Treatment of pineal region tumours: a review

ABSTRACT
Pineal region tumours affect children and adults and belong to numerous and various entities. The tumour site is relatively easy to localise nowadays with modern imaging techniques. However histopathological diagnosis remains difficult: it depends on well-defined criteria for each entity. Three histological groups are usually recognised according to the WHO classification for pineal parenchymal tumours (PPT): pineocytoma, pineoblastoma and PPT with intermediate differentiation. We have proposed a new classification with 4 histopathological grades correlated to survival. The treatment for each tumour type is different. Germ cell tumours are treated with chemotherapy and irradiation of the ventricular system, leading to an average complete remission rate of 90 % for pure germinoma. Mixed germ cells tumours, with or without tumour marker secretion, are treated initially with chemotherapy (carboplatin, VP 16 and Ifosfamide), and followed by surgery of a possible tumour remnant and focal irradiation. Treatment of other entities depends above all on surgery which can lead to significant tumour specimens for histopathological examination and complete resection in many cases. This treatment allows complete remission of benign cystic tumours and pineocytomas. For PPT with intermediate differentiation (PPTint), radiotherapy should be added to surgery but prognosis remains uncertain. For pineoblastomas, a combination of surgery, radiotherapy and chemotherapy is mandatory. Long-term follow up is useful for the detection of neurocognitive deficit, and of early (germ cell tumours) or late recurrences (PPT).

Keywords: pineal region tumour, germ cell tumour, primitive parenchymal pineal tumour, radiotherapy, chemotherapy, brain tumour.

Introduction
Pineal tumours are rare. They are mainly made up of three groups: pineal parenchymal tumours (PPT), glial tumours, and germ cell tumours. The classification according to histoprognosis remains difficult especially for PPT [1, 2]. The present review is based on the French national register for pineal region tumours, and on foreign cases resulting from international collaboration. In all, 452 cases were included from 1972 to 2006 (14% do not belong to the French register).

I - The pineal gland: anatomy, histology, physiology
The pineal gland is a small median organ. The pine cone shape explains its name and synonym (conarium).  Its dimensions are as follows: 6 to 8 mm long, 4 to 5 mm wide, and 2 to 3 mm thick. It weighs 0.15 to 0.20 g. As early as childhood, the pineal gland becomes cystic and calcified, making it a radiographic landmark.
The pineal gland is deep-seated in the brain at the junction of the diencephalon and the mesencephalon, in the posterior part of the third ventricle roof, just above the tectum of the mid brain, resting on the superior colliculi (anterior quadrigemina tuberculi) which create a groove under the corpus callosum, and it is covered by the velum interpositum. The posterior extremity of the third ventricle forms a small recess which extends into the pineal gland stalk made up of two laminae. The superior laminae separates into two peduncles (stria pinealis) which extend along the optic thalamus.
The pineal gland consists of a capsule, a glandular parenchyma, vessels and nerves. The conjunctive capsule expands within the gland creating the lobular aspect of the pineal parenchyma which combines pinealocytes and interstitial glial cells. The pinealocytes have a rounded or indented nucleus, with a small nucleolus and a stippled chromatin. The finely granular cytoplasm has club shaped extensions in contact with vessels. The ultrastructure of the pinealocyte shows vestigial organelles which recall the photoreceptor differentiation of the gland during phylogenesis.
The pineal gland receives afferent nervous fiber tracts coming from the superior cervical sympathic ganglia [3]. The pinealocytes synthetise melatonin under adrenergic control. Melatonin secretion has a circadian rhythm depending on the suprachiasmatic nuclei stimulated by the light intensity received by the eyes [4, 5].

II - – Tumours and pseudo tumours of the pineal region
Cysts of the pineal gland
During systematic post-mortem studies, glial cysts can be discovered, especially in aged patient, within the gland where they are often calcified. They are in fact pseudo-cysts which result either from a degenerative process of the parenchyma, or from pineal recess diverticulum sequestration.
Young adults, mainly women [6-12], may present oval or round cysts (1 to 3 cm diameter size). Sometimes no signs or symptoms exist: cysts are therefore diagnosed during NMR imaging for other causes. Cysts may also lead to compression of the aqueduct of Sylvius or of the midbrain tectum and become clinically obvious. Pineal apoplexy (haemorrhagic pineal mass)may be linked to clinically silent cysts or lead to cyst development [13].
On histopathology a cyst appears as mucoïd material inside a lining consisting of three layers. The intern gliotic layer is a piloïd gliosis which contains Rosenthal fibers and hemosiderin pigment, witness to old haemorrhages. This glial layer is surrounded by the compressed pineal parenchyma which often contains calcifications. The external layer is fibrous and reaches a sclerous and hypertrophied arachnoïd. When a a cyst is present, the lobular structure of the pineal gland is subjected to distorsions and is therefore rarely preserved. On small biopsy specimen, these cysts may lead to a complex differential diagnosis with either a pilocytic astrocytoma or a true PPT. Precise diagnosis is highly valuable to avoid undue radiation treatment. Immunochemical staining may help the diagnosis (table 1). The three-layered architecture of the cysts can be demonstrated immunohistochemically which also helps to distinguish between cysts and tumours.

Pineal parenchymal tumours
They represent less than a third of pineal region tumours. Their classification has been the subject of many controversies. The 2000 WHO classification [2] divides PPT into well differentiated pineocytoma (PC), WHO grade II tumours, into poor differentiated pineoblastoma (PB), WHO grade IV and into mixed PC-PB or PPT with intermediate differentiation (PPT int) without any defined grade. PC represents 30-60% of all pineal tumour cases in the main published series. We have defined a new classification in 4 grades based on a morphological and clinical study of a series of 66 PPT [1, 14]. The aim was to better define PC and PPT int grades and to clarify their treatment.

Pineocytoma
PCs are more frequent after 40 years of age and to be found equally in both sexes. PCs are non invasive tumours. They are well limited, firm, pinkish, non necrotic, sometimes haemorrhagic, tumours.
Two histological forms of PC are found: either typical PC or pleomorphic PC. The typical PC grows in diffuse layers which erase the lobular structure of the normal gland. The tumour cells form fibrillary pseudo rosettes of different size, sometimes confluent. The tumoural pinealocytes have relatively abundant cytoplasm, with an ovoïdal shape, and sometimes club shaped expansions, well seen after silver staining [15]. The cytoplasm is either eosinophilic or clear, and the nuclei round or indented. The interstitial tissue contains thin capillaries and hyalinised vessels [14, 16, and 17]. The pleomorphic form corresponds to a mixture of typical PC with large dystrophic cells centred by a hyperchromatic nucleus or with gangliocytic cells [15, 16, 18, and 19].
Both PC forms present neither mitosis, nor tumour necrosis. Tumour cells express strongly neuronal and neuroendocrine markers (neurofilaments, synaptophysin, chromogranin A) [14, 20]. Moreover these tumours may express neurosensorial markers (S antigen, rhodopsin) which recall the phylogenesis of the pineal gland [1, 21-24]. Sometimes serotonin and tryptophan hydroxylase, both implicated in the melatonin synthesis, may also be detected [25]. Data about the secretion and the release of melatonin by the tumour cells remain however controversial [5, 26]. Glial markers (GFAP, vimentin, S-100 protein) are found in the interstitial tissue (Table 1). The ultrastructure study of the tumour cells reveals characteristic pinealocytes organelles which confirm neurosensorial differentiation: vesicles crown rodlets which recall the photoreceptor synaptic ribbon, paired twisted filaments [27], and rare dense core vesicles.

Pineoblastoma
This embryonal, undifferentiated tumour presents analogies with medulloblastoma and other primitive neuroectodermal tumours (PNET). This tumour occurs during the first 2 decades of life with a greater incidence before the age of 10 years (mean age = 12.5 years with a 6 month to 36 year interval) and a slight preponderance in male patients [2]. Macroscopically, the tumour is often friable, and necrotic.  Histopathological study shows a monomorphic proliferation of small blue cells. These cells have a small cytoplasm around a rounded or carrot-shaped (in the pseudo-medulloblastic form) nucleus. The mitotic index is often high. The vessels may present endothelial hyperplasia, and necrosis areas are observed. Melanin pigments may be found in these tumours. Often either Homer-Wright type neuroblastic pseudo rosettes or the same Flexner-Wintersteiner rosettes as those seen in retinoblastoma are to be found [28-30]. It is interesting to note that pineoblastoma may be clinically associated to retinoblastoma leading to the peculiar trilateral retinoblastoma. PB is an undifferentiated tumour which expresses only slightly or focally neuronal or neuroendocrine markers (Table1). Tumour cell ultrastructural study shows rare organelles [14, 20, 31-33].

PPT with intermediate differenciation (PPT int.) and mixed PC/PB tumours
PPTs int. are found in the adult aged 20 to 40.  Its macroscopical aspect is almost the same as that of the PC. Different histological subtypes are described:

1. firstly a form highly lobulated by an endocrinoid  hyalinised vascular framework. This form is often erroneously upgraded as PB.
2. secondly a form with a diffuse architecture which may cause  differential diagnostic problems with oligodendrogliomas or neurocytomas.

Some PPTs int. have transitional aspects between PC and lobulated or diffuse PPT int [1].  The PPT s int. have cells with a relatively abundant cytoplasm, a round and regular nucleus, with stippled chromatin, and a more or less visible nucleolus. The number of mitoses and the expression of neuronal or neuroendocrine markers are variable (Table 1). Endothelial proliferation and necrosis foci may be observed.  Mixed PC/PB tumours are rare: they contain alternated typical PC and PB areas, the latter with necrosis foci and a high mitotic index.
The ultrastructure features are correlated with the level of differentiation of the PPT int. Some are rich in dense core vesicles and have a neuroendocrine differentiation. Other PPTs int., like pineocytomas, contain neurosensorial organelles [14, 33].

Toward a new classification
We have proposed a new histoprognostic classification based on the statistical correlation of patient survival with malignancy criteria (number of observed mitoses), neuronal, neuroendocrine, and/or neurosensorial (neurofilaments labelling) differentiation. Four prognosis grades are defined.
Grade I corresponds either to a typical pineocytoma or a pleomorphic PC with gangliocytic differentiation.
Grade IV corresponds to PB.
PPTs int. are divided in 2 grades : 1 - grade II tumours with less than 6 mitoses, and highly positive staining with anti-neurofilaments; 2 - grade III tumours for PPT int. with 6 or more mitoses, and those with less than 6 mitoses but without neurofilament immunostaining.
Mixed PC/PB are considered as grade III tumours.
The aim of this classification is to better define the prognosis of PPT s int. and of some PCs which are either under or overgraded.  Statistical analysis has demonstrated a significant difference in survival according to our new classification [1].

Glial tumours

Germ cell tumours
They represent less than 7% of the total of gonadal and extra gonadal tumours and 0.5 to 3.2 % of intracranial tumours of the adult, and 12% of those of childhood [45- 47]. Sixty five percent of intracranial germ cell tumours are located in the pineal region [48] where germinoma are the most frequent (30 to 50%). They are diagnosed before 20 years of age (with 65% between the age of 11 and 20). Pineal germ cell tumours appear essentially in boys before the age of 15 [49]. One of the most likely hypotheses is that these tumours may derive from gonadic totipotent germ cells. Their intracranial localisation can be explained by the aberrant migration of germ cells during embryogenesis. Residual cells may explain the origin of extragonadal germ cell tumours. The histopathological of these tumours is identical to gonadal germ cell tumours.
Germ cell tumours correspond to different embryonal or extraembryonal development stages. Germinoma, embryonal carcinoma, and teratoma correspond respectively to the malignant proliferation of the primitive germ cell, totipotent embryonal cells, and differentiated embryonal cells. Tumours of the yolk sac and choriocarcinoma may arise from extraembryonal cells.
Pure germinoma is also called « dysgerminoma » or « seminoma like pinealoma ». The latter term, based on the resemblance of germinoma with the fœtal pineal gland (large clear cells alternated with small dark round pineal cells), is erroneous as it creates confusion with pure PPT. This term ignores the common histogenesis of all germ cell tumours and must be abandoned. The other localisations of germinoma are the suprasellar or basal ganglia/thalamic regions. The term « ectopic pinealoma » for these sites must also be abandoned. The coexistence of both tumour sites is classic.

The germinoma
Germinoma accounts for 50% of pineal region germ cell tumours [49]. They are grey pink, friable, and soft. They tend to release their cells into the CSF and the arachnoid and to disseminate along the neuraxis.

Pure germinoma is characterized by large tumour cells with abundant clear cytoplasm rich in glycogen. Nuclei are round with prominent nucleoli. Traversing fibrovascular septa are infiltrated by small lymphocytes. Sometimes a florid granulomatous reaction may mimic neurosarcoidosis.
Diffuse placental alkaline phosphatase (PLAP) immunostaining is seen on the cell membranes and the cytoplasm. Five to 10% of germinoma cases are however PLAP negative. Immunostaining is positive for keratin and CD 117 (cKit) [50, 51]. Germinomas which contain syncitiotrophoblastic cells express beta HCG [47].

Teratomas (or dysembryomas)
These tumours contain different components which recall the differentiation of the three primitive germ layers (ectodermal, mesodermal, endodermal). They may be mature and/or immature. Teratomas are well circumscribed, polylobulated, and heterogeneous.

Mature teratomas (10 to 25% of pineal region germ cell tumours) are composed of mature differentiated tissue. As in dermoid cysts (mature teratoma) of the ovary, mature teratoma of the pineal region may contain hair, teeth, and cartilage.

Immature teratomas are constituted by immature tissues (developing nervous, digestive or cartilaginous tissues). Embryonal carcinoma may be considered as an element of the group of immature teratomas because it looks like an immature epithelial tissue which could be isolated or mixed with mature or immature teratoma.

Choriocarcinoma and yolk sac tumours
They arise from extra embryonal structures (endodermal sinus or the yolk sac) and are considered as secreting malignant germ cell tumours. Beta HCG is secreted by choriocarcinomas and alpha foeto-protein by yolk sac tumours. These tumour markers must be systematically measured in the blood and the CSF before surgery because they allow preoperative diagnosis. These markers are found at the microscopic level with immunochemistry [52].

Mixed malignant germ cell tumours correspond to a mature component associated with a malignant one (germinoma or not).
Immature teratomas, tumours with extraembryonal components, and mixed tumours represent a quarter of pineal germ cell tumours.
 
Other tumours and growing processes of the pineal region
They are diverse: meningiomas, choroid plexus tumours, rare lipomas, and exceptional melanomas. Metastases from primary tumours located outside the brain are rare (less than 3% of the pineal region tumours). Finally vascular malformations and arachnoid cysts can also be observed.

Imaging techniques and results [53]
The brain CT scan (figure 1 A)
It may show triventricular enlargement. The tumour is better seen after contrast media injection. There are no diagnosis specificities according to the histopathology of the pineal region tumour. The tumour often appears as a more or less homogeneous contrast enhanced lesion. Two tumour sites (pineal and supra sellar) of a germ cell pineal tumour are rarely visible. In certain cases cystic or necrotic aspects or calcifications are seen

NMR imaging
NMRI of the brain (Figure 1 B-3)
T1, T2 weighted and FLAIR sequences in the axial plan are completed with T1 weighted + contrast images in the three space plans. NMR imaging allows a diagnostic work-up locally and at distance for secondary subarachnoid deposits. No specific diagnostic criteria exist according to the histopathology of the tumour (figure 2, 3). [49, 53, personal communication]. classically the tumour is iso, hypo, or hyperintense in T1. There is a heterogeneous hypersignal in T2. Contrast enhancement is either intense and homogeneous, or heterogeneous with cystic and necrotic zones. Calcifications are rarely visible. Any lesion with a cavity is a problem for differential diagnosis with a cyst of the pineal gland. The practical way to approach the truth is to measure the size of the biggest lesion diameters in the three spatial planes and to observe their modifications with time. Normally the size of the cyst remains stable. NMRI can also detect bifocal tumour sites (pineal and suprasellar) which favour diagnosis of germinoma. NMRI helps to show tumour extension outside the pineal region toward the thalamus, the vermis and the lateral ventricles. Due to the high chemotherapy’s efficacy used in the treatment of germinomas these extensions are important to adapt radiotherapy to the primary tumour dimensions (registered before chemotherapy).

Spinal cord NMRI
Neuraxis NMRI must be systematic in the diagnostic work up of germinoma (5 to 10% spinal spread) or any other malignant tumour of the pineal region.

IV: Treatments
They vary according to the different PRT histopathological types.

Methods
Surgery
Treatment of the hydrocephalus
A ventriculo-cysternostomy (VCSt) is the treatment of choice. It opens a communication through the floor of the third ventricle toward the subarachnoidean spaces (cisterna pontis and cisterna magna) and may allow an open biopsy. Sometimes when it fails, a ventriculoperitoneal shunt is necessary to control intracranial hypertension. The patient’s clinical improvement gives time to complete the diagnostic work-up, and to study tumour marker levels. When the biopsy fails by this VCSt way a stereotactic biopsy is needed.

The biopsy
Stereotactic biopsy of pineal region tumours [54-55] is guided by NMRI and CT scan, under general or local anesthesia. Orientation of the biopsy instrument is antero-posterior and from out towards the axis of the brain. A specimen is almost always available and histopathologic diagnosis is made easily. Mortality has become low [55]. However morbidity risk linked to bleeding inside or around the tumour remains, especially when it is big or hard and pushed forward by the biopsy instruments. A small amount of tumour specimen sometimes makes the diagnosis difficult because of the heterogeneity of the tumours (mixed germ cell tumour, PPT, cysts). Given its size, the tumour specimen obtained during ventriculo-cysternostomy has the same disadvantages as those of stereotactic biopsy.

Direct surgical approach
It allows precise histological diagnosis, and often complete tumour removal, and CSF fluid discharge [56]. The tumour approach is difficult given the depth of the pineal region and the narrowness of access. Two modes of access are used. One is above the cerebellum, under the tentorium cerebelli. The other leads to the pineal region through a right para-sagittal occipital craniotomy, between the falx cerebri, the falx cerebelli, and the medial side of the occipital lobe. The disadvantage with the latter is possible hemianopsia if the occipital lobe is incidentally pushed too far apart. These techniques are both used with the patient lying either prone, or on his side, or even sitting. They have been improved by Lapras and Brotchi [57-58] with a significant decrease of morbidity and mortality. In all, the choice of approach depends on the tumour site and the experience of the neurosurgeon. These tumours, located in the posterior part of the 3rd ventricle, are less frequently operated on via an interthalamo trigonal approach.

Radiotherapy (Fig. 4 - 6)

Treatment techniques have improved during the last 10 years. Tumour treatment volume have to change according to histopathology and disease extension, from a limited target to a cranio-spinal irradiation of the whole ventricular system, and of all the meninges from the anterior part of the frontal lobes to the dura mater cul de sac near the second or third piece of the sacrum.

3D conformal focal radiotherapy (Fig. 4)
A non-invasive immobilization method is used to allow precise daily patient positioning over the course of treatment, with a non invasive relocatable stereotactic frame (see fig.4 with example of Brainlab R system used in Nice, France). The patient is in a supine position on a custom made or standard head support with a thermoplastic immobilization mask around the head: in routine 2 mm precision is obtained. A volumetric post-contrast computed tomography is acquired from a CT scanner with thin contiguous slices (2 to 3mm thickness) while the patient is immobilized in the treatment position. Two to 3 mm thin and contiguous axial and sagittal post-contrast T1 weighted NMR images of the whole brain are also necessary. Both sets of images are mixed by appropriate fusion software: CT Hounsfield units converted in electronic densities are basic elements for dosimetry. NMR images are used for contouring the tumour and the critical structures. The daily dose is delivered 5 times per week (classical fractionation) until the appropriate total dose has been delivered. According to our specification for PPT [1] the dose in the pineal target are, from grade 2 to 4, 50 Gy, 56 Gy and 56 Gy; in this two late cases a cranio-spinal irradiation of 36 Gy is recommended due to late (Gr 3) or  early (Gr 4) meningeal or spinal recurrence. In case of germ cell tumour see table 3 and 4, due to complex indications in doses and irradiated volumes according to histopathology, extension of disease and chemotherapy responses. Finally in PTPR a post operative irradiation of 50 Gy is recommended localized to the target volume. It should be discussed in the future according to the results of this strategy and new cases [42]. In rare true inoperable meningioma of the pineal region a dose of 50 Gy is recommended in the target volume as defined up. In rare malignant astrocytomas or ependymomas or metastasis the dose shall be adapted to the volume, location at the time of treatment.

Radiosurgery (Fig. 5, 6)
An invasive immobilization method is used: a stereotactical frame is fixed to the skull. The radiation dose is delivered in only one fraction to a less than 25mm diameter size tumour. Image fusion software is also necessary. GammaknifeR, CyberknifeR, dynamic conformal arctherapy with a linear accelerator are adequate for this radiation treatment.

Whole ventricle irradiation
This technique is used for pineal germinomas. Image fusion software is mandatory. A safety margin of 1 cm is usually added to the target volume.

Spinal cord irradiation
The patient is treated in a prone position in a made to measure immobilization shell.  The technique is complex and associates opposed coaxial photons fields for the brain and contiguous posterior electron fields for the spinal cord up to the lower part of the dura mater cul de sac. The junction between the different fields to obtain a homogenous dose along the whole spinal cord (and reduce the risk of radiation myelitis) is not the same every day. The total delivered dose is 24 -36 Gy. In children, the whole vertebra body has to be irradiated to avoid delayed dysharmonious growth.

Chemotherapy
Chemotherapy protocols differ according to tumour histopathology.

Malignant PPT (PB and grade IV tumours): a combination of Platinum compounds (Cisplatinum (CDDP) at 100 mg/m2 at day 1 or Carboplatin 500 mg/m2 at days 1 and 2) and Etoposide (VP 16) at 100 to150 mg/m2 at days 1, 2, and 3 is used for children and adults. Less often, a combination of Ifosfamide, VP 16, Fotemustine, and platinum is administered. For children the BB SFOP protocol is usual in France [60].

Malignant ependymomas and papillary tumours of the pineal region
The combination CDPP + VP 16 is used (personnal and register recommendation) (with doses as above for PPT). Temozolomide is a second line drug. In all, no evidence based protocol has been defined for these tumours

Malignant germ cell tumours
Carboplatin, VP 16, and Ifosfamide are often used. SFOP and SIOP propose the following protocol for children: 2 cycles of two consecutive sequences of 600 mg/m2 Carboplatin at Day 1 + 100 mg/m2 (SIOP) or 150 mg/m2 (SFOP) VP 16 at days 1, 2, and 3, then 1800 mg/m2 Ifosfamide at Days 22,23 and 24 + 100 mg/m2 (SIOP) or 150 mg/m2 (SFOP) VP 16. [61-62]. In routine, only Carboplatin and VP 16 are used for the treatment of pure germinoma. For mixed germ cell tumours the treatment protocol is based on 4 cycles (delivered at 21 days interval) of a combination of 20 mg/m² CDDP at days 1,2,3,4,5 + 100 mg/m2 VP16 at days 1,2,3 + 1500 mg/m2 Ifosfamide at days 1,2,3,4,5 [62-63].

V: Therapeutic strategies, prognosis and follow-up (Table 2 to 6)
Histopathological diagnosis determines the various treatment orientations. A search for tumour markers in the CSF and blood must be carried out for secreting germ cell tumours. A rise in the marker levels (alpha foeto protein and/or beta hCG) allows the diagnosis of an extra embryonal tumour cell population: chemotherapy will therefore be used first. For all other cases biopsy (see above) or direct surgical approach are mandatory. 

Pineal cysts of the pineal region
An asymptomatic cyst must not be resected. A cyst with symptoms of compression needs a CSF shunt. If the size and the symptoms increase, tumour resection is performed.

Pineal parenchymal tumours
Tumour resection is the treatment of choice, with very low morbity and mortality in expert hands in the past decade, in our large series.
For grade I (pineocytoma) surgery is the only treatment modality.
For grades II and III (PPT int) tumour resection is completed by post-operative radiotherapy. For grade II tumours focal conformal radiotherapy is necessary (up to a total dose of 54 Gy with classical fractionation). For grade III tumours extensive field treatment associates focal conformal radiotherapy of the pineal region tumour (54 Gy total dose) and whole spinal cord irradiation (36 Gy total dose). Prognosis differs with grade. Failures, are usually delayed (median = 13 years) and local for grade II tumours. They are more frequent for grade III tumours and in a shorter time (median = 6 years). They appear at the primary site and/or as spinal seeding [64].
Progression free survival and 15 years crude survival are respectively 40% and 53% for grade II tumours, and for grade III tumours 26% and 36% [64].

Pineoblastoma remains a therapeutic challenge. Its treatment is still the aim of different clinical phase I and II trials. Routine treatment combination is based on surgical resection, heavy chemotherapy regimen, and extensive field radiotherapy. Despite the treatment load, failures occur in 80% of cases with a worse prognosis for young patients [59, 64]. These failures occur at the primary or as seeding along the spinal cord or in bones [59,64,66]. The progression free survival is 20 % at 60 months and the median crude survival at 5 years is 20% and 0% at ten years [64]. All study failed to demonstrate any benefit for adjuvant chemotherapy [59, 67]. The most recent non randomized study in children [67] comprised few cases (14, 21%) of pineal among supra-tentorial PNET(68 cases), without central pathological review, called pineoblastoma. Surprisingly, the 5 years OS and EFS in this study for these 14 cases was 41%. An explanation of this good survival in infant and children, like in the randomly treated population in Jakacki publication ten years before, is probably due to some grade 3 PPT tumours or other histopathological tumours.

Glial tumours
Pilocytic astrocytoma 
Surgery is the main treatment. If resection is incomplete there is no role for radiotherapy unless the remaining tumour grows again and if no second surgery is advisable.

Infiltrating astrocytic or oligodendroglial glioma
Surgery is advised and completed by focal radiotherapy and chemotherapy according to grade and histological type.

Ependymal tumours
They need complete surgery when feasible followed by focal radiotherapy for high grade tumours.

Papillary tumours of the pineal region (PTPR)
Surgery is advised and followed by 50 Gy focal radiation treatment [40-41] given the high risk of local recurrence with surgery alone or surgery plus chemotherapy [personal communication 2007], (fig. 7-8). In our series gross total resection was the only clinical factor that tended to be associated with overall survival and recurrence (p = 0.10 and p = 0.16, respectively) but the correlation failed to achieve statistical significance. Due to the rarity of these tumors, data on the prognostic value of PTPR remain scarce. Kaplan-Meier analysis of our series provided 5-year estimates for overall survival and progression-free survival of 73% and 27% [40].
Germ cell tumours 
Histopathology is the main criterion for the therapeutic strategy [68].

Pure germinoma (αFP< 25 ng/mL ; βHCG < 50 IU/L in the serum and CSF ). No resection surgery is advisable. Biopsy only is mandatory (see above for modes of biopsy). For uni or bifocal tumours (supra-sellar and pineal region tumours) the standard treatment is craniospinal radiotherapy at 24 Gy total dose followed by a boost of 16 to 19 Gy focal radiotherapy on the initial tumour site (s).
Recent studies attempt to reduce the irradiated volume and the potential late delayed radiation neuropsychological sequelae by using post-operative first line chemotherapy. However, despite a major complete response rate to chemotherapy of 85% a high level of morbidity and of an early unacceptable recurrence level above 50% have been registered [68]. The evidence suggests that as smaller radiotherapy volume is used, recurrence rates increased: 2.3% after craniospinal irradiation; 7.6% after whole brain or ventricle irradiation; 23.3% after localised irradiation [73]. The question remains about how to define the most appropriate radiation volumes and the minimal doses needed to maintain the excellent results of cranio-spinal radiotherapy alone which gives a global survival and recurrence free survival of 97% in localised disease. The last trial of the SFOP (Société Française d’Oncologie Pédiatrique) and the B arm of the SIOP (Societe Internationale d’Oncologie Pédiatrique) study in progress examine the possibility of limiting the radiation target to the tumour site at a 40 Gy total dose after 4 cycles of Carboplatin based chemotherapy (see above). Analysis of recent results shows respectively for each study a recurrence level of 16.4% and 14% with a median follow up of 76 and 24 months [69-72].These failures may be late delayed: the median time for recurrence is 36 months in the SFOP trial. The analysis of the dose/volume relationship reveals that the majority of the failures are localized within the ventricles and in particular in the posterior and anterior cornu. Similar results are reported in the literature: median time to recurrence of 15.5% with chemotherapy and only focal radiotherapy of the tumour site versus 3.8% with exclusive cranio-spinal radiotherapy [72]. Overview of the recurrence sites demonstrates that failures after chemotherapy and focal radiotherapy are mainly ventricular: a systematic radiotherapy of the whole brain and total neuraxis is therefore not necessary. These results led SIOP to propose for its protocol chemotherapy combined with 24 Gy radiotherapy to the tumour site and the ventricles. If complete remission is observed after chemotherapy no complementary dose is delivered to the tumour site beyond 24 Gy as is the case for Japanese studies [74-75]. When there is still an objective tumour remnant at the end of chemotherapy, the total dose to the initial tumour site is 40 Gy. Published data lead to the recommendation of 24 Gy to the ventricles and 40-45 Gy to the tumour site when the patient is a child not involved in a clinical research study. Survival in children is 98% at 3 years [60]. The protocol for adult patients of the ANOCEF (Association de Neuro-oncologie d’Expression Française ; French Neuro-oncology Study Group) recommends  after  chemotherapy-induced complete remission 24 Gy radiotherapy limited to the third ventricle. 
In all, we retain that:

1. for the coming clinical trials, prospective analysis of late delayed cognitive sequelae at ten years is necessary;
2. if no response (stable disease or progression) to first line chemotherapy is observed the diagnosis of germinoma based on biopsy must be reconsidered and a tumour removal performed.  

A multifocal disease and/or a neuraxis spread ( diagnosed on ventriculo-cisternostomy biopsy or on brain or spinal cord NMR imaging or on CSF cytology) are treated with 24 Gy craniospinal radiotherapy completed by a 16 Gy boost on the initial tumour sites (primitive and metastatic). In cases treated with radiotherapy only, the results are identical to those obtained for localized forms: first line chemotherapy treatment becomes debatable.

Marker secreting pineal region germ cell tumours
First line chemotherapy treatment is used (see above). If at the end of the chemotherapy protocol complete response is not obtained, resection surgery must be performed for a mature or immature teratoma remnant.
When the response is complete, either after chemotherapy alone, or chemotherapy followed by surgery, focal and conformal radiotherapy of the initial growth tumour volume remains useful at a 54 Gy total dose (30 fractions).
Bad prognosis patients with marker secreting tumours (multifocal disease, brain and or neuraxis spread, tumour markers at a high level alpha foetoprotein more than 1000ng/ml) will be treated in the protocol with high dose chemotherapy and autologous bone marrow rescue to improve survival. Radiotherapy is added at the end of the chemotherapy protocol according to the following rules: craniospinal irradiation at 24 Gy and boost(s) up to 54 Gy on the initial tumour sites if possible. 

Mature and immature teratoma
Complete resection surgery is the aim of treatment. If an immature component is found at histopathology the post-operative treatment will be the same as the one used for secreting germ cell tumours.

Conclusion
The pineal region includes various tumour entities. Diagnosis and treatment of these tumours necessitate a multidisciplinary approach and an expert team, given the paucity of these tumours and the number of pitfalls at each step of management.
Our work is in progress to improve the knowledge about these tumours.

Expert Commentary and Five year view
Pineal tumours are rare and deserve national and international cooperation. A multicentric international cooperative study group is necessary, which could lead to a collection of clinical data and biological material, and promote clinical trials.
A systematic histological review is recommended given the variety of tumours and the possible pitfalls of diagnosis.
Direct surgical approach is often the treatment of choice: when necessary, patients have to be addressed to reference neurosurgery departments, given potential morbidity.
Many clinical trials are needed for chemo and radiosensitive tumours, and pineoblastomas.
For germinomas the role of radiotherapy has to be minimized in children to avoid neurocognitive consequences.  Chemotherapy morbidity must be clearly evaluated in these patients. For adults chemotherapy has to be avoided or studied in randomized trials and compared to radiotherapy alone.
Bad prognosis secreting germ cell tumours require a precise evaluation of dose intense chemotherapy with autologous bone marrow rescue. The definition of the most adequate radiotherapy doses and target volumes remains open.
Pineoblastoma patients are potential candidates for targeted therapies to improve the progression free interval and the overall survival: phase two studies must be systematic given the grim results obtained to date.

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Figure 1: germinoma.
MRI (sagittal) with gadolinium: left (A) pineal lesion: right (B) bifocal pineal and supra-sellar tumour.

Figure 2: MRI pineal tumour.
Top: axial T2 and T1 without and with gadolinium. Bottom: T1 after gadolinium enhancement (sagittal and coronal).

Figure 3: some identical radiological aspects of different pineal tumours.
A Germinoma; B Secreting tumour; C Choroid plexus carcinoma; D  PPT int; E  PTPR.

Figure 4 : 3D conformal radiotherapy
TDM and MRI fusion for precise delineation of the GTV. Isodoses of treatment (NUCLETRON IFS/VSS 1.1.2. Relocatable stereotactic frame BRAINLAB.

Figure 5 : Radiosurgery of PPT
Image fusion.

Figure 6 : Isodoses in case of radiosurgery
A: germinoma’s remnant; B: PPT’s recurrence at 18 y.

Figure 7: Germinoma’s recurrence.

Figure 8: PTPR’s recurrence. Initial tumour (right). First recurrence (middle) local ,after complete resection and 18 course of chemotherapy; Second recurrence (left) ,after second complete surgery and 3rd ventricle conformal  radiotherapy recurrence in whole ventricle (out of 3rd ventricle), cisternal and spinal.

Table 1: Immunohistochemical features of normal pineal gland, pineal cyst and pineal parenchymal tumours.

NP : normal pineal gland, PC : pineocytoma, PB : pineoblastoma, PPTint : pineal parenchymal tumour with intermediate differentiation, NF : neurofilaments, SYN : synaptophysin, ChrgA : chromogranin A, GFAP : gliofibrillar acid protein, VIM : vimentin,  IC : interstitial cells,  V : vessals, PV : perivascular, 0 : no labelling, +/- : slight labelling, ++ : moderate labelling, +++ : intense labelling.    

Table 2:

HYDROCEPHALUS and V3 TUMOUR
 

GERM CELLS MARKERS (GCT)

NEGATIVE                                                               POSITIVE

AFP<25 ng/ml and/or b HCG < 50 ui/ml     AFP>25 ng/ml and/or bHCG > 50 ui/ml

VENTRICULO-CISTERNOSTOMY                           BIOPSY
 

 PPT             GLIAL TUMOUR                      GCT                      OTHERS

PUR GERMINOMAS
                                          

UNI or BIFOCAL                                    CSF tumoral cells
                                                                   or spinal metastasis NMR (15%)
                                               

CHEMOTHERAPY 4 CYCLES                 Carbo 600 mg /m2+ VP16 450 mg /m2
                                                                       (Response 100% )

RADIOTHERAPY

CHILDREN VENTRICULAR CAVITY            SPINAL METASTASIS
                                                                    (30 Gy) Nevrax 24 Gy Pineal
                                                                     Boost 16 G

ADULT ONLY V 3 (24 Gy)
(3 Y SURVIVAL 98% - 12 % RECURENCE  curable)

SECRETING TUMOURS TREATMENT
                                                                              

 UNI or BIFOCAL                  CSF or SPINAL METASTASIS NRM  (10%)
                                        

CHEMIOTHERAPY 2 CYCLE
J1- J3  Carbo 600 mg /m2+ VP16 450 mg /m2
J21-J25 Ifo 1,8 g /m2 + VP16 450 mg /m2

 

 (IF REMNANT SURGERY)

    

LOCAL RADIOTHERAPY 55 Gy

(5 YEAR SURVIVAL 70-80% - 25 % RECURRENCE

Table 5:

PPT’ s TREATMENT

BIOPSY    lead PPT diagnosis (often not sufficient for grading)

COMPLETE SURGERY if POSSIBLE

PTPR’S TREATMENT

BIOPSY

 

 COMPLETE SURGERY IF POSSIBLE

 

3D WHOLE 3rd VENTRICLE RADIOTHERAPY 50 Gy