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Pineal Gland Tumors: a Review 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. Cancers 2021, 13, 1547 3 of 18 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,
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