The normal pineal gland is a complex structure located on the posterior wall of the third ventricle. It lacks a blood-brain barrier and has a unique histopathologic appearance with its parenchyma mostly composed of pineocytes and a few supportive astrocytes. Its diagnostically useful lobulated architecture is formed by highly vascularized connective tissue septae. The principal cells are pineocytes, which are specialized neurosecretory cells that produce melatonin, a hormone involved in circadian rhythm.1
Even though the predominant pathology encountered in the pineal region is neoplastic, pineal region tumors are quite rare, constituting less than 1% of all primary central nervous system (CNS) tumors. Of these, germ cell tumors constitute the majority (approximately 35%), followed by pineal parenchymal tumors (approximately 28%) and neuroepithelial neoplasms, including astrocytomas (mostly pilocytic), ependymomas, and papillary tumor of the pineal region (approximately 28% combined).2,3 Despite the common anatomic location and similar imaging findings, pineal region tumors are extremely heterogeneous with respect to their histopathology, natural history, and response to therapy. On account of the complexity of this region and its high vascularity, approximately 11% of biopsies are either nondiagnostic or misdiagnosed,3 highlighting the difficulty in obtaining sufficient tissue to make an accurate diagnosis.
This review highlights some of the recent changes in classifying/grading pineal parenchymal tumors, including a detailed discussion of a newly recognized tumor type, the papillary tumor of the pineal region.
Pineal parenchymal tumors constitute a morphologic continuum from pineocytoma [World Health Organization (WHO) grade I] to pineal parenchymal tumors of intermediate differentiation (PPTIDs; further stratified into WHO grades II or III) to the highly aggressive small round cell tumor, pineoblastoma (WHO grade IV). Although the histogenesis is not entirely clear, these tumors are thought to arise from pineocytes.4 Recently, papillary tumor of pineal tumor has been introduced in the WHO classification, 2007,5 as a tumor that is unique to this region, and analogous to the suspected histogenesis of chordoid glioma of the third ventricle from a circumventricular organ origin in the vicinity of the lamina terminalis, papillary tumor of pineal tumor is speculated to arise from the subcommissural organ (SCO).6–8 These tumors have been designated as WHO grades II or III based on a spectrum of malignant features and clinical outcome, although the histologic criteria to distinguish these 2 grades are not very well characterized and await additional studies.
PINEAL PARENCHYMAL TUMORS
Most pineal parenchymal tumors occur in adulthood with a slight female predominance. They remain localized to this region where they may compress adjacent structures including the cerebral aqueduct, brain stem, and cerebellum. Signs and symptoms therefore vary and relate to obstructive hydrocephalus, increased intracranial pressure with consequent headaches, nausea, vomiting, upward-gaze palsy (Parinaud syndrome), changes in mental status, and ataxia.
On magnetic resonance imaging, they are T2 bright with contrast enhancement on post-gadolinium T1 sequences, although the pattern of enhancement is variable. Whereas pineocytomas tend to enhance homogeneously, pineoblastomas show a more heterogeneous pattern9; PPTIDs show features in between. Cerebrospinal fluid (CSF) seeding may be present at the time of presentation, especially in pineoblastomas and the higher grade PPTIDs.2,10
All pineal parenchymal tumors typically display neuronal, neuroendocrine, and/or neurosensory differentiation. Proliferation rates11,12 assessed by Ki-67 immunohistochemistry and relative amounts of neuronal differentiation assessed by either electron microscopy or by immunohistochemistry10–13 are the 2 pathologic findings that have been most correlated with biologic behavior. The histologic subtype, staging at initial presentation, and response to initial treatment have also been statistically significant and independent prognostic factors.2,14 Lastly, tumor size has been found to be another independent prognostic factor in 1 series, with the risk of postoperative death being significantly higher for tumors over 4 cm in diameter.2 Given their rarity, there is no consensus to date on optimal treatment. Nonetheless, complete surgical resection is the mainstay therapy for low-grade tumors (pineocytomas and low-grade PPTIDs), whereas a multimodality approach of surgery, radiotherapy, and chemotherapy is the preferred treatment in high-grade tumors (high-grade PPTIDs and pineoblastomas).
Despite recent progress in the grading of these tumors, one of the largest series on pineal parenchymal tumors found a discrepancy of 10% between original and final diagnosis,2 indicating ongoing difficulties in classification. The considerable overlap in histopathology (especially for the PPTIDs) suggests that more objective criteria are still needed.
These tumors constitute 14% to 30% of all pineal parenchymal tumors.2,15 Most pineocytomas occur in adults from third to sixth decades, the mean age being 36.216 to 47 years.2 These tumors tend to be well circumscribed and compressive in nature.15
Histologically, they are well-differentiated, moderately cellular tumors composed of medium-sized neoplastic cells resembling mature pineocytes. The tumor cells are uniform and show a diffuse to loosely nested-growth pattern. The nuclei are round to oval or sometimes indented, with a delicate or “salt and pepper” chromatin. “Pineocytomatous rosettes” (also called pineocytic rosettes) are a distinctive feature of pineocytomas, but are not present in all cases. These structures resemble Homer Wright rosettes, but are composed of larger, more irregular fibrillary aggregates (ie, neuropil) surrounded by neoplastic cells with club-shaped terminations oriented toward the center, the latter best appreciated on a silver or neurofilament protein stain (Figs. 1A, B). Classic Homer Wright rosettes may also be present. Mitotic activity is generally low and the Ki-67 (MIB-1)-labeling index averages around 1.3% to 1.6%11,17 with a range of 0.1% to 3.3% in 1 study.17 Endothelial hyperplasia is not a usual feature, although it has been reported in scattered cases10; necrosis is typically absent.10 Ganglionic (approximately 11.4%) and glial differentiation (approximately 9.5%) can sometimes be observed.4,15,16,18
Rarely, these tumors feature scattered large pleomorphic cells with hyperchromatic nuclei reminiscent of the degenerative atypia commonly seen in other neuroendocrine neoplasms; this has been referred to as the pleomorphic variant (Fig. 1C). However, despite these atypical cells, they typically lack mitoses and do not seem to have any prognostic significance.19–21 Nonetheless, it remains important to be aware of this variant, as the presence of large pleomorphic cells may lead to erroneous upgrading especially in small biopsies.
Immunohistochemically, reactivity for glial fibrillary acidic protein (GFAP) is usually seen only focally (Fig. 1D), but these tumors show strong and widespread expression of neuronal [neuron-specific enolase (NSE), synaptophysin (Fig. 1E), and neurofilament protein (Fig. 1F)] and neuroendocrine (chromogranin A) markers.16 In rare cases, expression of retinal photoreceptor proteins: S-antigen and rhodopsin are noted.16
Genes coding for enzymes of melatonin biosynthesis (TPH and HIOMT) and those related to phototransduction in the retina (OPN4, RGS16, and CRB3) are highly expressed in pineocytomas.7 By comparative genomic hybridization (CGH), these tumors lack any consistent chromosomal gains or losses.17
Gross total resection has been set as the standard of care for these tumors, although in each case, this goal needs to be weighed against the associated risks of radical resection in this region.2,3,15,22,23
Pineocytomas are associated with a favorable outcome, with a 5-year overall survival ranging from 86% to 91%.2,14 Recurrences are uncommon in these tumors; in fact, no recurrences were noted in one of the largest studies.2
On small limited biopsies, it may be a diagnostic challenge to distinguish pineocytomas from the normal pineal gland or a pineal cyst.24 Whereas the pineocytomas generally form sheets or expanded lobules, normal pineal gland has small lobules and well-formed fibrovascular septae. A pineal cyst typically has 3-layered pattern (piloid gliosis with numerous Rosenthal fibers, compressed pineal parenchyma, and sclerotic leptomeningeal tissue).
At the most malignant end of the spectrum lies the pineoblastoma, a WHO grade IV tumor which constitutes about 24% to 50% of all pineal parenchymal tumors.2,15 These tumors occur commonly in children with a mean age of 12.6 years,2,16 but a relatively wide range of 1 to 39 years.16 These tumors are similar to other small round cell tumors of the CNS or primitive neuroectodermal tumors (PNETs), including a short clinical course and frequent development of meningeal and/or systemic metastasis. They tend to be ill-defined and invasive of their surroundings and are accompanied by leptomeningeal seeding15 in as many as 45% of cases.25
Histologically, they are classic CNS PNETs, with marked hypercellularity and a sheeted, nodular, or haphazard growth pattern. The individual tumor cells have minimal cytoplasm and contain hyperchromatic irregular nuclei, sometimes described as “carrot shaped.” The nuclear-cytoplasmic ratio is high, with frequent molding. Mitoses are frequent with variable amounts of necrosis, karyorrhexis, and apoptotic debris (Figs. 1G, H). These tumors may also display Homer Wright rosettes, desmoplastic foci, or anaplastic cytology similar to that encountered in medulloblastomas (ie, increased cell size, large nucleoli, cell wrapping, and apoptotic lakes). They may also show features in common with retinoblastoma, such as formation of fleurettes and Flexner-Wintersteiner rosettes.
Immunohistochemically, pineoblastomas almost always show at least focal expression of neuronal/neuroendocrine markers, although the intensity of reactivity is less than pineocytomas; they are almost always positive for synaptophysin (Fig. 1I) and NSE, with some showing focal positivity for chromogranin A and neurofilament protein. GFAP immunoreactivity is focal and variable. The average Ki-67-labeling index is 27.2%, with a range of 16.9% to 40.2%.17
Genes that are highly expressed in pineoblastomas include UBEC2, TERT, TEP1, PRAME, CD24, and various transcription factors (POU4F2, SOX4, and HOXD13).7
When pineoblastomas occur in patients with bilateral retinoblastoma, they have been designated as “trilateral retinoblastoma”; such cases have been shown to harbor a germ-line mutation of the RB gene and are associated with a more aggressive outcome than the sporadic counterparts.26 Chromosome 1p rearrangements are the most frequent cytogenetic alterations seen in pineoblastomas.17 Similar to atypical teratoid/rhabdoid tumors (AT/RT), 22q losses may be encountered, although INI1 (BAF47) studies should be pursued in such cases, as AT/RTs may also present in the pineal region and some are predominantly PNET-like with surprisingly few rhabdoid cells.
Treatment usually includes surgery, radiotherapy, and chemotherapy.3,22,27 Craniospinal irradiation is the standard of care and reduces the risks of both local recurrences and distant metastasis.
Similar to CNS embryonal tumors other than medulloblastomas, the prognosis is extremely poor. Patients typically have a relatively short clinical course and high risk of CSF and/or systemic metastasis,15 including frequent spinal relapses.2,14 The median survival time varies from 162 to 25 months,16 with 5-year survival times being reported as only approximately 10%.2
As an embryonal tumor, the differential diagnosis of pineoblastoma is broad, especially when the localization of the tumor is not restricted to the pineal region but extends to the third and fourth ventricles or cerebellum. The latter is particularly problematic as there is a significantly better prognosis for medulloblastoma, but it may be virtually impossible to distinguish this consideration from pineoblastoma based on morphology and immunophenotype alone. Genetic studies occasionally help with medulloblastomas frequently showing isochromosome 17 (in about 30% to 40% cases)28 and pineoblastomas more commonly showing 1p rearrangements.
As mentioned earlier, AT/RTs can sometimes be seen in the pineal region and can have a predominant PNET-like component mimicking pineoblastoma. AT/RT is even more aggressive than pineoblastoma and therapy differs. As such, this distinction is important. Rhabdoid areas may be present only focally or in rare cases, be absent altogether. A high index of suspicion is therefore warranted, especially in patients below 3 years of age. Similarly, the presence of carcinoma-like or sarcoma-like foci should raise a strong suspicion of AT/RT, even in the absence of classic rhabdoid cells, as these features are otherwise rare in pineoblastoma. Immunohistochemistry and/or genetic studies should be performed in doubtful cases. Loss of INI1 (BAF47) immunoreactivity is seen in most of AT/RTs. Mutation and losses of the INI1/hSNF5/SMARCB1 gene on chromosome 22q11.2 locus are also typical29 and have significant additional implications for the patient's family when they are germline.
PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION
In between the 2 extremes of differentiation, the pineal parenchymal tumor of intermediate differentiation has clearly been the most problematic category in terms of both classification and treatment.4,13,15,16,18,30 The reported incidence of these tumors is highly variable reflecting the difficulties in establishing clinically relevant and reproducible definitional criteria.15 It was first introduced by Schild et al15 in 1993. They constitute approximately 20% to 62% of cases2,10,15 and occur mostly in adults with a slight predominance in women. The imaging findings are similar to those observed in other pineal region tumors and are not distinctive.
PPTIDs can have 3 different morphologic subtypes2: (1) lobulated tumor growth pattern with rich vascularity (endocrine-like; Fig. 1J), (2) diffuse growth pattern mimicking oligodendroglioma or neurocytoma (Fig. 1K), and (3) a transitional form with lobulated and/or diffuse architecture areas intermixed with regions containing well-formed pineocytomatous rosettes (ie, pineocytoma-like regions; Fig. 1L). The tumor cells in PPTIDs generally have less cytoplasm than pineocytomas and show moderate nuclear atypia. Mitotic count is variable and can range from 0 to 16 per 10 high-power fields (HPFs); necrosis may sometimes be seen and endothelial hyperplasia is present in a large number of cases. The average Ki-67-labeling index is 10.1%, with a range of 8% to 11.8%.17
Immunophenotypically, these tumors show diffuse expression of neuronal markers (synaptophysin and NSE), although neurofilament expression may be variable. They are also positive for chromogranin A and are negative for epithelial markers, such as cytokeratin (CK).
On the basis of Jouvet et al's10 study on PPTIDs and recently adopted by the WHO, these tumors can further be divided in 2 subgroups although definite criteria have yet to be established. In general, low-grade PPTIDs (corresponding to WHO grade II) consist of transitional, lobulated, or diffuse growth patterns, strongly express neurofilament protein, and have fewer than 6 mitoses per 10 HPFs.
High-grade PPTIDs (WHO grade III) consist of lobulated or diffuse growth patterns (ie, no pineocytoma-like regions) with ≥6 mitoses per 10 HPFs (Figs. 1M, N) and limited neurofilament immunostaining. The Ki-67-labeling index is similarly increased (Fig. 1O). Focal necrosis, leptomeningeal infiltration, and vascular proliferation may also be observed.
On the basis of CGH data,17 PPTIDs are thought to be cytogenetically more similar to pineoblastomas. Using reverse-transcription-polymerase chain reaction on 13 PPTIDs, PRAME, CD24, POU4F2, and HOXD13 (same genes overexpressed in pineoblastomas) were more robustly expressed in the high-grade than in the low-grade PPTIDs.7 Higher grade tumors also display gains of 12q and losses of chromosome 22.17
Although an aggressive treatment with a combination of surgery, radiotherapy, and chemotherapy may be reasonable for high-grade PPTIDs,31 it remains unclear whether patients with low-grade PPTIDs benefit from radiotherapy after gross total surgical resection.32
A mitotic index greater than 6 per 10 HPFs and necrosis have been found to be associated with poorer outcome, whereas immunostaining for neurofilament protein is associated with better survival,10 accounting for some of the currently recommended grading criteria. Relapse is more frequent in high-grade (56%) than low-grade PPTIDs (26%).2 Spinal dissemination is also more common in high-grade (36%) than in low-grade (7%) tumors.2 The estimated 5-year survival rates range from 39% in high-grade PPTIDs patients to 74% in patients with low-grade PPTIDs patients.2
PPTIDs mostly need to be distinguished from the pineocytomas and pineoblastomas as the lines of distinction remain somewhat blurred. As mentioned above, some cases are morphologically similar to oligodendroglioma, although this diagnosis would be exceptional in the pineal region and oligodendrogliomas are easily distinguished from PPTIDs by their immunoprofile and frequent 1p/19q codeletion pattern genetically. Rare high-grade PPTIDs have large epithelioid cells that may raise diagnostic considerations of metastatic carcinoma or germ-cell tumors, both of which are easily ruled out immunohistochemically.
PAPILLARY TUMOR OF THE PINEAL REGION
These tumors were first described in 2003 by Jouvet et al6 in a series of 6 patients, as a novel neoplasm with distinct anatomic, histologic, and immunophenotypic characteristics. Since then, over 60 cases have been reported.6,8,33–41 Some of these same tumors had most likely been called pineal parenchymal tumors, ependymomas, choroid plexus tumors, papillary meningiomas, and metastatic papillary carcinomas of unknown primary in the past.
Clinically, these tumors can occur in both children and adults with a wide age range of 5 to 66 years. Nonetheless, they are more common in adults with a slight female preponderance.6,8,33–41 On imaging, they are well-circumscribed, solid masses with or without a cystic component. They are usually hyperintense on T2-weighted magnetic resonance images and are T1 isointense, with contrast-enhancement after gadolinium administration (Fig. 2). However, in a few cases, T1 hyperintensity has been noted42 and it has been proposed to be related to their intrinsic secretory function.
The histologic hallmark of these tumors, as implied by the name, is the papillary architecture (Figs. 3A–F), which is variable in prominence from case to case with some solid areas also typically present. The solid areas are cellular and are composed of sheets of epithelioid tumor cells with variable perivascular pseudorosettes and true rosettes/tubules. The papillary areas are composed of fibrovascular cores, lined by pseudostratifed to true multilayered pale-to-eosinophilic tall columnar-to-cuboidal cells. Sometimes, the tumor cells may show a signet-ring appearance (Figs. 3B, C). Necrosis is almost always noted in these tumors (Fig. 3F). However, endothelial proliferation is only rarely observed. Mitotic activity and proliferation indices are moderate in these tumors.33,34,38,40
Papillary tumors of pineal region consistently show immunoreactivity for CKs (KL1, AE1/AE3, CAM 5.2, and CK18), which is more prominent in the papillary component and may also show small dot-like intracytoplasmic inclusions (Fig. 3G). They have also been shown to express epithelial membrane antigen (EMA), especially in the perivascular region, which again may be dot-like. Focal weak CK7 and CK5/6 immunoreactivities have also been reported; although they are almost always negative for CK20 in the few reported cases. Vimentin positivity is seen mostly in tumor cells adjacent to the vessel walls (Fig. 3H). They also show widespread cytoplasmic and nuclear expression of S100 protein and are diffusely positive for NSE (Figs. 3I, J). Expression of GFAP has been reported only focally in perivascular tumor cells in a few cases (Fig. 3K). Papillary tumors of pineal region, like pineal parenchymal tumors, express microtubule-associated protein-2, neural cell adhesion molecule, and sometimes express synaptophysin (Fig. 3L) and chromogranin. However, they almost never show immunoreactivity for neurofilament protein. Recently, strong bcl-2 expression has been reported in a case of papillary tumors of pineal region with a high proliferation index43; and its role in neuroendocrine differentiation and neoplastic transformation is still speculated.
More recently, Cohan et al44 have reported a single case of PPTIDs with papillary features in an adult woman. This tumor was found to have immunophenotypic characteristics similar to PPTIDs, but with additional focal areas of immunoreactivity typical of papillary tumors of pineal region. These findings are intriguing; whether this tumor represents a continuum of primary pineal region tumors or is a hybrid tumor remains to be established as our understanding of these tumors evolves.
Electron microscopy has shown basally located ovoid or indented nuclei and abundant cytoplasm rich in organelles. The organelles include rare dense core vesicles, microtubules, numerous clear and coated vesicles, numerous mitochondria, abundant rough endoplasmic cisternae, glycogen granules, and intermediate filaments. Microvilli and zipper-like junctions are abundant at the apical pole and numerous interdigitated ependymal-like processes are present at the basal pole.6 These ultrastructural findings support both ependymal and secretory features of papillary tumors of pineal region. It is indeed intriguing that although these tumors have been shown to have secretory activity ultrastructurally, they usually lack synaptophysin and chromogranin A expression immunohistochemically.
The genetic profile of papillary tumor of pineal region has been characterized by CGH in a few cases, which have shown chromosomal losses affecting 10 and 22q, as well as gains on chromosomes 4, 8, 9, and 12.35
Although the exact cell of origin is not entirely clear, papillary tumors of pineal region have been proposed to arise from specialized ependyma of the SCO,6 which is present in humans during embryonic development and persists as a vestigial remnant in adults.45 This speculation is supported by expression of nestin and CK in these tumors. In addition, a cDNA microarray study has shown high expression of genes that are also expressed in the SCO, namely ZFH4, RFX3, TTR, and CGRP, supporting the hypothesized histogenetic origin from this site.7
Primary papillary neoplasms of CNS can pose a significant diagnostic challenge because of their rarity and overlapping morphologies; the main differential diagnosis includes other papillary neoplasms, such as papillary ependymoma, choroid plexus tumors, papillary meningioma, astroblastoma, and metastatic papillary carcinoma. There is also a mention in the literature of entities such as papillary pineocytoma23 and malignant pineocytoma with papillary features46 in the differential diagnosis, which do not exists in the current WHO classification.
On the basis of immunohistochemical work-up, some of the possibilities can be easily excluded whereas others may be more challenging, requiring a broader panel of antibodies (Table 1) and/or electron microscopy. Papillary tumors of pineal region usually show strong expression of keratins whereas papillary meningiomas generally lack immunoreactivity for keratins. In contrast, they frequently express EMA and progesterone receptor to variable degrees. Although papillary tumors of pineal region usually lack robust features of neuroendocrine differentiation, it is a diagnostic characteristic of pineal parenchymal tumors. Distinguishing papillary tumor of pineal region from metastatic papillary carcinoma of unknown primary may be quite challenging, although nestin positivity is not often seen in the latter.47 In addition, strong EMA positivity and high-proliferative activity are more typical of metastatic carcinoma. Unlike choroid plexus tumors, most papillary tumors of pineal region do not express Kir7.1 and stanniocalcin 1, but do express microtubule-associated protein-2. EMA positivity, in papillary tumors of pineal region, may be akin to the dot-like pattern seen in ependymomas and it may be challenging to distinguish the 2 in some cases despite ancillary work-up. However, GFAP positivity is typically widespread in ependymomas and mostly lacking in papillary tumors of pineal region. Electron microscopy can also be helpful, with ependymomas showing zipper-like junctions and microvilli, but lacking the secretory features typically encountered in papillary tumors of pineal region.
Metastatic melanoma is known as the great mimicker and must be considered in the pineal region as well. Morphologically, although the tumor cells may vary from epithelioid to spindled, the nuclear characteristics are different from papillary tumors of pineal region because of the presence of prominent nucleoli and intranuclear cytoplasmic inclusions. Intracytoplasmic pigment, when present, can be of considerable help. Nonetheless, in difficult cases lacking the characteristic nuclear morphology and pigment, expression of melanocytic markers (HMB45, Melan A, and MART-1) can easily establish the diagnosis.
Owing to the rarity of these tumors, clinical experience remains limited and standardized therapy awaits more detailed studies. Nonetheless, these tumors often recur; 1 series reporting a high incidence of 51.6%.34 Therefore, although there is no consensus as to the best therapy for these tumors, aggressive local therapy with maximal surgical resection and adjuvant radiotherapy has been advocated. The use of adjuvant radiotherapy remains controversial with some contradictory data in the literature; whereas Fevre-Montange et al34 showed no significant survival difference in patients undergoing gross total resection with or without adjuvant radiation therapy, another smaller study showed a survival benefit in patients receiving radiation.8
PROGNOSIS AND PREDICTIVE FACTORS
Papillary tumor of pineal region is considered WHO grade II or III, although clear criteria separating these have yet to be provided. Most cases correspond to a low-grade malignancy (ie, WHO grade II) (Figs. 3A–C), with higher-grade cases showing increased mitotic activity, necrosis, and/or cytologic anaplasia (Figs. 3D–F). Younger patients (age <30 y) tend to have higher mitotic counts and Ki-67 proliferation indices, although a precise correlation between patient age and prognosis has not been found thus far.34 Disease progression is noted in nearly two-thirds of the cases34 and 5-year estimates of overall and progression-free survival are found to be approximately 73% and 27%, respectively.34 Incomplete surgical resection and a mitotic index higher than 5 per 10 HPFs seem to correlate with decreased survival and recurrence.34 These tumors have frequent local recurrences with rare reports of CSF dissemination.34,39
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pineal parenchymal tumors; papillary tumor of the pineal region
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