stereotactic biopsy. Since approximately one-third of pineal lesions are benign, open surgery may be potentially curative as well as diagnostic [34,44-46]. Furthermore, an open procedure minimizes sampling error, and tumor debulking may obviate the need for CSF diversion if obstructive hydrocephalus is present [43,46].

However, an attempt at gross total resection is not widely accepted for several reasons:

●Except for well-encapsulated teratomas, few pineal region tumors are amenable to complete resection because of local or regional extension [34].

●Many tumors require multimodality therapy once a diagnosis is established. As an example, GCTs are highly sensitive to both chemotherapy and radiation therapy (RT), and the best results have been achieved with these modalities. (See "Intracranial germ cell tumors", section on 'Management of germinomas'.)

●CSF seeding, as evidenced by positive cytology, requires craniospinal radiation and adjuvant chemotherapy regardless of tumor type. In this setting, the use of RT and chemotherapy may obviate the need for an extensive resection.

●Any potential benefit from open resection must be balanced against procedural risks. New or worsening visual deficits may occur in up to one-third of patients, although most improve over time [34]. Depending upon surgical expertise, the risk of permanent morbidity from open pineal gland surgery is 3 to 10 percent [34,44], while operative mortality rates range from 4 to 10 percent [47,48]. The most serious complications are related to postoperative hemorrhage in a subtotally resected malignant tumor.

Contemporary microsurgical techniques may provide a more effective and relatively safe approach to pineal region tumors [49]. These techniques provide an alternative to stereotactic biopsy in some cases. The most commonly used surgical approaches are supracerebellar/infratentorial and occipital transtentorial [48]. A purely endoscopic approach is sometimes possible as well.

Positron emission tomography (PET) may be a useful technique following surgery to determine whether viable tumor is still present and to assist in further treatment planning. In this setting, imaging with 11C-methionine appears to be more specific and possibly more sensitive than contrast-enhanced MRI [50,51]. PET imaging with 11C-methionine also appears to be more specific than 18-F fluorodeoxyglucose PET (FDG-PET) [52].

PINEAL PARENCHYMAL TUMORS — The normal pineal gland is composed of parenchymal (epithelial) and interstitial cells. Approximately 20 percent of pineal tumors arise from the epithelial cells and are termed "pineal parenchymal tumors." Pineal parenchymal tumors classically result in preexisting pineal calcification at the periphery of the lesion [27]. They are classified histologically into pineocytomas (grade 1), pineoblastomas (grade 4), pineal parenchymal tumor of intermediate differentiation (grade 2 or 3), papillary tumor of the pineal region (grade 2 or 3), and SMARCB1-mutant desmoplastic myxoid tumor of the pineal region [17].

Histogenesis and histology — Pinealocytes are specially modified neuronal cells similar to the photoreceptor cells in the retina, and phylogenetic studies have shown the evolution of the pineal from a photoreceptor organ to a secretory gland. Pineal parenchymal tumors share morphologic and immunohistochemical (IHC) features of cells from both the developing human pineal gland and the retina. Clinical evidence of their shared histogenesis is the occurrence of bilateral familial retinoblastoma with pineoblastoma (the trilateral retinoblastoma syndrome). (See 'Trilateral retinoblastoma' below.)

Using IHC, parenchymal cells (pinealocytes) are positive for neuron-specific enolase (NSE) and synaptophysin, supporting their neuroendocrine nature. Both pineocytomas and pineoblastomas stain for NSE, and IHC may be used to distinguish pineal parenchymal tumors from astrocytic tumors. By contrast, interstitial cells show immunoreactivity to glial fibrillary acidic protein (GFAP), S-100, and vimentin, supporting their glial origin. Cone-rod homeobox (CRX) protein is expressed in pineal tumors and retinoblastoma but not in the glial tumors, a property that can help to discriminate pineal tumors from glial tumors [11].

Pineocytomas and pineoblastomas each account for a little less than one-half of all pineal parenchymal tumors. The remainder are comprised of pineal parenchymal tumors with intermediate differentiation and papillary tumors of the pineal region.

Pineocytoma — Pineocytomas are World Health Organization (WHO) grade 1 brain tumors [17]. Pineocytomas are well circumscribed and generally do not seed the cerebrospinal fluid (CSF).

Microscopically, pineocytomas are composed of sheets of mature-appearing cells arranged in lobules, with rare or absent mitotic figures, and no pleomorphism, hyperchromatic nuclei, or necrosis. The cells are separated by a connective tissue stroma, giving a pseudolobular appearance reminiscent of normal pineal gland architecture. Characteristic pineocytomatous rosettes are arranged around central areas of eosinophilic fibrillar material. The absence of these rosettes (ie, lack of neuronal differentiation) is associated with a poorer prognosis [53,54].

Pineoblastoma — Pineoblastomas correspond to WHO grade 4 tumors. These are highly malignant, infiltrative tumors, with a significant potential for leptomeningeal and extracranial dissemination and a poor prognosis [21,54-56].

Pineoblastomas are more cellular than pineocytomas; they are composed of patternless sheets of densely packed, mitotically active small cells with round to irregular nuclei, and scant cytoplasm. Necrosis is common. Pineoblastomas lack pineocytomatous rosettes, but can have Homer-Wright or Flexner-Wintersteiner rosettes, which are indicative of retinoblastic differentiation. Because the histopathology of pineoblastoma is not distinctive, location in the pineal region is important for distinguishing pineoblastoma from nonpineal embryonal tumors like medulloblastoma and tumors previously called primitive neuroectodermal tumors (PNETs) [17].

An understanding of the molecular pathogenesis of pineoblastoma is evolving. Deoxyribonucleic acid (DNA) methylation profiling has identified four distinct subtypes within the core pineoblastoma (PB) subgroup: PB-RB1, PB-MYC/FOXR2, PB-miRNA1, and PB-miRNA2 [57-59].

●PB-RB1 and PB-MYC/FOXR2 group tumors affect young children. In a Rare Brain Tumor Consortium registry study, patients with RB1-altered and MYC/FOXR2-altered tumors were much younger (median age 1.3 to 1.4 years) with dismal survival (five-year overall survival 37.5 and 28.6 percent, respectively) [58]. PB-RB1 tumors show alterations in the RB transcriptional corepressor 1 (RB1) gene and may develop in the setting of congenital retinoblastoma, a condition known as "trilateral" retinoblastoma (see "Retinoblastoma: Clinical presentation, evaluation, and diagnosis"). PB-MYC/FOXR2 tumors contain recurrent alterations in the MYC gene region and overexpression of the forkhead box R2 (FOXR2) gene.

●PB-miRNA1 and PB-miRNA2 groups affect older children and follow a more favorable course. They are characterized by mutually exclusive alterations in genes involved in miRNA biogenesis, including dicer 1, ribonuclease III (DICER1), drosha ribonuclease III (DROSHA), and DGCR8 microprocessor complex subunit (DGCR8). They may be sporadic or may represent one manifestation of the DICER1 tumor predisposition syndrome (MIM #601200).

Pineal parenchymal tumors of intermediate differentiation — Pineal parenchymal tumors of intermediate differentiation (PPTID) are classified as grade 2 or 3 according to the WHO classification [17]. Approximately 70 to 80 percent harbor small in-frame insertions in the kelch repeat and BTB domain containing 4 (KBTBD4) gene, which is involved in ubiquitination [60-63].

PPTID have poorly differentiated tumor cells with round nuclei, moderately high cellularity, mild nuclear atypia, and occasional mitoses. They lack pineocytomatous rosettes. Tumor cell density and proliferation index are elevated in grade 3 tumors. The presence of a KBTBD4 mutation is useful in distinguishing PPTID from pineoblastoma for tumors with mixed histopathologic features [61].

PPTID are rare tumors, primarily affecting adults. In various series, the median age at diagnosis ranges from 30 to 53 years [61,63-65]. In children, PPTID is primarily seen in adolescents [60]. Both local and leptomeningeal recurrences can occur (image 3) [63].

Five-year overall survival rates range from 54 to 70 percent [63,64]. Grade 2 tumors are associated with improved survival compared with grade 3 tumors in some but not all studies [63,64]. Gross total resection and younger age are also associated with longer survival. The prognostic role and benefit of adjuvant therapy is yet to be elucidated, and more molecular and biologic research is needed to further optimize clinical management [64].

Papillary tumor of the pineal region — Papillary tumor of the pineal region is a rare neuroepithelial tumor with variable biological behavior that appears to correspond to WHO grade 2 or 3.

Histologically, papillary tumors of the pineal region are characterized by a papillary architecture and epithelial cytology, with immunoreactivity for cytokeratin and GFAP. Ependymal-like differentiation is often seen (eg, true rosettes). The presence of ependymal, secretory, and neuroendocrine organelles on ultrastructural analysis suggests that the cell of origin may be specialized ependymal cells of the subcommissural organ [17]. These tumors must be distinguished pathologically from pineal metastasis of adenocarcinoma, papillary ependymoma, and choroid plexus tumors.

Papillary tumors of the pineal region frequently show loss of chromosomes 10, 3, and 22q and gains of 8p and 12 [66]. Chromosome 10 harbors the phosphatase and tensin homolog (PTEN) gene [67]. The inactivation of PTEN by mutation or epigenetic silencing has been observed in a variety of brain tumors, including high-grade gliomas. Taken together, these findings indicate that PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway may play a role in the biology of papillary tumor of the pineal region and suggest a potential therapeutic target [67].

Desmoplastic myxoid tumor, SMARCB1-mutant — Desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant, is a newly described pineal parenchymal tumor as of the 2021 WHO classification [17]. Histologically, tumor cells are embedded in a loose myxoid matrix that has areas of heavily collagenized material. The proliferation index is low, and there are no malignant features. Loss of SMARCB1 expression in tumor cells is a defining feature, reflecting recurrent alterations in the SMARCB1 gene.

The clinical behavior and prognosis of desmoplastic myxoid tumors are not yet well defined. They present similarly to other pineal parenchymal tumors, with signs of increased intracranial pressure, hydrocephalus, or eye movement abnormalities. In a small series of seven patients, three patients were alive with stable disease at 48 months, one was alive with tumor progression, and three had died from the disease [68]. The median age at diagnosis was 40 years (range, 15 to 61 years).

Presentation and diagnosis — The clinical presentation of pineal parenchymal tumors is similar to that of other tumors arising in the pineal gland area. (See 'Presenting features' above.)

The interval between symptom onset and diagnosis may be as short as one month in patients with pineoblastoma, while symptom duration can be as long as several years in those with pineocytomas. Pineocytomas have a peak incidence at age 30 to 35, and there is a slight male predominance. By contrast, the median age at diagnosis for pineoblastomas is eight years of age with a higher predominance in children younger than five years of age.

Neuroradiology — Neuroimaging features of pineal parenchymal tumors are nonspecific. (See 'Neuroimaging' above.)

A pineal parenchymal tumor with a cystic or partially cystic appearance can mimic a typical pineal cyst in imaging appearance. This can be problematic since benign cystic lesions are identified by MRI in 1 to 4 percent of healthy subjects. Longitudinal follow-up with serial imaging may be necessary to distinguish between the two entities; rarely, surgical intervention may be required to obtain a definite diagnosis [69-71]. (See 'Pineal cysts' below.)

Papillary tumors of the pineal region have been described predominantly in adults. Unlike other pineal parenchymal tumors, there is a slight female predominance [72-74]. Papillary tumors of the pineal region appear to be mildly lobulated, partially cystic, heterogeneously enhanced masses, and usually cause obstructive hydrocephalus. They are relatively large (2.5 to 4 cm) and well circumscribed, with low T1 and increased T2 signal as well as contrast enhancement on MRI [74].

Prognosis — The main prognostic indicators are disease extent and histologic subtype [75]. Tumors with leptomeningeal or spinal metastases have a poor prognosis regardless of treatment.

Pineocytomas have the best prognosis, followed by pineal parenchymal tumors of intermediate differentiation, and then pineoblastomas. Tumor biology may be more aggressive in younger children with pineoblastoma, who also present more frequently with high-risk features at diagnosis and have poorer response rates to neoadjuvant postoperative chemotherapy [76]. Nonetheless, a subset of pineocytomas can behave aggressively and show a proclivity for symptomatic recurrence or malignant transformation from pineocytoma to pineal parenchymal tumor of intermediate differentiation [77,78].

Papillary tumors of the pineal region constitute a rare entity, and the data are too limited to provide accurate guidance regarding prognosis. In several case series, 15 of 21 patients experienced recurrences even after total resection [74,79]. There has been a case report of papillary tumor of the pineal region in a young boy that was noteworthy for early CSF dissemination and relentless progression; the outcome was fatal despite the aggressive chemotherapy and radiation therapy (RT) [72]. The only prognostic factor currently identified in the literature is whether or not surgical resection was complete [72,73,80].

Expression of the protooncogene Bcl-2 was detected in the tumor cells of a patient with papillary tumor of the pineal region of high proliferation index, suggesting that Bcl-2 might be related to the malignancy of this neoplasm [81]. Increased mitotic and proliferative activity has also been associated with a worse prognosis and may prove to be useful in identifying patients at increased risk for recurrence [82].

Treatment — The treatment of pineal parenchymal tumors must be guided by the histologic subtype. Successful treatment of pineocytomas requires surgery with or without RT, while the best results with pineoblastomas are seen with multimodality approaches that include chemotherapy.

CSF diversion — The optimal surgical strategy to treat acute hydrocephalus in patients with pineal tumors is uncertain. CSF diversion (ventriculoperitoneal [VP] shunt or third ventriculostomy [83,84]) may be necessary in symptomatic patients, although debulking surgery may obviate the need for this procedure. (See 'Initial approach' above.)

When CSF diversion is necessary, endoscopic third ventriculostomy can be carried out at the same time as the biopsy and is preferred over VP shunts, which can be complicated by infection, shunt malfunction, subdural hematoma, and, rarely, tumor seeding [39,85-87]. (See "Infections of cerebrospinal fluid shunts".)

Surgical resection — Some series report long-term survival with surgery alone, even in patients with pineoblastomas [28,34,75]. Indeed, for pineoblastomas, gross total surgical resection appears to correlate with improved survival [88]. Patients with symptomatic recurrent pineocytomas should also be considered for surgical resection of the lesion [77].

Radiation — Postoperative adjuvant RT is frequently (but not universally) recommended, and local control is dose dependent. This was illustrated in a series of 30 patients with pineal parenchymal tumors (9 pineocytomas, 15 pineoblastomas, 4 intermediate, and 2 mixed), 22 of whom received adjuvant RT. Among those treated with RT, there were fewer local failures among patients treated to ≥50 Gy compared with those receiving lesser doses (0 of 12 versus 6 of 7, respectively).

The importance of craniospinal irradiation (CSI) for patients with metastatic involvement or the potential to seed CSF (ie, all non-pineocytomatous pineal parenchymal tumors) was demonstrated in a series of 135 patients with histologically confirmed pineal tumors and other germ cell tumors (GCTs). The incidence of leptomeningeal recurrence was significantly lower among patients receiving CSI compared with those who did not. The five-year survival rates were 86 and 49 percent for pineocytomas and non-pineocytoma pineal parenchymal tumors, respectively [89].

Adjuvant RT is not universally recommended after gross total resection of a pineocytoma [28,34]. Some authors advocate adjuvant RT for only those pineocytomas that lack neuronal differentiation and that behave more like pineoblastomas [28].

Stereotactic radiosurgery — Stereotactic radiosurgery (SRS) is emerging as a useful treatment alternative for pineocytomas, although experience is limited [40,90,91]. SRS allows for precise radiation fields to minimize damage to the surrounding brain, and the risks of general anesthesia and craniotomy are avoided. (See "Stereotactic cranial radiosurgery".)

SRS is increasingly being used to treat pineal region tumors, either as an additional therapy after conventional treatments or as a primary treatment. This was illustrated by a series of 49 patients with pineal tumors, including nine with pineal parenchymal tumors, who were treated with SRS [92]. Survival rates at 5 and 10 years were 100 and 67 percent, respectively, in those with pineal parenchymal tumors.

In another more recent series, the efficacy of interstitial radiosurgery (IRS) was evaluated in 18 patients with pineal parenchymal tumors (8 pineocytomas, 10 malignant pineal parenchymal tumors) who were treated with IRS using stereotactically guided iodine-125 seed implantation (125I-IRS) as either primary or salvage therapy. Overall actuarial five- and eight-year survival rates after IRS were 100 and 86 percent, respectively, for pineocytomas, and the overall actuarial five-year survival rate was 78 percent for high-grade pineal parenchymal tumors. Follow-up MRI showed complete remission in 72 percent (13 of 18) and partial remission in 28 percent (5 of 18) of the cases [93]. Due to the low rate of side effects, IRS may develop into an attractive alternative to microsurgery in de novo diagnosed pineocytomas. In malignant pineal parenchymal tumors, IRS may be routinely applied in a multimodality treatment schedule supplementary to conventional irradiation [93].

Chemotherapy as part of multimodality therapy — The similarity of pineoblastomas to medulloblastomas in terms of their clinical behavior and tendency for leptomeningeal seeding has led to the use of similar chemotherapy regimens in patients with pineoblastoma as part of a multimodality approach [44,94-99]. (See "Treatment and prognosis of medulloblastoma", section on 'Chemotherapy'.)

Chemotherapy has been used to delay RT in very young children, for whom the long-term neurocognitive and developmental side effects of CSI are a major concern. (See "Treatment and prognosis of medulloblastoma", section on 'Neurocognitive impairment'.)

Results with this approach have been disappointing, however, and the optimal approach remains uncertain, as is illustrated by the following examples:

●In the largest series, 25 children with pineal pineoblastomas were treated as part of a Children's Cancer Group trial [98]. Infants received the eight-in-one multidrug chemotherapy regimen only (methylprednisolone, vincristine, lomustine or carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, and cyclophosphamide, all administered within 12 hours on day 1), while the other 17 patients received CSI, and were randomly assigned to either vincristine, lomustine, and prednisone, or the eight-in-one regimen. All infants developed progressive disease within four months. By contrast, 61 percent of the older children who received both CSI and chemotherapy remained progression free at three years. Outcome was not better with the more toxic eight-in-one chemotherapy regimen compared with the three-drug regimen [100].

●In a Pediatric Oncology Group (POG) study, 11 children with pineoblastoma under three years of age were treated with chemotherapy (alternating cycles of vincristine plus cyclophosphamide and cisplatin plus etoposide for up to 23 months) and delayed RT [101]. Only one child had a partial response after two months of chemotherapy, and all died of progressive disease, most within one year.

●In the Head Start (HS) I, II, and III trials, 23 children with pineoblastoma were enrolled prospectively between 1991 and 2009 [102]. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue. Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. Median age was 3.1 years (range, 5 months to 5.7 years). The five-year progression-free survival (PFS) and overall survival (OS) were 9.7 percent (95% CI 2.6-36.0 percent) and 13 percent (95% CI 4.5 to 37.5 percent), respectively. Only three patients survived beyond five years.

●In the National Cancer Database, a total of 211 pediatric patients (age 0 to 17 years) with histologically-confirmed pineoblastoma diagnosed between 2004 and 2015 were identified [103]. Older patients (age ≥4 years) experienced improved overall survival compared with younger patients (age <4 years). Older patients and those residing in high-income regions received radiotherapy more frequently. Radiotherapy was independently associated with improved survival in older but not younger patients. The benefits of radiotherapy were more pronounced in patients receiving surgery than in those not receiving surgery.

The importance of RT as a component of the initial treatment of embryonal tumors is also supported by the German HIT-SKK87 and HIT-SKK92 protocols, as well as the Canadian pediatric brain tumor protocol [104,105].

In an effort to improve overall survival and event-free survival and to decrease radiation exposure, more intensive approaches to chemotherapy are being investigated.

As an example, the Head Start protocols treated children with newly diagnosed pineoblastoma utilizing intensified induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic rescue [106]. The five-year event-free and overall survival rates were 39 and 49 percent, respectively, and patients with nonpineal supratentorial embryonal tumors fared significantly better than those patients with pineal tumors (pineoblastoma). Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 out of 20) were alive without exposure to RT.

A pilot study for supratentorial embryonal tumors that used risk-adapted CSI (dose of 23.4 Gy for patients with gross tumor resection and no metastatic disease; 36 to 39.6 Gy for patients with >1.5 cm² residual disease and/or metastatic disease) and an RT boost to the primary site to 55.8 Gy followed by cyclophosphamide-based dose-intensive chemotherapy demonstrated encouraging results: five-year event-free survival rates for standard and high-risk patients of 75 and 60 percent, respectively [107].

Eleven patients with pineoblastoma (aged 4 to 21 years) were treated in the multicenter prospective HIT 2000 trial [108]. Postoperative hyperfractionated RT with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity, while survival rates appeared comparable or superior to those of most other series.

Trilateral retinoblastoma — Trilateral retinoblastoma consists of unilateral or bilateral retinoblastoma associated with an intracranial neuroblastic tumor. The intracranial tumors are typically located in the pineal region, but can also exist in the suprasellar or parasellar regions. More than 50 percent are diagnosed at the time of retinoblastoma diagnosis; the remaining tumors occur subsequent to initial diagnosis, typically before the age of five years. Treatment of retinoblastoma, including trilateral retinoblastoma, is reviewed separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome".)

INTRACRANIAL GERM CELL TUMORS — Intracranial germ cell tumors (GCTs) are discussed separately. (See "Intracranial germ cell tumors".)

GLIOMAS — The approach to patients with glioma is discussed separately. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

PINEAL MENINGIOMA — Meningiomas are relatively common tumors in adults and account for approximately 20 percent of all intracranial tumors. Meningiomas constitute approximately 8 percent of pineal region tumors, and pineal meningiomas account for less than 1 percent of all meningiomas [109]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)

Pineal meningiomas are most commonly encountered after the second decade of life. However, they may occur at any age or even during fetal development. In children, they are uncommon but not rare lesions with a slight male predominance [110]. Most meningiomas are benign (World Health Organization [WHO] grade 1), slow-growing lesions, but some are classified as atypical (WHO grade 2) or malignant (WHO grade 3).

Meningiomas in the pineal region may originate either from the velum interpositum or from the falcotentorial junction [111]. In children, meningiomas arising from velum interpositum with no dural attachment are more prevalent than those arising from the falcotentorial junction [112].

Presentation — The usual clinical presentation for a patient with a pineal meningioma is with headaches and other signs of elevated intracranial pressure, ataxia, and/or ocular abnormalities [113], but not the typical Parinaud syndrome that is associated with other pineal region tumors (table 3). Tinnitus or hearing loss can be observed in up to 30 percent at diagnosis. Overall, the commonest presenting symptoms are seizures, increased intracranial pressure, and focal neurologic deficits (76, 71, and 39 percent, respectively) [110].

Neuroimaging — Pineal meningiomas may present with dural attachment and compromise of the venous system or, less commonly, as free-lying masses without dural attachment [114]. Calcification is common and is characteristically located at the lesion margins rather than in the center. On MRI, meningiomas have well-defined margins, and attachments to the falx can be appreciated on sagittal images.

Cerebral angiography may be needed to delineate the relationship between the tumor and the surrounding vessels, particularly before any surgery or embolization. Attention to the venous phase of the study is important because if the major basal veins fail to opacify preoperatively, the patient may be able to tolerate the venous occlusion that is usually required for a major resection.

Management — Surgical resection is the primary form of therapy for pineal meningiomas. Tumors are usually excised in a piecemeal fashion, as identification and preservation of the vein of Galen may prove difficult [109]. Incompletely resected tumors and high-grade lesions are frequently treated with fractionated radiotherapy or stereotactic radiosurgery (SRS).

The overall therapeutic approach to meningiomas is discussed separately. (See "Management of known or presumed benign (WHO grade 1) meningioma".)

PINEAL CYSTS — Asymptomatic pineal cysts are usually an incidental neuroimaging finding. In a retrospective study of 1000 consecutive MRIs, true pineal cysts (5 mm or larger in diameter) were found in 0, 1.8, and 2.6 percent of children ≤12 years of age, teenagers, and adults, respectively [115]. Their main importance is in their differentiation from cystic tumors such as pineocytomas, low-grade astrocytomas, and teratomas [116].

On CT, pineal cysts are hypodense with respect to cerebrospinal fluid (CSF), and occasionally there is evidence of recent intra-cyst hemorrhage. Cyst walls may or may not show contrast enhancement, and calcifications within the wall are found in approximately one-half of cases [117]. To be considered a typical pineal cyst, the lesion should have all of the following characteristics on MRI [69,70]:

●A round or ovoid area of signal abnormality centered on the pineal recess

●Internal homogeneity on T2-weighted imaging

●Signal intensity follows CSF on T1- and T2-weighted images (ie, hypointense to white matter on T1-weighted images and hyperintense on T2-weighted images)

●No marginal lobularity or nodular contrast enhancement

●A wall thickness of <2 mm

With high-resolution MRI, pineal cysts may have fine internal trabeculations or septations [118], but they should not have additional characteristics of pineal parenchymal tumors such as internal or nodular wall enhancement on postcontrast images [69].

Natural history — Most pineal cysts are silent and remain so for years; some may even spontaneously collapse [70,119-121]. In the largest natural history study that included 409 consecutive patients with a pineal cyst identified on MRI (median age 43 years, 12 percent ≤20 years of age), the rate of cyst growth was 5 percent with a median follow-up of 10.3 years [121]. The rate of spontaneous cyst shrinkage was 14 percent. No patients required surgical intervention over the follow-up period.

Symptomatic cysts — Symptomatic pineal cysts are usually larger than those ones found incidentally [117,122]. The incidence of symptomatic pineal cysts is highest in young women between 21 and 30 years of age [123], leading to the hypothesis that hormonal influences contribute to their etiology [123,124]. Symptoms may be caused by aqueductal compression resulting in hydrocephalus [125], obstruction of the vein of Galen, or compression of the collicular plate, leading to Parinaud syndrome [126].

Treatment — Small, asymptomatic pineal cysts require no therapy. If cysts become symptomatic by causing hydrocephalus, several treatment options can be considered. CSF diversion is not routinely recommended as sole therapy because of the lack of histologic confirmation and the fact that symptoms associated with direct mass effect may not improve [127]. Open or stereotactic cyst resection is considered by some the only guarantee of permanent cure and can obviate the need for CSF shunting [128,129].

Stereotactic cyst aspiration relieves the mass effect while at the same time providing a histologic diagnosis [122]. In general, the morbidity is lower than with open procedures, although the risk of recurrence after aspiration alone is unknown. Instillation of radioactive phosphorus 32 (P32) into the cyst cavity may be considered for recurrent cysts.

Some authors advocate imaging follow-up for typical pineal cysts to document stability with time, particularly for cysts larger than 10 to 14 mm, under the assumption that they may enlarge or become symptomatic, whereas others advocate clinical follow-up only if there are no atypical features or symptoms [130]. Others suggest that pineal cysts can be followed clinically rather than with serial imaging [119,120]. However, the preference for follow-up imaging of individual clinicians and patients may vary.

SUMMARY AND RECOMMENDATIONS

●Epidemiology and classification – Pineal gland tumors are rare central nervous system (CNS) tumors, the most common of which are germ cell tumors (GCTs) and pineal parenchymal tumors. (See 'Epidemiology' above and 'Classification' above.)

●Clinical presentation – Pineal tumors can cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. Common signs and symptoms are headaches, lethargy, and signs of increased intracranial pressure. Up to 75 percent of patients with pineal tumors have Parinaud syndrome, a constellation of neuro-ocular symptoms that result from pressure on the pretectal region (the dorsal aspect of the rostral or upper midbrain). (See 'Presenting features' above.)

●Evaluation – The initial evaluation should include imaging of the entire neuraxis and cytology examination of the CSF, to rule out leptomeningeal spread of the tumor. Serum and CSF should also be assessed for elevated tumor markers (alpha-fetoprotein and beta-human chorionic gonadotropin [beta-hCG]) to detect a possible GCT. (See 'Staging work-up' above.)

●Diagnosis – Although features on neuroradiologic imaging may suggest a specific histologic diagnosis, a biopsy is necessary in most cases to establish the diagnosis and to permit appropriate treatment. Tissue may be obtained either by stereotactic biopsy or open surgery.

When the patient's condition permits, we suggest an open surgical approach, rather than a stereotactic biopsy (Grade 2C). Open biopsy may allow gross total resection in some cases, and this may constitute adequate therapy for low-grade lesions. (See 'Tissue diagnosis' above.)

●Management of pineal parenchymal tumors

•For patients with pineal parenchymal tumors, we recommend surgical resection if technically feasible without causing severe neurologic dysfunction, rather than radiation therapy (RT) alone (Grade 1B).

•For patients with evidence of leptomeningeal tumor spread, and for those thought to be at high risk for leptomeningeal spread based upon tumor histology, we recommend craniospinal irradiation (CSI) (Grade 1B).

•For patients with high-grade lesions (ie, pineoblastomas), we suggest the addition of intensive chemotherapy to surgery and/or RT as part of a multimodality approach (Grade 2C). (See 'Treatment' above.)

●Management of pineal germ cell tumors – The management of patients with intracranial GCTs, the most frequent tumor arising in the pineal gland, is discussed separately. (See "Intracranial germ cell tumors".)