cancers

Review Pineal Gland Tumors: A Review

Gaia Favero 1,* , Francesca Bonomini 1,2 and Rita Rezzani 1,2

1 Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; [email protected] (F.B.); [email protected] (R.R.) 2 Interdipartimental University Center of Research “Adaption and Regeneration of Tissues and Organs (ARTO)”, University of Brescia, 25123 Brescia, Italy * Correspondence: [email protected]

Simple Summary: Pineal neoplasms are tumors with different and variable morphological, histolog- ical, and radiological characteristics and, consequently different diagnosis and management. Due to their rarity, pineal tumors may be misdiagnosed. Pineal tumors, are divided into germ cell tumors, pineal parenchymal tumors and tumors that derive from adjacent structures. In this review, we report the clinical relevance of the main pineal gland tumors, underlining the importance of studying the triggering causes of pineal region carcinogenesis, to realize appropriate diagnosis and, consequently, better clinical management.

Abstract: The pineal gland is a small, pinecone-shaped endocrine gland that participates in the biological rhythm regulation of vertebrates. The recognized major product of the pineal gland is melatonin—a multifunctional endogenous indoleamine. Accumulating evidence suggests that the pineal gland is important for preserving ideal health conditions in vertebrate. Tumors of the pineal region account for approximately 3–11% of pediatric brain neoplasms but fewer than 1% of brain neoplasms in adults. It is fundamental to expand advanced imaging techniques together with both



 clinical and laboratory knowledge, to help to differentiate among pineal neoplasms and thus facilitate accurate primary diagnoses and proper therapeutic interventions. In this review, we report the gross Citation: Favero, G.; Bonomini, F.; anatomy of the pineal gland and its functional significance and discuss the clinical relevance of pineal Rezzani, R. Pineal Gland Tumors: gland tumors, underlining the importance of identifying the leading causes of pineal region masses. A Review. Cancers 2021, 13, 1547. https://doi.org/10.3390/ Keywords: cancers13071547 pineal gland; brain neoplasms; pineal germ cell tumors; pineal parenchymal tumor; pineal metastasis

Academic Editor: Marilena Vered

Received: 11 February 2021 Accepted: 26 March 2021 1. Introduction Published: 27 March 2021 The Pineal Gland The pineal gland is a pinecone-shaped neuroendocrine gland located in the epithala- Publisher’s Note: MDPI stays neutral mus that participates in the biological rhythm regulation of vertebrates. The gland projects with regard to jurisdictional claims in posteriorly and inferiorly into the quadrigeminal cistern, and the anatomic boundaries published maps and institutional affil- include the backside of the third ventricle wall forming the gland’s base, the splenium of iations. the corpus callosum superiorly, and the thalamus surrounding both sides [1–4]. Figure1 shows the location of the pineal gland in the human brain. The pineal gland’s primary purpose is the production and immediate release of melatonin, a pleiotropic and multifunctional indoleamine [5–10], into the blood [11]. Copyright: © 2021 by the authors. The pineal gland possesses two populations of cells: about 95% are pinealocytes Licensee MDPI, Basel, Switzerland. with dendritic processes, and the other 5% are neuroglial supporting cells that resemble This article is an open access article astrocytes. Both these types of cells can form neoplasms, as well as residual germ cells from distributed under the terms and primordial neural crest cell migration and cells derived from nearby structures [1,2,12–16]. conditions of the Creative Commons The pineal gland may, unfortunately, harbor a variety of neurosurgical diseases such as Attribution (CC BY) license (https:// pineal cysts, different pineal tumors, and vascular malformations, including cavernous, creativecommons.org/licenses/by/ arteriovenous malformations and aneurysms. 4.0/).

Cancers 2021, 13, 1547. https://doi.org/10.3390/cancers13071547 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 19 Cancers 2021, 13, x 2 of 19

Cancers 2021, 13, 1547 2 of 18 asas pineal pineal cysts, cysts, different different pineal pineal tumors, tumors, and and vascular vascular malformations, malformations, including including cavernous, cavernous, arteriovenousarteriovenous malformations malformations and and aneurysms. aneurysms.

FigureFigure 1. 1.Human Human pinealpineal pineal gland gland gland ( a()a and)( aand) and its its anatomic its anatomic anatomic boundaries boundaries boundaries (b). (b The ().b The). pineal The pineal pineal gland gland gland is visible is isvisible visible in yellow in inyellow yellow (a). Anatomage (a ).(a Anatomage). Anatomage Inc.— Inc.—AnatomageAnatomageInc.—Anatomage Table EDU.Table Table TheEDU. EDU. 3D The renderingThe 3D 3D rendering rendering of the cadaverof ofthe the cadaver cadaver data is data from data is Anatomage isfrom from Anatomage Anatomage Table. Table. Table.

2.2. 2.Pineal Pineal Pineal Gland Gland Gland Tumors Tumors Tumors PinealPinealPineal neoplasms neoplasms areare are fairly fairly fairly uncommon uncommon uncommon tumors, tu tumors,mors, and and and they they they are are predominantly are predominantly predominantly childhood child- child- hoodmalignancieshood malignancies malignancies representing representing representing 3–11% 3–11% of3–11% all pediatricof of all all pediatric pediatric brain brain tumors brain tumors tumors compared compared compared to <1% to ofto <1% brain<1% of of braintumorsbrain tumors tumors in adults in in adults [1 adults,14,17 [1,14,17–20].– [1,14,17–20].20]. Age, sex, Age, Age, and sex, ethnicitysex, and and ethnicity mayethnicity modulate may may modulate modulate the relative the the incidencerelative relative in- of in- cidencepinealcidence neoplasms of of pineal pineal neoplasms [21 neoplasms]. Pineal [21] tumors [21]. Pineal. Pineal are classifiedtumors tumors are as:are classified germ classified cell as: tumors, as: germ germ pinealcell cell tumors, tumors, parenchymal pineal pineal parenchymaltumorsparenchymal and tumors tumors tumors that and and derive tumors tumors from that that adjacent derive derive from anatomical from adjacent adjacent structures. anatomical anatomical Germinoma structures. structures. isGer- theGer- most common pineal tumor, representing up to 50% of pineal tumors in Europe, the United minomaminoma is isthe the most most common common pineal pineal tumor, tumor, repr representingesenting up up to to 50% 50% of of pineal pineal tumors tumors in in States and Japan [1,22,23]. In a series of 370 pineal tumors in patients aged 3–73 years, it Europe,Europe, the the United United States States and and Japan Japan [1,22,23]. [1,22,23]. In In a seriesa series of of 370 370 pineal pineal tumors tumors in in patients patients was observed that 27% were germinomas; 26% were astrocytomas; 12% were pineoblas- agedaged 3–73 3–73 years, years, it itwas was observed observed that that 27% 27% were were germinomas; germinomas; 26% 26% were were astrocytomas; astrocytomas; 12% 12% tomas; 12% were pineocytomas; 4.3% were ependymomas; 4.3% were teratomas; 2.7% were werewere pineoblastomas; pineoblastomas; 12% 12% were were pineocytomas; pineocytomas; 4.3% 4.3% were were ependymomas; ependymomas; 4.3% 4.3% were were ter- ter- ganglioglioneuromas, lymphomas, meningiomas, metastases, and pineal cysts; 1.6% were atomas;atomas; 2.7% 2.7% were were ganglioglioneuromas, ganglioglioneuromas, lymphomas, lymphomas, meningiomas, meningiomas, metastases, metastases, and and pin- pin- mixed embryonal cell tumors (embryonal carcinomas)/malignant teratomas; 1.1% were ealeal cysts; cysts; 1.6% 1.6% were were mixed mixed embryonal embryonal cell cell tumors tumors (embryonal (embryonal carcinomas)/malignant carcinomas)/malignant ter- ter- choriocarcinomas; and 0.54% were oligodendrogliomas [24] (Figure2). atomas;atomas; 1.1% 1.1% were were choriocarcinomas; choriocarcinomas; and and 0.54% 0.54% were were oligodendrogliomas oligodendrogliomas [24] [24] (Figure (Figure 2). 2).

Figure 2. Pineal tumor classification. FigureFigure 2. 2.Pineal Pineal tumor tumor classification. classification.

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Pineal region masses may produce nonspecific signs and symptoms, and they usually cause syndromes of mass effect, including headaches, aqueductal stenosis, and hydro- cephalus, or compressive hypothalamic syndromes, such as diabetes insipidus and slowed growth [13,16,25]. A mass in the pineal area may also interfere with the normal func- tion of the pineal gland. Pineal tumors associated with acute and rapidly progressive hydrocephalus may be clinically managed via external ventriculostomy, endoscopic third ventriculostomy, ventriculoperitoneal/ventriculoatrial shunts, or direct removal [26]. It is fundamental to expand advanced imaging techniques, together with both clinical and laboratory knowledge to help to differentiate among the pineal neoplasms and thus realize accurate primary diagnoses and correct treatment and patient management plans. Open surgical resection and stereotactic or endoscopic biopsy are needed for pineal tissue diagnosis [27,28]. However, stereotactic biopsy seems to be associated with a higher risk of hemorrhage in pineal region tumors [18,29]. In practice, the diagnosis of pineal region neoplasms is based on clinical presentation, imaging, and pathology results. Serum and cerebrospinal fluid (CSF) biomarkers complement these standard diagnostic techniques by providing additional data before invasive procedures are performed [1,12,30]. Therefore, research into novel diagnostic markers, therapeutic approaches and follow-up guidelines is fundamental. In this review, we report the features and clinical relevance of the main pineal gland tumors, underlining the importance of studying the triggering causes of pineal region masses, to enable effective primary diagnosis and, consequently, correct treatment and clinical management.

2.1. Germ Cell Tumors Germ cell neoplasms are derived from primordial germ cells that develop primarily in the gonads but also in the anterior mediastinum, pineal gland, and brain [31]. Germ cell neoplasms account for 0.5–3.2% of primary intracranial tumors in adults and 11.8% of the same in children. Germ cell tumors are predominantly found in male patients. Pineal germ cell tumors account for about 50% of intracranial germ cell tumors [3] and seem to be more common in Asian populations [3,32]. Germ cell tumor can be classified into six types: germinomas, choriocarcinomas, teratomas, embryonal carcinomas, yolk sac tumors and mixed germ cell tumors (characterized by the features of at least two of the above-cited tumor types) [3,13,33].

2.1.1. Germinomas Germinomas are the most common pineal tumor type, representing up to 50% of pineal tumors in Europe, the United States, and Japan [22,23]. Only 8% of central nervous system germinoma cases show the simultaneous involvement of pineal and suprasellar regions, and these are called bifocal germinomas [26,34,35]. Germinomas are not encap- sulated tumors and thus may invade adjacent brain structures and, through the CSF, disseminate along the brain surface. Germinomas present cellular sheets or lobules of uniform germinoma cells with large round nuclei, prominent nucleoli, and clear cytoplasm with connective tissue septal bands and full of capillaries, lymphocytes, and, occasionally, granulomas [3,36]. Furthermore, germinomas present significant amounts of lipids and macromolecules compared to other pineal gland tumors [37,38]. Germinomas are malignant tumors characterized by a mix of large multipotential primitive germ cells and smaller cells that resemble lymphocytes. Germinomas often present severe inflammatory infiltrates [20]. Furthermore, corticosteroid treatment seems to be able to modify the patient’s immunological defense, enabling the immune system to suppress the tumor [20,39]. On imaging, germinomas show heterogeneous features, often presenting as solid or solid/cystic masses with engulfed calcifications (Figure3), different to pineal parenchymal tumors, which exhibit prominent calcifications [14,31,40]. Cancers 2021, 13, 1547 4 of 18 Cancers 2021, 13, x 4 of 19

Figure 3. Pineal germinoma magnetic resonance imaging (MRI). Pineal tumor hypointense on T1 Figure 3. Pineal germinoma magnetic resonance imaging (MRI). Pineal tumor hypointense on T1 weighted image (T1WI) (A), hyperintense on T2WI (B) and with homogeneous contrast enhance- weightedment (C). image The arrow (T1WI) identifies (A), hyperintense hyperdense on mass T2WI with (B) and calcification with homogeneous at computed contrast tomography enhancement (D). In (Canother). The arrow patient, identifies a larger hyperdense germinoma, mass isointense with calcification on T1WI ( atE). computed Reprinted tomography with permission (D). In from another Reis patient,et al. (2006) a larger [41]. germinoma, John Wiley and isointense Sons—2021 on T1WI (License (E). Number Reprinted 5034711197310). with permission from Reis et al. (2006) [41]. John Wiley and Sons—2021 (License Number 5034711197310). Imaging alone does not allow us to distinguish among germinomas, nongerminoma- tousImaging germ cell alone tumors does and not pi allowneal usparenchymal to distinguish tumors. among Theref germinomas,ore, a complete nongerminoma- evaluation tousis fundamental. germ cell tumors In fact, and germinomas pineal parenchymal are diagnosed tumors. using Therefore, imaging a completetogether evaluationwith serum isand fundamental. CSF markers. In fact,These germinomas tumors present are diagnosedhigh serum using and CSF imaging expression together of oncoproteins with serum andsuch CSF as markers.alpha-fetoprotein, These tumors beta presenthuman highchorionic serum gonadotropin, and CSF expression lactate ofdehydrogenase, oncoproteins suchand asplacental alpha-fetoprotein, alkaline phosphatase beta human [6]. chorionic gonadotropin, lactate dehydrogenase, and placentalThe alkalinetreatment phosphatase regimens used [6]. against germinomas include chemo- and radio-therapy The treatment regimens used against germinomas include chemo- and radio-therapy or a combination of both, resulting in a positive prognosis and five-year survival of at least or a combination of both, resulting in a positive prognosis and five-year survival of at least 90% [14]. Germinomas are very radiosensitive neoplasms and respond well to specific 90% [14]. Germinomas are very radiosensitive neoplasms and respond well to specific chemotherapy [13,14,20,31,42–45]. Furthermore, for germinoma, stereotactic radiosurgery chemotherapy [13,14,20,31,42–45]. Furthermore, for germinoma, stereotactic radiosurgery seems to be effective in improving standard adjuvant treatment or in the case of recur- seems to be effective in improving standard adjuvant treatment or in the case of recur- rence [21]. rence [21].

2.1.2.2.1.2. Choriocarcinomas Choriocarcinomas PinealPineal choriocarcinomaschoriocarcinomas are uncommon uncommon ma malignantlignant nongerminomatous nongerminomatous germ germ cell cell ne- neoplasmsoplasms (accounting (accounting for for fewer fewer than than 5% 5% of all pineal masses)masses) [[13]13] andand thethe most most aggressive aggressive formform of of gestational gestational trophoblastic trophoblastic disease. disease. Choriocarcinoma Choriocarcinoma showsshows aa poor poor survival survival rate rate withwith respect respect to to other other germ germ cell cell tumors tumors [46 [46,47,47]. Median]. Median overall overall survival survival of primary of primary intracra- intra- nialcranial pure pure choriocarcinoma choriocarcinoma was 22was months 22 months and theand three- the three- and five-yearand five-year survival survival rate was rate 45.8%was 45.8% [48]. Primary [48]. Primary intracranial intracranial choriocarcinoma choriocarcinoma mainly mainly affects affects young young men (3–22 men years (3–22 ofyears age), of who age), present who present precocious precocious puberty. pubert Thesey. tumorsThese tumors do not showdo not distinctive show distinctive symp- toms,symptoms, but patients but patients affected affected by choriocarcinoma by choriocarcinoma have mainly have reported mainly headaches, reported headaches, vomiting, nausea,vomiting, visual nausea, impairment, visual impairment, polydipsia, polydips polyuriaia, andpolyuria endocrinologic and endocrinologic alterations alterations [46,49]. Choriocarcinomas[46,49]. Choriocarcinomas present stromal presentvascular stromal vascular ducts that ducts form that blood form lakes blood and lakes intratumoral and intra- hemorrhagictumoral hemorrhagic necrosis, allnecrosis, factors all strictly factors correlated strictly withcorrelated a poor with prognosis a poor [2 ,46prognosis,50,51]. On[2,46,50,51]. imaging, choriocarcinomasOn imaging, choriocarcinomas appear as ovoid, appear heterogeneous, as ovoid, heterogeneous, and slightly hyperdense and slightly masseshyperdense (Figure masses4). (Figure 4).

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Figure 4. Pineal choriocarcinoma MRI. Susceptibility-weighted imaging (A), T2WI (B) and pineal Figure 4. Pineal choriocarcinoma MRI. Susceptibility-weighted imaging (A), T2WI (B) and pineal heterogeneous mass on heterogeneous mass on T1WI (C,D). The arrows identify the faint peripheral enhancement after the T1WI (C,D). The arrows identify the faint peripheral enhancement after the intravenous administration of gadolinium (E). intravenous administration of gadolinium (E). Reprinted with permission from Causil et al. (2016) Reprinted with permission[46]. Elsevier—2021 from Causil (License et al. Number: (2016) [46 5034730033295).]. Elsevier—2021 (License Number: 5034730033295). Qi et al. [50] observed sinusoids that expressed laminin and not CD34, thus identifying Qi et al. [50] observed sinusoids that expressed laminin and not CD34, thus identify- tumor vasculogenic mimicry. Blood may flow from tumor vessels that express CD34 to ing tumor vasculogenic mimicry. Blood may flow from tumor vessels that express CD34 sinusoids, leading to blood clotting, the extension of blood lakes and sinusoids, and, some- to sinusoids, leading to blood clotting, the extension of blood lakes and sinusoids, and, times, hemorrhagic necrosis. Choriocarcinoma is also linked with elevated levels of both sometimes, hemorrhagic necrosis. Choriocarcinoma is also linked with elevated levels of CSF and plasma human chorionic gonadotropin [50]. Choriocarcinomas and germinomas both CSF and plasma human chorionic gonadotropin [50]. Choriocarcinomas and ger- are both associated with elevated beta human chorionic gonadotropin expression [1,52,53]. minomas are both associated with elevated beta human chorionic gonadotropin expres- Unfortunately, classic treatments frequently fail due to choriocarcinomas being ex- sion [1,52,53]. tremely resistant tumors. The first clinical choice is total resection (even if the patient Unfortunately,does not presentclassic hydrocephalus).treatments frequently However, fail due to treat to choriocarcinomas choriocarcinoma, abeing mix ofex- total tumor tremely resistantremoval, tumors. chemotherapy, The first clinical and radiotherapy choice is total is frequently resection (even used asif the a therapeutic patient does combination not presentand hydrocephalus). seems to show However, positive outcomes to treat choriocarcinoma, [46–49]. a mix of total tumor re- moval, chemotherapy, and radiotherapy is frequently used as a therapeutic combination and seems 2.1.3.to show Teratomas positive outcomes [46–49]. Intracranial teratomas account for up to 50% of fetal brain neoplasms; in neonates, they 2.1.3. Teratomascomprise 33% of intracranial tumors, but they comprise only 2%–4% of intracranial tumors Intracranialin patients teratomas aged <15account years for [54 up,55 to]. Intracranial50% of fetal teratomasbrain neoplasms; typically in arise neonates, from the pineal they comprisegland 33% and of involve intracranial the third tumors, ventricle but [they54]. Pinealcomprise teratomas only 2%–4% have a of male intracranial predominance that tumors in variespatients from aged 2:1 <15 to 8:1years and [54,55]. an overall Intracranial survival ofteratomas 90–100% typically [26]. Histologically, arise from the teratomas are pineal glandclassified and involve into: (1)the mature third ventricle tumors, [54]. which Pineal show teratomas completely have differentiated a male predomi- tissue; (2) imma- nance that turevaries tumors, from 2:1 which to 8:1 present and an a combinationoverall survival of fetal- of 90–100% and mature-type [26]. Histologically, tissue elements and teratomas elementsare classified from into: all three (1) germmature layers tumors, and (3)which teratomas showwith completely malignant differentiated transformation, which tissue; (2) immatureinvolves thetumors, malignant which degeneration present a combination of mature of tissue fetal- [and14,56 mature-type]. Teratomas tissue are neoplasms elements andcharacterized elements from by multipotential all three germ cells layers that and revert (3) toteratomas normal organogenesis, with malignant usually trans- producing formation,tissues which involves representing the malignant a combination degeneration of two or of more mature of the tissue embryological [14,56]. Teratomas layers of ectoderm, are neoplasmsmesoderm, characterized and endoderm by multipotential [13,14]. Pineal cells teratomas that revert can to be normal partially organogenesis, or totally encapsulated, usually producingbut can alsotissues be unencapsulatedrepresenting a combination and locally invasiveof two or [ 13more]. On of imaging,the embryological these pineal tumors layers of ectoderm,present foci mesoderm, of fat, calcification and endoderm and [1 cystic3,14]. regions Pineal teratomas [13,54]. On can MRI, be partially teratomas or appear as totally encapsulated,lobular, multiloculated, but can also andbe unenca heterogeneouslypsulated and wide locally masses invasive [14] (Figure [13]. On5). imag- ing, these pineal tumors present foci of fat, calcification and cystic regions [13,54]. On MRI,

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Cancers 2021, 13, 1547 6 of 18 teratomas appear as lobular, multiloculated, and heterogeneously wide masses [14] (Fig- ure 5).

Figure 5. PinealFigure teratoma 5. Pineal MRI. teratoma Sagittal MRI. T1 image Sagittal (A T1), axial image T1 ( (AB),) andaxial sagittal T1 (B) and contrast-enhanced sagittal contrast-enhanced T1 (C) images. T1 Reprinted (C) images. Reprinted with permission from Peterson et al. (2012) [54]. Elsevier—2021 (License with permission from Peterson et al. (2012) [54]. Elsevier—2021 (License Number: 5034851378505). Number: 5034851378505).

2.2. Pineal Parenchymal2.2. Pineal Tumors Parenchymal Tumors Pineal parenchymalPineal tumors parenchymal are neuroepithelial tumors are neuroepithelial neoplasms arising neoplasms from pineocytes. arising from pineocytes. These tumors are uncommon accounting for fewer than 1% of all primitive central ner- These tumors are uncommon accounting for fewer than 1% of all primitive central nerv- vous system tumors and constituting 15% to 30% of pineal gland tumors [57,58]. Pineal ous system tumors and constituting 15% to 30% of pineal gland tumors [57,58]. Pineal parenchymal tumors present different features, grades, and levels of aggressiveness [33]. parenchymal tumors present different features, grades, and levels of aggressiveness [33]. The World Health Organization (WHO) recognizes pineal parenchymal tumors in four The World Health Organization (WHO) recognizes pineal parenchymal tumors in four distinct categories: pineocytomas, pineoblastomas, papillary pineal tumors, and pineal distinct categories: pineocytomas, pineoblastomas, papillary pineal tumors, and pineal parenchymal tumors of intermediate differentiation [14,57,59,60]. parenchymal tumors of intermediate differentiation [14,57,59,60]. Pineal parenchymal tumors seem to have no sexual predominance and occur most Pineal parenchymal tumors seem to have no sexual predominance and occur most frequently in pediatric patients [13,14,58]. Patients mainly report headaches, vomiting frequently in pediatric patients [13,14,58]. Patients mainly report headaches, vomiting (correlated with increased intracranial pressure due to the blockade of the ventricular sys- (correlated with increased intracranial pressure due to the blockade of the ventricular sys- tem) and gait ataxia [1,26,57,61,62]. Pineal parenchymal cell tumors consistently produce tem) and gait ataxiaa hypomelatoninemic [1,26,57,61,62]. Pineal or hypermelatoninemic parenchymal cell tumors state [63 consistently]. However, produce exogenous melatonin a hypomelatoninemicsupplementation or hypermelatoninemic after pinealectomy state may [63]. mitigate However, the exogenous ensuing syndrome melatonin [1 ,64,65]. Pineal supplementationparenchymal after pinealectomy tumors aremay negative mitigate for the the ensuing three syndrome tumor markers [1,64,65]. alpha-fetoprotein, Pineal beta parenchymal tumorshuman are chorionic negative gonadotropin, for the three and tumor placental markers alkaline alpha-fe phosphatasetoprotein, [beta1]. However, hu- synapto- man chorionicphysin gonadotropin, is expressed and inplacental pineal parenchymal alkaline phosphatase tumors of [1]. intermediate However, differentiation,synapto- and neu- physin is expressedronal marker in pineal positivity parenchymal is not relatedtumors to of histological intermediate grade, differentiation, mitosis, proliferation and index, or neuronal markerprognosis positivity [66 is]. Thenot related standard to treatmenthistological for grade, pineal mitosis, parenchymal proliferation tumors index, is radiation. Surgery or prognosis [66].is another The standard possible treatmenttreatment option;for pineal however, parenchymal it has a mortality tumors is rate radiation. of 5%–10% [1,24], and Surgery is anothereven possible after complete treatment tumor option; removal, however, many it patientshas a mortality present rate recurrence. of 5%–10% Hence, adjuvant [1,24], and evenradiation after complete or chemotherapy tumor removal, or a mix many of both patients is often present suggested recurrence. with theHence, aim of improving adjuvant radiationsurvival or chemotherapy [1,61,62]. Thus, or appropriate a mix of both and is close often follow-up suggested is with also fundamental.the aim of improving survival [1,61,62]. Thus, appropriate and close follow-up is also fundamental. 2.2.1. Pineocytomas 2.2.1. PineocytomasPineocytomas are slow-growing grade I/II pineal parenchymal neoplasms derived Pineocytomasfrom theare pinealslow-growing epithelium grade [1,15 I/,51II ,pineal60,67]. parenchymal They are tumors neoplasms characterized derived by well-different- from the pinealiated epithelium mature cells[1,15,51,60,67]. arranged in They sheets are that tumors are virtually characterized indiscernible by well-differ- from the healthy pineal entiated matureparenchyma cells arranged [13,14 in, 68sheets]. They that are are circumscribed, virtually indiscernible unencapsulated from the tumors healthy that may remain pineal parenchymalocally [13, confined.14,68]. They Pineocytomas are circumscribed, may arise unencapsulated at all ages but are tumors more frequentthat may in adults aged remain locally30 confined. to 60 years Pineocytomas old [14,69]. may arise at all ages but are more frequent in adults aged 30 to 60On years MRI, old pineocytomas [14,69]. appear as hyperintense, round or lobular masses [2,14,15,56,70] On MRI,(Figure pineocytomas6). appear as hyperintense, round or lobular masses [2,14,15,56,70] (Figure 6).

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Figure 6. Pineocytoma MRI. The asterisk indicates the homogeneous mass in the pineal gland. FigureFigure 6.6. Pineocytoma MRI. MRI. The The asterisk asterisk indicates indicates the the homogeneous homogeneous mass mass in the in thepineal pineal gland. gland. ReprintedReprinted with with permission permission from from Smirniotopoulos Smirniotopoulos et et al. al. (1992) (1992) [13]. [13]. Radiological Radiological Society Society North North Reprinted with permission from Smirniotopoulos et al. (1992) [13]. Radiological Society North America–2021.America–2021. Small Small pineocytomas pineocytomas often often do do not not indu inducece symptoms, symptoms, but but if if they they are are of of large large dimen- dimen- America–2021. Small pineocytomas often do not induce symptoms, but if they are of large dimensions, sions,sions, they they may may induce induce obstructive obstructive hydrocepha hydrocephaluslus and and Parinaud Parinaud syndrome, syndrome, defined defined as as upward upward gazetheygaze palsy, may palsy, induce pupillary pupillary obstructive light-near light-near hydrocephalus dissociation, dissociation, and and and convergence convergence Parinaud syndrome,retraction retraction nystagmus definednystagmus as [15]. upward[15]. The The five- gazefive- andpalsy,and twenty-year twenty-year pupillary light-nearsurvival survival rates dissociation,rates ar are,e, respectively, respectively, and convergence 100% 100% and and retraction 76% 76% [21,26]. [21,26]. nystagmus For For pineocytomas, pineocytomas, [15]. The five-stereo- stereo- and tactictwenty-yeartactic radiosurgery radiosurgery survival seems seems rates to to are, be be highly respectively, highly effective effective 100% as as a and aprimary primary 76% [treatment,21 treatment,,26]. For so pineocytomas,so stereotactic stereotactic radiosur- radiosur- stereotactic geryradiosurgerygery alone alone may may seems be be considered considered to be highly appropriate appropriate effective as clinic clinic a primaryalal management management treatment, for for so pineocytomas stereotacticpineocytomas radiosurgery [21,28,71,72]. [21,28,71,72]. alone may be considered appropriate clinical management for pineocytomas [21,28,71,72]. 2.2.2.2.2.2. Pineoblastomas Pineoblastomas 2.2.2. Pineoblastomas AsAs previously previously reported, reported, pine pinealal parenchymal parenchymal cell cell tumors tumors also also include include pineoblasto- pineoblasto- mas,mas, Asaggressive, aggressive, previously grade grade reported, IV IV neoplasms neoplasms pineal parenchymal derived derived from from cell primitive primitive tumors alsoneuroectoderm neuroectoderm include pineoblastomas, [1,17]. [1,17]. They They accountaggressive,account for for grade40% 40% of of IV parenchymal parenchymal neoplasms derived pineal pineal fromcancer cancer primitives.s. Pineoblastomas Pineoblastomas neuroectoderm are are undifferentiated, undifferentiated, [1,17]. They account em- em- bryonalforbryonal 40% tumors of tumors parenchymal categorized categorized pineal as as primitive cancers.primitive Pineoblastomasneur neuroectodermaloectodermal are tumors. tumors. undifferentiated, Si Similarmilar to to other embryonalother prim- prim- tumors categorized as primitive neuroectodermal tumors. Similar to other primitive itiveitive neuroectodermal neuroectodermal tumors, tumors, pineoblastomas pineoblastomas are are extremely extremely aggressive aggressive and and present present a a neuroectodermal tumors, pineoblastomas are extremely aggressive and present a poor poorpoor prognosis prognosis and and aggressive aggressive clinical clinical behavior behavior due due to to the the frequent frequent invasion invasion of of adjacent adjacent prognosis and aggressive clinical behavior due to the frequent invasion of adjacent struc- structurestructure andand CSFCSF dissemination,dissemination, withwith reportedreported five-yearfive-year survivalsurvival ratesrates ofof <60%<60% ture and CSF dissemination, with reported five-year survival rates of <60% [23,57,73,74]. [23,57,73,74].[23,57,73,74]. The The highest highest incidence incidence is is in in childhood, childhood, particularly particularly in in children children less less than than 2 2 The highest incidence is in childhood, particularly in children less than 2 years old, where yearsyears old,old, wherewhere pineoblastomaspineoblastomas cancan occuroccur inin combinationcombination withwith retinoblastomasretinoblastomas pineoblastomas can occur in combination with retinoblastomas [13,14,26,59,75]. Adult [13,14,26,59,75].[13,14,26,59,75]. Adult Adult cases cases are are very very rare, rare, and and for for this this reason, reason, limited limited data data are are currently currently cases are very rare, and for this reason, limited data are currently available for the effort to availableavailable forfor thethe efforteffort toto developdevelop aa stanstandarddard managementmanagement coursecourse forfor thethe diseases.diseases. develop a standard management course for the diseases. Pineoblastomas are malignant, PineoblastomasPineoblastomas are are malignant, malignant, unencapsulated unencapsulated tumors tumors that, that, unfortunately, unfortunately, may may often often re- re- unencapsulated tumors that, unfortunately, may often recur and also disseminate through- curcur and and also also disseminate disseminate throughout throughout the the cranio craniospinalspinal axis, axis, as as well well as as presenting presenting metasta- metasta- out the craniospinal axis, as well as presenting metastasis all over the body, such as in the sissis all all over over the the body, body, such such as as in in the the calvaria calvarial lbones, bones, vertebrae, vertebrae, lungs, lungs, peritoneum, peritoneum, mandi- mandi- calvarial bones, vertebrae, lungs, peritoneum, mandible, and pelvis [59,76–78] (Figure7). ble,ble, and and pelvis pelvis [59,76–78] [59,76–78] (Figure (Figure 7). 7).

FigureFigure 7. 7. Pineoblastoma PineoblastomaPineoblastoma MRI. MRI. Preoperative Preoperative Preoperative MRI MRI MRI ( A(A (–AC––C),C), MRI), MRI MRI 1.5 1.5 1.5 months months months after after after surger surger surgeryyy showing showing showing spinal spinal spinal metastasis metastasis metastasis ( D(D).). (Re-D Re-). printedprinted with with permission permission from from Huo Huo et et al al. (2020). (2020) [79]. [79]. Dove Dove Medical Medical Press—2021. Press—2021. Reprinted with permission from Huo et al. (2020) [79]. Dove Medical Press—2021.

PineoblastomasPineoblastomas are are composed composed of of undifferentiated undifferentiated or or immature immature pineal pineal cells cells [13,74]. [13,74]. SynaptophysinSynaptophysin and and chromogranin chromogranin are are markers markers of of primitive primitive neuroendocrine neuroendocrine tumors tumors that that

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Pineoblastomas are composed of undifferentiated or immature pineal cells [13,74]. Synaptophysin and chromogranin are markers of primitive neuroendocrine tumors that maymay bebe expressedexpressed in pineoblastomas pineoblastomas and and detec detectabletable in in the the serum serum or orCSF CSF [1,80]. [1,80 The].The mo- molecularlecular background background of ofpineob pineoblastomalastoma is is not not clearly clearly known. However, recentrecent studiesstudies showedshowed thatthat thethe DICER1 DICER1 and and DROSHA DROSHA genes, genes, involved involved in in microRNA microRNA dysregulation, dysregulation, are are fundamentalfundamental to to pineoblastoma pineoblastoma carcinogenesis carcinogenesis [ 81[81,82].,82]. AggressiveAggressive surgical surgical resection resection is is the the first-line first-line therapy therapy against against pineoblastoma. pineoblastoma. Notably, Nota- radiotherapybly, radiotherapy after after resection resection helps helps in increasing in increasing patient patient survival. survival. As As also also reported reported for for otherother pinealpineal glandgland tumors, combined therapy therapy seems seems to to be be an an effective effective approach approach [59]. [59 ].A Areport report from from the the International International Gamma Gamma Knife Knife Research Research Foundation Foundation described described actuarial actuarial local localcontrol control and andsurvival survival rates rates following following the thestereo stereotactictactic radiosurgery radiosurgery of ofpineoblastomas pineoblastomas of of27% 27% and and 48% 48% at at5 years 5 years [29]. [29 Recently,]. Recently, Jing Jing et al. et [59] al. [59evaluated] evaluated 213 213adult adult patients patients with withpineoblastomas pineoblastomas and observed and observed that young that young patients, patients, especially especially those thosenot receiving not receiving radio- radiotherapytherapy during during their theirinitial initial treatment, treatment, often often had hadextremely extremely poor pooroutcomes outcomes [59,83]. [59 ,This83]. Thisstudy study suggested suggested that thatbeam beam radiotherapy radiotherapy does does not improve not improve overall overall patient patient survival. survival. Fur- Furthermore,thermore, tumors tumors that that invade invade tissue tissue near near the the pineal pineal gland gland are are more more aggressive aggressive than than tu- tumorsmors confined confined to to the the pineal pineal gland, gland, increasing increasing the the risk of patientpatient deathdeath aboutabout threefold.threefold. JingJing et et al. al. [ 59[59]] also also reported reported that, that, for for every every 1 mm1 mm increase increase in in tumor tumor size, size, the the risk risk of deathof death is reducedis reduced by by 4%, 4%, so tumorso tumor size size may may not not be consideredbe considered a prognostic a prognostic factor. factor.

2.2.3.2.2.3. PapillaryPapillary TumorsTumors PinealPineal papillarypapillary tumorstumors areare uncommonuncommon WHOWHO gradegrade IIII oror IIIIII neuroepithelialneuroepithelial neo-neo- plasmsplasms [[14,15,56].14,15,56]. Among them, 68% 68% have have been been found found to to recur recur at ata mean a mean follow-up follow-up of of4.2 4.2years years (with (with overall overall survival survival rates rates of 73% of at 73% 5 years at 5 and years 58% and at 58%10 years), at 10 and years), in a andpediatric in a pediatricpopulation, population, 47% of papillary 47% of tumors papillary of tumorsthe pineal of gland the pineal recurred gland at recurreda mean follow-up at a mean of follow-up6.5 years [83,84]. of 6.5 years The age [83, 84of]. patients The age presenting of patients pineal presenting papillary pineal tumors papillary is 15 tumorsmonths isto 1567 months years and to 67there years is anda mild there female is a mild prevalence. female prevalence.The main symptom The main reported symptom by reported patients by patients with pineal papillary tumors is headaches, which are related to obstructive with pineal papillary tumors is headaches, which are related to obstructive hydrocephalus hydrocephalus [85–89]. [85–89]. Pineal papillary tumors at MRI appear as partially cystic masses with obstructive Pineal papillary tumors at MRI appear as partially cystic masses with obstructive hydrocephalus (Figure8). hydrocephalus (Figure 8).

Figure 8. Pineal papillary tumor MRI before (A) and after 15 years of treatments (B). Reprinted with Figure 8. Pineal papillary tumor MRI before (A) and after 15 years of treatments (B). Reprinted permission from Fernández-Mateos et al. (2018) [90]. Elsevier—2021 (License Number: with permission from Fernández-Mateos et al. (2018) [90]. Elsevier—2021 (License Number: 5034870401490). 5034870401490). Pineal papillary tumors show some papillary morphological features forming epen- Pineal papillary tumors show some papillary morphological features forming ependy- dymal rosettes and pseudorosettes. The rosetted cells have thick processes resting on col- mal rosettes and pseudorosettes. The rosetted cells have thick processes resting on collagen lagen from adjacent blood vessels. Vascular connective tissue present various layers of from adjacent blood vessels. Vascular connective tissue present various layers of cells cells with a large cuboidal or columnar epithelial-like growth pattern. These cells show with a large cuboidal or columnar epithelial-like growth pattern. These cells show small small round/oval nuclei, stippled chromatin, small nucleoli, and eosinophilic cytoplasm with distinct cell borders [61,83,85,90,91]. Mitotic figures are uncommon, whereas necrosis

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round/oval nuclei, stippled chromatin, small nucleoli, and eosinophilic cytoplasm with distinct cell borders [61,83,85,90,91]. Mitotic figures are uncommon, whereas necrosis is often present [83,91]. It is important to underline that pineal papillary tumors present wide morphological variability [82,92–95]. Apart from the characteristic papillary structures, papillary tumors have morphological features in common with other papillary-like tumors that occur in the pineal region, including pineal parenchymal neoplasms, choroid plexus papillomas, papillary ependymomas, metastatic papillary carcinomas, papillary menin- giomas, and germ cell tumors, which complicates the clinical diagnosis [60,83,87,92,96,97]. These pineal tumors often present increased proliferative activity (Ki67/MIB1 prolifer- ation index) [90], which is correlated with worse prognosis. Immunohistochemically, papillary tumors are also positive for S100, CAM 5.2, and prealbumin. Pineal papillary tumors usually show neuron-specific enolase reactivity but do not present neurofilament proteins—interesting papillary tumor features that may help in differentiating them from pineal parenchymal tumors with intermediate differentiation, whereas—MAP-2 is used for differentiating them from choroid plexus papillomas in diagnosis [17,60,98,99]. Pineal papillary tumors often recur, and radiotherapy is frequently effective [14,60,92,99,100]. Radiotherapy and chemotherapy are both used in initial tumor management and in cases of recurrences after gross total resection; however, the optimal adjuvant therapy is actually not known [99]. Stereotactic radiosurgery seems to be effective against pineal papillary tumors, but a high rate of local recurrence is also observed after this treatment. Recurrence can be safely and successfully managed by repeat stereotactic radiosurgery [21].

2.2.4. Pineal Parenchymal Tumors of Intermediate Differentiation Pineal parenchymal tumors of intermediate differentiation are uncommon tumors aris- ing from the pineal parenchyma that present features between those of pineocytomas and pineoblastomas [62,101–103]. Pineal parenchymal tumors of intermediate differentiation can occur at all ages. They appear more commonly among women, teenagers, and middle-aged patients [51,58,62,101]. Pineal parenchymal tumors of intermediate differentiation are often considered to be not a single disease, but a spectrum of grade II and III pineal parenchy- mal tumors, thus explaining the huge variation in the behavior of these tumors [101,104]. Although grading criteria for differentiating pineal parenchymal tumors of intermediate differentiation of grades II and III have not actually been established, the 2007 WHO Classifi- cation of Central Nervous System Tumors considers as outcome predictors both proliferative activity and immunoreactivity for neurofilament protein [102,105]. Thus, WHO grade II pineal parenchymal tumors of intermediate differentiation may present as lobulated or diffuse with a higher expression of neurofilaments, 0–5 mitoses per 10 high-power fields and moderate MIB1 labeling indices (ranging from 3% to 10% [101,106–108]). Pineal parenchy- mal tumors of intermediate differentiation show moderate cellularity, mild-to-moderate atypical nuclei, and low-to-moderate mitoses [101]. Choque-Velasquez et al. [102] reported that, on MRI, pineal parenchymal tumors of intermediate differentiation tend to appear as isointense lesions on T1WI and hypointense masses on T2WI, with some cystic components, and a complete contrast enhancement (Figure9). Multiple cystic elements may also be observed. Pineal calcifications may be engulfed or peripherally displaced by the mass [15]. These tumors present positive expression for synaptophysin, neurofilament, chromogranin A, and renal S antigen. Cancers 2021, 13, 1547 10 of 18 Cancers 2021, 13, x 10 of 19

Figure 9. Pineal parenchymal tumors of intermediate differentiation MRI. Preoperative MRI (A), Figure 9. Pineal parenchymal tumors of intermediate differentiation MRI. Preoperative MRI (A), postoperative MRI showing a very small residual pineal lesion (B). MRI before (C) and after (D) postoperative MRI showing a very small residual pineal lesion (B). MRI before (C) and after (D) radi- radiation therapy. Reprinted with permission from Choque- Velasquez et al. (2019) [102]. Else- ationvier—2021 therapy. (License Reprinted Number: with permission 5035440109275) from. Choque- Pineal parenchymal Velasquez et tumors al. (2019) of [intermediate102]. Elsevier—2021 differ- (Licenseentiation Number: may be 5035440109275).morphologically Pineal classified parenchymal into (1) lobulated tumors of endocrine-like intermediate differentiation and highly vascular may be morphologicallylesions; (2) those classified with diffuse into (1)growth lobulated patterns, endocrine-like similar to andoligodendrogliomaneurocytomas; highly vascular lesions; (2) those and with (3) diffusethose of growth transitional patterns, type, similar with areas to oligodendrogliomaneurocytomas; of lobulated and diffuse growth andpatterns, (3) those correlated of transitional with type,areas with of pineocytomatous areas of lobulated rosettes and diffuse [82,102,109]. growth patterns,Recently, correlatedWu et al. [103] with areasreported of pineocytomatous that CD24 and rosettesPRAME [82 may,102 be,109 novel]. Recently, markers Wu useful et al. [for103 the] reported grading that and CD24 prognostic and PRAME evaluation may beof pineal novel markersparen- usefulchymal for tumors the grading of intermediate and prognostic differentiation evaluation ofan pineald, thus, parenchymal useful in therapeutic tumors of decision-making. intermediate differ- The best treatment for pineal parenchymal tumors of intermediate differentiation has not yet been entiation and, thus, useful in therapeutic decision-making. The best treatment for pineal parenchymal found, partly due to the low numbers of reported cases. The maximal surgical removal of the tu- tumors of intermediate differentiation has not yet been found, partly due to the low numbers of mor is the optimal treatment in practice for pineal parenchymal tumors of intermediate differenti- reportedation. However, cases. The even maximal after comp surgicallete removalsurgical tumor of the tumorremoval, is thema optimalny patients treatment experience in practice recur- for pinealrence. parenchymal Hence, adjuvant tumors radio- of intermediateor chemo-therapy, differentiation. or a mix of However, both, is often even recommended after complete to surgical im- tumorprove removal,patient survival. many patients A report experience from the recurrence.International Hence, Gamma adjuvant Knife Research radio- or chemo-therapy,Foundation de- or ascribed mix of both,actuarial is often local recommended control and survival to improve rates patientfollowing survival. stereotactic A report radiosurgery from the on International pineal Gammaparenchymal Knife Researchtumors of Foundationintermediate described differentia actuarialtion of 50% local and control 56%, andrespectively, survival ratesat 5 years following stereotactic[19,26]. radiosurgery on pineal parenchymal tumors of intermediate differentiation of 50% and 56%, respectively, at 5 years [19,26]. 3. A Brief Overview of Other Neoplastic and Non-Neoplastic Pineal Masses 3.3.1. A BriefPineal Overview Metastasis of Other Neoplastic and Non-Neoplastic Pineal Masses 3.1. Pineal Metastasis Metastatic cancer spreading to the pineal gland is exceedingly uncommon and orig- inatesMetastatic from lung cancer carcinoma spreading in most to thecases pineal (Figure gland 10). is Other exceedingly tumors uncommonthat have documented and orig- inatescases of from metastases lung carcinoma to the pineal in most gland cases are pancreatic, (Figure 10 ).esophageal Other tumors and bladder that have neoplasms docu- mented[110–113]. cases of metastases to the pineal gland are pancreatic, esophageal and bladder neoplasms [110–113].

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FigureFigure 10. 10.Pineal Pineal metastasismetastasis from lung ad adenocarcinoma.enocarcinoma. Brain Brain MRI MRI sagittal sagittal (A (A), ),coronal coronal (B ()B and) and transverse (C) sections showing the pineal gland metastatic mass. Computed tomography show- transverse (C) sections showing the pineal gland metastatic mass. Computed tomography showing ing a lung nodule over the left hilar region in the lower right corner (D). Image from Abdallah et a lung nodule over the left hilar region in the lower right corner (D). Image from Abdallah et al. al. (2020) [110]—Ochsner Journal. (2020) [110]—Ochsner Journal. Metastasis to the central nervous system is usually an end-stage disease features and Metastasis to the central nervous system is usually an end-stage disease features the treatment of pineal region metastases varies due to systemic conditions and neurolog- and the treatment of pineal region metastases varies due to systemic conditions and ical symptoms [111,112]. However, Hogan et al. [111] described, for the first time, a suc- neurological symptoms [111,112]. However, Hogan et al. [111] described, for the first time, cessful treatment of metastatic prostate cancer that had spread to the pineal gland. The a successful treatment of metastatic prostate cancer that had spread to the pineal gland. Thepineal pineal metastasis metastasis was was treated treated with with stereotactic stereotactic radiosurgery, radiosurgery, and, and, after after 9 months, 9 months, the thepin- pinealeal metastatic metastatic mass mass was was significantly significantly smaller. smaller. BlasBlas JohnJohn et al. al. [114] [114 ]discussed discussed an an uncomm uncommonon case case of an of adult an adult woman woman with an with esoph- an esophagealageal primitive primitive neuroectodermal neuroectodermal tumor tumor that thatpresented presented pineal pineal gland gland metastasis. metastasis. The Thehead headcomputed computed tomography tomography of the of patient the patient showed showed tumo tumorr invasion invasion of the of third the third ventricle, ventricle, with withincipient incipient hydrocephalus. hydrocephalus. The Thepatient patient underwent underwent a craniotomy a craniotomy of the of posterior the posterior fossa fossa with witha supracerebellar a supracerebellar infratentorial infratentorial approach approach to to the the pineal pineal region region and anan externalexternal ventricle ventricle drainage.drainage. Histopathologically, Histopathologically, the the tumor tumor appeared appeared rich rich in in cellular cellular density, density, forming forming lobes. lobes. TheThe metastatic metastatic cellscells showed scant cytoplasm, cytoplasm, elongated elongated atypical atypical nuclei, nuclei, and and abundant abundant mi- mitotictotic figures figures with with up up to to10 10mitoses mitoses in one in one high-power high-power field. field. Foci Foci of necrosis of necrosis andand areas areas with withabundant abundant electrocautery electrocautery artifacts artifacts were were also also observed. observed. These These areas areas had aa lowerlower cellularcellular densitydensity and and peripheral peripheral calcification, calcification, suggestive suggestive of of a a pineoblastoma. pineoblastoma. InIn termsterms ofof imuno- imuno- histochemistryhistochemistry the the pineal pineal tumor tumor showed showed a a patchy patchy expression expression of of synaptophysin, synaptophysin, a a diffuse diffuse andand strong strong expression expression of of CD99 CD99 and and weak weak expression expression of of the the cytokeratins cytokeratins AE1/AE3 AE1/AE3 and and CAMCAM 5.2. 5.2. Partial Partial resection resection of of the the pineal pineal metastasis metastasis was was performed. performed. The The patient patient was was given given chemotherapy;chemotherapy; however, however, tumor tumor progression progression was was observed. observed.

3.2.3.2. Pineal Pineal Cysts Cysts Non-neoplasticNon-neoplastic pinealpineal cysts are frequently frequently observed observed during during both both MRI MRI scans scans and and au- autopsytopsy studies, studies, and and the the prevalence prevalence of of benign benign pineal pineal cysts cysts ranges ranges between between 0.6% 0.6% and and 23% 23% in inthe the general general population population [115–121]. [115–121 Pineal]. Pineal cyst cysts,s, usually usually considered considered normal normal anatomical anatomical var- iations, are present at all ages but mainly in adult women in the fourth decade of life. Symptomatic cysts are more frequent among young women [116,119,122].

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Cancers 2021, 13, x 12 of 19 variations, are present at all ages but mainly in adult women in the fourth decade of life. Symptomatic cysts are more frequent among young women [116,119,122]. It is, in our opinion, important to at least introduce pineal cysts because they are It is, in our opinion, important to at least introduce pineal cysts because they are pin- pineal non-neoplastic masses that are relatively common in the general population, and a eal non-neoplastic masses that are relatively common in the general population, and a heterogeneous group of tumors, such as pineoblastomas, astrocytomas, meningiomas and heterogeneous group of tumors, such as pineoblastomas, astrocytomas, meningiomas and pineocytomas, may feature a cystic nature on MRI, without showing hemorrhage within pineocytomas, may feature a cystic nature on MRI, without showing hemorrhage within the masses [119,123]. Pineal cysts present an inner glial layer, a middle layer of pineal the masses [119,123]. Pineal cysts present an inner glial layer, a middle layer of pineal tissue and an outer fibrous capsule. On MRI scans, benign pineal cysts appear as round or tissue and an outer fibrous capsule. On MRI scans, benign pineal cysts appear as round ovoid areas of signal abnormality in the pineal region [120,124] (Figure 11). or ovoid areas of signal abnormality in the pineal region [120,124] (Figure 11).

FigureFigure 11. 11.Pineal Pineal cyst cyst MRI. MRI. The The asterisk asterisk indicates indicates the the pineal pineal cyst. cyst. Reprinted Reprinted with with permission permission from from Májovský et al. (2017) [124]—Elsevier—2021 (License Number 5020240575766). Májovský et al. (2017) [124]—Elsevier—2021 (License Number 5020240575766).

BarboriakBarboriak etet al.al. [[125]125] undertookundertook aa follow-upfollow-up MRIMRI studystudy and,and, interestingly,interestingly, observed observed thatthat pineal pineal cysts cysts usually usually remain remain stable. stable. Only Only a a fewfew pineal pineal cyst cyst cases cases may may enlarge, enlarge, making making themthem ofof neurologicalneurological significance.significance. Large Large cysts cysts typically typically exert exert a amass mass effect effect on on the the cerebral cere- bralaqueduct, aqueduct, encircling encircling venous venous structures structures and the and dorsal the dorsal midbrain. midbrain. The most The reported most reported symp- symptoms,toms, correlated correlated to theto compression the compression of the surrounding of the surrounding structures, structures, are headaches, are headaches, vertigo, vertigo,visual and visual oculomotor and oculomotor disturbances, disturbances, and obst andructive obstructive hydrocephalus hydrocephalus [117,119,125]. [117,119 Symp-,125]. Symptomatictomatic pineal pineal cysts are cysts divided are divided into three into syndromes: three syndromes: (1) paroxysmal (1) paroxysmal headaches headaches and gaze andpalsy; gaze (2) palsy;chronic (2) headaches, chronic headaches, papilledema, papilledema, gaze paresis, gaze and paresis, hydrocephalus; and hydrocephalus; and (3) pin- andeal apoplexy (3) pineal with apoplexy acute with hydrocephalus. acute hydrocephalus. The last is Thethe least last isfrequent the least but frequent most dangerous but most dangerousform. In practice, form. In there practice, are no there accepted are no therapeu acceptedtic therapeuticindications indicationsor criteria for or intervention criteria for interventionand/or follow-up. and/or However, follow-up. only However, a few patients only a fewwith patients pineal cysts with requires pineal cysts treatment. requires In treatment.fact, as previously In fact, as reported, previously pineal reported, cysts pineal usually cysts have usually no clinical have no implications clinical implications and are andasymptomatic are asymptomatic [119,126,127]. [119,126 ,127]. Choque-VelasquezChoque-Velasquez et et al. al. [117 [117]] reported reported in their in their recent recent case series case thatseries surgically that surgically treated pinealtreated cysts pineal represent cysts represent a progressive a progressive disease disease with acutewith acute or progressive or progressive hydrocephalus hydroceph- atalus the at final the final stage. stage. The The authors authors also also suggested suggested that that young young women women with with active active sexual sexual hormonehormone statusstatus (aged (aged >10-years) >10-years) comprisecomprise thethe patientpatientgroup group at at the the highest highest risk risk for for pineal pineal cystcyst progression.progression.

4.4. ConclusionsConclusions AsAs reportedreported inin thethe presentpresent review review and and summarized summarized inin TableTable1 ,1, pineal pineal neoplasms neoplasms are are heterogeneousheterogeneous tumors tumors with with different different histological, histological, morphological, morphological, and and radiological radiological features fea- and,tures consequently, and, consequently, different different diagnosis diagnosis and management. and management.

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Table 1. The table summarizes the main characteristics of pineal gland tumors.

Histological Incidence, Age and Sex Morphology/Histology Subtype Distribution Not encapsulated tumors with variable proportions of germinoma cellular sheets or Most common pineal tumor Germ Cell lobules composed of a mixture of large (>50% of pineal tumors in Europe, Germinomas Tumors multipotential primitive germ cells and the United States, and Japan). smaller cells that resemble lymphocytes. Male predominance. Often presented inflammatory infiltrates. Rare pineal tumor (<5% of all Tumors with stromal vascular channels that pineal masses). Choriocarcinomas form blood lakes and intratumoral Young men predominance hemorrhagic necrosis. (3–22 years of age). Encapsulated tumors with multipotential Second most common pineal Teratomas cells that recapitulate normal organogenesis. tumors. (Teratoma may also be unencapsulated). Male predominance. Unencapsulate tumors with About 14–30% of all pineal Pineal well-differentiated mature cells arranged parenchymal tumors. Parenchymal Pineocytomas in sheets. More common in adults Tumor Pineocytic rosettes. (30–60 years old). 40% of all pineal parenchymal tumors. Pineoblastomas Undifferentiated or immature pineal cells. Highest incidence in children less of 2 years old. Slightly female predominance. Tumors with partially papillary structures lined by slightly polymorphic cells forming Papillary Tumors ependymal rosettes and pseudorosettes. The Rare pineal parenchymal tumors. rosetted cells had thick processes resting on collagen surrounding the vessels. Rare pineal parenchymal tumors Pineal Parenchymal which may occur in all ages. Pseudolobulated architecture with multiple Tumors of Intermediate Slightly female predominance cystic components. Differentiation (teenagers and middle-aged women).

Furthermore, due to their rarity, pineal tumors may be misdiagnosed. Establishing a means of specific tissue diagnosis for patients with pineal region tumors is needed to distinguish among the variety of possible histomorphological tumor subtypes. In the last decade, specialized surgical and stereotactic techniques have evolved to provide specific, safer, and more effective options for obtaining, at least, correct tissue diagnosis. Advanced microsurgical techniques combined with improved preoperative management and postoperative critical care methods have made surgical resection the optimal therapy for almost all pineal tumors. However, the identification of new therapeutic targets and the development of more effective adjuvant therapies, as well as follow-up guidelines, are needed to improve pineal tumor outcomes.

Author Contributions: Conceptualization, R.R. and G.F.; critically analyzed literature, G.F. and F.B.; wrote the manuscript draft, G.F. and F.B.; drew and acquired figures and table, G.F.; supervised and improved the manuscript content, R.R. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. Cancers 2021, 13, 1547 14 of 18

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