Practice Essentials
The pineal gland is a pinecone-shaped neuroendocrine gland whose main purpose is to produce melatonin and release it into the blood. [1] Tumors of the pineal region are uncommon. They predominantly occur during childhood, representing 3-11% of all pediatric brain tumors, while representing less than 1% of adult brain tumors. [2, 3]
The pineal region is one of the most complex neoplastic areas in the brain, both anatomically and pathologically. Due to the variety of cell types in the pineal region (pinealocytes, endothelial cells, nerve endings from sympathetic innervation, glial cells, and ependymal cells), numerous different neoplasms are found there. Pineal neoplasms are typically classified as germ cell tumors (GCTs), pineal parenchymal cell tumors, tumors from adjacent structures, and other miscellaneous tumors and cysts. [4, 5, 6, 7] :
Signs and symptoms
Pineal tumors may cause a mass effect on other parts of the brain and can block the normal flow of cerebrospinal fluid (CSF), raising intracranial pressure (ICP). Common signs and symptoms of a pineal tumor include headache, nausea and vomiting, vision changes, trouble with eye movements, tiredness, memory problems, and balance or coordination problems. [8] Patients presenting with signs and symptoms suggesting raised ICP must undergo head computed tomography (CT) scanning or magnetic resonance imaging (MRI) to assess the need for emergent management.
Clinical manifestations of pineal region tumors can be as varied as their diverse histology. Prodromal periods can last from weeks to years. Therefore, a rigorous and uniform preoperative workup is requisite for all patients thought to harbor a pineal region tumor. Endocrine abnormalities should be investigated prior to surgery. See the image below.
Gadolinium-enhanced MRI of a 33-year-old woman who presented with visual loss, amenorrhea, and diabetes insipidus. MRI shows germinomatous invasion of the pineal gland (large arrowhead), optic chiasm (long arrow), pituitary stalk (small arrowhead), and the floor of the third ventricle (short arrow).
Management
Initial management of patients with pineal-region tumors should be directed at managing hydrocephalus and establishing a diagnosis. Evaluation should include the following:
- High-resolution MRI of the head with gadolinium contrast
- Measurement of serum and CSF markers
- Cytologic examination of CSF, if available
- Evaluation of pituitary function, if endocrine abnormalities are suspected
- Visual field examination, if suprasellar extension of the tumor is noted on MRI
- Surgical biopsy, if needed to establish a diagnosis.
Management of hydrocephalus, if present, should be prioritized and treated with CSF diversion via endoscopic third ventriculostomy (ETV). After acute management and diagnosis, treatment depends on tumor type.
MRI is necessary for evaluating tumors of the pineal region. MRI allows for evaluation of tumor characteristics, vascularity, relationship to surrounding structures as well as the presence of CSF obstruction. [9] Although tumor type cannot be reliably determined by MRI alone, some tumor types have characteristic features (see Table 1, below). [7, 10]
Following imaging, CSF should be collected and cytologically examined. CSF and serum should be measured for tumor markers. Increased levels of alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (beta-hCG) are pathognomonic for certain GCTs, [11, 12] so significant increases in either of those markers obviates tissue diagnosis and surgery (see Table 2, below). [11, 12, 4, 13] In this circumstance, chemotherapy and radiation can be started immediately. [13, 4] These markers may also be used for monitoring response to therapy. [14]
In the absence of AFP and beta-hCG, tissue diagnosis is necessary. [15, 16] Currently, there are no accepted diagnostic markers in serum or CSF for pineal parenchymal tumors. [4]
Treatment of GCTs may include some combination of surgery, chemotherapy, and radiation (see the algorithm below). Germinomas are among the most radiosensitive tumors, and they can be treated with radiation alone or the combination of radiation and chemotherapy. Non-germinomatous germ cell tumors (NGGCTs)—specifically, embryonal carcinomas, yolk sac tumors, and choriocarcinomas—are more aggressive. For these tumors, chemotherapy and extensive craniospinal irradiation (CSI) is required. Similarly, immature teratomas receive CSI and chemotherapy, while mature teratomas may only require surgical resection if gross total resection is achieved. [17] Mixed GCTs should be treated according to their most malignant component. [18]
While GCTs are treated primarily with radiation and chemotherapy, pineal parenchymal tumors are treated with resection, chemotherapy, radiation, and potentially stereotactic radiosurgery (SRS). Pineocytomas are treated primarily with surgery. Subtotal resection of pineocytoma may be followed by postoperative radiation. [19] Pineoblastomas are highly aggressive tumors that requires surgical resection as well as combination CSI, tumor boost, and chemotherapy. [20]
For pineal parenchymal tumors of intermediate differentiation, treatment depends on the degree of invasion. [21] Locally limited disease is treated with surgical resection alone. Locally invasive or disseminated disease is treated with resection, CSI and chemotherapy. [22]
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]
Anatomy and Physiology
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]
Pathophysiology
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] :
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Pineocytomas – Slow-growing grade I/II tumors derived from the pineal epithelium; usually occur in persons age 20 to 64 years.
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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]
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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]
History of the Procedure
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]
Epidemiology
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.
Prognosis
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]
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Gadolinium-enhanced MRI of a 33-year-old woman who presented with visual loss, amenorrhea, and diabetes insipidus. MRI shows germinomatous invasion of the pineal gland (large arrowhead), optic chiasm (long arrow), pituitary stalk (small arrowhead), and the floor of the third ventricle (short arrow).
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Noncontrast MRI of a pineocytoma in a 40-year-old man presenting with acute hydrocephalus. At surgery, the high signal area (arrow) turned out to be acute hemorrhage.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T1-weighted noncontrast sagittal scan shows isointense tumor, which has obstructed the aqueduct of Sylvius (arrow) to cause hydrocephalus.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T2-weighted noncontrast axial scan shows the tumor as hyperintense to brain matter but hypointense to cerebrospinal fluid (CSF).
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MRI of a 21-year-old man with a germinoma in the pineal region. Homogenous gadolinium enhancement of the tumor is shown on this T1-weighted contrast-enhancing sagittal scan.
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Sagittal MRI of a heterogeneous mixed germ cell tumor of the pineal region in a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma.
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Gross tissue specimens were obtained from a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma. Gross tissue specimens reflect heterogeneity of various germ cell components.
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T1-weighted contrast-enhancing sagittal MRI from a 41-year-old man with a pineocytoma. The tumor enhances homogeneously with gadolinium, except for a cystic portion.
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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.
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This micrograph shows osteoid bone with surrounding periosteal tissue and mesenchymal stroma occurring within a mature teratoma of the pineal region.
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This micrograph features cartilaginous tissue observed within a mature teratoma of the pineal region.
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Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.
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Endodermal sinus tumor with a characteristic Schiller-Duval body.
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Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.
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Pineocytoma consisting of benign, well-differentiated cells forming rosettes.
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MRI of a 44-year-old woman 10 years after resection of a mixed pineal cell tumor. The tumor has recurred in the pineal region (arrow) and has seeded the fourth ventricle (arrowheads).
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The right side of this image shows 3 operative approaches to the pineal region. Appropriate patient positioning for each approach is on the left. Number 1 is the supracerebellar-infratentorial approach, number 2 is the occipital-transtentorial approach, and number 3 is the parietal-interhemispheric approach.
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The left drawing is a sagittal view of a patient with a pineal region tumor. The right drawing shows a sagittal view of the supracerebellar/infratentorial approach to the pineal region.
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Biopsy specimen from an intracranial germ cell tumor. arge tumor cells with large nuclei; prominent nucleoli; and abundant, clear cytoplasm (rich in glycogen) are noted among reactive inflammatory cells.
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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.].
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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.].
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Demographics and imaging findings of pineal tumors.
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Markers of pineal tumors.
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Management of pineal tumor.
