Practice Essentials
Anatomy and pathophysiology
The pineal gland develops during the second month of gestation as a diverticulum in the diencephalic roof of the third ventricle. It is flanked by the posterior and habenular commissures in the rostral portion of the midbrain directly below the splenium of the corpus callosum. The velum interpositum is found rostral and dorsal to the pineal gland and contains the internal cerebral veins, which join to form the vein of Galen. [1]
In their 1954 pineal tumor study, Ringertz and colleagues defined the pineal region as bound by the splenium of the corpus callosum and the tela choroidea dorsally, the quadrigeminal plate and the midbrain tectum ventrally, the posterior aspect of the third ventricle rostrally, and the cerebellar vermis caudally. [2] Important anatomic considerations include the presence of deep venous structures.
The pineal gland is richly innervated with sympathetic noradrenergic input from a pathway that originates in the retina and courses through the suprachiasmatic nucleus of the hypothalamus and the superior cervical ganglion. Upon stimulation, the pineal gland converts sympathetic input into hormonal output by producing melatonin, which has regulatory effects upon hormones such as luteinizing hormone and follicle-stimulating hormone. [1]
The pineal gland is a neuroendocrine transducer that synchronizes hormonal release with phases of the light-dark cycle by means of its sympathetic input. However, the exact relationship between the pineal gland and human circadian rhythm remains unclear and is an area of active investigation.
Pineal region tumors are derived from cells located in and around the pineal gland. The principal cell of the pineal gland is the pineal parenchymal cell, or the pinocyte. This cell is a specialized neuron related to retinal rods and cones. The pinocyte is surrounded by a stroma of fibrillary astrocytes, which interact with adjoining blood vessels to form part of the blood-pial barrier.
The pathophysiology of pineal region tumors is mostly the result of anatomic compression of adjacent structures, although local infiltration of neural structures can lead to symptoms in cases of highly invasive tumor. In some cases, neuroendocrine dysfunction is precipitated by specific factors secreted by the tumor. [3, 4]
Types and grades
Pineal tumors can be one or a mix of several different types. They can be slow growing or fast growing. The World Health Organization (WHO) has a grading system for brain tumors. They are grouped as grade I, II, III, or IV. Grade I is the slowest growing. Grade IV is the most aggressive and grows and spreads faster. Tumors of the pineal gland may be one of the following types [5, 6, 7, 8] :
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Pineocytomas are slow-growing (grade I or II) tumors that usually appear between ages 20 and 64, but they can appear at any age. People with pineocytomas tend to have a good outcome.
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Pineal parenchymal tumors are intermediate-grade (grade II or III) tumors. Pineal parenchymal tumors and papillary pineal tumors may occur at any age.
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Papillary pineal tumors are intermediate-grade (grade II or III) tumors.
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Pineoblastomas are very rare, aggressive, and fast-growing (grade IV) tumors. They are almost always cancerous. These tumors most often affect people younger than 20 years.
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Mixed pineal tumors are a combination of slow- and fast-growing cell types.
Signs and symptoms
Pineal tumors are not always cancerous, but they do cause problems as they grow because they press against other parts of the brain and can block the normal flow of cerebrospinal fluid (CSF), raising intracranial pressure (ICP) inside the skull. Researchers do not know the cause of pineal tumors. Genes and environment may play a role. [5]
Tumors of the pineal region have varied histology that generally can be divided into germ cell and non–germ cell derivatives. Most tumors are the result of displaced embryonic tissue, malignant transformation of pineal parenchymal cells, or transformation of surrounding astroglia. [9, 10] No specific genetic mutations have been associated with sporadic pineal region tumors.
Fast-growing tumors may cause worse symptoms. Common signs and symptoms of a pineal tumor include headache, nausea and vomiting, vision changes, trouble with eye movements, tiredness, memory problems, and balance or coordination problems. [5]
(Pineal tumors are shown below.)
Gadolinium-enhanced MRI of a 33-year-old woman who presented with visual loss, amenorrhea, and diabetes insipidus. MRI shows germinomatous invasion of the pineal gland (large arrowhead), optic chiasm (long arrow), pituitary stalk (small arrowhead), and the floor of the third ventricle (short arrow).
Noncontrast MRI of a pineocytoma in a 40-year-old man presenting with acute hydrocephalus. At surgery, the high signal area (arrow) turned out to be acute hemorrhage.
MRI of a 21-year-old man with a germinoma in the pineal region. This T1-weighted noncontrast sagittal scan shows isointense tumor, which has obstructed the aqueduct of Sylvius (arrow) to cause hydrocephalus.
Indications for neurosurgical intervention relate to the severity and the chronicity of clinical presentation. Symptoms of pineal region tumors can be as varied as their diverse histology. Prodromal periods can last from weeks to years. Therefore, a rigorous and uniform preoperative workup is a requisite for all patients thought to harbor a pineal region tumor.
Endocrine abnormalities should be investigated prior to surgery. Patients presenting with signs and symptoms of raised ICP must undergo head computed tomography (CT) scanning or magnetic resonance imaging (MRI) to assess the need for emergent management. Subsequent nonemergent workup of a patient with a pineal region tumor can be divided into radiologic and laboratory studies. [11, 12, 13]
Management
Initial management of patients with pineal region tumors should be directed at treating hydrocephalus and establishing a diagnosis. Preoperative evaluation should include (1) high-resolution MRI of the head with gadolinium; (2) measurement of serum and CSF markers, if available; (3) cytologic examination of CSF, if available; (4) evaluation of pituitary function, if endocrine abnormalities are suspected; and (5) visual field examination, if suprasellar extension of the tumor is noted on MRI. The ultimate management goal should be to refine adjuvant therapy based on tumor pathology. [11, 12, 13]
Relatively few contraindications specifically preclude surgical treatment of pineal region tumors. Medical clearance for general anesthesia is a requisite, as is preoperative evaluation of neck motion (ie, tolerance of flexion) before a supracerebellar/infratentorial approach is planned.
Treatment includes radiation, chemotherapy, and surgery. [14, 15, 16, 17, 18]
History of the Procedure
In the early part of the 20th century, pineal region surgery had poor outcomes, with operative mortality approaching 90%. From Horsley's initial attempt at removing a pineal mass in 1910 through development of the lateral transventricular approach in 1931 by Van Wagenan, primitive anesthetic technique and lack of an operating microscope hindered pineal region surgery. [19]
In 1948, Torkildsen argued for abandoning aggressive surgical resection in favor of CSF diversion followed by empiric radiotherapy. [20] If the patient did not respond to radiation, a surgical procedure to remove radioresistant tumor was performed. The algorithm of CSF diversion, radiation, and observation sometimes was successful; however, patients with benign lesions were exposed to unnecessary and ineffective radiation.
Modification of this treatment strategy led to the radiation test heralded by Japanese clinicians whose patient population consisted of an inordinately high percentage of radiosensitive germinomas. According to this protocol, patients were administered small doses of radiation and were followed radiologically. Pineal tumors that decreased in size were presumed to be radiosensitive, and a full course of radiation was instituted. Patients not responding to radiotherapy underwent surgical exploration. Despite the low dose of radiation initially used, significant long-term morbidity remained associated with this strategy, particularly in children.
The advent of microsurgical techniques and stereotactic procedures in the latter part of the 20th century obviated the need for empiric radiotherapy without tissue diagnosis. Therapeutic decision-making now is based on tumor histology rather than on radiation responsiveness. Currently, initial surgical management for tissue diagnosis and possible resection is the standard of care for most children with pineal region tumors. [21]
Epidemiology
Tumors of the pineal area are rare and account for only 1% of intracranial tumors in adults, but they do account for up to 8% of the intracranial tumors in children. However, because of the number of different types of of tumors in the pineal area, incidence and prevalence vary greatly. For example, pineocytomas mostly occur in adults aged 20-60 years, and papillary tumors of the pineal area can be seen in individuals between 1 and 70 years. Pioneoblastoma is the most aggressive of the pineal parenchymal tumors and is typically seen in young children. Germinomas account for up to 50% of pineal parenchymal tumors and are more common in males aged 20 years or younger. [6, 8, 1]
Prognosis
The relative 5-year survival rate for pineal region tumors in 2021 was 69.5%, but many factors can affect prognosis. These include tumor grade and type, cancer traits, patient age and health at the time of diagnosis, and patient response to treatment. [22]
Vuong and coworkers reported on prognostic factors and survival trends for pineal gland tumors and found that chemotherapy adversely affected patient outcomes and should be considered carefully in specific circumstances to avoid its harmful effects. Younger age at diagnosis, female gender, germ cell tumor histology, and no chemotherapy use were indicators for an improved prognosis. Advances in serology, imaging, and pathology enable earlier and more accurate diagnosis and tumor staging, while improvements in surgical techniques, radiation, and chemotherapy are key changes leading to more effective treatment and management of patients. [23]
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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.
