Pineal Tumors

The pineal gland develops during the second month of gestation as a diverticulum in the diencephalic roof of the third ventricle and is extra-axial. The pineal gland is located posterior to the third ventricle and extends inferiorly and posteriorly into the quadrigeminal cistern. It is bordered superiorly by the splenium of the corpus callosum and internal cerebral veins, inferiorly by the tectum of the midbrain, and bilaterally by the thalamus. See Pineal Gland Anatomy.

The pineal gland is richly innervated with sympathetic noradrenergic input from a pathway that originates in the retina and courses through the suprachiasmatic nucleus of the hypothalamus and the superior cervical ganglion. Upon stimulation, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects on hormones such as luteinizing hormone and follicle-stimulating hormone.[24] The pineal gland synchronizes hormonal release with phases of the light-dark cycle by means of its sympathetic input. However, the exact relationship between the pineal gland and human circadian rhythm remains unclear and is an area of active investigation.[25]

Two cell populations make up the pineal gland: pinealocytes (95%) and neuroglial supportive cells (5%). Pinealocytes are specialized neurons most similar to retinal rods and cones. Tumors may form from either of these two cell types, or from remaining germ cells from the neural crest or cells from nearby structures.[7, 24, 26]

The pathophysiology of pineal region tumors is mostly the result of anatomic compression of adjacent structures, although local infiltration of neural structures can lead to symptoms and neurologicl dysfunction in instances of highly invasive tumor. In some cases, neuroendocrine dysfunction is precipitated by specific factors secreted by the tumor or by tumor invasion of local structures.[27, 28]  [10]

Types and grades

Pineal region tumors can be categorized into GCTs and parenchymal tumors.

Pineal parenchymal tumors are classified by the World Health Organization (WHO) into the following four subtypes[29] :

• Pineocytomas – Slow-growing grade I/II tumors derived from the pineal epithelium; usually occur in persons age 20 to 64 years.
• Pineal parenchymal tumors of intermediate differentiation – Arise from pineal parenchymal tissue, typically include features of both pineoblastomas and pinceocytomas, and are intermediate-grade (grade II or III) tumors ^{[30, 31, 32]}
• Pineal papillary tumors – Uncommon neoplasms that are thought to arise from ependymocytes of the sub-commissural organ, located in the lining of the posterior commissure ^[33]
• Pineoblastomas – Aggressive grade IV tumors derived from the neuroectoderm; these typically occur in persons younger than 20 years, and are most common in those younger than 2 years

Pineal GCTs account for the majority of intracranial germ cell tumors.[34] There are six types: germinomas, teratomas, choriocarcinomas, yolk sack tumors, embryonal carcinomas, and mixed GCTs. GCTs 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. Although GCTs typically develop in the gonads, they can also develop in the brain, mediastinum, and pineal gland.[14]

In first few decades of the 20th century, pineal region surgery had poor outcomes with high operative mortality.[35] From Horsley’s initial attempt at removing a pineal mass in 1910 via an infratentorial approach, followed by later development of the lateral transventricular approach in 1931 by Van Wagenan, primitive anesthetic technique and lack of an operating microscope hindered pineal region surgery.[36] The first successful operation was conducted by Fedor Krause in 1913, where he used the infratentorial-supracerebellar approach to completely remove the pineal tumor from a 10-year-old boy.[35]

In 1948, Torkildsen argued for abandoning aggressive surgical resection in favor of CSF diversion followed by empiric radiotherapy.[37, 35] 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 was infrequently successful.[38] Later, in 1956, Bohuslav Zapletal attempted to bring the infratentorial-supracerebellar approach back to life with his publication of his results after treating 4 patients.[39] However, it was not until Bennet M. Stein, who at the time was the chairman of the Neurosurgery at the Columbia University College of Physicians and Surgeons, published his experience with 6 patients that the infratentorial-supracerebellar approach finally became popularized.[40]

Not until the 1970s, with the advent of microsurgical techniques, improvement in neurocritical care and use of the operating microscope together, were surgeons finally able to resect with far more radical approaches, and with these advances came minimal associated morbidity and mortality.[35] Further, with the improvement in stereotactic procedures, surgeons had greater access to the pineal region for biopsy and thus more targeted therapies.[35]

Tumors of the pineal area are rare and account for less than 1% of all adult primary brain tumors.[29] However, they are more common in children, representing 3 to 11% of primary brain tumors.[2, 22] Pineal tumors are more common in Asian countries. GCTs make up to 80% of these tumors.[14, 41] In the United States, pineal tumors are more common among persons of Asian or Pacific Island descent, and similarly, these tumors are predominantly GCTs.{ref105-INVALID REFERENCE}

The relative 5-year survival rate for pineal region tumors in 2021 was 69.5%, but many factors can affect prognosis.[42]

For parenchymal tumors, prognosis is most dependent on subtype and extent of disease. Spread to the leptomeninges or spine adversely affects prognosis despite subtype.[43] Pineocytomas are associated with the best outcomes, while pineoblastomas, the most aggressive subtype, are associated with the worst outcomes amongst these parenchymal tumors. Moreover, pineoblastomas typically have even worse outcomes when present in children, as these tumors typically have more high-risk features at diagnosis and have worse responses to chemotherapy.

The prognosis for pineal parenchymal tumors of intermediate differentiation typically resides between those for pineocytomas and pineoblastomas. Depending on the individual tumor, a pineal parenchymal tumor of intermediate differentiation may have more aggressive features, such as local invasion or dissemination, leading to worse outcomes.[22] Papillary tumors are so rare that there is poor accuracy regarding prognosis.

For pineal GCTs, prognosis is contingent on histology and tumor markers. NGGCTs, such as yolk sac tumors, choriocarcinoma, embryonal carcinoma and mixed malignant GCTs, are typically associated with higher risk. Mature teratomas are considered intermediate risk. Germinomas and immature teratomas are associated with low risk.[14]

AFP and beta-hCG are typically secreted by NGGCTs and immature teratomas. AFP levels above 1000 ng/mL are associated with poor prognosis, while similar levels of beta-hCG are not associated with any worse prognosis.[44]

Voung et al reviewed pineal gland tumors regardless of type from 1975-2016.[45] Interestingly, they found that chemotherapy did not lead to a survival advantage and adversely affected patients with non-GCTs. They suggested that consideration of its use should be limited to specific circumstances, to avoid its harmful effects. Notably, these associations were not observed in those patients with GCTs. Examining survival rates of pineal tumors over four distinct time periods, they found that 1-,3-, and 5-year survival rates have been steadily increasing, with rates of 72.2%, 48.9% and 45.6% respectively during 1975-1984, improving to 89.0%, 82.6%, and 79.3% respectively from 2005-2016.[45] Younger age at diagnosis, female sex, germ cell tumor histology, and the absence of chemotherapy were indicators for an improved prognosis.[45]

Signs and symptoms associated with pineal tumors are typically secondary to compression of the midbrain, with associated neurologic dysfunction.[46, 10] Further, large growth may lead to obstruction of CSF structures, specifically the aqueduct of Sylvius, leading to hydrocephalus and signs and symptoms of increased intracranial pressure (ICP), such as headaches and lethargy.[10]  If left untreated, hydrocephalus may lead to obtundation and death. Compression of the superior colliculi may lead to gaze palsy and Parinaud syndrome. The rapidity of onset of signs and symptoms depends on the speed of tumor growth.

Children with pineal region tumors can present with endocrine dysfunction. Pseudoprecocious puberty is the most common endocrine disturbance. However, the mechanism by which pineal tumors causes precocious puberty remains unclear. Hypotheses include production of gonadotropins by the tumor, and invasion of the median eminence with subsequent loss of inhibition of sexual or gonadotrophic function.[10] Diabetes insipidus and hypogonadism have also been observed.[47]

Common signs associated with pineal tumors include the following:

• Ataxia
• Papilledema
• Loss of upward gaze
• Tremor
• Altered pupillary reflexes
• Hyperactive deep tendon reflexes

As mentioned previously, compression of the superior colliculi may result in Parinaud syndrome, an ocular gaze disorder. This syndrome is seen in up to 75% of patients with pineal tumors.[48] Further compression of the periaqueductal gray region may cause mydriasis, convergence spasm, pupillary inequality, and convergence or refractory nystagmus. Impairment of downward gaze 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.

The workup for tumors in the pineal region requires high-resolution magnetic resonance imaging (MRI) of the brain and spine with and without contrast, and serum/cerebrospinal fluid (CSF) markers. Tissue biopsy may also be required.

MRI is crucial for assessing tumor size, vascularity, associated anatomic relationships, and degree of hydrocephalus if present. Pineal tumors typically displace superior vessels of the deep venous system, and consequently, identifying venous structures is especially important.[49]

CSF should be obtained, if lumbar puncture is considered safe for the patient, and examined cytologically. If lumbar puncture is deemed unsafe, CSF can be collected at the time of surgery. CSF and serum should be examined for markers, including alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (beta-hCG). Significant increases in either of these markers can be pathognomonic for GCTs and eliminate the need for tissue diagnosis and surgery.[11, 12, 4, 13]  In this circumstance, chemotherapy and radiation can be started right away.[4, 13]  In the absence of those markers, radiographic, CSF, and serum studies may provide some insight into tumor type, but these studies should not replace tissue diagnosis.[15]  [16]

For more information, see Pineal Germinoma Imaging.

Tumor markers are most helpful in the workup of patients with germ cell tumors (GCTs). Because GCTs retain molecular characteristics of their primordial lineage, increased levels of AFP and beta-hCG are pathognomonic for certain GCTs.[11, 12, 50, 51, 52] See Table 2, below.

Markers of pineal tumors.

The presence of AFP suggests features of yolk sac tissue. Yolk sac tumors characteristically have considerably high levels of AFP, while embryonal cell carcinomas as well as immature teratomas may present with elevated, but lower, levels of AFP.  Meanwhile, beta-hCG suggests the presence of trophoblastic tissue. Choriocarcinomas present with markedly high levels of beta-hCG, while some embryonal cell carcinomas and germinomas with syncytiotrophoblastic cells present with lesser elevations.[50, 12, 51, 13] Lastly, germinomas have been associated with elevated levels of placental alkaline phosphatase.[53]

In both serum and CSF, the standard upper limit of normal for AFP is 10 ng/mL, and that for beta-hCG is 50 mIU/mL.[54] However, a pathologic study of 58 intracranial GCTs by Hu et al recommended diagnostic cut-off points for beta-hCG of ≥ 8.2 IU/L in CSF and ≥ 2.5 IU/L in serum.[55] AFP levels > 1000 ng/mL are associated with poor prognosis, while similar levels of beta-hCG are not associated with any worse prognosis.[44]

Pineal parenchymal cell tumor markers are less well characterized than their GCT counterparts. Associated proteins include melatonin and the S antigen.[56, 57]  Neither of those proteins has proved valuable in the diagnosis of pineal parenchymal tumors.[9, 4]

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

GCTs arise from the neoplastic transformation of residual primordial tissue derived from ectoderm, mesoderm, or endoderm. Each tumor subtype represents the malignant correlate of a distinct stage of embryonic development. In some cases, the stage of tissue development can be identified by distinct radiographic features. On MRI studies, germinomas are isointense or slightly hyperintense to adjacent brain on T1-weighted images, isointense or slightly hyperintense to adjacent brain on T2, and have strong homogeneous contrast enhancement.[58] (See Table 1, below.)

Demographics and imaging findings of pineal tumors.

Additionally, due to hypercellularity, germinomas demonstrate greater restriction compared with adjacent tissue on diffusion-weighted imaging (DWI). The germinoma tumor itself does not calcify, but  it promotes calcification of the pineal gland, and that calcification is subsequently engulfed by the tumor.[10]

On MRI, teratomas are typically lobular and multiloculated. They typically demonstrate widely heterogeneous features due to the presence of all 3 germ layers and include irregular or ring enhancement.[10, 7]  The presence of fat and calcification may help to distinguish teratoma from other pineal tumor types.[10]

Differentiation of non-germinomatous germ cell tumors (NGGCTs) is not possible with imaging alone.[10] Choriocarcinoma is highly vascular and may present with areas of intratumoral hemorrhage. Embryonal carcinoma tends to present with a more cystic character compared with germinomas. Yolk sac tumors do not have characteristic imaging findings and are similar to other GCTs.[19]

Imaging of pineal parenchymal tumors reflects the biology of pineocytomas. Generally, pineocytomas will present more homogeneously, while pineoblastomas will present more heterogeneously and are typically larger.[47] Nevertheless, pineal parenchymal tumors share many radiographic features, making distinguishing among tumor types difficult. Unlike germinomas, pineal parenchymal tumors intrinsically calcify. Calcification occurs along the tumor periphery, giving rise to an “exploded” pattern, which directly contrasts with germinomas and their associated “engulfed” calcification pattern. However, like germinomas, solid components of these tumors are often hypercellular, demonstrating restricted diffusion on DWI.[10]

Pineocytomas and pineoblastomas are hypointense to isointense to adjacent brain on T1 imaging, and isointense to adjacent brain on T2. Papillary tumors are typically well-defined with variable T1 signal, but hyperintense to adjacent brain on T2.[59] Cystic areas are also commonly seen.[60]

Other lesions that can appear in the pineal region include astrocytomas, which can arise from the glial stroma of the pineal gland or surrounding tissue. These tumors are typically hypointense to adjacent brain on T1 and hyperintense to adjacent brain on T2.[61] However, they may have variable enhancement patterns. Calcium may also be present, potentially complicating diagnosis on imaging.

Meningiomas typically have intense homogeneous enhancement with well-circumscribed borders. They are typically isointense, but may be hypointense to grey matter on T1 and may be hyperintense to grey matter on T2.[62] Some meningiomas can have an enhancing dural tail. This sign was originally considered pathognomonic but was subsequently found in a variety of disorders.[63]

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.

Benign cysts of the pineal gland are diagnosed more frequently with increased use of MRI for standard workups unrelated to the pineal region. Cysts are quite common, with reported rates as high as 40% in an autopsy series. They are typically oval, filled with proteinaceous or bloody fluid, and often have a thin rim of calcification. Patients are typically asymptomatic.

On MRI, pineal cysts are hypointense to isointence compared with grey matter on T1 and isointense to hyperintense compared with grey matter on T2.[64, 19] Pineal cysts may be difficult to distinguish from low-grade cystic astrocytomas on radiographic criteria alone. Any doubts about diagnosis should be addressed by careful observation of the patient via serial MRI scans to ensure that the lesion is not growing. If these cysts cause obstructive hydrocephalus or show evidence of progression, surgical resection is indicated.

Lastly, MRI of the spine with gadolinium should be performed upon presentation to assess for extent of disease.

The pineal gland has varying architecture. Some pineal glands have a lobular shape, separated by connective tissue, while others may have more abundant connective tissue, creating an insular pattern.[65] Regardless of the architecture, the pineal gland is made up of follicles and lines of pinealocytes and glial tissue.[66]

Pineal parenchymal tumors arise from pinealocytes, a type of parenchymal cell, or a pinealocyte precursor. They account for 15% to 30% of pineal gland tumors.[67, 68]  Pinealocytes are modified neuronal cells similar to photoreceptors in the retina.[7, 24, 43] They stain positive for synaptophysin.[69]  Among each subtype, tumors present with different grades and features.

Pineocytomas are World Health Organization (WHO) grade I/II tumors. They are made up of dense sheets of mature-appearing cells that are indistinguishable from normal pineal parenchyma.[2] Pseudorosettes are characteristic of pineocytomas and are not found in normal tissue.[29]

Pineoblastomas are WHO grade IV tumors derived from primitive neuroectoderm.[4] They are highly aggressive and associated with the worst prognosis among pineal parenchymal tumors.[6, 68] These tumors are made up of undifferentiated pineal cells.[47] Compared with pineocytomas, they are far less organized and more cellular.[70] They are made up of dense sheets of small round blue cells, due to their high nucleus-to-cytoplasm ratio. The growth pattern is not typically associated with any features. However, Homer-Wright or Flexner-Wintersteiner rosettes may be occasionally seen.[70] See the images below.

Pineocytoma consisting of benign, well-differentiated cells forming rosettes.

Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.

Macroscopically, pineal parenchymal tumors of intermediate differentiation appear similarly to pineocytomas with well-circumscribed borders.[70, 22]  Microscopically, they have two patterns, which may even co-exist. A diffuse lobular pattern is characterized by loosely defined lobules separated by large vessels, while the diffuse pattern is characterized by large rosettes.[70, 22]

Papillary tumors are WHO grade II or III tumors, and they are uncommon.[2] They show similar histologic characteristics to pineocytomas, including rosette-like features.[7]

GCTs are the most prevalent neoplasms of the pineal region.[6] Germinomas make up 60-80% of all GCTs and 50% of all pineal gland tumors.[6] NGGCTs fall along a spectrum of differentiation.[71] The least differentiated is embryonal cell carcinoma, with further differentiation described as either embryonic or extraembryonic. Immature and mature teratomas result from maturation along embryonic cell lines, whereas the the yolk sac tumor and choriocarcinoma result from extra-embryonic differentiation.[72]

Description and classification of a given lesion may be confounded when more than one type of germ cell component is found in a surgical specimen. Mixed GCTs are the result of simultaneous differentiation along more than one pathway such that, at presentation, 2 or more characterized components are recognized.[73]  An example of this is teratocarcinoma—an embryonal carcinoma that contains elements of an immature teratoma.

Germinomas are typically characterized by sheets or lobules of large, round tumor cells with large nuclei, prominent nucleoli, glycogen-rich cytoplasm and septal bands of connective tissue. In addition, capillaries, lymphocytes, and granulomas may be present.[34, 74] In these cases, periodic acid–Schiff staining and placental alkaline phosphatase staining help identify tumor cells.[74]

Similarly, embryonal cell carcinoma tumor consists of cells with large nuclei and prominent nucleoli arranged in papillary, glandular, or solid structures.[74] Typically, eosinophilic droplets are identified in the cytoplasm.[74]

Teratomas can be composed of a mixture of tissues derived from all 3 germinal layers, with varying degrees of differentiation.[7] Mature teratomas are made up of fully differentiated tissues with absent mitotic activity, while immature teratomas consist of embryonal tissues with high mitotic activity.[74] See the images below.

Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.

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.

Yolk sac tumors include either columnar or flattened epithelium-like cells arranged in reticular, papillary or endodermal patterns.[74] As in embryonal cell carcinoma, eosinophilic-hyaline globules may be present in the cytoplasm. The hallmark of yolk sac tumors are Schiller-Duval bodies present in the endodermal sinus patterns.[74] See the image below.

Endodermal sinus tumor with a characteristic Schiller-Duval body.

Lastly, choriocarcinoma is composed of cells either resembling cytotrophoblasts or syncytiotrophoblasts assembled in nest-like structures.[74]

Treatment of pineal region tumors is complex. Various strategies exist for managing associated signs and symptoms, such as hydrocephalus or local mass effect, and achieving cytoreduction/oncologic control. The choice of strategies depends on the clinical presentation, the presence of hydrocephalus, results of cerebrospinal fluid (CSF) and serum tumor marker studies, the presence of metastatic disease, and the patient's age and general medical status.

When a patient presents with manifestations of hydrocephalus, decompression of the ventricles is the first priority.[41] Treatment typically begins with endoscopic third ventriculostomy (ETV) for relief of the obstruction, followed by inspection of the CSF for dissemination, sampling of the CSF, and biopsy of the tumor. The tumor may be resected endoscopically if indicated.[75] If ETV is contraindicated or unavailable, a ventriculoperitoneal shunt could be placed, but this carries the risk of peritoneal dissemination.[76] If hydrocephalus is emergently life-threatening, an external ventricular drain may be placed at bedside.

For patients with positive tumor markers, treatment depends on tumor type. Treatment may include a combination of radiotherapy, chemotherapy, and resection. Most patients cannot be confidently diagnosed with tumor markers and therefore histological diagnosis via tissue biopsy is required. Surgical resection may be indicated depending on tumor type.

Below is an algorithm to aid in decision making.

Management of pineal tumor.

Germ Cell Tumors

Germinomas may be treated with radiation or a combination of radiation and chemotherapy. They are among the most radiosensitive tumors, with patients experiencing long-term tumor-free survival rates greater than 90% from radiation alone in most published series. However, radiation therapy poses risks of long-term adverse effects and current standard of care includes adjuvant chemotherapy to allow for reduced doses of radiation. Chemotherapy alone results in cure in less than 50% of cases and is not recommended.[14]

For localized germinomas, radiation is delivered to the tumor bed and the whole ventricle instead of the whole brain. Bifocal disease of pineal and suprasellar regions is treated as localized disease.[77] For disseminated or recurrent germinomas, more extensive craniospinal irradiation (CSI) is recommended.[78]

Non-germinomatous germ cell tumors (NGGCTs) are more aggressive and significantly less responsive to radiation, with a 5-year survival rate of 30-40% when this treatment is used alone. This category includes embryonal carcinoma, yolk sac tumor, and choriocarcinoma. For these patients, chemotherapy and CSI is recommended.[79]

Teratomas are less responsive to radiation alone and due to histologic heterogeneity, no standard radiation recommendations exist. Immature teratomas are generally treated with chemotherapy and CSI. Mature teratomas may require only resection, if the surgeon is able to achieve gross total resection.[17]

Some tumors may contain multiple germ cell types. Treatment of these mixed GCTs should be based on their most malignant component.[18]

Surgical safe maximal resection is recommended when chemotherapy and radiation fail to shrink the tumor. This may be referred to as “second-look surgery.” The stable mass may be the remaining original tumor, concurrent teratoma, or fibrosis.[80] Small residual tumor after otherwise good response to treatment generally does not require surgical intervention and can be monitored, though this is an area of debate.[81]

Rarely, GCTs will progress quickly during or after treatment with chemotherapy. This phenomenon is called "growing teratoma syndrome", and it is more common in NGGCTs and immature teratomas. Treatment includes complete resection followed by chemotherapy and radiation.[82]

Pineal Parenchymal Tumors

Pineocytomas are primarily treated surgically. Asymptomatic pineal parenchymal tumors can be managed conservatively, but if enlarged and symptomatic, gross total resection is generally curative. For those with subtotal resection, postoperative radiotherapy is administered.[19]

Pineoblastomas are highly aggressive tumors that requires surgical resection as well as combination CSI radiotherapy, tumor boost, and chemotherapy.[20]

For pineal parenchymal tumors of intermediate differentiation, treatment is dependent on degree of invasion.[21] Disease that is limited locally is treated with surgical resection alone. Locally invasive or disseminated disease is treated with resection, CSI and chemotherapy.[22]

Lastly, papillary tumors of the pineal region are typically treated with resection, CSI and chemotherapy. They frequently recur, but CSI has been shown to be effective both in initial management and at recurrence.[23]

Complications of Radiation and Chemotherapy

For almost all tumors, adjuvant chemotherapy plus radiotherapy is standard of care[24] . The exceptions include pineocytomas and mature teratomas. Specifically, radiotherapy is included in protocols as early as three years old.[24]

Radiation therapy is associated with significant toxicities to endocrine, bone and neurocognitive function. Before the use of chemotherapy, these feared radiation-associated toxicities challenged the field and dose of radiation used to treat pineal tumors.[83, 84]  These toxicities eventually prompted the use of adjuvant chemotherapy to reduce exposure to irradiation.[84]

A long term study following children and adults with pineal parenchymal tumors found that there were no severe side effects from radiation treatment. Side effects included transient blindness and sepsis due to leukopenia. Neurotoxicity was not observed. However, growth and neurocognitive effects were difficult to assess given that many of the pineoblastoma patients died within 2 years of treatment.[85]

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 dose to 2500 to 3000 cGy. An additional dose directed at the tumor bed can be administered subsequently.

Several studies have shown that patients receiving less than 5000 cGy are at risk for recurrence, strongly suggesting that this is the optimal total dose of radiation. For children with malignant germ cell tumors, standard treatment consists of focal radiotherapy followed by radiation to the ventricular field. The application of radiotherapy depends on the histology of the tumor being treated.

The dramatic success of radiotherapy in treating children with germinoma has precluded extensive consideration of chemotherapy as a first-line treatment for older children. Chemotherapy should be considered as first-line treatment only for very young children. Some authors advocate treating children with chemotherapy prior to radiation in an effort to reduce radiation exposure and its associated morbidity.

Radiosurgery

Stereotactic radiosurgery (SRS) is a surgical intervention that relies on a coordinate system to deliver focused radiation at small targets in the body. In the treatment of pineal gland tumors, it is considered standard of care for pineocytomas. Further, for GCTs and pineoblastomas, it can be used in conjunction with chemotherapy and radiation.[24, 86]

Approaches for Biopsy

When nonoperative diagnosis with tumor markers cannot be achieved, tissue diagnosis is vital for patients with pineal region tumors. There are multiple approaches to specimen collection with distinct advantages and disadvantages.[24]

Stereotactic biopsy has been described as the procedure of choice for obtaining a tissue diagnosis in situations such as widely disseminated disease, clearly invasive malignant tumor, or patients with multiple medical problems. Early experience with stereotactic biopsies resulted in morbidity and mortality specifically related to targeting of periventricular structures adjacent to the deep venous system. However, current studies show that stereotactic biopsy is a safe and efficient means of obtaining a tissue diagnosis.[87]

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.[88, 89, 90, 91, 92, 93] In recent years, techniques have been developed to perform endoscopic third ventriculostomy and an endoscopic biopsy of the pineal region with a single burr hole.[94, 95, 96]  This dual approach is beneficial in addressing hydrocephalus as well as establishing a tissue diagnosis.

Patients may undergo open resection as a primary surgical treatment. While this carries the advantage of complete tumor resection and a decrease in tissue sampling error, not all tumor types require surgical removal and the patient may be subjected to undue risk from the procedure. For example, patients with germinomas are generally treated with radiation and chemotherapy alone. For patients with benign lesions, surgical resection can be curative. For patients with malignant tumor components, evidence suggests that surgical debulking may improve response to postoperative adjuvant therapy. Gross total tumor resection also provides ample tissue specimen to the neuropathologist for diagnosis.

 Open versus Endoscopic Resection

Pineal tumors can be resected through open or endoscopic approaches. The open approach remains the standard of care. However, techniques in endoscopic surgery continue to improve. As endoscopic resection is shown to be a safe and effective method of gross total resection, it may be utilized more frequently.[97, 98, 99]

Strategies for open resection of pineal region tumors are categorized as supratentorial or infratentorial. The infratentorial workhorse is the supracerebellar infratentorial approach (SCIT). Supratentorial approaches include occipital transtentorial (OTT), interhemispheric transcallosal (IHTC), and the rarely used transcortical transventricular (TTV) approach. The choice of approach depends on the surgeon’s experience and comfort. Many of these approaches are interchangeable, although there are several caveats. Improvements in surgical techniques and neuroanesthesia have significantly lowered morbidity and mortality rates associated with pineal region surgery.

Infratentorial supracerebellar approach

The infratentorial supracerebellar approach utilizes the natural corridor created between the tentorium and the cerebellum and is ideal for tumors inferior to deep cerebral veins. See the images below. The main disadvantage associated with this approach is limited access to tumors that extend above the deep venous complex, anteriorly into the third ventricle, or with extensive lateral growth.

View during a infratentorial supracerebellar approach from the operative microscope. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].

Pre and postoperative MRI from a patient with a pineal tumor resected via supracerebellar infratentorial approach. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].

Suboccipital exposure begins with linear midline incision from above the torcular and external occipital protuberance down to the level of C4.[76] Arachnoid adhesions and midline bridging veins between the dorsal surface of the cerebellum and tentorium are cauterized in order to open the infratentorial corridor. This allows for the cerebellum to separate easily from the tentorium with minimal retraction. Here, with retraction, the arachnoid covering the pineal region can be observed. Utilizing the surgical microscope, the tumor is then debulked with a variety of tools including suction, cautery, tumor forceps, and ultrasonic aspirator. If the tumor is completely removed, the surgeon should have a direct view into the third ventricle.[76]

The lateral suboccipital approach is a modification of the SCIT approach that utilizes a paramedian corridor to the pineal region.[100] This modification avoids the many medial vermian bridging veins, which would normally be sacrificed in the midline approach. A modified lateral decubitus position should be used. The approach begins with a lateral suboccipital craniotomy, which exposes the transverse sinus. Unilateral suboccipital craniotomy protects the cerebellum, torcula, and contralateral transverse sinus, reducing morbidity. Next, retraction sutures are placed to gently rotate and elevate the transverse sinus, expanding the lateral supracerebellar corridor.[100]

Previous reports have noted that this paramedian approach is insufficient in providing the necessary view for resecting large pineal region tumors.[101] However, a 2016 study reported that this approach was sufficient for resection of pineal region tumors > 3 cm.[100]

Occipital transtentorial approach

A 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 main disadvantage of the supratentorial approach is the difficulty associated with removing a tumor that lies below the convergence of the deep venous system. The occipital transtentorial approach can result in visual defects secondary to occipital lobe retraction and associated damage to the calcarine cortex.

A three-quarter prone position is ideal for the occipital transtentorial approach. This approach divides the tentorium, allowing for exposure of the quadrigeminal plate and access to tumors that extend inferiorly. The operating microscope helps to identify the straight sinus where it lies adjacent to the tentorium. The tentorium is divided and the falx is retracted for greater exposure. The arachnoid covering the tumor as well as the quadrigeminal plate can be seen. Tumor is then debulked and resected.[76]

Interhemispheric transcallosal approach

This is one of the oldest approaches that creates a corridor between the falx and the brain to the pineal region along the parieto-occipital junction and can reach tumors with anterior extension into the third ventricle. It requires a wide craniotomy, roughly 8 cm in length, to provide flexibility in avoiding bridging veins. A limitation of this approach is that it cannot be used for tumors that extend below the collicular plate. Complications of the transcallosal interhemispheric approach may result from excessive retraction on the parietal lobe.

Prone or sitting positions can be used. It begins with a wide U-shaped scalp flap extending across the midline and reflected laterally. This is followed by a wide craniotomy over the vertex. This creates flexibility for the corridor between the falx and hemisphere along the parieto-occipital junction.[76] The parietal lobe and falx are retracted. The corpus callosum is identified, by its white appearance, via the operating microscope, and its pericallosal arteries are retracted. The corpus callosum is then opened approximately 2 cm, which typically does not lead to postoperative impairment.[76] After an opening is created, the dorsal surface of the tumor as well as the deep venous system should be appreciated. Sacrifice of greater than one vein would have deleterious consequences. Here, the tumor can be debulked and dissected.[76]

Transcortical transventricular approach

This approach reaches the pineal region by transversing the right lateral ventricle. It is a historical approach that is now rarely used, as it requires a cortical incision and provides limited exposure. Patients may suffer visual field deficits. Stereotactic guidance is used as an aid, and eloquent cortex is avoided.[76]

If an intraoperative diagnosis of malignant tumor is made, the patient must be evaluated for spinal metastasis. The most sensitive radiographic modality for screening is complete spinal MRI with and without gadolinium. The first MRI scan should be timed at least 2 weeks after surgery because spinal canal enhancement can occur in the early postoperative period.

Equivocal findings on the initial postoperative scan warrant a repeat scan within 1 to 2 weeks. Radiographic artifacts secondary to surgery regress while drop metastasis remains stable or increases in size over time. The role for postoperative lumbar puncture and subsequent CSF analysis for cytology is questionable. The presence of abnormal cells postoperatively does not correlate well with spinal metastasis, as it may instead be due to spillage during surgery.

Timing for follow-up cranial MRI varies depending upon tumor histology and degree of resection. To estimate the extent of resection, MRI brain is acquired within 48 hours of surgery. Scans performed after this period may exhibit postoperative enhancement and cannot be reliably interpreted. The significance of residual tumor depends upon tumor histology. Regardless of tumor type, long-term follow-up is required for all patients with pineal region tumors to monitor for recurrence.

Lifelong follow-up of children with pineal region tumors is required. These tumors can recur locally or can appear distally long after diagnosis. In addition, patients can present later in life with new tumor formation (eg, meningioma).

MRI scans should be obtained on a periodic basis as determined by tumor histology of the original diagnosis, the extent of resection, and the presence of metastasis at the time of diagnosis.

Tumor marker studies for patients with GCTs should also be performed on a periodic basis, even if markers were not abnormal at the time of diagnosis.

The most common complications following pineal region surgery include extraocular movement dysfunction, ataxia, and altered mental status.[102] Many such neurologic findings are transient, with eventual significant improvement or complete resolution. Factors contributing to increased incidence of surgical complications include prior radiation treatment, severe preoperative neurologic deficit, malignant tumor pathology, and invasive tumor characteristics.

The most devastating complication of pineal region tumor surgery is postoperative hemorrhage into a subtotally resected tumor bed. Hemorrhage may be delayed for several days and is most commonly associated with vascular tumors such as pineal cell tumors. Venous infarction, with or without hemorrhage, is another grave complication. Less-common postoperative complications include shunt malfunction, hemorrhage during ETV and aseptic meningitis. In addition, supratentorial approaches can result in seizures, hemianopsia, or hemiparesis.

A 2022 study by Shepard et al reported outcomes of 68 patients following resection of pineal tumors.[103] Almost half the patients (45.6%) experienced at least one adverse outcome within 30 days after surgery. These included worsening hydrocephalus and focal motor deficits. Importantly, the mortality rate within 30 days of surgery was 5.9%, a stark contrast to the high mortality rates of a century prior.[35] Mortality was often due to intratumoral hemorrhage. Gross total resection, improved performance status, and low histopathologic grade were associated with improved survival.[103]

The prognosis for patients with pineal region tumors depends on 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 this tumor.

Children with NGGCTs have a significantly worse prognosis than do children with germinomas, pineocytoma,s or pineoblastomas. There is no standard of care 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 GCTs have been shown to respond to chemotherapy, as have some pineocytomas and pineoblastomas, although to a lesser degree. Radiosurgery may be a consideration for all recurrences measuring less than 3 cm in diameter.