2.5 Pineal physiology and pathophysiology, including pineal tumours

The pineal gland is innervated mainly by sympathetic nerve fibres that inform the gland of the prevailing light-dark cycle and acts as a neuroendocrine transducer. The gland is located behind the third ventricle in the centre of the brain and is a highly vascular organ formed by neuroglial cells and parenchymal cells or pinealocytes. The latter synthesize melatonin as well as other indoleamines and peptides.

The main pineal hormone melatonin (N-acetyl-5-methoxytryp-tamine) exhibits an endogenous circadian rhythm, reflecting signals originating in the suprachiasmatic nucleus; environmental lighting entrains the rhythm, by altering its timing. Independently of sleep, pineal melatonin is inhibited by light and stimulated during darkness, thanks to the neural input by a multisynaptic pathway that connects the retina, through the suprachiasmatic nucleus of the hypothalamus, preganglionic neurons in the upper thoracic spinal cord and postganglionic sympathetic fibres from the superior cervical ganglia, with the pineal gland.

Melatonin deficiency may produce sleeping disorders, behavioural problems, or be associated with precocious or delayed puberty in children, while chronically elevated melatonin has been observed in some cases of hypogonadotropic hypogonadism (1, 2).

The main clinical problem related to the pineal gland is that of pineal tumours. They are rare, and 10 times more common in children than in adults and mainly derive from the three types of cell (3, 4) (Box 2.5.1).

Astrocytic tumours may affect children and adults of any age. Pylocytic astrocytomas usually present before the age of 20 years, with no sex predilection, while other types are more frequent in adults.

While parenchymal tumours secrete melatonin, they differ in their degree of malignancy, pineoblastomas (WHO grade IV, Table 2.5.1) being highly malignant, aggressive and of rapid growth (similar to other primitive neuroectodermal tumours such as neuroblastomas or medulloblastomas), while pinealocytomas are mostly benign (WHO grade I, Table 2.5.1). Histologically, pineocytomas characteristically present pineocytomatous rosettes, while pineoblastomas are populated by small, highly undifferentiated cells, often present with haemorrhagic or necrotic components, but rarely calcifications. However, most parenchymal tumours are either mixed or show intermediate differentiation (WHO grades II and III, Table 2.5.1).

Germ cell tumours, histologically and biologically homologous to gonadal germ cell neoplasms, will characteristically present positive markers for α-fetoprotein (AFP) and b-human chorionic gonadotrophin (b-hCG), with more (teratomas) or less differentiation (germinomas), as well as intermediate degrees (yolk sac tumours).

Very rarely, pineal region tumours may derive from meningothelial, mesenchymal, ependymal, choroid plexus elements and peripheral nerves, giving rise to gangliogliomas, melanocytic neoplasms, atypical teratoid/rhabdoid tumours, meningiomas, cavernous angiomas, haemangiopericytomas or neurinomas/neurofibromas, apart from lymphomas or metastases.

Clinical presentation of pineal tumours depends on age at onset and histology (7). Over 90% present with raised intracranial pressure, often with obstructive hydrocephalus; initial symptoms are frequently headache, nausea, vomiting, and decreased vision; 50–70% of patients refer visual signs such as diplopia, cranial nerve palsies, papilloedema, and ptosis or Parinaud’s syndrome (failure of upward gaze, pupillary dilatation and diminution of pupillary light reflex) due to pressure on the pretectal region. Compression on the brain, cerebellum, hypothalamus, and pituitary may cause paralysis of other cranial nerves, ataxia, diabetes insipidus, and hypopituitarism. Pineal tumours may interfere with puberty, due to either pressure of the tumour on the hypothalamic centres which govern gonadotrophin secretion, excessive melatonin secretion by pinealocyte tumours causing delayed puberty in adolescents, or reduction of the potential antigonadotropic effect of melatonin, which, together with b-hCG secretion by destructive germ cell tumours could explain precocious puberty in prepubertal children.

(8–11). The recent WHO classification of these tumours grade them from I to IV (Table 2.5.1) (3, 4). Pineocytomas (grade I) present more often in adults over the age of 25 years, without sex predilection, evolve slowly (interval between onset of symptoms and surgery may be of several years), do not invade contiguous tissue, or seed the cerebrospinal fluid (CSF). Nonspecific presenting manifestations reflect compression of neighbouring structures (tectal plate, aqueduct of Sylvius, cerebellum, brainstem, hypothalamus, pituitary) such as increased intracranial pressure, changes in mental status, neuro-ophthalmological, brain stem, and/or cerebellum dysfunction, hypopituitarism, and hyperprolactinaemia. Rarely intratumoral haemorrhage (pineal apoplexy) with subarachnoid extravasation may occur. Concurrent uveoretinitis in occasional patients with pineocytomas probably reflects the common photoreceptor activity of pineal and retinal cells. No metastases and a 5-year survival >90% have been reported.

Pineoblastomas (grade IV) typically appear before the age of 20 years, most often in young children, but there are reports in adults, with a slight male preponderance. Presenting symptoms of this least differentiated and most aggressive pineal parenchymal tumour are more rapidly progressive and of shorter duration (interval between initial symptoms and surgery may be less than a month). Median postsurgical survival varies from 24 to 30 months. They are locally invasive and prone to disseminate through the CSF, often fatal, but may be controlled in some cases by a multimodality combination of aggressive surgery, radiotherapy, and chemotherapy. The association of a pineoblastoma in a child with familial bilateral retinoblastoma (due to a germline retinoblastoma gene mutation) is known as a trilateral retinoblastoma, with a median survival of only 6 months. Intermediate grades II and III represent different degrees of differentiation and prognosis (Table 2.5.1).

These arise around the third ventricle, most commonly in the pineal region, but may also be seen in the suprasellar compartment; 5–10% of patients harbour both lesions. Ninety per cent appear under the age of 20 years and are more frequent in males than females (2.5:1), except suprasellar lesions, which are more common in females. An increased risk of intracranial germ cell tumours has been associated with Klinefelter’s syndrome, Down’s syndrome, and neurofibromatosis type 1 (12, 13).

Pineal meningiomas, gangliogliomas, ependymomas, lipomas and pineal metastases, most frequently of breast or lung origin, may occur, often with other brain metastases; symptoms and signs reflect the extent of the disease (14, 15).

An appropriate tissue specimen for accurate histological diagnosis and determining tumour type is critical to optimize subsequent management. Serum AFP (synthesized mainly by yolk sac tumours, and teratomas) and b-hCG (in choriocarcinomas or germinomas) concentrations are of diagnostic utility if markedly elevated in serum and/or cerebrospinal fluid (CSF). Measurement of these markers in CSF for initial staging, and if positive, for follow-up are useful. CSF cytological examination should be delayed at least 2 weeks after surgery to increase the chance of reflecting true dissemination of viable tumour rather than postoperative tumour spillage. If these markers are clearly raised, histological verification may not be required.

Biopsies may be obtained by classic surgical routes (posterior interhemispheric transcallosal, suboccipital transtentorial, and infratentorial-supracerebellar routes) or by microsurgical techniques, with significantly reduced perioperative mortality rates (<2%). A neuroendoscopic or stereotactic biopsy is reasonably safe and well tolerated (7, 16) in experimented hands, but the diagnosis of mixed or intermediate tumours may be difficult without extensive tissue sampling. In any case, operative risk should be balanced with the risk of not obtaining an accurate histological diagnosis, with prognostic implications. In cases of nondiagnostic or equivocal biopsies or indicative of a benign tumour (mature teratoma, meningioma), surgery is recommended.

An MRI will disclose the size and extension of the tumour and possible metastases, but cannot accurately identify the histological nature, which relies on biopsy or serum/CSF tumour markers. In the more malignant tumours (pineoblastomas, germinomas, teratomas) the spine as well as the brain should be imaged, since spread into the subarachnoid space and the spine is frequent.

Neuroimaging of astrocytic tumours can vary; MRI usually shows hypodensity on T₁-weighted images and hyperintensity on T₂-weighted images; gadolinium enhancement is uncommon, except if active tumour progression occurs. Among parenchymal tumours, pineocytomas appear as noninvasive, solid masses in the posterior third ventricular region, and tend to be smaller (<3 cm in general), rounder, hypodense, homogeneous masses with dispersed calcifications, particularly peripheral, which enhance heterogeneously or diffusely on CT and MRI, and present a lesser degree of hydrocephalus. Macrocystic presentation is rare but small cysts may be present. T₁-weighted images are hypointense while T₂ are hyperintense. Haemorrhage and necrosis are exceptional.

Pineoblastomas are larger, lobulated, homogeneous tumours, rarely calcified and present with a greater degree of hydrocephalus and local invasion of contiguous brain or leptomeninges; they may exhibit distant subarachnoid and extracranial metastases, more frequently in young females; they are hyperdense and enhance homogeneously on CT (Fig. 2.5.1), while on MRI they appear as hypointense to isointense on T₁-weighted images and enhance diffusely or heterogeneously with contrast (Fig. 2.5.2, Fig. 2.5.3, and Fig. 2.5.4). Haemorrhage and necrosis are common (Fig. 2.5.5).

Germ cell tumours (except teratomas) appear as solid masses on MRI, iso- or hyperdense, and enhance after contrast (Fig. 2.5.6 and Fig. 2.5.7); small nodular calcifications may be seen on CT-scans. Teratomas tend to contain intratumoral cysts next to calcifications and low attenuation signals, typical of fat. Haemorrhages are common in choriocarcinomas and mixed neoplasms.

Surgery, chemotherapy and radiation are used in the treatment of pineal region tumours. Surgery, either open, stereotactic or endoscopic, is used to obtain a biopsy, mandatory in the majority of cases to obtain a definite histological diagnosis (7). Morbidity and cure rates have improved over the past years thanks to a greater understanding of the nature of the different tumours, more accurate neurosurgical experience, selective use of chemotherapy, and the introduction of modern irradiation techniques. However, because of the rarity of pineal tumours, it is difficult to conduct large, prospective, multicentre international studies to define their optimal management.

Treatment depends on histology obtained after surgery, which apart from the biopsy can resolve intracranial hypertension with a ventricular shunt (atrial or peritoneal) and perform partial debulking of the tumour if possible; total resection is rarely possible (Table 2.5.2).

Treatment for astroglial-derived malignant gliomas is local radiotherapy to the tumor (54 Gy), either conventional or stereotaxic, while surgery may be curative for the more benign pylocytic astrocytomas.

Pineocytomas only require local radiotherapy to the tumor (54 Gy). In pinealoblastomas, a high probability of spinal seedlings should lead to craniospinal radiotherapy, since they are radiosensitive (25–30 Gy on the neuroaxis with a pineal boost of 40 Gy aimed at more effective local disease control). However, routine craniospinal irradiation has been questioned and may not be necessary in patients with negative staging. Stereotaxic radiosurgery may control local progression and minimize damage to the surrounding brain, which is especially important in prepubertal patients, in whom total brain irradiation is associated with neurocognitive dysfunction, endocrinopathy, second malignancies, vascular complications, and spinal growth impairment. However, it may be associated with a high risk of marginal recurrence and distant metastases, and is not considered the treatment of choice for infiltrative but curable tumours. Furthermore, complications such as ataxic gait and gaze palsy have been reported after radiosurgery, In young children chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine, which alone is not curative, may allow a lower dose of radiotherapy to have similar effects. In older children with pineoblastoma, craniospinal irradiation is followed by chemotherapy (even though its role on final outcome is not fully defined). Autologous haematopoietic stem cell-supported high-dose chemotherapy is currently being investigated with some initial promising results, although experience is limited (17).

In mixed or intermediate pineal parenchymal cells (grade II or III, Table 2.5.1), apart from local radiotherapy, craniospinal irradiation and chemotherapy should be considered with increasing number of mitoses and less differentiation (7–11).

Surgery is not considered curative in germinomas, which are radiosensitive and should therefore receive local radiotherapy (7, 12, 13). Unless firmly confident of negative staging (by negative tumour markers—AFP and b-hCG—in blood and CSF, and negative MRI), craniospinal radiotherapy should be offered given the high probability of spinal seedlings. Germinomas are also highly chemosensitive, and excellent responses to postoperative cisplatin and cyclophosphamide have been reported. Survival is high (>90% at 5 years) in patients with localized pure germinomas, using either chemotherapy or focal radiotherapy or craniospinal irradiation, while focal irradiation alone has a worse outcome. In metastatic germinomas, craniospinal irradiation is the treatment of choice (25–35 Gy to the spine and a local pineal boost of 40 Gy). Lower irradiation doses are currently being considered, especially if adjuvant chemotherapy is offered (12). Bifocal lesions in the pineal and hypothalamus should be considered localized germinomas rather than metastatic disease, and receive irradiation to both locations.

Other germ cell tumours are less radiosensitive than germinomas, with a poor survival after radiotherapy alone (median survival of under 2 years) and require multimodality treatment (12, 13). Surgical resection after tumour reduction with initial chemotherapy with cisplatin, etoposide, and isofosfamide is a modern alternative. Tumour markers are useful for follow-up. Combining chemotherapy with radiotherapy (local up to 54 Gy or craniospinal up to 36 Gy) may increase long-term survival to 80%.

Surgery is the treatment of choice of pineal meningiomas and other localized pineal tumours if possible; alternatively localized stereotactic radiosurgery may be offered with good long-term prognosis (7).

Masses in the pineal region are most commonly non-neoplastic cysts, incidentally discovered at autopsy or on a radiographic work-up for symptoms not reasonably attributed to the cyst. Very rarely they act as a mass lesion and produce signs of increased intracranial pressure, by compressing the aqueduct (obstructive hydrocephalus) or tectal plate (Parinaud’s syndrome). On MRI they appear as a 1–3 cm mass, equally or slightly more dense than CSF in T1-weighted image studies and which brightly enhance in T2-weighted images, reflecting their fluid nature; evidence of haemorrhage and peripheral calcification may be found. If asymptomatic, pineal cysts do not generally require treatment; if large enough to increase intracranial pressure, resection may be necessary, with an excellent long-term outcome (7).