Article Title: Pineal Gland Anatomy and Tumors

Author: Almutazballlah Qablan.

Editor: Aseel Rabadi , Dr Omar Jbarah 

Keywords: Pineal gland, Pineal tumor, Pineocytoma, Pineal parenchymal tumor with intermediate differentiation, Pineoblastoma, Papillary tumor of the pineal region, Pineal germinoma, Choriocarcinoma, Teratoma.

1. Introduction

The pineal gland is a tiny gland in the brain. It secretes melatonin; a hormone that affects sleep-wake cycles¹. During the second month of gestation, the pineal gland appears as a cellular evagination of undifferentiated cells with a little amount of cytoplasm. Subsequently, it undergoes remarkable cellular differentiation, leading to the appearance of the adult gland by the end of the first year of life². Histologically, human pineal gland parenchyma is composed mainly of pinealocytes with a few neuroglial supporting cells and subdivided into lobules by a highly vascularized connective tissue stroma^1,3.

Pineal region tumors are rare, accounting for 1% of all the primary CNS tumors in adults, and up to 8% in children. Multiple pathologies are associated with this region because of the variety of cells in it, in addition to the various structures located adjacent to it ^3,13.

Pineal region tumors are classified into those arising from the pineal parenchyma, germ cell neoplasms, metastasis from other organs, and lesions arising from adjacent structures ³. Germ cell tumors make up the majority (about 35%), followed by pineal parenchymal tumors (about 28%) and neuroepithelial tumors, including astrocytomas (mostly pilocytic), ependymomas, and papillary tumors of the pineal region (about 28% combined) ⁴.

2. Pineal Gland Anatomy

The pineal gland is a small endocrine gland (10 to 14 mm) located in the midline of the brain, at the posterior wall of the third ventricle. In the coronal view, the gland is located below the splenium of the corpus callosum and above and posterior to the tectum of the midbrain ³.

The pineal gland lacks a blood-brain barrier and has a unique histopathologic appearance, with its parenchyma composed mainly of pineocytes and a few neuroglial supporting cells such as astrocytes. Pinealocytes, the principal cells in the gland, are specialized neurosecretory cells that produce the hormone melatonin and secrete it in a circadian rhythm⁵.  They also exhibit some neurosensory features as they receive information from the environment about the light-dark cycle to feedback the central nervous system⁶.

Anatomically, structures surrounding the pineal gland are the third ventricle (pineal recess) anteriorly, while the internal cerebral veins, the vein of Galen (posteriorly), stria medullaris, splenium of the corpus callosum, and velum interpositum makes the superior border. Habenular nuclei lie anterosuperiorly. Whereas, inferiorly, the superior colliculi of the midbrain fill the place and the posterior commissure is found anteroinferiorly. Also, the superior cerebellar cistern makes the posteroinferior border⁷, (see figure(1)).

Figure (1): Human pineal gland and its anatomical boundaries. The 3D rendering of the cadaver data is from Anatomage Table.

3. Pathophysiology, Etiology, and Surgical approach.

Multiple pathologies are associated with this region because of the variety of cells inside it and structures located adjacent to it. Another key point is those pineal region tumors are diverse in origin because of their proximity to multiple anatomical structures³.

Pineal region tumors are classified into those arising from the pineal parenchyma, germ cell tumors, metastasis from other organs, and lesions arising from adjacent structures³. Pineal parenchymal tumors in their turn are also classified into pineocytoma, pineoblastoma, pineal parenchymal tumor with intermediate differentiation, and lastly papillary tumors.³

Still, the pineal gland is a common locus for the sequestration of embryonic germ cells. Thus, germ cell tumors are among the most common pathologies found in this region¹¹. They usually occur sporadically¹². However, there was found to be an association with Klinefelter syndrome, Down syndrome, and Neurofibromatosis type 1 ^13,14. They’re on their behalf divided into germinomatous germ cell tumors like germinoma, nongerminomatous germ cell tumors like choriocarcinoma, yolk sac tumor, and finally teratomas.

3.1. Pineal Parenchymal Tumor

Pineal parenchymal tumors are rare neuroepithelial neoplasms, accounting for less than 1% of intracranial neoplasms and constituting 15% to 30% of pineal gland tumors^15,16. They originate from pineocytes or their precursors. The pineal parenchymal tumors have been recognized by the World Health Organization (WHO) in four distinct categories: pineocytomas, pineoblastomas, papillary pineal tumors, and pineal parenchymal tumors of intermediate differentiation ^3,15,17.

Most pineal parenchymal tumors occur in the pediatric age group with no sexual predominance ^17,16. They remain localized to the pineal region where they may compress adjacent structures including the cerebral aqueduct, brain stem, and cerebellum. So, the signs and symptoms vary and are related mostly to obstructive hydrocephalus, increased intracranial pressure with consequent headaches, nausea, vomiting, upward gaze palsy (Parinaud syndrome), changes in mental status, and ataxia. Pineal parenchymal cell tumors can also produce a hypomelatoninemic or hypermelatoninemic state ^13,17,18,19.

Alpha fetoprotein, beta-human chorionic gonadotropin, and placental alkaline phosphatase are three tumor markers that are found negative in pineal parenchymal tumors¹⁹. However, synaptophysin is expressed in pineal parenchymal tumors of intermediate differentiation, and neuronal marker positivity has no relationship to histological grade, mitosis, proliferation index, or prognosis²⁰.

Radiation is the standard treatment for pineal parenchymal tumors. But, another possible treatment option is surgery; however, it has a mortality rate of 5%–10% ¹⁹, and even after complete tumor removal, recurrence presents in many patients. Therefore, adjuvant radiation or chemotherapy, or both are often suggested with the aim of improving survival²¹.

3.1.1. Pineocytoma

Pineocytoma is a  slow-growing grade I/II pineal parenchymal tumor derived from the pineal epithelium. They are characterized by the well-differentiated mature cells that are arranged in sheets. They are circumscribed, unencapsulated tumors that mostly remain locally confined ^22,23.

Small pineocytomas often do not induce symptoms, but if they are large, they may induce obstructive hydrocephalus and Parinaud syndrome, defined as an upward gaze palsy, pupillary light-near dissociation, and convergence retraction nystagmus²².

They can be seen at any age but are more frequent in adults aged from 20 to 60 years of old¹⁶. Pineocytomas are more frequently seen in females. They account for 14-30% of pineal parenchymal tumors. The 5-year survival was 86%–91%, and there were no reported relapses after gross total resection. Recurrences are uncommon in these tumors ^3,16,24,25. Stereotactic radiosurgery has been set as a primary treatment for these tumors ²⁶.

As shown in figure (2), Pineocytomas appear as hyperintense, round or lobular masses on MRI ¹⁶.

Figure (2): Pineocytomas sagittal T1 C+. Case courtesy of Dr Elshan Abdullayev.

3.1.2. Pineoblastoma

Pineoblastoma is a highly malignant grade IV tumor¹⁹  that is an undifferentiated, embryonal tumor described as a primitive neuroectodermal lesion.  It accounts for 24-50% of all pineal parenchymal tumors. It is more frequently seen in females^10,23.

Pineoblastomas are unencapsulated tumors that may often recur and also spread throughout the craniospinal axis, as well as metastasize to other parts of the body, such as the skull, vertebrae, lungs, peritoneum, mandible, and pelvis^27,23.

Pineoblastomas are the most aggressive pineal parenchymal tumors and have a poor prognoses because of their frequent invasion to the adjacent structures and CSF dissemination, with reported five-year survival rates of <60% ¹⁷.

The highest incidence is in childhood, particularly in children who are less than 2 years of old, where pineoblastomas can occur in combination with retinoblastomas¹⁷. Patients with hereditary bilateral retinoblastoma are prone to suprasellar or pineal neuroblastic tumors, a condition called trilateral retinoblastoma is seen in up to 5% of the pineoblastomas cases ²⁸.

Synaptophysin and chromogranin are markers of primitive neuroendocrine tumors that can be expressed in pineoblastomas and can be detected in the serum or the CSF¹⁹. The molecular background of pineoblastoma remains unknown. However, recent studies have shown that the DICER1 and DROSHA genes, which are implicated in microRNA dysregulation, are fundamental to pineoblastoma carcinogenesis²⁹.

Aggressive surgical resection is the first-line therapy against pineoblastoma. It is worth mentioning that radiotherapy after resection helps to increase a patient’s survival. As it has also been reported in other pineal gland tumors, combination therapy appears to be an effective approach ²⁷.

3.1.3. Pineal Parenchymal Tumor of Intermediate Differentiation

Pineal parenchymal tumors of intermediate differentiation are uncommon tumors arising from the pineal parenchyma that show common features between pineocytomas and pineoblastomas³⁰.

They can occur at all ages and more commonly appear in women, adolescents, and middle-aged patients³⁰. Pineal parenchymal tumors of intermediate differentiation are not often considered as a single disease, but rather as a spectrum of grade II and III pineal parenchymal tumors, which explains the huge variation in the behavior of these tumors^22,30.

Multiple cystic elements can also be observed. Pineal calcifications may be engulfed or peripherally displaced by the mass²². These tumors show positive expression for synaptophysin, neurofilament, chromogranin A, and renal S antigens²³.

Pineal parenchymal tumors of intermediate differentiation tended to present on MRI as isointense lesions on T1WI and hypointense masses on T2WI, with some cystic components, and a complete contrast enhancement³¹. Figure (3).

Figure (3): Pineal parenchymal tumors of intermediate differentiation (a) sagittal T1 (b) coronal T2.  Case courtesy of Assoc Prof Frank Gaillard.

No best treatment has been found for pineal parenchymal tumors of intermediate differentiation, partly due to the low numbers of reported cases. The maximal surgical removal of the tumor is the treatment of choice in practice for pineal parenchymal tumors of intermediate differentiation. However, even after complete surgical removal of the tumor, many patients experience recurrence. Hence, radiotherapy or other adjuvant chemotherapy, or a combination of both, is often recommended to improve patient survival^32,33.

3.1.4. Papillary tumor of the pineal region

These tumors were first described in 2003 by Jouvet et al³⁴, as a new tumor with distinct anatomic, histologic, and immunophenotypic features. Because of its rarity, a histological grading criterion has not yet been established, but most likely according to WHO they are considered as grade II or III neuroepithelial neoplasms^16,4.

Papillary tumors have the broadest range of ages among the pineal parenchymal tumors, which are seen from 1-70 years of age, with a mild female prevalence⁴.

The main symptom reported by patients with pineal papillary tumors is headache associated with obstructive hydrocephalus³⁵.

It is important to emphasize that pineal papillary tumors present with a wide morphological diversity. Apart from the distinct papillary structures, papillary tumors have morphological features in common with other papillary-like tumors that occur in the pineal region, including choroid plexus papillomas, papillary ependymomas, metastatic papillary carcinomas, papillary meningiomas, and germ cell tumors, which complicates the clinical diagnosis³⁶.

On MRI, pineal papillary tumors appear as partially cystic masses with obstructive hydrocephalus³⁵ as shown in figure (4).

Figure (4): Pineal papillary tumors appear in sagittal T1. Case courtesy of Dr Ali Alsmair.

Pineal papillary tumors often recur, and radiotherapy is often effective³⁷. Both radiotherapy and chemotherapy are used in the initial management of the tumor and in cases of recurrence after total resection; however, the optimal adjuvant therapy is still unknown. Stereotactic radiosurgery appears to be effective against pineal papillary tumors, but a high rate of local recurrence has also been observed after this treatment. Recurrence can be safely and successfully managed by repeating stereotactic radiosurgery²⁶.

3.2. Germ Cell Tumors

Germ cell tumors are derived from primitive germ cells that develop primarily in the gonads but also in the anterior mediastinum, pineal gland, and brain³⁸. Germ cell tumors represent 0.5-3.2% and 11.8% of primary intracranial tumors in adults and children, respectively. They are predominantly found in male patients and account for about 50% of intracranial germ cell tumors, appearing to be more common in the Asian population³⁹. Germ cell tumors can be classified into six types: germinomas, choriocarcinomas, teratomas, embryonal carcinomas, yolk sac tumors, and mixed germ cell tumors (characterized by the features of at least two of the above-cited tumor types)³⁹.

3.2.1 Germinoma

Germinomas are the most common type of pineal tumor, accounting for up to 50% of pineal tumors in Europe, the United States, and Japan^23,40. It is more common in males⁴⁰. Most cases were less than 20 years of age at the time of assessment.

Only 8% of CNS germinomas’ cases show the simultaneous involvement of pineal and suprasellar regions, and these are called bifocal germinomas^23,41. Germinomas are not encapsulated tumors and therefore may invade adjacent brain structures and, through the CSF, spread along the brain surface.

Germinomas are malignant tumors characterized by a mixture of large pluripotent primordial germ cells and smaller lymphocyte-like cells. However, they often show severe inflammatory infiltrates. With that being said, corticosteroid treatment appears to be able to modulate the patient’s immune defense, enabling the immune system to suppress the tumor^42,10.

On imaging, germinomas show heterogeneous features, often presenting as solid or solid-cystic masses with sunken calcifications, different from that in pineal parenchymal tumors, which show prominent calcifications^38,43. Figure (5).

Figure (5): Pineal germinomas. (a) sagittal T1 C+ fat sat. (b) axial T1 C+ fat sat.  Case courtesy of Dr Angel Donato.

Imaging alone does not allow us to distinguish germinomatous from nongerminomatous germ cell tumors and pineal parenchymal tumors. Therefore, a full evaluation is essential³⁸. In fact, germinomas are diagnosed using imaging along with serum and CSF markers. These tumors present with high expression in serum and CSF oncoproteins such as alpha-fetoprotein, beta-human chorionic gonadotropin, lactate dehydrogenase, and placental alkaline phosphatase³.

The treatment regimens used against germinomas include chemotherapy, radiotherapy, or a combination of both, resulting in a favorable prognosis and a five-year survival of at least 90% ¹⁶. Germinomas are radiosensitive tumors that respond well to specific chemotherapies⁴².  Furthermore, for germinoma, stereotactic radiosurgery appears to be effective in improving standard adjuvant treatment or in the case of recurrence²⁶.

3.2.2. Choriocarcinoma

Pineal choriocarcinomas are uncommon malignant nongerminomatous germ cell tumors (representing less than 5% of all pineal masses) ^44,45 being the most aggressive form of gestational trophoblastic diseases. Choriocarcinoma shows a poor survival rate with in relation to other germ cell tumors⁴⁵. The median survival rate for primary intracranial pure choriocarcinoma was 22 months, and the three- and five-year survival rate was 45.8%. Primary intracranial choriocarcinoma mainly affects young men (3–22 years of age), with precocious puberty ^4,46.

These tumors do not present with distinctive symptoms, but patients affected by choriocarcinoma mainly reported headaches, vomiting, nausea, visual impairment, polydipsia, polyuria, and endocrinologic alterations⁴⁵.

On imaging, choriocarcinomas show ovoid, heterogeneous, and slightly hyperdense masses⁴.

They are associated with elevated levels of both CSF and plasma human chorionic gonadotropin⁴⁷. Both Choriocarcinomas and germinomas are associated with elevated beta-human chorionic gonadotropin expression¹⁹.

Unfortunately, classic treatments often fail because choriocarcinomas are extremely resistant. The first clinical choice is complete resection (even if the patient does not present with hydrocephalus). However, for their treatment, a combination of complete tumor removal, chemotherapy and radiotherapy is often used and appears to show positive results⁴⁵.

3.2.3. Teratoma

Intracranial teratomas constitute up to 50% of fetal brain tumors. In neonates, they make up 33% of intracranial tumors, but only 2%–4% of intracranial tumors in patients aged <15 years⁴⁶. Intracranial teratomas usually arise from the pineal gland and involve the third ventricle⁴⁸. Pineal teratomas have a male predominance and a survival rate of 90-100% ^4,49.

Teratoma are tumors characterized by pluripotent cells of normal organogenesis, usually producing a tissue presenting a combination of two or more of the embryological layers of ectoderm, mesoderm, and endoderm ^16,47. Pineal teratomas can be partially or completely encapsulated but can be also unencapsulated and locally invasive⁴⁴.

On imaging, these pineal tumors show foci of fat, calcification, and cystic areas¹⁶. On MRI, teratomas appear as lobular, multiloculated, and heterogeneously wide masses¹⁶ as in Figure(6).

Figure (6): Pineal region teratoma. (a) coronal T1 C+. (b) axial T2. Case courtesy of Dr. Bruno Di Muzio.

Their definitive treatment is complete surgical resection. The occipital transtentorial approach is a safe, effective, and practical approach for surgical removal of these lesions without any major complications whatsoever ^32,49.

4. Clinical Presentation ¹⁰

Clinical presentation of all of the tumors of the pineal region are secondary to obstructive hydrocephalus and compression of the tectum as mentioned before. Thus, regardless of the pathological condition, the results of the physical examination will be similar for all of them.

Hydrocephalus causes a history of headache, nausea, blurry vision, sleepiness, drowsiness, failure to thrive, macrocephaly, or coma. On examination, we look for bilateral optic nerve swelling, bilateral sixth nerve palsy, and for Cushing’s triad. Cushing’s triad consists of bradycardia, irregular respirations, and hypertension.

On the other hand, compression of the tectum (Parinaud syndrome) causes a history of difficulty walking upstairs and diplopia. On examination we look for any compression of the vertical gaze center at the rostral interstitial nucleus of the medial longitudinal fasciculus which leads to paralysis of the upwards gaze and conjugate downward gaze, compression of the pretectal nucleus in the superior colliculus which leads to light-near dissociation, and for any damage to the supranuclear fibers of the third nerve at the posterior midbrain which leads to Convergence-retraction nystagmus and eyelid retraction (Collier sign).

5. Diagnosis

Serum tumor markers are indicated when certain tumors are suspected, including AFP, b-HCG, and placental alkaline phosphatase. While CSF analysis is indicated if there is no hydrocephalus or during endoscopy and it is useful for most tumors^10,48. (See figure (7)).

Figure (7): Cerebrospinal fluid (CSF) tumor markers. Contributed by Miguel Mayol Del Valle, MD.

Brain magnetic resonance imaging (MRI) with and without gadolinium enhancement is the gold standard for evaluating pineal region tumors. However, if MRI is not available, head-computed tomographic (CT) scan, angiography, and ultrasound (in infants) can be helpful¹⁰.

Brain MRI will show homogenous enhancement, except those which appear with heterogeneous cellularity. Dense tumors, such as pineoblastomas and germinomas, will have limited diffusion on the diffusion-weighted images. However, pineal cysts are non-enhancing and usually have a thin wall; therefore, a thick wall excludes a cyst^51,10.

Calcifications are often present and are easily identifiable on a head CT scan and can sometimes point into the correct direction of diagnosis. Pineal parenchymal tumors (e.g., pineocytomas or pineoblastomas) tend to disperse peripheral calcification, while germ cell tumors tend to engulf the calcifications. To keep this in mind, remember that pineoblastomas tend to blast the calcifications apart¹⁰.

Many tumors of the pineal region may seed locally or distally. Thus, a complete spinal MRI can be considered as part of the initial evaluation. Local invasion and remote seeding are important for prognosis and may alter the initial management and the adjuvant therapy¹⁰.

Findings that could indicate a worse prognosis include local invasion (mostly seen in pineoblastomas and germ cell tumors), CSF seeding (pineoblastomas seeds distally and germinomas seeds proximally), and extensive peritumor edema¹⁰.

6.   Treatment ¹⁰

Basically, the treatment depends mainly on the pathology and the age of the patient;

 

• Radiotherapy is mostly done for germinomas and is reserved for patients who are > 3 years old.
• Chemotherapy alone is given for patients who are less than 3 years of old.
• Chemotherapy plus radiotherapy are combined and given for all the non-germinomatous germ cell tumors and germinomatous germ cell tumors if the patient is less than 3 years old.
• Surgical resection is mainly used for pineal parenchymal tumors, mature teratomas, and residual tumors that did not recover after chemotherapy and radiotherapy. The surgical approach to the pineal region is selected based on the specific location of the pathology and the surgeon’s preference. They include:

1.     Paramedian infratentorial supracerebellar resection:⁵²

The most flexible approach is to remove most of the tumor in the pineal region. It is useful for all tumors of the pineal region, except for large tumors that extend laterally and inferiorly. A left-sided suboccipital craniotomy is performed to protect the torcula, right-side veins, and dural sinuses, including the transverse sinus.

2. Midline infratentorial supracerebellar resection: ⁵³

Performed by a bilateral midline suboccipital craniotomy. The limitations of this approach are the limited lateral or inferior visualization caused by the angle of the tentorium and the obstructive apex of the culmen, respectively. As a result, all midline bridging vermian veins are almost always sacrificed.

 

3.     Occipital transtentorial resection:⁵⁴

Performed through a unilateral occipital craniotomy and especially useful for large pineal region tumors that extend laterally and inferiorly. The limitations of this approach are; anatomic orientation difficulties, the need to divide the tentorium, and the possibility of homonymous hemianopia caused by the retraction of the occipital lobe.

In the end, it is necessary to screen the full neuroaxis with all pineal region tumors. Prognosis and treatment dramatically vary depending on the spread of the tumor into the CSF. Distant CSF seeding (except for germinomas), and drop metastasis have poor prognoses. MRI of the brain, cervical, thoracic, and lumbar spine with and without contrast are required for proper neuroaxis screening. Spinal radiotherapy as a prophylactic treatment is debatable.

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