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Report 2013: Tumors of the pineal region
Pineal parenchymal tumours and pineal cysts Tumeurs du parenchyme pinéal et kystes de la glande pinéale A. Jouvet a,∗,b , A. Vasiljevic a,b , J. Champier b , M. Fèvre Montange b a b
Service de pathologie et de neuropathologie, centre de biologie et pathologie Est, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron, France Inserm U1028, CNRS UMR5292, équipe neuro-oncologie et neuro-inflammation, centre de recherche en neurosciences de Lyon, 69372 Lyon, France
a r t i c l e
i n f o
Article history: Received 25 March 2013 Received in revised form 12 April 2013 Accepted 15 April 2013 Available online xxx Keywords: Pineal parenchymal tumours Pineocytoma Pineoblastoma Pineal parenchymal tumours with intermediate differentiation
a b s t r a c t Background and purpose. – Pineal parenchymal tumours (PPTs) and pineal cysts represent one third of the pineal region lesions. PPTs are subdivided into pineocytoma (PC), pineoblastoma (PB) and PPT with intermediate differentiation (PPTID). We report morphological and immunochemical features which permit to grade these tumours. Methods. – The description of histopathological features and grading is based on a large cooperative series and on the WHO 2007 classification. Results. – PCs occur in adults between the third and the sixth decade of life. PBs typically occur in children. PPTIDs have a peak incidence in young adults between 20 and 40 years of age. There is no sex preference. PC is characterized by a uniform cell proliferation with large fibrillary pineocytomatous rosettes. PB is a high-density tumour composed of small blue cells with hyper-chromatic, round or carrot shaped nuclei. PPTIDs have lobulated or diffuse patterns. Grading is based on morphological features, count of mitoses and neurofilament protein (NFP) expression. PCs (grade I) have no mitosis and NFP is highly expressed in pineocytomatous rosettes. PBs (grade IV) are high mitotic tumours and present low or no expression of NFPs. PPTIDs are grade II when mitoses are fewer than 6 for 10 high-power fields and NFPs are expressed, and are grade III when mitoses are greater or equal to 6 or are fewer than 6 with NFPs lowly expressed. Pineal cysts may be differentiated from PPTs by the high expression of NFPs and no expression of Ki-67. © 2014 Published by Elsevier Masson SAS.
r é s u m é Mots clés : Tumeur du parenchyme pinéal Pinéalocytome Pinéaloblastome Tumeur du parenchyme pinéal à différenciation intermédiaire
Contexte et objectifs. – Les tumeurs du parenchyme pinéal (TPP) et les kystes de la glande pinéale représentent 30 % des processus expansifs de la région pinéale. Les TPP comprennent les pinéalocytomes (PC), les pinéaloblastomes (PB) et les TPP à différenciation intermédiaire (TPPDI). À partir d’une série multicentrique, nous avons établi un classement en quatre grades reconnu par l’OMS en 2007 : grade I (PC), grades II et III (TPPDI) et grade IV (PB). Méthodes. – La description histopathologique, les données des immunomarquages et le grading sont basés sur la classification de l’OMS. Résultats. – Les PC sont des tumeurs de l’adulte. Les PB s’observent le plus souvent chez l’enfant. Les TPPDI sont des tumeurs de l’adulte jeune. Il n’y a pas de prévalence de sexe. Les PC présentent de larges pseudorosettes fibrillaires au sein d’une prolifération de cellules pinéalocytaires, n’ont pas de mitoses et expriment les neurofilaments (NF). Les PB correspondent à une prolifération de petites cellules bleues indifférenciées aux noyaux hyperchromatiques ronds ou en forme de carottes, aux index mitotique et de prolifération élevés. L’architecture des TPPDI est lobulée endocrinoïde ou diffuse sans pseudorosette. Les TPPDI grade II ont moins de six mitoses pour dix champs × 400 et une forte expression de NF. Les TPPDI grade III ont soit six ou plus de six mitoses pour dix champs soit moins de six mitoses mais une faible expression de NF. Les kystes de la glande pinéale expriment très fortement les NF. © 2014 Publie´ par Elsevier Masson SAS.
∗ Corresponding author. E-mail address: [email protected] (A. Jouvet).
Tumours of the pineal region (TPRs) are rare, accounting for 2 to 3% of all intracranial tumours. Neuroepithelial tumours, such as pineal parenchymal tumours (PPTs), glial tumours and papillary tumours of the pineal region (PTPRs) represent approximately 50% of tumours in the pineal region. Germ cells tumours account
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for 30% of the TPR. Miscellaneous tumoural lesions (meningiomas, metastases) and non-neoplastic lesions (pineal cysts, arachnoidal cysts, vascular malformations) correspond to the last 20% of TPR. All histopathological and clinical data of TPRs are collected in a National Registry in Lyon (Hôpital Neurologique, Groupement Hospitalier Est) that contains more than 500 cases. This report is focused on the pathological classification of PPTs and on glial cysts that need to be distinguished from pineal tumours, particularly pineocytoma. PTPRs, described as a novel neoplasm in pineal region, are presented in another section.
The gross appearance of PPTIDs is similar to that of PCs. The tumours are circumscribed, soft in texture and lacking gross evidence of necrosis. 1.4. Microscopy
PPTs account for approximately 30% of tumours in the pineal region [4]. Our registry of TPRs includes 173 cases of PPTs in 2012 from 19 French centers, 53 were cases from Lyon (Neurosurgical Hospital). Histopathologically, they constitute a morphologic continuum from slowly growing well-differentiated lesions to highly proliferative tumours. In a literature review of 16 papers covering 326 PPTs, 145 (44%) were found to be PCs [4]. This percentage might be overestimate, as some PPTIDs were classified as PCs before the 2007 WHO classification. PCs account for 14% to 30% of all PPTs [5] and may present at any age, but mostly occur in adults, with a peak incidence between the third and sixth decades of life [3]. There is no gender preference. PBs typically occur in children, with a mean age of 12.6 years, but adults may also be affected [4,6], with reports of individual patients older than 60 years [7–8]. There is no gender predilection. The relative frequency of PPTIDs varies in the literature because, in some reports, this intermediate group of tumours was considered as PCs or PBs, reflecting the difficulties in establishing reproducible definitional criteria. If only studies with a true intermediate group are considered, PPTIDs represent 20 to 62% of PPTs [4,9–10]. These studies clearly indicate that tumours with mixed or intermediate features are not uncommon among pineal parenchymal neoplasms. These neoplasms occur mostly in adults, with a peak incidence in young adults between 20 and 40 years of age. Most present as localized disease. Dissemination via the cerebrospinal fluid (CSF) is less common than for PBs [4,7,11].
Typical PCs are composed of well-differentiated tumour cells that resemble pineocytes and grow in a sheet-like pattern. The tumour cells are remarkably uniform, with a sparse, eosinophilic cytoplasm, short processes and round-to-oval nuclei with finely dispersed chromatin and inconspicuous nucleoli. Silver impregnation techniques highlight short cytoplasmic processes, often with bulbous or club-shaped terminations. Micro-calcifications may be seen. Mitotic figures are absent or exceedingly rare. Necrosis is very rare. The most characteristic feature of the PC is the formation of relatively large, sometimes confluent “pineocytomatous” rosettes (Fig. 1A). These structures appear as ovoid eosinophilic areas composed of a delicate meshwork of tumour cell processes. Pineocytomatous rosettes are similar to neuroblastic rosettes of the Homer Wright type, but considerably larger. A subset of PCs is characterized by the presence of large ganglionic cells and/or pleomorphic multinucleated giant cells [2,12–13]. They show no evidence of significant proliferative activity and have an indolent biological behaviour. PBs are composed of densely packed small cells with a scant cytoplasm, hyper-chromatic, round or oval nuclei and high nuclear/cytoplasmic ratios. They resemble other small cells or PNETs of the CNS (Fig. 1B). The tumour cells grow in patternless sheets, usually without any obvious lobular architecture. Pineocytomatous rosettes are absent. However, PBs often contain neuroblastic rosettes of the Homer Wright type or retinoblastic rosettes of the Flexner–Wintersteiner type. Large cell/anaplastic features, as seen in medulloblastomas, can be present. PBs occasionally show evidence of advanced photoreceptor differentiation, with the formation of “fleurettes”. Rare tumours contain cells with melanin pigment. Mitotic figures are frequent. Apoptotic bodies and areas of necrosis may be prominent, the latter sometimes being associated with micro-calcifications. Vessels are usually thinwalled, but focal endothelial proliferation may be seen. Histologically, PPTIDs present variable features [2]. These include an endocrine-like lobular architecture (Fig. 1C) or a more diffuse growth of isomorphic tumour cells with round nuclei and a clear cytoplasm (Fig. 1D). Such neoplasms should not be mistaken for neurocytoma or oligodendroglioma. Another phenotype, reported as a “transitional variant”, has mixed lobular/diffuse areas, in addition to regions with a PC-like morphology. Finally, some rare tumours may present with a biphasic pattern combining the typical features of PCs and PBs. These mixed PC/PB may correspond to pineoblastoma with residual pineal gland. Neoplastic cells have less cytoplasm than in PCs, but it is still visible on standard staining. Nuclear atypia is moderate. Mitotic activity is usually present in intermediate tumours, but may vary considerably. Foci of necrosis or vascular proliferation have been reported in subsets of PPTIDs, although they lack the primitive “small blue cell” appearance of PBs [2]. A pleomorphic variant may be encountered in low-grade PPTIDs [13].
1.3. Macroscopic examination
1.5. Immunohistochemistry
PCs are circumscribed, grey or grey-brown tumours, with a cut surface that is homogeneous and often finely granular. Some show degenerative changes, such as small cysts. Necrosis is rare. PBs are poorly demarcated, soft or gelatinous, grey-pink tumours. Haemorrhagic and necrotic areas may be present. The tumours often destroy the pineal gland, bulge into the posterior third ventricle and compress the colliculi and the aqueduct.
PCs are immunopositive for neuron specific enolase (NSE), synaptophysin (SYN) (Fig. 2A) and NFPs (Fig. 2B), with strong reactivity in pineocytomatous rosettes. Immunoreactivity for several other neuronal or neuroendocrine antigens, including class III betatubulin, microtubule-associated protein 2 (MAP2), tau protein and chromogranin A, is also common [2,14–15]. In pleomorphic PCs, the pleomorphic cells show strong expression of SYN and NFPs
1. Pineal parenchymal tumours 1.1. Introduction and historical considerations The study of PPT in our institution began in the 1990s with an ultrastructural study of 20 cases [1]. A prognosis classification was proposed in 2000 on a multicentric series of 66 cases [2]. This classification in four grades of PPTs is based on morphological patterns, on mitotic count and immunohistochemical staining for neurofilament proteins (NFPs). The 2007 WHO classification subdivides this continuum into three distinct tumour categories: pineocytoma (PC) (Grade I), pineal parenchymal tumour of intermediate differentiation (PPTID) (Grades II and III) and pineoblastoma (PB) (Grade IV) [3]. 1.2. Incidence, age and sex distribution
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Fig. 1. Light microscopy features of PPTs (hemalum, phloxine, saffron staining). A. Typical pineocytoma: uniform cell proliferation with large “pineocytomatous” rosettes. B. Pineoblastoma: tumour with dense cellularity. Small blue cells with round or carrot shaped hyper-chromatic nuclei. C and D. PPTs with intermediate differentiation (PPTIDs): proliferation of neoplastic cells harbouring round uniform nuclei. Lobulated PPTID with endocrine-like vasculature (C), diffuse PPTID with neurocytoma-like growth (D). Aspects microscopiques des tumeurs du parenchyme pinéal (TPP) (hemalun, phloxine, safran). A. Pinéalocytome typique : prolifération de cellules monomorphes avec de larges pseudorosettes pinéalocytaires fibrillaires. B. Pinéaloblastome : tumeur d’une grande densité cellulaire, constituée de petites cellules bleues avec des noyaux ronds ou en forme de carottes hyperchromatiques. C et D. TPP avec différenciation intermédiaire (TPPDI) : prolifération de cellules tumourales aux noyaux ronds monomorphes. TPPDI lobulée avec une vascularisation endocrinoïde (C). TPPDI diffuse ressemblant à un neurocytome (D).
Fig. 2. Immunohistochemical features of PPTs. A and B. Pineocytomas: strong reactivity of synaptophysin (A) and high expression of NFPs (B) in “pineocytomatous” rosettes. C. Pineal parenchymal tumour of intermediate differentiation (PPTID): tumoural cells expressed NFPs. D. Ki-67 labelling index (LI) in PPTID. E. Pineoblastoma: The Ki-67 Li is very high. Profil immunohistochimique des TPP. A et B. Pinéalocytome : forte expression de la synaptophysine (A) et des neurofilaments (B) dans les pseudorosettes pinéalocytaires. C. Tumeur du parenchyme pinéal à différenciation intermédiaire (TPPDI) : marquage anti-neurofilaments des cellules tumourales. D. Index de prolifération avec anti-Ki-67 des TPPDI. E. Pinéaloblastome : index de prolifération avec anti-Ki-67 élevé.
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and sometimes chromogranin A [12–13]. PCs can demonstrate a photoreceptor-like immunophenotype, with patchy positivity for retinal S-antigen and/or rhodopsin [16–17]. They also express hydroxy-indole-O-methyltransferase (HIOMT), the enzyme that catalyses the final reaction in melatonin biosynthesis [18]. S-100 protein (S100P) immunoreactivity is seen in the interstitial astrocytic cells and sometimes in the neoplastic cells, to varying degrees. Glial fibrillary acidic protein (GFAP) expression is seen in reactive astrocytes [2,14]. Proliferative activity, as assessed by the Ki-67 labelling index (LI), is low [10,15,19]. In PBs, a dot-like or diffuse immunoreactivity for SYN is commonly detected [2,6]. NSE expression is also found, while immunoreactivity for NFPs and/or chromogranin A is inconsistent and tends to be restricted to individual tumour cells [2,6]. PBs can contain cells with immunoreactivity for photoreceptor markers, such as retinal S-antigen [17] or CRX [20]. GFAP and PS100 immunoreactivity is rare [2]. In PPTIDs, expression of neuronal markers is variable. Cytoplasmic SYN labelling is usually diffuse and of variable intensity. NFPs can be expressed in a variable number of cells, and this variability has been used together with morphology and proliferation to discriminate low-grade from high-grade PPTIDs (Fig. 2C). Chromogranin A may be seen in PPTIDs, especially those with a pseudolobulated architecture [2]. 1.6. Proliferation PCs grow slowly, and the Ki-67 labelling index (LI) is very low [19,21]. The Ki-67 LI of PB is very high (mean: 36.4 ± 6.2) [19] (Fig. 2E). The mean Ki-67 LI is significantly different for PPTIDs Grade II and Grade III (Grade II: 5.2 ± 0.4, Grade III: 11.2 ± 2.0) [19] (Fig. 2D). 1.7. Electron microscopy PCs are composed of clear cells with a varying numbers of dark cells, sometimes joined by zonula adherents [1]. Their cytoplasm is relatively abundant and contains well-developed organelles, including smooth and rough endoplasmic reticulum, Golgi complex, mitochondria, multi-vesicular bodies and lysosomes. The tumour cells share many ultrastructural features with normal pineocytes, such as dense-core (neurosecretory) vesicles, clear (synaptic-type) vesicles, vesicle-crowned rodlets (synaptic ribbons), paired twisted filaments and “fibrous filaments” [1,22–25]. Tumour cell processes are filled with microtubules and terminate in vesicle-rich club-like expansions, which may show synapse-like junctions. Some tumours show signs of photoreceptor differentiation, including the presence of cytoplasmic annulate lamellae, as well as cilia with a 9 + 0 configuration [1]. In line with ultrastructural findings for other CNS PNETs, PBs contain poorly differentiated cells with a scant cytoplasm and few short processes without the bulbous terminations typically seen in PCs [1,15,26]. Scant microtubules and occasional dense-core vesicles may be observed. However, specialized structures, such as paired twisted filaments, vesicle-crowned rodlets or synaptic junctions, are absent. PPTIDs display an intermediate appearance, with short cytoplasmic processes and rare bulbous endings. In pseudolobulated PPTIDs, the organelles characteristic of neurosensory/photoreceptor differentiation are usually absent, but the cell processes contain oriented microtubules, clear synaptic-like vesicles and dense-cored vesicles. 1.8. Molecular genetics Cytogenetic studies on PCs are rare and have not shown any clinically relevant non-randomly distributed abnormalities. In
conventional cytogenetic studies, PCs present both numerical and structural aberrations, but the results have not been very consistent. In three conventional cytogenetic studies, the karyotype of PCs was mostly pseudodiploid and the common abnormalities included losses of chromosomes 4, 5, 14 and 15 and, in two patients, loss of all, or part, of chromosomes 22, 11 and 1 was observed [25,27–28]. On comparative genomic hybridization (CGH), these tumours lack any consistent gains or losses [29]. TP53 mutation and p53 protein accumulation were not detected in five PCs [30]. Conventional or CGH cytogenetic studies on PBs have shown both numerical and structural abnormalities [29,31–33]. The karyotypes are mostly near-diploid, but hyper-tetraploidy has been reported. Recurrent aberrations include gains on chromosome arms 1q, 5p, 5q, 6p and 14q and losses of chromosomes 20 and 22, as well as isochromosome 17q (i[17q]), or unbalanced gain of 17q. In cytogenetic reports of 13 PBs, i[17q] or unbalanced 17q gain was described in four cases, including two tumours and two cell lines [32–33]. In contrast, CGH studies have shown that most PBs do not exhibit 17q gain [29,34]. Thus, whether PBs are genetically related to CNS PNETs or medulloblastomas remains unclear. In vitro, PB cell lines showed enhanced N-myc expression in the absence of MYCN gene amplification, in contrast to the situation in medulloblastomas [35–36]. No TP53 mutations were demonstrated in four PBs [30]. The RB1 gene has not been studied for genetic alterations in sporadic PBs [32]. However, studies on knock-out mice indicate that the simultaneous inactivation of P53 and RB1 results in an increased rate of PBs [37]. The majority of PBs develop sporadically. However, patients with germline mutations in the retinoblastoma tumour suppressor gene and familial retinoblastoma syndrome have an increased risk of developing PBs, a condition known as “trilateral retinoblastoma” [38–40]. PBs that arise in this setting have a more aggressive course than sporadic cases [41]. However, no specific abnormalities of chromosome 13q in the region of the RB1 gene have been found in conventional or CGH cytogenetic studies [29,33]. One case of PB associated with familial adenomatous polyposis has been reported as a potential variant of Turcot’s syndrome type 2, an inherited disease involving the adenomatous polyposis coli (APC) gene and characterized by a predisposition to colonic neoplasms and brain tumours, specifically medulloblastomas [42]. This case remains isolated, and no association has been made between APC gene mutation and PB, in contrast to the firm association between mutation of this gene and medulloblastomas. One CGH study of PPTIDs showed that the profile is close to that of PBs in terms of chromosome 22 loss and that PPTIDs and PBs display similar proportions of chromosomal imbalances per case (5.3 for PPTIDs and 5.6 for PBs) [29]. 1.9. Biological behaviour, prognosis and grading PCs are usually associated with a favourable prognosis after treatment (5-year overall survival ranging from 86% to 91%) and do not metastasize [4,11]. The literature is primarily composed of case reports and small case series, in which low-grade PPTIDs were sometimes considered as PCs. A recent review of 64 publications describing 168 patients indicated that surgical resection is the appropriate treatment for these tumours [43]. Adjuvant fractionated radiotherapy does not improve the rate of tumour control or survival when used to treat a subtotal resected tumour, but close radiological follow-up is recommended [43–44]. However, other authors reported that radiosurgery has a role as an alternative primary treatment modality for small lesions, as well as in the treatment of residual and recurrent tumours [45–46]. In contrast, PBs are locally invasive and tend to disseminate via the CSF, requiring aggressive treatment. In adults, stereotactic biopsy or open surgery is usually followed by adjuvant radiotherapy and chemotherapy [7–8,47–48]. Nevertheless, the prognosis
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is poor, as indicated by a median survival time of 16 months and a 5-year survival rate of 10% in a retrospective series of 18 patients [4]. More recent data indicate a slightly better median overall survival for adult patients, ranging from 25.7 to 77 months [7–8]. The extent of disease at diagnosis (local versus disseminated tumour growth), the histology (PB versus PPTID) and the degree of residual disease after initial treatment are independent prognostic factors in adult patients [7]. The prognosis for PBs in infants younger than 18 months is dismal [49]. In older children treated with radiotherapy and chemotherapy, a 3-year progression-free survival rate of 61% has been reported; however, this is at the cost of severe developmental adverse effects in children younger than 9 years of age [49]. In children with supra-tentorial PNETs, tumours located in the pineal region appear to be associated with a better outcome than cerebral tumours [50–51]. Trilateral retinoblastoma is a usually fatal disease, with an average survival time of less than 1 year [39–40]. The clinical outcome for patients with PPTID is highly variable, so the WHO classification does not assign a definite grade to these neoplasms. Other studies have proposed that intermediate tumours can be subdivided histologically into two grades associated with significantly different outcomes: grade II for tumours with fewer than six mitoses per 10 high-power fields and strong NFP expression and grade III for tumours with either six or more mitoses per 10 high-power fields or fewer than six mitoses per 10 high-power fields, but with negligible NFP immunoreactivity [2,4]. Event-free and overall survivals are significantly better for patients with grade II tumours, the 5-year survival rates being 74% for grade II and 42% for grade III tumours [4]. In a series of 37 adult patients with PPTIDs that were not stratified by grading, the median overall survival was 165 months and the 5- and 10-year survival rates were 80 and 72%, respectively [7]. The Ki-67 LI is a useful additional information when predicting tumour grading [21]. 1.10. Differential diagnosis The distinction between PCs and normal pineal gland can be difficult when only small biopsy specimens are available. However, in normal pineal gland, lobulation is more prominent, but proliferative activity and pineocytomatous rosettes are absent. Immunostaining for neuronal markers highlights the lobularity of the normal pineal gland. The distinction between PC and PPTID relies upon identifying prominent pineocytomatous rosettes and lower proliferation indices in PCs. The differential diagnosis of PBs includes embryonal tumours that can seed or infiltrate the pineal region, in particular, medulloblastoma, supra-tentorial PNETs and high-grade small-cell gliomas. CRX immunolabelling might distinguish PB from PNET [20,52]. PBs have also to be distinguished from PPTIDs, which can also be of high grade. The distinction hinges upon cellularity, cytology atypia, mitotic activity, the presence of necrosis and Ki-67 LI. In adults, metastatic small-cell carcinoma can be distinguished from PB by immunoreactivity for epithelial markers, such as cytokeratins. Malignant germ cell tumours can resemble PBs on imaging, but the two can usually be easily distinguished histologically. PPTIDs should not be mistaken for neurocytoma or oligodendroglioma. The clear cells and sheet-like growth patterns of some oligodendrogliomas and neurocytomas, as well as the presence of fibrillary areas or perivascular neuritic processes in the latter, may lead to misdiagnosis, but PPTIDs do not express Olig2 or NeuN. PPTIDs need to be distinguished from PCs and PBs on the basis of histopathological criteria, mitotic activity and NFP expression. More particularly, high-grade PPTIDs need to be distinguished
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from PBs, which, in contrast, present a higher cellular density and small cells with a scant cytoplasm surrounding an hyper-chromatic nucleus. 2. Pineal cysts 2.1. Incidence, age and sex distribution Glial cysts of the pineal gland (pineal cysts) are common incidental findings on MRI, with reported incidences of cysts larger than 5 mm ranging from 1.4% to 4.3% in healthy subjects [53–54]. Autopsy data suggest a prevalence of up to 40% in the elderly, when cysts larger than 2 mm across are considered [55]. Rare studies have suggested a higher incidence in females [56–59]. 2.2. Macroscopic examination Macroscopically, pineal cysts are filled with a clear or pale yellow proteinaceous fluid and have a smooth lining, which sometimes shows siderotic discoloration due to old haemorrhage. 2.3. Microscopy Histological examination demonstrates a characteristic pattern in the cyst wall. This consists of a paucicellular and finely fibrillary gliotic inner layer, with Rosenthal fibres, eosinophilic granular bodies and some deposits of haemosiderin. Indeed, haemorrhage may rarely cause an abrupt onset of symptoms, a condition referred to as “pineal cyst apoplexy” [54]. The gliotic layer is bordered by pineal parenchyma and an outer fibrovascular capsule. The pineal tissue is sharply demarcated from the inner gliotic layer and often appears somewhat disorganized due to chronic compression. However, its lobular architecture is usually still recognizable and the small calcifications of the normal pineal gland (“acervulus” or “brain sand”) are still present. 2.4. Immunohistochemistry Immunohistochemistry shows strong expression of GFAP and PS100 in the gliotic layer of the cyst wall. The adjacent pineal parenchyma stains strongly for SYN. The strong NFP immunopositivity makes the lobularity of the pineal parenchyma much more obvious [2]. Proliferative activity, as determined by the Ki-67 LI, is absent. 2.5. Electron microscopy At the ultrastructural level, the normal and cystic pineal glands are characterized by the juxtaposition of clear and dark cells. The dark cells contain numerous organelles, specifically clusters of mitochondria, dense-core vesicles, “synaptic ribbons” and paired twisted filaments [1,60]. 2.6. Differential diagnoses The two principal differential diagnoses to pineal cyst are PC and pilocytic astrocytoma. On MRI, PCs are not truly cystic [61] and pineal cysts are stable lesions [62]. Microscopically, PCs are recognized by their pineocytomatous rosettes and lack the normal lobularity of the pineal gland. In addition, PCs are rarely cystic and do not form a gliotic zone with Rosenthal fibres and haemosiderin deposits. In contrast to pilocytic astrocytomas, which are rare in the pineal gland, the gliotic layer of a pineal cyst is less cellular and lacks a biphasic architecture with compact and microcystic areas. However, the diagnosis is particularly challenging on small biopsy
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specimens when tectal glioma coexists with fragments of a pineal cyst. 2.7. Histogenesis The origin of pineal cysts is unknown. Various hypotheses have been raised, including a dysembryogenetic origin, development from a diverticulum of the third ventricle or a degenerative or post-haemorrhagic origin [54,58,63]. References [1] Jouvet A, Fèvre Montange M, Besanc¸on R, Derrington E, Saint-Pierre G, Belin MF, et al. Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumours. Acta Neuropathol 1994;88:334–48. [2] Jouvet A, Saint-Pierre G, Fauchon F, Privat K, Bouffet E, Ruchoux MM, et al. Pineal parenchymal tumours: a correlation of histological features with prognosis in 66 cases. Brain Pathol 2000;10:49–60. [3] Nakazato Y, Jouvet A, Scheithauer BW. Tumours of the pineal region. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer; 2007. p. 122–7. [4] Fauchon F, Jouvet A, Paquis P, Saint-Pierre G, Mottolese C, Ben Hassel, et al. Parenchymal pineal tumours: a clinicopathological study of 76 cases. Int J Radiat Oncol Biol Phys 2000;46:959–68. [5] Dahiya S, Perry A. Pineal tumours. Adv Anat Pathol 2010;17:419–27. [6] Mena H, Armonda RA, Ribas JL, Ondra SL, Rushing EJ. Nonneoplastic pineal cysts: a clinicopathologic study of twenty-one cases. Ann Diagn Pathol 1997;1:11–8. [7] Lutterbach J, Fauchon F, Schild SE, Chang SM, Pagenstecher A, Volk B, et al. Malignant pineal parenchymal tumours in adult patients: patterns of care and prognostic factors. Neurosurgery 2002;51:44–55. [8] Lee JY, Wakabayashi T, Yoshida J. Management and survival of pineoblastoma: an analysis of 34 adults from the Brain Tumour Registry of Japan. Neurol Med Chir (Tokyo) 2005;45:132–41. [9] Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, et al. Pineal parenchymal tumours. Clinical, pathologic, and therapeutic aspects. Cancer 1993;72:870–80. [10] Arivazhagan A, Anandh B, Santosh V, Chandramouli BA. Pineal parenchymal tumours – utility of immunohistochemical markers in prognostication. Clin Neuropathol 2008;27:325–33. [11] Schild SE, Scheithauer BW, Haddock MG, Wong WW, Lyons MK, Marks LB, et al. Histologically confirmed pineal tumours and other germ cell tumours of the brain. Cancer 1996;78:2564–71. [12] Kuchelmeister K, von Borcke IM, Klein H, Bergmann M, Gullotta F. Pleomorphic pineocytoma with extensive neuronal differentiation: report of two cases. Acta Neuropathol 1994;88:448–53. [13] Fèvre Montange M, Szathmari A, Champier J, Mokhtari K, Chrétien F, Coulon A, et al. Pineocytoma and parenchymal tumours of intermediate differentiation presenting cytologic pleomorphism: a multicenter study. Brain Pathol 2008;18:354–9. [14] Coca S, Vaquero J, Escandon J, Moreno M, Peralba J, Rodriguez J. Immunohistochemical characterization of pineocytomas. Clin Neuropathol 1992;11:298–303. [15] Numoto RT. Pineal parenchymal tumours: cell differentiation and prognosis. J Cancer Res Clin Oncol 1994;120:683–90. [16] Korf HW, Klein DC, Zigler JS, Gery I, Schachenmayr W. S-antigen-like immunoreactivity in a human pineocytoma. Acta Neuropathol 1986;69:165–7. [17] Perentes E, Rubinstein LJ, Herman MM, Donoso LA. S-antigen immunoreactivity in human pineal glands and pineal parenchymal tumours. A monoclonal antibody study. Acta Neuropathol 1986;71:224–7. [18] Fukuda T, Akiyama N, Ikegami M, Takahashi H, Sasaki A, Oka H, et al. Expression of hydroxyindole-O-methyltransferase enzyme in the human central nervous system and in pineal parenchymal cell tumours. J Neuropathol Exp Neurol 2010;69:498–510. [19] Fèvre Montange M, Vasiljevic A, Frappaz D, Champier J, Szathmari A, Aubriot Lorton MH, et al. Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study. Neuropathol Appl Neurobiol 2012;38:87–94. [20] Santagata S, Maire CL, Idbaih A, Geffers L, Corell M, Holton H, et al. CRX is a diagnostic marker of retinal and pineal lineage tumours. PLoS One 2009;4, http://dx.doi.org/10.1371/journal.pone.0007932 [e7932]. [21] Zhu L, Ren G, Li K, Liang ZH, Tang WJ, Ji YM, et al. Pineal parenchymal tumours: minimum apparent diffusion coefficient in prediction of tumour grading. J Int Med Res 2011;39:1456–63. [22] Hassoun J, Gambarelli D, Peragut JC, Toga M. Specific ultrastructural markers of human pinealomas. A study of four cases. Acta Neuropathol 1983;62:31–40. [23] Hassoun J, Devictor B, Gambarelli D, Peragut JC, Toga M. Paired twisted filaments: a new ultrastructural marker of human pinealomas? Acta Neuropathol 1984;65:163–5. [24] Fèvre Montange M, Jouvet A, Privat K, Korf HK, Champier J, Reboul A, et al. Immunohistochemical, ultrastructural, biochemical and in vitro studies of a pineocytoma. Acta Neuropathol 1998;95:532–9.
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Report 2013: Tumors of the pineal region
Pineal parenchymal tumours and pineal cysts Tumeurs du parenchyme pinéal et kystes de la glande pinéale A. Jouvet a,∗,b , A. Vasiljevic a,b , J. Champier b , M. Fèvre Montange b a b
Service de pathologie et de neuropathologie, centre de biologie et pathologie Est, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron, France Inserm U1028, CNRS UMR5292, équipe neuro-oncologie et neuro-inflammation, centre de recherche en neurosciences de Lyon, 69372 Lyon, France
a r t i c l e
i n f o
Article history: Received 25 March 2013 Received in revised form 12 April 2013 Accepted 15 April 2013 Available online xxx Keywords: Pineal parenchymal tumours Pineocytoma Pineoblastoma Pineal parenchymal tumours with intermediate differentiation
a b s t r a c t Background and purpose. – Pineal parenchymal tumours (PPTs) and pineal cysts represent one third of the pineal region lesions. PPTs are subdivided into pineocytoma (PC), pineoblastoma (PB) and PPT with intermediate differentiation (PPTID). We report morphological and immunochemical features which permit to grade these tumours. Methods. – The description of histopathological features and grading is based on a large cooperative series and on the WHO 2007 classification. Results. – PCs occur in adults between the third and the sixth decade of life. PBs typically occur in children. PPTIDs have a peak incidence in young adults between 20 and 40 years of age. There is no sex preference. PC is characterized by a uniform cell proliferation with large fibrillary pineocytomatous rosettes. PB is a high-density tumour composed of small blue cells with hyper-chromatic, round or carrot shaped nuclei. PPTIDs have lobulated or diffuse patterns. Grading is based on morphological features, count of mitoses and neurofilament protein (NFP) expression. PCs (grade I) have no mitosis and NFP is highly expressed in pineocytomatous rosettes. PBs (grade IV) are high mitotic tumours and present low or no expression of NFPs. PPTIDs are grade II when mitoses are fewer than 6 for 10 high-power fields and NFPs are expressed, and are grade III when mitoses are greater or equal to 6 or are fewer than 6 with NFPs lowly expressed. Pineal cysts may be differentiated from PPTs by the high expression of NFPs and no expression of Ki-67. © 2014 Published by Elsevier Masson SAS.
r é s u m é Mots clés : Tumeur du parenchyme pinéal Pinéalocytome Pinéaloblastome Tumeur du parenchyme pinéal à différenciation intermédiaire
Contexte et objectifs. – Les tumeurs du parenchyme pinéal (TPP) et les kystes de la glande pinéale représentent 30 % des processus expansifs de la région pinéale. Les TPP comprennent les pinéalocytomes (PC), les pinéaloblastomes (PB) et les TPP à différenciation intermédiaire (TPPDI). À partir d’une série multicentrique, nous avons établi un classement en quatre grades reconnu par l’OMS en 2007 : grade I (PC), grades II et III (TPPDI) et grade IV (PB). Méthodes. – La description histopathologique, les données des immunomarquages et le grading sont basés sur la classification de l’OMS. Résultats. – Les PC sont des tumeurs de l’adulte. Les PB s’observent le plus souvent chez l’enfant. Les TPPDI sont des tumeurs de l’adulte jeune. Il n’y a pas de prévalence de sexe. Les PC présentent de larges pseudorosettes fibrillaires au sein d’une prolifération de cellules pinéalocytaires, n’ont pas de mitoses et expriment les neurofilaments (NF). Les PB correspondent à une prolifération de petites cellules bleues indifférenciées aux noyaux hyperchromatiques ronds ou en forme de carottes, aux index mitotique et de prolifération élevés. L’architecture des TPPDI est lobulée endocrinoïde ou diffuse sans pseudorosette. Les TPPDI grade II ont moins de six mitoses pour dix champs × 400 et une forte expression de NF. Les TPPDI grade III ont soit six ou plus de six mitoses pour dix champs soit moins de six mitoses mais une faible expression de NF. Les kystes de la glande pinéale expriment très fortement les NF. © 2014 Publie´ par Elsevier Masson SAS.
∗ Corresponding author. E-mail address: [email protected] (A. Jouvet).
Tumours of the pineal region (TPRs) are rare, accounting for 2 to 3% of all intracranial tumours. Neuroepithelial tumours, such as pineal parenchymal tumours (PPTs), glial tumours and papillary tumours of the pineal region (PTPRs) represent approximately 50% of tumours in the pineal region. Germ cells tumours account
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for 30% of the TPR. Miscellaneous tumoural lesions (meningiomas, metastases) and non-neoplastic lesions (pineal cysts, arachnoidal cysts, vascular malformations) correspond to the last 20% of TPR. All histopathological and clinical data of TPRs are collected in a National Registry in Lyon (Hôpital Neurologique, Groupement Hospitalier Est) that contains more than 500 cases. This report is focused on the pathological classification of PPTs and on glial cysts that need to be distinguished from pineal tumours, particularly pineocytoma. PTPRs, described as a novel neoplasm in pineal region, are presented in another section.
The gross appearance of PPTIDs is similar to that of PCs. The tumours are circumscribed, soft in texture and lacking gross evidence of necrosis. 1.4. Microscopy
PPTs account for approximately 30% of tumours in the pineal region [4]. Our registry of TPRs includes 173 cases of PPTs in 2012 from 19 French centers, 53 were cases from Lyon (Neurosurgical Hospital). Histopathologically, they constitute a morphologic continuum from slowly growing well-differentiated lesions to highly proliferative tumours. In a literature review of 16 papers covering 326 PPTs, 145 (44%) were found to be PCs [4]. This percentage might be overestimate, as some PPTIDs were classified as PCs before the 2007 WHO classification. PCs account for 14% to 30% of all PPTs [5] and may present at any age, but mostly occur in adults, with a peak incidence between the third and sixth decades of life [3]. There is no gender preference. PBs typically occur in children, with a mean age of 12.6 years, but adults may also be affected [4,6], with reports of individual patients older than 60 years [7–8]. There is no gender predilection. The relative frequency of PPTIDs varies in the literature because, in some reports, this intermediate group of tumours was considered as PCs or PBs, reflecting the difficulties in establishing reproducible definitional criteria. If only studies with a true intermediate group are considered, PPTIDs represent 20 to 62% of PPTs [4,9–10]. These studies clearly indicate that tumours with mixed or intermediate features are not uncommon among pineal parenchymal neoplasms. These neoplasms occur mostly in adults, with a peak incidence in young adults between 20 and 40 years of age. Most present as localized disease. Dissemination via the cerebrospinal fluid (CSF) is less common than for PBs [4,7,11].
Typical PCs are composed of well-differentiated tumour cells that resemble pineocytes and grow in a sheet-like pattern. The tumour cells are remarkably uniform, with a sparse, eosinophilic cytoplasm, short processes and round-to-oval nuclei with finely dispersed chromatin and inconspicuous nucleoli. Silver impregnation techniques highlight short cytoplasmic processes, often with bulbous or club-shaped terminations. Micro-calcifications may be seen. Mitotic figures are absent or exceedingly rare. Necrosis is very rare. The most characteristic feature of the PC is the formation of relatively large, sometimes confluent “pineocytomatous” rosettes (Fig. 1A). These structures appear as ovoid eosinophilic areas composed of a delicate meshwork of tumour cell processes. Pineocytomatous rosettes are similar to neuroblastic rosettes of the Homer Wright type, but considerably larger. A subset of PCs is characterized by the presence of large ganglionic cells and/or pleomorphic multinucleated giant cells [2,12–13]. They show no evidence of significant proliferative activity and have an indolent biological behaviour. PBs are composed of densely packed small cells with a scant cytoplasm, hyper-chromatic, round or oval nuclei and high nuclear/cytoplasmic ratios. They resemble other small cells or PNETs of the CNS (Fig. 1B). The tumour cells grow in patternless sheets, usually without any obvious lobular architecture. Pineocytomatous rosettes are absent. However, PBs often contain neuroblastic rosettes of the Homer Wright type or retinoblastic rosettes of the Flexner–Wintersteiner type. Large cell/anaplastic features, as seen in medulloblastomas, can be present. PBs occasionally show evidence of advanced photoreceptor differentiation, with the formation of “fleurettes”. Rare tumours contain cells with melanin pigment. Mitotic figures are frequent. Apoptotic bodies and areas of necrosis may be prominent, the latter sometimes being associated with micro-calcifications. Vessels are usually thinwalled, but focal endothelial proliferation may be seen. Histologically, PPTIDs present variable features [2]. These include an endocrine-like lobular architecture (Fig. 1C) or a more diffuse growth of isomorphic tumour cells with round nuclei and a clear cytoplasm (Fig. 1D). Such neoplasms should not be mistaken for neurocytoma or oligodendroglioma. Another phenotype, reported as a “transitional variant”, has mixed lobular/diffuse areas, in addition to regions with a PC-like morphology. Finally, some rare tumours may present with a biphasic pattern combining the typical features of PCs and PBs. These mixed PC/PB may correspond to pineoblastoma with residual pineal gland. Neoplastic cells have less cytoplasm than in PCs, but it is still visible on standard staining. Nuclear atypia is moderate. Mitotic activity is usually present in intermediate tumours, but may vary considerably. Foci of necrosis or vascular proliferation have been reported in subsets of PPTIDs, although they lack the primitive “small blue cell” appearance of PBs [2]. A pleomorphic variant may be encountered in low-grade PPTIDs [13].
1.3. Macroscopic examination
1.5. Immunohistochemistry
PCs are circumscribed, grey or grey-brown tumours, with a cut surface that is homogeneous and often finely granular. Some show degenerative changes, such as small cysts. Necrosis is rare. PBs are poorly demarcated, soft or gelatinous, grey-pink tumours. Haemorrhagic and necrotic areas may be present. The tumours often destroy the pineal gland, bulge into the posterior third ventricle and compress the colliculi and the aqueduct.
PCs are immunopositive for neuron specific enolase (NSE), synaptophysin (SYN) (Fig. 2A) and NFPs (Fig. 2B), with strong reactivity in pineocytomatous rosettes. Immunoreactivity for several other neuronal or neuroendocrine antigens, including class III betatubulin, microtubule-associated protein 2 (MAP2), tau protein and chromogranin A, is also common [2,14–15]. In pleomorphic PCs, the pleomorphic cells show strong expression of SYN and NFPs
1. Pineal parenchymal tumours 1.1. Introduction and historical considerations The study of PPT in our institution began in the 1990s with an ultrastructural study of 20 cases [1]. A prognosis classification was proposed in 2000 on a multicentric series of 66 cases [2]. This classification in four grades of PPTs is based on morphological patterns, on mitotic count and immunohistochemical staining for neurofilament proteins (NFPs). The 2007 WHO classification subdivides this continuum into three distinct tumour categories: pineocytoma (PC) (Grade I), pineal parenchymal tumour of intermediate differentiation (PPTID) (Grades II and III) and pineoblastoma (PB) (Grade IV) [3]. 1.2. Incidence, age and sex distribution
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Fig. 1. Light microscopy features of PPTs (hemalum, phloxine, saffron staining). A. Typical pineocytoma: uniform cell proliferation with large “pineocytomatous” rosettes. B. Pineoblastoma: tumour with dense cellularity. Small blue cells with round or carrot shaped hyper-chromatic nuclei. C and D. PPTs with intermediate differentiation (PPTIDs): proliferation of neoplastic cells harbouring round uniform nuclei. Lobulated PPTID with endocrine-like vasculature (C), diffuse PPTID with neurocytoma-like growth (D). Aspects microscopiques des tumeurs du parenchyme pinéal (TPP) (hemalun, phloxine, safran). A. Pinéalocytome typique : prolifération de cellules monomorphes avec de larges pseudorosettes pinéalocytaires fibrillaires. B. Pinéaloblastome : tumeur d’une grande densité cellulaire, constituée de petites cellules bleues avec des noyaux ronds ou en forme de carottes hyperchromatiques. C et D. TPP avec différenciation intermédiaire (TPPDI) : prolifération de cellules tumourales aux noyaux ronds monomorphes. TPPDI lobulée avec une vascularisation endocrinoïde (C). TPPDI diffuse ressemblant à un neurocytome (D).
Fig. 2. Immunohistochemical features of PPTs. A and B. Pineocytomas: strong reactivity of synaptophysin (A) and high expression of NFPs (B) in “pineocytomatous” rosettes. C. Pineal parenchymal tumour of intermediate differentiation (PPTID): tumoural cells expressed NFPs. D. Ki-67 labelling index (LI) in PPTID. E. Pineoblastoma: The Ki-67 Li is very high. Profil immunohistochimique des TPP. A et B. Pinéalocytome : forte expression de la synaptophysine (A) et des neurofilaments (B) dans les pseudorosettes pinéalocytaires. C. Tumeur du parenchyme pinéal à différenciation intermédiaire (TPPDI) : marquage anti-neurofilaments des cellules tumourales. D. Index de prolifération avec anti-Ki-67 des TPPDI. E. Pinéaloblastome : index de prolifération avec anti-Ki-67 élevé.
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and sometimes chromogranin A [12–13]. PCs can demonstrate a photoreceptor-like immunophenotype, with patchy positivity for retinal S-antigen and/or rhodopsin [16–17]. They also express hydroxy-indole-O-methyltransferase (HIOMT), the enzyme that catalyses the final reaction in melatonin biosynthesis [18]. S-100 protein (S100P) immunoreactivity is seen in the interstitial astrocytic cells and sometimes in the neoplastic cells, to varying degrees. Glial fibrillary acidic protein (GFAP) expression is seen in reactive astrocytes [2,14]. Proliferative activity, as assessed by the Ki-67 labelling index (LI), is low [10,15,19]. In PBs, a dot-like or diffuse immunoreactivity for SYN is commonly detected [2,6]. NSE expression is also found, while immunoreactivity for NFPs and/or chromogranin A is inconsistent and tends to be restricted to individual tumour cells [2,6]. PBs can contain cells with immunoreactivity for photoreceptor markers, such as retinal S-antigen [17] or CRX [20]. GFAP and PS100 immunoreactivity is rare [2]. In PPTIDs, expression of neuronal markers is variable. Cytoplasmic SYN labelling is usually diffuse and of variable intensity. NFPs can be expressed in a variable number of cells, and this variability has been used together with morphology and proliferation to discriminate low-grade from high-grade PPTIDs (Fig. 2C). Chromogranin A may be seen in PPTIDs, especially those with a pseudolobulated architecture [2]. 1.6. Proliferation PCs grow slowly, and the Ki-67 labelling index (LI) is very low [19,21]. The Ki-67 LI of PB is very high (mean: 36.4 ± 6.2) [19] (Fig. 2E). The mean Ki-67 LI is significantly different for PPTIDs Grade II and Grade III (Grade II: 5.2 ± 0.4, Grade III: 11.2 ± 2.0) [19] (Fig. 2D). 1.7. Electron microscopy PCs are composed of clear cells with a varying numbers of dark cells, sometimes joined by zonula adherents [1]. Their cytoplasm is relatively abundant and contains well-developed organelles, including smooth and rough endoplasmic reticulum, Golgi complex, mitochondria, multi-vesicular bodies and lysosomes. The tumour cells share many ultrastructural features with normal pineocytes, such as dense-core (neurosecretory) vesicles, clear (synaptic-type) vesicles, vesicle-crowned rodlets (synaptic ribbons), paired twisted filaments and “fibrous filaments” [1,22–25]. Tumour cell processes are filled with microtubules and terminate in vesicle-rich club-like expansions, which may show synapse-like junctions. Some tumours show signs of photoreceptor differentiation, including the presence of cytoplasmic annulate lamellae, as well as cilia with a 9 + 0 configuration [1]. In line with ultrastructural findings for other CNS PNETs, PBs contain poorly differentiated cells with a scant cytoplasm and few short processes without the bulbous terminations typically seen in PCs [1,15,26]. Scant microtubules and occasional dense-core vesicles may be observed. However, specialized structures, such as paired twisted filaments, vesicle-crowned rodlets or synaptic junctions, are absent. PPTIDs display an intermediate appearance, with short cytoplasmic processes and rare bulbous endings. In pseudolobulated PPTIDs, the organelles characteristic of neurosensory/photoreceptor differentiation are usually absent, but the cell processes contain oriented microtubules, clear synaptic-like vesicles and dense-cored vesicles. 1.8. Molecular genetics Cytogenetic studies on PCs are rare and have not shown any clinically relevant non-randomly distributed abnormalities. In
conventional cytogenetic studies, PCs present both numerical and structural aberrations, but the results have not been very consistent. In three conventional cytogenetic studies, the karyotype of PCs was mostly pseudodiploid and the common abnormalities included losses of chromosomes 4, 5, 14 and 15 and, in two patients, loss of all, or part, of chromosomes 22, 11 and 1 was observed [25,27–28]. On comparative genomic hybridization (CGH), these tumours lack any consistent gains or losses [29]. TP53 mutation and p53 protein accumulation were not detected in five PCs [30]. Conventional or CGH cytogenetic studies on PBs have shown both numerical and structural abnormalities [29,31–33]. The karyotypes are mostly near-diploid, but hyper-tetraploidy has been reported. Recurrent aberrations include gains on chromosome arms 1q, 5p, 5q, 6p and 14q and losses of chromosomes 20 and 22, as well as isochromosome 17q (i[17q]), or unbalanced gain of 17q. In cytogenetic reports of 13 PBs, i[17q] or unbalanced 17q gain was described in four cases, including two tumours and two cell lines [32–33]. In contrast, CGH studies have shown that most PBs do not exhibit 17q gain [29,34]. Thus, whether PBs are genetically related to CNS PNETs or medulloblastomas remains unclear. In vitro, PB cell lines showed enhanced N-myc expression in the absence of MYCN gene amplification, in contrast to the situation in medulloblastomas [35–36]. No TP53 mutations were demonstrated in four PBs [30]. The RB1 gene has not been studied for genetic alterations in sporadic PBs [32]. However, studies on knock-out mice indicate that the simultaneous inactivation of P53 and RB1 results in an increased rate of PBs [37]. The majority of PBs develop sporadically. However, patients with germline mutations in the retinoblastoma tumour suppressor gene and familial retinoblastoma syndrome have an increased risk of developing PBs, a condition known as “trilateral retinoblastoma” [38–40]. PBs that arise in this setting have a more aggressive course than sporadic cases [41]. However, no specific abnormalities of chromosome 13q in the region of the RB1 gene have been found in conventional or CGH cytogenetic studies [29,33]. One case of PB associated with familial adenomatous polyposis has been reported as a potential variant of Turcot’s syndrome type 2, an inherited disease involving the adenomatous polyposis coli (APC) gene and characterized by a predisposition to colonic neoplasms and brain tumours, specifically medulloblastomas [42]. This case remains isolated, and no association has been made between APC gene mutation and PB, in contrast to the firm association between mutation of this gene and medulloblastomas. One CGH study of PPTIDs showed that the profile is close to that of PBs in terms of chromosome 22 loss and that PPTIDs and PBs display similar proportions of chromosomal imbalances per case (5.3 for PPTIDs and 5.6 for PBs) [29]. 1.9. Biological behaviour, prognosis and grading PCs are usually associated with a favourable prognosis after treatment (5-year overall survival ranging from 86% to 91%) and do not metastasize [4,11]. The literature is primarily composed of case reports and small case series, in which low-grade PPTIDs were sometimes considered as PCs. A recent review of 64 publications describing 168 patients indicated that surgical resection is the appropriate treatment for these tumours [43]. Adjuvant fractionated radiotherapy does not improve the rate of tumour control or survival when used to treat a subtotal resected tumour, but close radiological follow-up is recommended [43–44]. However, other authors reported that radiosurgery has a role as an alternative primary treatment modality for small lesions, as well as in the treatment of residual and recurrent tumours [45–46]. In contrast, PBs are locally invasive and tend to disseminate via the CSF, requiring aggressive treatment. In adults, stereotactic biopsy or open surgery is usually followed by adjuvant radiotherapy and chemotherapy [7–8,47–48]. Nevertheless, the prognosis
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is poor, as indicated by a median survival time of 16 months and a 5-year survival rate of 10% in a retrospective series of 18 patients [4]. More recent data indicate a slightly better median overall survival for adult patients, ranging from 25.7 to 77 months [7–8]. The extent of disease at diagnosis (local versus disseminated tumour growth), the histology (PB versus PPTID) and the degree of residual disease after initial treatment are independent prognostic factors in adult patients [7]. The prognosis for PBs in infants younger than 18 months is dismal [49]. In older children treated with radiotherapy and chemotherapy, a 3-year progression-free survival rate of 61% has been reported; however, this is at the cost of severe developmental adverse effects in children younger than 9 years of age [49]. In children with supra-tentorial PNETs, tumours located in the pineal region appear to be associated with a better outcome than cerebral tumours [50–51]. Trilateral retinoblastoma is a usually fatal disease, with an average survival time of less than 1 year [39–40]. The clinical outcome for patients with PPTID is highly variable, so the WHO classification does not assign a definite grade to these neoplasms. Other studies have proposed that intermediate tumours can be subdivided histologically into two grades associated with significantly different outcomes: grade II for tumours with fewer than six mitoses per 10 high-power fields and strong NFP expression and grade III for tumours with either six or more mitoses per 10 high-power fields or fewer than six mitoses per 10 high-power fields, but with negligible NFP immunoreactivity [2,4]. Event-free and overall survivals are significantly better for patients with grade II tumours, the 5-year survival rates being 74% for grade II and 42% for grade III tumours [4]. In a series of 37 adult patients with PPTIDs that were not stratified by grading, the median overall survival was 165 months and the 5- and 10-year survival rates were 80 and 72%, respectively [7]. The Ki-67 LI is a useful additional information when predicting tumour grading [21]. 1.10. Differential diagnosis The distinction between PCs and normal pineal gland can be difficult when only small biopsy specimens are available. However, in normal pineal gland, lobulation is more prominent, but proliferative activity and pineocytomatous rosettes are absent. Immunostaining for neuronal markers highlights the lobularity of the normal pineal gland. The distinction between PC and PPTID relies upon identifying prominent pineocytomatous rosettes and lower proliferation indices in PCs. The differential diagnosis of PBs includes embryonal tumours that can seed or infiltrate the pineal region, in particular, medulloblastoma, supra-tentorial PNETs and high-grade small-cell gliomas. CRX immunolabelling might distinguish PB from PNET [20,52]. PBs have also to be distinguished from PPTIDs, which can also be of high grade. The distinction hinges upon cellularity, cytology atypia, mitotic activity, the presence of necrosis and Ki-67 LI. In adults, metastatic small-cell carcinoma can be distinguished from PB by immunoreactivity for epithelial markers, such as cytokeratins. Malignant germ cell tumours can resemble PBs on imaging, but the two can usually be easily distinguished histologically. PPTIDs should not be mistaken for neurocytoma or oligodendroglioma. The clear cells and sheet-like growth patterns of some oligodendrogliomas and neurocytomas, as well as the presence of fibrillary areas or perivascular neuritic processes in the latter, may lead to misdiagnosis, but PPTIDs do not express Olig2 or NeuN. PPTIDs need to be distinguished from PCs and PBs on the basis of histopathological criteria, mitotic activity and NFP expression. More particularly, high-grade PPTIDs need to be distinguished
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from PBs, which, in contrast, present a higher cellular density and small cells with a scant cytoplasm surrounding an hyper-chromatic nucleus. 2. Pineal cysts 2.1. Incidence, age and sex distribution Glial cysts of the pineal gland (pineal cysts) are common incidental findings on MRI, with reported incidences of cysts larger than 5 mm ranging from 1.4% to 4.3% in healthy subjects [53–54]. Autopsy data suggest a prevalence of up to 40% in the elderly, when cysts larger than 2 mm across are considered [55]. Rare studies have suggested a higher incidence in females [56–59]. 2.2. Macroscopic examination Macroscopically, pineal cysts are filled with a clear or pale yellow proteinaceous fluid and have a smooth lining, which sometimes shows siderotic discoloration due to old haemorrhage. 2.3. Microscopy Histological examination demonstrates a characteristic pattern in the cyst wall. This consists of a paucicellular and finely fibrillary gliotic inner layer, with Rosenthal fibres, eosinophilic granular bodies and some deposits of haemosiderin. Indeed, haemorrhage may rarely cause an abrupt onset of symptoms, a condition referred to as “pineal cyst apoplexy” [54]. The gliotic layer is bordered by pineal parenchyma and an outer fibrovascular capsule. The pineal tissue is sharply demarcated from the inner gliotic layer and often appears somewhat disorganized due to chronic compression. However, its lobular architecture is usually still recognizable and the small calcifications of the normal pineal gland (“acervulus” or “brain sand”) are still present. 2.4. Immunohistochemistry Immunohistochemistry shows strong expression of GFAP and PS100 in the gliotic layer of the cyst wall. The adjacent pineal parenchyma stains strongly for SYN. The strong NFP immunopositivity makes the lobularity of the pineal parenchyma much more obvious [2]. Proliferative activity, as determined by the Ki-67 LI, is absent. 2.5. Electron microscopy At the ultrastructural level, the normal and cystic pineal glands are characterized by the juxtaposition of clear and dark cells. The dark cells contain numerous organelles, specifically clusters of mitochondria, dense-core vesicles, “synaptic ribbons” and paired twisted filaments [1,60]. 2.6. Differential diagnoses The two principal differential diagnoses to pineal cyst are PC and pilocytic astrocytoma. On MRI, PCs are not truly cystic [61] and pineal cysts are stable lesions [62]. Microscopically, PCs are recognized by their pineocytomatous rosettes and lack the normal lobularity of the pineal gland. In addition, PCs are rarely cystic and do not form a gliotic zone with Rosenthal fibres and haemosiderin deposits. In contrast to pilocytic astrocytomas, which are rare in the pineal gland, the gliotic layer of a pineal cyst is less cellular and lacks a biphasic architecture with compact and microcystic areas. However, the diagnosis is particularly challenging on small biopsy
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specimens when tectal glioma coexists with fragments of a pineal cyst. 2.7. Histogenesis The origin of pineal cysts is unknown. Various hypotheses have been raised, including a dysembryogenetic origin, development from a diverticulum of the third ventricle or a degenerative or post-haemorrhagic origin [54,58,63]. References [1] Jouvet A, Fèvre Montange M, Besanc¸on R, Derrington E, Saint-Pierre G, Belin MF, et al. Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumours. Acta Neuropathol 1994;88:334–48. [2] Jouvet A, Saint-Pierre G, Fauchon F, Privat K, Bouffet E, Ruchoux MM, et al. Pineal parenchymal tumours: a correlation of histological features with prognosis in 66 cases. Brain Pathol 2000;10:49–60. [3] Nakazato Y, Jouvet A, Scheithauer BW. Tumours of the pineal region. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer; 2007. p. 122–7. [4] Fauchon F, Jouvet A, Paquis P, Saint-Pierre G, Mottolese C, Ben Hassel, et al. Parenchymal pineal tumours: a clinicopathological study of 76 cases. Int J Radiat Oncol Biol Phys 2000;46:959–68. [5] Dahiya S, Perry A. Pineal tumours. Adv Anat Pathol 2010;17:419–27. [6] Mena H, Armonda RA, Ribas JL, Ondra SL, Rushing EJ. Nonneoplastic pineal cysts: a clinicopathologic study of twenty-one cases. Ann Diagn Pathol 1997;1:11–8. [7] Lutterbach J, Fauchon F, Schild SE, Chang SM, Pagenstecher A, Volk B, et al. Malignant pineal parenchymal tumours in adult patients: patterns of care and prognostic factors. Neurosurgery 2002;51:44–55. [8] Lee JY, Wakabayashi T, Yoshida J. Management and survival of pineoblastoma: an analysis of 34 adults from the Brain Tumour Registry of Japan. Neurol Med Chir (Tokyo) 2005;45:132–41. [9] Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, et al. Pineal parenchymal tumours. Clinical, pathologic, and therapeutic aspects. Cancer 1993;72:870–80. [10] Arivazhagan A, Anandh B, Santosh V, Chandramouli BA. Pineal parenchymal tumours – utility of immunohistochemical markers in prognostication. Clin Neuropathol 2008;27:325–33. [11] Schild SE, Scheithauer BW, Haddock MG, Wong WW, Lyons MK, Marks LB, et al. Histologically confirmed pineal tumours and other germ cell tumours of the brain. Cancer 1996;78:2564–71. [12] Kuchelmeister K, von Borcke IM, Klein H, Bergmann M, Gullotta F. Pleomorphic pineocytoma with extensive neuronal differentiation: report of two cases. Acta Neuropathol 1994;88:448–53. [13] Fèvre Montange M, Szathmari A, Champier J, Mokhtari K, Chrétien F, Coulon A, et al. Pineocytoma and parenchymal tumours of intermediate differentiation presenting cytologic pleomorphism: a multicenter study. Brain Pathol 2008;18:354–9. [14] Coca S, Vaquero J, Escandon J, Moreno M, Peralba J, Rodriguez J. Immunohistochemical characterization of pineocytomas. Clin Neuropathol 1992;11:298–303. [15] Numoto RT. Pineal parenchymal tumours: cell differentiation and prognosis. J Cancer Res Clin Oncol 1994;120:683–90. [16] Korf HW, Klein DC, Zigler JS, Gery I, Schachenmayr W. S-antigen-like immunoreactivity in a human pineocytoma. Acta Neuropathol 1986;69:165–7. [17] Perentes E, Rubinstein LJ, Herman MM, Donoso LA. S-antigen immunoreactivity in human pineal glands and pineal parenchymal tumours. A monoclonal antibody study. Acta Neuropathol 1986;71:224–7. [18] Fukuda T, Akiyama N, Ikegami M, Takahashi H, Sasaki A, Oka H, et al. Expression of hydroxyindole-O-methyltransferase enzyme in the human central nervous system and in pineal parenchymal cell tumours. J Neuropathol Exp Neurol 2010;69:498–510. [19] Fèvre Montange M, Vasiljevic A, Frappaz D, Champier J, Szathmari A, Aubriot Lorton MH, et al. Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study. Neuropathol Appl Neurobiol 2012;38:87–94. [20] Santagata S, Maire CL, Idbaih A, Geffers L, Corell M, Holton H, et al. CRX is a diagnostic marker of retinal and pineal lineage tumours. PLoS One 2009;4, http://dx.doi.org/10.1371/journal.pone.0007932 [e7932]. [21] Zhu L, Ren G, Li K, Liang ZH, Tang WJ, Ji YM, et al. Pineal parenchymal tumours: minimum apparent diffusion coefficient in prediction of tumour grading. J Int Med Res 2011;39:1456–63. [22] Hassoun J, Gambarelli D, Peragut JC, Toga M. Specific ultrastructural markers of human pinealomas. A study of four cases. Acta Neuropathol 1983;62:31–40. [23] Hassoun J, Devictor B, Gambarelli D, Peragut JC, Toga M. Paired twisted filaments: a new ultrastructural marker of human pinealomas? Acta Neuropathol 1984;65:163–5. [24] Fèvre Montange M, Jouvet A, Privat K, Korf HK, Champier J, Reboul A, et al. Immunohistochemical, ultrastructural, biochemical and in vitro studies of a pineocytoma. Acta Neuropathol 1998;95:532–9.
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