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; francesca.bonomini@unibs.it (F.B.); rita.rezzani@unibs.it (R.R.)
2 Interdipartimental University Center of Research “Adaption and Regeneration of Tissues and
Organs (ARTO)”, University of Brescia, 25123 Brescia, Italy
* Correspondence: gaia.favero@unibs.it

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/
cancers13071547
Keywords: 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]. Figure 1
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 cysts,
pineal different
cysts, pineal
different tumors,
pineal and
tumors, vascular
and malformations,
vascular including
malformations, cavernous,
including cavernous,
arteriovenous malformations and aneurysms.
arteriovenous malformations and aneurysms.

Figure
Figure 1. 1.
1.
Figure Human
Human
Human pineal
pineal gland
gland
pineal (a)and
(a)
gland and
(a) itsits
and anatomic
anatomic
its boundaries
boundaries
anatomic (b).(b).
boundaries The The
(b). pineal
pineal
The gland
gland
pineal is is
visible
is visible
gland in in
in yellow
visible yellow (a). Anatomage
(a). Anatomage
yellow (a). Inc.—
Anatomage
Inc.—Anatomage
Anatomage Table
Table EDU.
Inc.—Anatomage EDU.
The
Table 3DThe
EDU. 3D3D rendering
rendering
The ofof
thethe
of the cadaver
rendering cadaver
data isdata
cadaver from isAnatomage
data from
is Anatomage
from Table. Table.
Anatomage Table.

2. Pineal
2.2.Pineal
PinealGland
Gland
Gland Tumors
Tumors
Tumors
Pineal
Pineal neoplasms
neoplasms
Pineal neoplasms are
arearefairly
fairly uncommon
uncommon
fairly uncommon tumors,
tumors, and
tumors, and they
they
and areare
they arepredominantly
predominantly
predominantly child-
childhood
child-
hood malignancies
malignancies representing 3–11% of all pediatric brain tumors
hood malignancies representing 3–11% of all pediatric brain tumors compared to brain
representing 3–11% of all pediatric brain tumors comparedcompared
to <1% to <1%
of <1% ofof
brain
tumors tumors in adults [1,14,17–20]. Age, sex, and ethnicity may modulate
brain tumors in adults [1,14,17–20]. Age, sex, and ethnicity may modulate the relativeofin-
in adults [1,14,17–20]. Age, sex, and ethnicity may modulate the the
relative relative
incidence in-
pineal
cidence neoplasms
cidence ofof
pineal
pineal [21]. Pineal [21].
neoplasms
neoplasms tumors
[21]. are classified
Pineal
Pineal tumors
tumors as:
are germ cell as:
classified
are classified tumors,
germ
as: germ pineal
cell parenchymal
tumors,
cell tumors, pineal
pineal
tumors
parenchymaland tumors
tumors that
and derive
tumors from
that adjacent
derive anatomical
from adjacent structures.
parenchymal tumors and tumors that derive from adjacent anatomical structures. anatomical Germinoma
structures. isGer-
the
Ger-
most
minoma common pineal tumor, representing up to 50% of pineal tumors in Europe, the United
minoma is the most common pineal tumor, representing up to 50% of pineal tumorsinin
is the most common pineal tumor, representing up to 50% of pineal tumors
States and
Europe, the Japan
United [1,22,23].
States In aJapan
and series[1,22,23].
of 370 pineal
InIn tumors
a series in
ofof
370patients
pineal aged
tumors 3–73
ininyears, it
patients
Europe, the United States and Japan [1,22,23]. a series 370 pineal tumors patients
was observed
aged 3–73 years,that 27%observed
it it
was were germinomas;
that 27% 26%germinomas;
were were astrocytomas;
26% were 12% were pineoblas-
astrocytomas; 12%
aged 3–73 years, was observed that 27% were germinomas; 26% were astrocytomas; 12%
tomas;
were 12% were pineocytomas;
pineoblastomas; 12% were 4.3% were ependymomas;
pineocytomas; 4.3% were 4.3% were teratomas;
ependymomas; 4.3% 2.7%
were were
ter-
were pineoblastomas; 12% were pineocytomas; 4.3% were ependymomas; 4.3% were ter-
ganglioglioneuromas,
atomas; 2.7% were lymphomas, meningiomas,
ganglioglioneuromas, lymphomas, metastases, and pineal
meningiomas, cysts; 1.6%
metastases, and were
pin-
atomas; 2.7% were ganglioglioneuromas, lymphomas, meningiomas, metastases, and pin-
mixed
eal embryonal
cysts; 1.6% were cell tumors
mixed (embryonal
embryonal cell carcinomas)/malignant
tumors (embryonal teratomas; 1.1% were
carcinomas)/malignant ter-
eal cysts; 1.6% were mixed embryonal cell tumors (embryonal carcinomas)/malignant ter-
choriocarcinomas;
atomas; 1.1% were and 0.54% were
choriocarcinomas; oligodendrogliomas
and 0.54% were [24] (Figure
oligodendrogliomas2). [24] (Figure 2).2).
atomas; 1.1% were choriocarcinomas; and 0.54% were oligodendrogliomas [24] (Figure

Figure 2. 2.
Figure Pineal tumor
Pineal classification.
tumor classification.
Figure 2. Pineal tumor 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, 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 (Figure 3), 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-
weighted
ment (C).image (T1WI)identifies
The arrow (A), hyperintense on mass
hyperdense T2WI with
(B) and with homogeneous
calcification contrast
at computed enhancement
tomography (D). In
(C). The arrow identifies hyperdense mass with calcification at computed tomography
another patient, a larger germinoma, isointense on T1WI (E). Reprinted with permission (D). Infrom
another
Reis
patient, a larger
et al. (2006) [41].germinoma, isointense
John Wiley and on T1WI
Sons—2021 (E). Number
(License Reprinted with permission from Reis et al.
5034711197310).
(2006) [41]. John Wiley and Sons—2021 (License Number 5034711197310).
Imaging alone does not allow us to distinguish among germinomas, nongerminoma-
tousImaging alone
germ cell doesand
tumors notpineal
allow us to distinguish
parenchymal among
tumors. germinomas,
Therefore, nongerminoma-
a complete evaluation
tous
is fundamental. In fact, germinomas are diagnosed using imaging together evaluation
germ cell tumors and pineal parenchymal tumors. Therefore, a complete with serum
isand
fundamental.
CSF markers. In fact,
Thesegerminomas are diagnosed
tumors present high serumusing imaging
and CSF together
expression with serum
of oncoproteins
and CSF markers. These tumors present high serum and CSF expression of oncoproteins
such as alpha-fetoprotein, beta human chorionic gonadotropin, lactate dehydrogenase,
such
and as alpha-fetoprotein,
placental beta human[6].
alkaline phosphatase chorionic gonadotropin, lactate dehydrogenase, and
placental alkaline phosphatase [6].
The treatment regimens used 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.Choriocarcinomas
2.1.2. Choriocarcinomas
Pinealchoriocarcinomas
Pineal choriocarcinomas are are uncommon
uncommonmalignant
malignantnongerminomatous
nongerminomatousgerm germcellcell
ne-
oplasms (accounting for fewer than 5% of all pineal masses) [13] and the most
neoplasms (accounting for fewer than 5% of all pineal masses) [13] and the most aggressive aggressive
formofofgestational
form gestationaltrophoblastic
trophoblasticdisease.
disease.Choriocarcinoma
Choriocarcinomashows showsaapoorpoorsurvival
survivalraterate
withrespect
with respecttotoother
other germ
germ cell
cell tumors
tumors [46,47].
[46,47]. Median
Median overall
overall survival
survival of primary
of primary intra-
intracra-
cranial pure choriocarcinoma was 22 months and the three- and five-year
nial pure choriocarcinoma was 22 months and the three- and five-year survival rate was survival rate
was 45.8% [48]. Primary intracranial choriocarcinoma mainly affects
45.8% [48]. Primary intracranial choriocarcinoma mainly affects young men (3–22 years young men (3–22
ofyears
age),ofwho
age), who present
present precocious
precocious puberty.puberty. These tumors
These tumors do notdistinctive
do not show show distinctive
symp-
symptoms,
toms, but patients
but patients affected affected by choriocarcinoma
by choriocarcinoma have mainly have mainlyheadaches,
reported reported headaches,
vomiting,
vomiting,
nausea, nausea,
visual visual impairment,
impairment, polydipsia,polydipsia,
polyuria andpolyuria and endocrinologic
endocrinologic alterations
alterations [46,49].
[46,49]. Choriocarcinomas
Choriocarcinomas presentvascular
present stromal stromal vascular
ducts that ducts
formthat form
blood blood
lakes andlakes and intra-
intratumoral
tumoral hemorrhagic
hemorrhagic necrosis, allnecrosis,
factors all factors
strictly strictly with
correlated correlated
a poor with a poor
prognosis prognosis
[2,46,50,51].
[2,46,50,51]. On imaging, choriocarcinomas appear as ovoid, heterogeneous,
On imaging, choriocarcinomas appear as ovoid, heterogeneous, and slightly hyperdense and slightly
hyperdense
masses masses
(Figure 4). (Figure 4).
 Cancers 2021, 13, 1547 5 of 18
ncers 2021, 13, x 5 of 19

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 from Causil
[46]. Elsevier—2021 et al. Number:
(License (2016) [46]. Elsevier—2021 (License Number: 5034730033295).
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, classic hydrocephalus).
does not present treatments frequently fail due
However, to choriocarcinomas
to treat choriocarcinoma, abeing ex-total tumor
mix of
tremely resistant tumors. The first clinical choice is total resection (even if the patient does
removal, chemotherapy, and radiotherapy is frequently used as a therapeutic combination
not presentand
hydrocephalus).
seems to showHowever, to treat choriocarcinoma,
positive outcomes [46–49]. a mix of total tumor re-
moval, chemotherapy, and radiotherapy is frequently used as a therapeutic combination
and seems2.1.3.
to show positive outcomes [46–49].
Teratomas
Intracranial teratomas account for up to 50% of fetal brain neoplasms; in neonates, they
2.1.3. Teratomas
comprise 33% of intracranial tumors, but they comprise only 2%–4% of intracranial tumors
Intracranial teratomas
in patients account
aged <15 yearsfor up to Intracranial
[54,55]. 50% of fetal teratomas
brain neoplasms;
typicallyinarise
neonates,
from the pineal
they comprisegland33%
andofinvolve
intracranial tumors,
the third but [54].
ventricle they Pineal
comprise only 2%–4%
teratomas have aof intracranial
male predominance that
tumors in varies
patients
fromaged
2:1<15 years
to 8:1 and[54,55]. Intracranial
an overall teratomas
survival of 90–100%typically arise from the
[26]. Histologically, teratomas are
pineal gland and involve the third ventricle [54]. Pineal teratomas have a male predomi-
classified into: (1) mature tumors, which show completely differentiated tissue; (2) imma-
nance thatturevaries from 2:1
tumors, to 8:1
which and an
present overall survival
a combination of 90–100%
of fetal- [26]. Histologically,
and mature-type tissue elements and
teratomas elements
are classified
from into: (1) germ
all three mature tumors,
layers which
and (3) showwith
teratomas completely
malignant differentiated
transformation, which
involves the
tissue; (2) immature malignant
tumors, whichdegeneration of matureoftissue
present a combination fetal-[14,56]. Teratomastissue
and mature-type are neoplasms
elements and characterized
elements fromby multipotential
all three germcells thatand
layers revert
(3) to normal organogenesis,
teratomas with malignant usually
trans- producing
formation,tissues representing
which involves a combination
the malignant of two or of
degeneration more of the
mature embryological
tissue layers of ectoderm,
[14,56]. Teratomas
mesoderm, and endoderm [13,14]. Pineal teratomas can be partially
are neoplasms characterized by multipotential cells that revert to normal organogenesis, or totally encapsulated,
but can also
usually producing be unencapsulated
tissues and locally invasive
representing a combination of two or[13].
moreOnofimaging, these pineal tumors
the embryological
present foci
layers of ectoderm, of fat, calcification
mesoderm, and endoderm and [13,14].
cystic regions [13,54]. On
Pineal teratomas canMRI, teratomas
be partially or appear as
lobular, multiloculated,
totally encapsulated, but can also and heterogeneouslyand
be unencapsulated wide masses
locally [14] (Figure
invasive [13]. On 5). imag-
ing, these pineal tumors present foci of fat, calcification and cystic regions [13,54]. On MRI,
s 2021, 13, x 6 of 19

Cancers 2021, 13, 1547 6 of 18

teratomas appear as lobular, multiloculated, and heterogeneously wide masses [14] (Fig-
ure 5).

Figure
Figure 5. Pineal 5. Pineal
teratoma teratoma
MRI. SagittalMRI. Sagittal
T1 image T1axial
(A), imageT1(A), axialsagittal
(B) and T1 (B) and sagittal contrast-enhanced
contrast-enhanced T1 Reprinted
T1 (C) images.
(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
2.2. Pineal Parenchymal Parenchymal Tumors
Tumors
Pineal parenchymal tumors are neuroepithelial neoplasms arising from pineocytes.
Pineal parenchymal tumors are neuroepithelial neoplasms 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 ataxia [1,26,57,61,62]. Pineal
a hypomelatoninemic parenchymal cell tumors
or hypermelatoninemic consistently
state [63]. However,produce
exogenous melatonin
a hypomelatoninemic or hypermelatoninemic state [63]. However, exogenous
supplementation after pinealectomy may mitigate the ensuing syndrome melatonin [1,64,65]. Pineal
supplementation after pinealectomy
parenchymal tumors aremaynegative
mitigatefor
thethe
ensuing
three syndrome
tumor markers[1,64,65]. Pineal
alpha-fetoprotein, beta
parenchymal tumors
human are negative
chorionic for the threeand
gonadotropin, tumor markers
placental alpha-fetoprotein,
alkaline phosphatase [1]. betaHowever,
hu- synapto-
man chorionicphysin
gonadotropin,
is expressedandinplacental alkaline phosphatase
pineal parenchymal tumors of[1]. However,differentiation,
intermediate synapto- and neu-
physin is expressed in pineal parenchymal tumors of intermediate differentiation,
ronal marker positivity is not related to histological grade, mitosis, proliferation and index, or
neuronal marker positivity
prognosis is The
[66]. not related
standardto treatment
histologicalforgrade,
pinealmitosis, proliferation
parenchymal tumors index,
is radiation. Surgery
or prognosis [66].
is another possible treatment option; however, it has a mortality is
The standard treatment for pineal parenchymal tumors radiation.
rate of 5%–10% [1,24], and
Surgery is another
even possible treatment
after complete option;
tumor however,
removal, manyit patients
has a mortality
presentrate of 5%–10%
recurrence. Hence, adjuvant
[1,24], and even after complete
radiation tumor removal,
or chemotherapy many
or a mix patients
of both present
is often recurrence.
suggested Hence,
with the aim of improving
adjuvant radiation or chemotherapy
survival [1,61,62]. Thus,orappropriate
a mix of bothandisclose
oftenfollow-up
suggested is with the aim of
also fundamental.
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
from the
Pineocytomas are pineal epithelium
slow-growing [1,15,51,60,67].
grade They are tumors
I/II pineal parenchymal characterized
neoplasms by well-different-
derived
from the pinealiated mature cells
epithelium arranged inThey
[1,15,51,60,67]. sheetsarethat are virtually
tumors indiscernible
characterized from the healthy pineal
by well-differ-
entiated matureparenchyma [13,14,68].
cells arranged They
in sheets areare
that circumscribed, unencapsulated
virtually indiscernible tumors
from the that may remain
healthy
pineal parenchyma [13,14,68]. They are circumscribed, unencapsulated tumors that mayin adults aged
locally confined. Pineocytomas may arise at all ages but are more frequent
remain locally30confined.
to 60 years old [14,69]. may arise at all ages but are more frequent in
Pineocytomas
adults aged 30 to 60On MRI,old
years pineocytomas
[14,69]. appear as hyperintense, round or lobular masses [2,14,15,56,70]
On MRI,(Figure 6).
pineocytomas appear as hyperintense, round or lobular masses
[2,14,15,56,70] (Figure 6).
Cancers 2021, 13, 1547 7 of 18
Cancers
Cancers2021,
2021,13,
13,x x 7 7ofof1919

Figure
Figure6. Pineocytoma MRI. The asterisk indicates the homogeneous mass ininthe pineal gland.
Figure 6.6. Pineocytoma
Pineocytoma MRI. MRI.TheTheasterisk
asteriskindicates
indicatesthe thehomogeneous
homogeneous massmass the pineal
in the gland.
pineal gland.
Reprinted
Reprintedwith withpermission
permissionfrom fromSmirniotopoulos
Smirniotopoulosetetal. al.(1992)
(1992)[13].
[13].Radiological
RadiologicalSocietySocietyNorth
North
Reprinted with permission from Smirniotopoulos et al. (1992) [13]. Radiological Society North
America–2021.
America–2021.Small Smallpineocytomas
pineocytomasoften oftendodonot
notinduce
inducesymptoms,
symptoms,but butififthey
theyareareofoflarge
largedimen-
dimen-
America–2021.
sions, Small pineocytomas often do not induce symptoms, but if they are of large dimensions,
sions, they may induce obstructive hydrocephalus and Parinaud syndrome, defined asupward
they may induce obstructive hydrocephalus and Parinaud syndrome, defined as upward
they
gaze may
gazepalsy,
palsy, induce obstructive
pupillary
pupillary light-near
light-nearhydrocephalus
dissociation,
dissociation,and and
and Parinaud syndrome,
convergence
convergence retraction defined
retractionnystagmus
nystagmus as[15].
upward
[15].The gaze
Thefive-
five-
palsy,
and pupillary light-near
andtwenty-year
twenty-year survival
survivalratesdissociation,
ratesare, and convergence
are,respectively,
respectively, 100%
100%and andretraction
76%
76%[21,26].nystagmus
[21,26]. For [15]. The five-
Forpineocytomas,
pineocytomas, and
stereo-
stereo-
tactic
tacticradiosurgery
twenty-year survival
radiosurgery seems
ratestoto
seems be
behighly
are, highlyeffective
respectively, asasaand
100%
effective aprimary treatment,
76% [21,26].
primary For so
treatment, sostereotactic
stereotacticradiosur-
pineocytomas, stereotactic
radiosur-
gery
geryalone
alonemay
radiosurgery may be
beconsidered
seems considered
to be highly appropriate
effective asclinical
appropriate clinical
a primarymanagement
treatment,for
management sopineocytomas
for pineocytomas
stereotactic [21,28,71,72].
[21,28,71,72].
radiosurgery 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
AsAspreviously
previouslyreported,
reported,pineal
pinealparenchymal
parenchymalcell celltumors
tumorsalsoalsoinclude
includepineoblasto-
pineoblasto-
mas,As
mas, previously
aggressive,
aggressive, reported,
grade
gradeIV pineal parenchymal
IVneoplasms
neoplasms derived
derivedfrom cellprimitive
from tumors also
primitive include pineoblastomas,
neuroectoderm
neuroectoderm [1,17].
[1,17].They
They
aggressive,
account grade IV neoplasms derived from primitive neuroectoderm
account for 40% of parenchymal pineal cancers. Pineoblastomas are undifferentiated,em-
for 40% of parenchymal pineal cancers. Pineoblastomas are [1,17]. They
undifferentiated, account
em-
for 40% tumors
bryonal
bryonal oftumors
parenchymal
categorizedpineal
categorized cancers.
primitivePineoblastomas
asasprimitive neuroectodermal
neuroectodermal are undifferentiated,
tumors.
tumors. Similar embryonal
Similartotoother
otherprim-
prim-
tumors
itive categorized as primitive neuroectodermal extremelytumors. Similar to other primitive
itiveneuroectodermal
neuroectodermaltumors,tumors,pineoblastomas
pineoblastomasare are extremelyaggressive
aggressiveand andpresent
presentaa
neuroectodermal
poor tumors, pineoblastomas are extremely aggressive and present a poor
poorprognosis
prognosisand andaggressive
aggressiveclinical
clinicalbehavior
behaviordue duetotothethefrequent
frequentinvasion
invasionofofadjacent
adjacent
prognosis
structure and aggressive clinical behavior due to the frequent invasion of adjacent struc-
structure andand CSFCSF dissemination,
dissemination, with with reported
reported five-year
five-year survival
survival rates
rates ofof <60%
<60%
ture and CSF
[23,57,73,74]. dissemination, with reported five-year survival rates of <60% [23,57,73,74].
[23,57,73,74]. The highest incidence is in childhood, particularly in children less than22
The highest incidence is in childhood, particularly in children less than
The highest incidence is in childhood, particularly in children less than 2 years old, where
years
years old,
old, where
where pineoblastomas
pineoblastomas can can occur
occur inin combination
combination with with retinoblastomas
retinoblastomas
pineoblastomas can occur in combination with retinoblastomas [13,14,26,59,75]. Adult
[13,14,26,59,75].
[13,14,26,59,75].Adult
Adultcases
casesare arevery
veryrare,
rare,and
andforforthis
thisreason,
reason,limited
limiteddata
dataarearecurrently
currently
cases are very rare, and for this reason, limited data are currently available for the effort to
available
available forfor the
the effort
effort toto develop
develop aa standard
standard management
management course course for
for the
the diseases.
diseases.
develop a standard management course for the diseases. Pineoblastomas are malignant,
Pineoblastomas
Pineoblastomasare aremalignant,
malignant,unencapsulated
unencapsulatedtumors tumorsthat,
that,unfortunately,
unfortunately,may mayoften
oftenre-
re-
unencapsulated tumors that, unfortunately, may often recur and also disseminate through-
cur and also disseminate throughout the craniospinal axis, as well as presenting
cur and also disseminate throughout the craniospinal axis, as well as presenting metasta- metasta-
out the craniospinal axis, as well as presenting metastasis all over the body, such as in the
sis
sisall
allover
overthethebody,
body,such
suchasasininthe
thecalvarial
calvarialbones,
bones,vertebrae,
vertebrae,lungs,
lungs,peritoneum,
peritoneum,mandi-
mandi-
calvarial bones, vertebrae, lungs, peritoneum, mandible, and pelvis [59,76–78] (Figure 7).
ble,
ble,and
andpelvis
pelvis[59,76–78]
[59,76–78](Figure
(Figure7).7).

Figure
Figure7.
Figure 7.7.Pineoblastoma
PineoblastomaMRI.
Pineoblastoma MRI.Preoperative
MRI. PreoperativeMRI
Preoperative MRI
MRI (A–C),
(A–C),MRI
(A–C),MRI1.5
MRI1.5months
months
1.5 after
after
months surgery
surgery
after showing
showing
surgery spinal
spinal
showing metastasis
metastasis
spinal (D). Re-
(D).(D).
metastasis Re-
printed
printedwith
withpermission
permissionfrom
fromHuo
Huoetetal.
al.(2020)
(2020)[79].
[79].Dove
DoveMedical
MedicalPress—2021.
Press—2021.
Reprinted with permission from Huo et al. (2020) [79]. Dove Medical Press—2021.

Pineoblastomas
Pineoblastomasare
arecomposed
composedofofundifferentiated
undifferentiatedororimmature
immaturepineal
pinealcells
cells[13,74].
[13,74].
Synaptophysin
Synaptophysinand
andchromogranin
chromograninare
aremarkers
markersofofprimitive
primitiveneuroendocrine
neuroendocrinetumors
tumorsthat
that
Cancers 2021, 13, 1547 8 of 18

Cancers 2021, 13, x 8 of 19

Pineoblastomas are composed of undifferentiated or immature pineal cells [13,74].

Synaptophysin and chromogranin are markers of primitive neuroendocrine tumors that
may be
may be expressed
expressed in in pineoblastomas
pineoblastomasand anddetectable
detectableininthe theserum
serum or or
CSF [1,80].
CSF TheThe
[1,80]. mo-
lecular background of pineoblastoma is not clearly known.
molecular background of pineoblastoma is not clearly known. However, recent studies However, recent studies
showedthat
showed thatthe
theDICER1
DICER1and andDROSHA
DROSHAgenes, genes,involved
involvedin inmicroRNA
microRNAdysregulation,
dysregulation,are are
fundamental to pineoblastoma carcinogenesis
fundamental to pineoblastoma carcinogenesis [81,82]. [81,82].
Aggressivesurgical
Aggressive surgicalresection
resectionis is thethe first-line
first-line therapy
therapy against
against pineoblastoma.
pineoblastoma. Nota-
Notably,
bly, radiotherapy after resection helps in increasing patient survival.
radiotherapy after resection helps in increasing patient survival. As also reported for As also reported for
other pineal
other pineal gland
gland tumors,
tumors, combined
combined therapytherapy seems
seemstotobe beananeffective
effectiveapproach
approach[59]. A
[59].
Areport
report from
from the International
the International Gamma
Gamma Knife Research
Knife Research Foundation
Foundation described actuarial
described local
actuarial
control
local and and
control survival rates
survival following
rates following thethestereotactic
stereotactic radiosurgery
radiosurgery of of
pineoblastomas
pineoblastomasof
27%
of 27%and and48% 48% at at
5 years
5 years[29]. Recently,
[29]. Recently,JingJing
et al.
et [59] evaluated
al. [59] 213 213
evaluated adultadult
patients with
patients
pineoblastomas and observed that young patients, especially
with pineoblastomas and observed that young patients, especially those not receiving those not receiving radio-
therapy during
radiotherapy theirtheir
during initial treatment,
initial oftenoften
treatment, had had
extremely poorpoor
extremely outcomes [59,83].
outcomes This
[59,83].
study
This suggested
study suggestedthat that
beam radiotherapy
beam radiotherapy doesdoes
not improve
not improve overall patient
overall survival.
patient Fur-
survival.
thermore, tumors
Furthermore, tumors thatthat
invade
invade tissue
tissuenear
nearthethe
pineal
pinealgland
glandareare
more
more aggressive
aggressive than tu-
than
tumors confinedtotothe
mors confined thepineal
pinealgland,
gland, increasing
increasing the the risk of patient
patient death
death about
about threefold.
threefold.
Jing
Jingetetal.
al.[59]
[59]also
alsoreported
reportedthat, that,forforevery
every 1 mm
1 mm increase
increase in in
tumor
tumorsize, thethe
size, riskrisk
of death
of deathis
reduced by 4%, so tumor size may not be considered
is reduced by 4%, so tumor size may not be considered a prognostic factor. a prognostic factor.

2.2.3.
2.2.3.Papillary
PapillaryTumors
Tumors
Pineal
Pineal papillary tumors
papillary tumors are
are uncommon
uncommon WHO WHO grade
grade IIII or
or III
III neuroepithelial
neuroepithelial neo-
neo-
plasms [14,15,56]. Among them, 68% have been found to recur
plasms [14,15,56]. Among them, 68% have been found to recur at a mean at a mean follow-up
follow-up of of
4.2
4.2 years
years (with
(with overall
overall survival
survival ratesrates of at
of 73% 73% at 5 and
5 years years58%
andat58% at 10 and
10 years), years),
in aand in a
pediatric
pediatric population,
population, 47% of tumors
47% of papillary papillary
of tumors of gland
the pineal the pineal gland
recurred at recurred at a meanof
a mean follow-up
follow-up
6.5 years [83,84]. The age of patients presenting pineal papillary tumors is 15 tumors
of 6.5 years [83,84]. The age of patients presenting pineal papillary months isto
15
67months to 67
years and years
there is and there
a mild is a mild
female female prevalence.
prevalence. The mainreported
The main symptom symptombyreported
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 (Figure 8).
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
Cancers 2021, 13, 1547 9 of 18

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 (Figure 9). 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-
ation therapy.(License
vier—2021 Reprinted with permission
Number: from Choque-
5035440109275). Velasquez ettumors
Pineal parenchymal al. (2019)
of [102]. Elsevier—2021
intermediate differ-
(License Number: 5035440109275). Pineal parenchymal tumors of intermediate differentiation
entiation may be morphologically classified into (1) lobulated endocrine-like and highly vascular may be
morphologically
lesions; (2) thoseclassified into (1)
with diffuse lobulated
growth endocrine-like
patterns, similar to and highly vascular lesions; (2) thoseand
oligodendrogliomaneurocytomas; with
(3)
those of
diffuse transitional
growth type,
patterns, with areas
similar of lobulated and diffuse growth and
to oligodendrogliomaneurocytomas; patterns, correlated
(3) those with
of transitional
areaswith
type, of pineocytomatous
areas of lobulatedrosettes [82,102,109].
and diffuse Recently,correlated
growth patterns, Wu et al. [103] reported
with areas that CD24 and
of pineocytomatous
rosettes [82,102,109]. Recently, Wu et al. [103] reported that CD24 and PRAME may be pineal
PRAME may be novel markers useful for the grading and prognostic evaluation of paren-
novel markers
chymal tumors of intermediate differentiation and, thus, useful in therapeutic decision-making.
useful for the grading and prognostic evaluation of pineal parenchymal tumors of 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-
reported cases. The
ation. However, maximal
even surgical removal
after complete of the tumor
surgical tumor removal,is the optimal
many treatment
patients in practice
experience recur- for
pineal
rence.parenchymal tumors
Hence, adjuvant of intermediate
radio- differentiation.
or chemo-therapy, or a mix ofHowever, even recommended
both, is often after complete to surgical
im-
tumor
proveremoval, many patients
patient survival. A reportexperience
from the recurrence.
International Hence,
Gamma adjuvant radio- or chemo-therapy,
Knife Research Foundation de- or
ascribed actuarial
mix of both, localrecommended
is often control and survival rates patient
to improve following stereotactic
survival. radiosurgery
A report from the on pineal
International
parenchymal
Gamma tumors ofFoundation
Knife Research intermediatedescribed
differentiation
actuarialof 50%
localand 56%,and
control respectively, at 5 years
survival rates following
[19,26].
stereotactic 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 Brief
PinealOverview
Metastasisof Other Neoplastic and Non-Neoplastic Pineal Masses
3.1. Pineal Metastasis
Metastatic cancer spreading to the pineal gland is exceedingly uncommon and orig-
inatesMetastatic cancer
from lung spreading
carcinoma to the
in most pineal
cases gland
(Figure 10).isOther
exceedingly
tumors uncommon and orig-
that have documented
inates from lung carcinoma in most cases (Figure 10). Other tumors that have docu-
cases of metastases to the pineal gland are pancreatic, esophageal and bladder neoplasms
mented
[110–113].cases of metastases to the pineal gland are pancreatic, esophageal and bladder
neoplasms [110–113].
Cancers 2021, 13, 1547 11 of 18
Cancers 2021, 13, x 11 of 19

Figure10.
Figure 10.Pineal
Pineal metastasis
metastasis from
from lung
lung adenocarcinoma.
adenocarcinoma. Brain
BrainMRI
MRIsagittal
sagittal(A),
(A),coronal (B)(B)
coronal 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.
pineal metastasis was treated with stereotactic radiosurgery, and, after 9 months, the pin-
The pineal metastasis was treated with stereotactic radiosurgery, and, after 9 months, the
eal metastatic
pineal metastatic mass
mass was
wassignificantly
significantlysmaller.
smaller.
Blas John et al. [114] discussed
Blas John et al. [114] discussed an an uncommon
uncommon case of an
case ofadult woman
an adult with an
woman esoph-
with an
ageal primitive neuroectodermal tumor that presented pineal gland
esophageal primitive neuroectodermal tumor that presented pineal gland metastasis. Themetastasis. The head
computed
head computedtomography
tomography of theofpatient showed
the patient tumor
showed invasion
tumor of the
invasion ofthird ventricle,
the third with
ventricle,
incipient
with hydrocephalus.
incipient hydrocephalus. The The
patient underwent
patient a craniotomy
underwent a craniotomy of the
of posterior fossafossa
the posterior with
a supracerebellar infratentorial approach to the pineal region and an external
with a supracerebellar infratentorial approach to the pineal region and an external ventricle ventricle
drainage.Histopathologically,
drainage. Histopathologically,the thetumor
tumorappeared
appearedrichrichinincellular
cellulardensity,
density,forming
forminglobes.
lobes.
The metastatic cells showed scant cytoplasm, elongated atypical nuclei,
The metastatic cells showed scant cytoplasm, elongated atypical nuclei, and abundant and abundant mi-
totic figures with up to 10 mitoses in one high-power field. Foci of necrosis
mitotic figures with up to 10 mitoses in one high-power field. Foci of necrosis and areas and areas with
abundant
with abundantelectrocautery
electrocautery artifacts were
artifacts werealso
alsoobserved.
observed.These
Theseareas
areas had
had aa lower
lowercellular
cellular
densityand
density andperipheral
peripheralcalcification,
calcification,suggestive
suggestiveofofaapineoblastoma.
pineoblastoma.In Interms
termsofofimuno-
imuno-
histochemistrythe
histochemistry thepineal
pinealtumor
tumorshowed
showedaapatchy
patchyexpression
expressionofofsynaptophysin,
synaptophysin,a adiffuse
diffuse
and strong expression of CD99 and weak expression of the cytokeratins
and strong expression of CD99 and weak expression of the cytokeratins AE1/AE3 and AE1/AE3 and
CAM 5.2. Partial resection of the pineal metastasis was performed. The
CAM 5.2. Partial resection of the pineal metastasis was performed. The patient was given patient was given
chemotherapy;however,
chemotherapy; however,tumortumorprogression
progressionwas wasobserved.
observed.

3.2.
3.2.Pineal
PinealCysts
Cysts
Non-neoplastic
Non-neoplasticpineal
pineal cysts
cysts are frequently
frequently observed
observedduring
duringboth
bothMRI
MRI scans
scans and
and au-
autopsy studies,and
topsy studies, andthe
theprevalence
prevalenceofofbenign
benignpineal
pinealcysts
cystsranges
rangesbetween
between0.6%
0.6%and
and23%
23%in
inthe
thegeneral
general population
population [115–121].
[115–121]. Pineal
Pineal cysts,
cysts, 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].
Cancers 2021, 13, 1547 12 of 18

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).

Figure11.
Figure 11.Pineal
Pinealcyst
cystMRI.
MRI.The
Theasterisk
asteriskindicates
indicatesthe
thepineal
pinealcyst.
cyst.Reprinted
Reprintedwith
withpermission
permissionfrom
from
Májovský et al. (2017) [124]—Elsevier—2021 (License Number 5020240575766).
Májovský et al. (2017) [124]—Elsevier—2021 (License Number 5020240575766).

Barboriaketetal.
Barboriak al.[125]
[125]undertook
undertookaafollow-up
follow-upMRI MRIstudy
studyand,
and,interestingly,
interestingly,observed
observed
that pineal cysts usually remain stable. Only a few pineal cyst cases
that pineal cysts usually remain stable. Only a few pineal cyst cases may enlarge, making may enlarge, making
them of neurological significance. Large cysts typically exert a mass
them of neurological significance. Large cysts typically exert a mass effect on the cere- effect on the cerebral
aqueduct,
bral aqueduct,encircling venous
encircling structures
venous and the
structures anddorsal midbrain.
the dorsal The most
midbrain. The reported symp-
most reported
toms, correlated
symptoms, to theto
correlated compression
the compression of the surrounding
of the surrounding structures, are headaches,
structures, vertigo,
are headaches,
visual and
vertigo, oculomotor
visual disturbances,
and oculomotor and obstructive
disturbances, hydrocephalus
and obstructive [117,119,125].
hydrocephalus Symp-
[117,119,125].
tomatic pinealpineal
Symptomatic cysts are divided
cysts into three
are divided intosyndromes:
three syndromes:(1) paroxysmal headaches
(1) paroxysmal and gaze
headaches
palsy;
and gaze(2) palsy;
chronic(2)headaches, papilledema,
chronic headaches, gaze paresis,
papilledema, gazeandparesis,
hydrocephalus; and (3) pin-
and hydrocephalus;
and (3) pineal apoplexy with acute hydrocephalus. The last is the least frequentdangerous
eal apoplexy with acute hydrocephalus. The last is the least frequent but most but most
form. In practice,
dangerous form. In there are nothere
practice, accepted
are notherapeutic indications indications
accepted therapeutic or criteria for
orintervention
criteria for
and/or follow-up.
intervention and/or However,
follow-up. only a few patients
However, only a few withpatients
pineal cysts
with requires treatment.
pineal cysts requiresIn
fact, as previously
treatment. In fact, as reported,
previouslypineal cysts
reported, usually
pineal cystshave no clinical
usually have noimplications and are
clinical implications
asymptomatic
and [119,126,127].
are asymptomatic [119,126,127].
Choque-Velasquez
Choque-Velasquezet et al. al.
[117] reported
[117] in their
reported recentrecent
in their case series
case that surgically
series treated
that surgically
pineal
treatedcysts
pinealrepresent a progressive
cysts represent diseasedisease
a progressive with acute or progressive
with acute hydrocephalus
or progressive hydroceph-
at theatfinal
alus stage.stage.
the final TheTheauthors
authors alsoalso
suggested
suggested that young
that young women
womenwithwithactive
activesexual
sexual
hormone
hormonestatus
status(aged
(aged>10-years)
>10-years)comprise
comprisethe thepatient
patientgroup
groupatatthethehighest
highestrisk
riskfor
forpineal
pineal
cyst
cystprogression.
progression.

4.4.Conclusions
Conclusions
As
Asreported
reportedin
inthe
thepresent
presentreview
reviewandandsummarized
summarizedin inTable
Table1,1,pineal
pinealneoplasms
neoplasmsareare
heterogeneous tumors with different histological, morphological, and radiological features
heterogeneous tumors with different histological, morphological, and radiological fea-
and,
turesconsequently, different
and, consequently, diagnosis
different and management.
diagnosis and management.
Cancers 2021, 13, 1547 13 of 18

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

References
1. Carr, C.; O’Neill, B.E.; Hochhalter, C.B.; Strong, M.J.; Ware, M.L. Biomarkers of pineal region tumors: A review. Ochsner J. 2019,
19, 26–31. [CrossRef]
2. Fèvre-Montange, M.; Vasiljevic, A.; Champier, J.; Jouvet, A. Histopathology of tumors of the pineal region. Future Oncol. 2010, 6,
791–809. [CrossRef]
3. Nagasawa, D.T.; Lagman, C.; Sun, M.; Yew, A.; Chung, L.K.; Lee, S.J.; Bui, T.T.; Ooi, Y.C.; Robison, R.A.; Zada, G.; et al. Pineal
germ cell tumors: Two cases with review of histopathologies and biomarkers. J. Clin. Neurosci. 2017, 38, 23–31. [CrossRef]
[PubMed]
4. Fernández-Palanca, P.; Méndez-Blanco, C.; Fondevila, F.; Tuñón, M.J.; Reiter, R.J.; Mauriz, J.L.; González-Gallego, J. Melatonin as
an antitumor agent against liver cancer: An updated systematic review. Antioxidants 2021, 10, 103. [CrossRef] [PubMed]
5. Moretti, R.; Zanin, A.; Pansiot, J.; Spiri, D.; Manganozzi, L.; Kratzer, I.; Favero, G.; Vasiljevic, A.; Rinaldi, V.E.; Pic, I.; et al.
Melatonin reduces excitotoxic blood-brain barrier breakdown in neonatal rats. Neuroscience 2015, 311, 382–397, Erratum in:
Neuroscience 2016, 315, 296. [CrossRef] [PubMed]
6. Reiter, R.J.; Tan, D.X.; Fuentes-Broto, L. Melatonin: A multitasking molecule. Prog. Brain Res. 2010, 181, 127–151. [CrossRef]
7. Favero, G.; Moretti, E.; Bonomini, F.; Reiter, R.J.; Rodella, L.F.; Rezzani, R. Promising antineoplastic actions of melatonin. Front.
Pharmacol. 2018, 9, 1086. [CrossRef] [PubMed]
8. Favero, G.; Lonati, C.; Giugno, L.; Castrezzati, S.; Rodella, L.F.; Rezzani, R. Obesity-related dysfunction of the aorta and prevention
by melatonin treatment in ob/ob mice. Acta Histochem. 2013, 115, 783–788. [CrossRef]
9. Shafabakhsh, R.; Mirzaei, H.; Asemi, Z. Melatonin: A promising agent targeting leukemia. J. Cell Biochem. 2020, 121, 2730–2738.
[CrossRef]
10. Tan, D.X.; Manchester, L.C.; Hardeland, R.; Lopez-Burillo, S.; Mayo, J.C.; Sainz, R.M.; Reiter, R.J. Melatonin: A hormone, a tissue
factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res. 2003, 34, 75–78. [CrossRef]
11. Reiter, R.J.; Rosales-Corral, S.; Sharma, R. Circadian disruption, melatonin rhythm perturbations and their contributions to chaotic
physiology. Adv. Med. Sci. 2020, 65, 394–402. [CrossRef] [PubMed]
12. Mayol Del Valle, M.; De Jesus, O. Pineal gland cancer. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2020.
13. Smirniotopoulos, J.G.; Rushing, E.J.; Mena, H. Pineal region masses: Differential diagnosis. Radiographics 1992, 12, 577–596.
[CrossRef]
14. Tamrazi, B.; Nelson, M.; Blüml, S. Pineal region masses in pediatric patients. Neuroimaging Clin. N. Am. 2017, 27, 85–97. [CrossRef]
[PubMed]
15. Wang, K.Y.; Chen, M.M.; Malayil Lincoln, C.M. Adult primary brain neoplasm, including 2016 World Health Organization
classification. Radiol. Clin. N. Am. 2019, 57, 1147–1162. [CrossRef] [PubMed]
16. Wang, K.Y.; Chen, M.M.; Malayil Lincoln, C.M. Adult primary brain neoplasm, including 2016 World Health Organization
classification. Neuroimaging Clin. N. Am. 2021, 31, 121–138. [CrossRef]
17. Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO
classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114, 97–109, Erratum in Acta Neuropathol. 2007,
114, 547. [CrossRef]
18. Abbassy, M.; Aref, K.; Farhoud, A.; Hekal, A. Outcome of single-trajectory rigid endoscopic third ventriculostomy and biopsy
in the management algorithm of pineal region tumors: A case series and review of the literature. Childs Nerv. Syst. 2018, 34,
1335–1344. [CrossRef]
19. Ostrom, Q.T.; Gittleman, H.; Xu, J.; Kromer, C.; Wolinsky, Y.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS Statistical Report:
Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol. 2016, 18,
v1–v75. [CrossRef]
20. Schipmann, S.; Keurhorst, D.; Köchling, M.; Schwake, M.; Heß, K.; Sundermann, B.; Stummer, W.; Brentrup, A. Regression of
pineal lesions: Spontaneous or iatrogenic? A case report and systematic literature review. World Neurosurg. 2017, 108, 939–947.
[CrossRef]
21. Iorio-Morin, C.; Kano, H.; Huang, M.; Lunsford, L.D.; Simonová, G.; Liscak, R.; Cohen-Inbar, O.; Sheehan, J.; Lee, C.C.; Wu, H.M.;
et al. Histology-stratified tumor control and patient survival after stereotactic radiosurgery for pineal region tumors: A report
from the International Gamma Knife Research Foundation. World Neurosurg. 2017, 107, 974–982. [CrossRef]
22. Nomura, K. Epidemiology of germ cell tumors in Asia of pineal region tumor. J. Neurooncol. 2001, 54, 211–217. [CrossRef]
23. Villano, J.L.; Propp, J.M.; Porter, K.R.; Stewart, A.K.; Valyi-Nagy, T.; Li, X.; Engelhard, H.H.; McCarthy, B.J. Malignant pineal
germ-cell tumors: An analysis of cases from three tumor registries. Neuro Oncol. 2008, 10, 121–130. [CrossRef]
24. Regis, J.; Bouillot, P.; Rouby-Volot, F.; Figarella-Branger, D.; Dufour, H.; Peragut, J.C. Pineal region tumors and the role of
stereotactic biopsy: Review of the mortality, morbidity, and diagnostic rates in 370 cases. Neurosurgery 1996, 39, 907–912,
discussion 912–914. [CrossRef]
25. Seilanian Toosi, F.; Aminzadeh, B.; Faraji Rad, M.; Nekooei, S.; Nahidi, M.; Keykhosravi, E. Pineal and suprasellar germinoma
cooccurence with vertebra plana: A case report. Brain Tumor Res. Treat. 2018, 6, 73–77. [CrossRef] [PubMed]
26. Choque-Velasquez, J.; Resendiz-Nieves, J.; Jahromi, B.R.; Colasanti, R.; Raj, R.; Vehviläinen, J.; Tynninen, O.; Collan, J.; Niemelä,
M.; Hernesniemi, J. Extent of resection and long-term survival of pineal region tumors in Helsinki neurosurgery. World Neurosurg.
2019, 131, e379–e391. [CrossRef]
Cancers 2021, 13, 1547 15 of 18

27. Cho, A.; Cho, S.S.; Buch, V.P.; Buch, L.Y.; Lee, J.Y.K. Second Window Indocyanine Green (SWIG) near infrared fluorescent
transventricular biopsy of pineal tumor. World Neurosurg. 2020, 134, 196–200. [CrossRef] [PubMed]
28. Mathieu, D.; Iorio-Morin, C. Stereotactic radiosurgery for pineal region tumors. Prog. Neurol. Surg. 2019, 34, 173–183. [CrossRef]
[PubMed]
29. Field, M.; Witham, T.F.; Flickinger, J.C.; Kondziolka, D.; Lunsford, L.D. Comprehensive assessment of hemorrhage risks and
outcomes after stereotactic brain biopsy. J. Neurosurg. 2001, 94, 545–551. [CrossRef]
30. Chiba, K.; Aihara, Y.; Komori, T.; Kawamata, T. Placental alkaline phosphatase in cerebrospinal fluid as a biomarker for optimizing
surgical treatment strategies for pineal region germ cell tumors. Brain Tumor Pathol. 2020, 37, 60–68. [CrossRef]
31. Sadiq, Q.; Khan, F.A. Germ cell seminoma. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2020.
32. Takami, H.; Perry, A.; Graffeo, C.S.; Giannini, C.; Narita, Y.; Nakazato, Y.; Saito, N.; Nishikawa, R.; Matsutani, M.; Ichimura, K.;
et al. Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo
Clinic and Japanese consortium cohorts. J. Neurosurg. 2020, 31, 1–11. [CrossRef]
33. Korogi, Y.; Takahashi, M.; Ushio, Y. MRI of pineal region tumors. J. Neurooncol. 2001, 54, 251–261. [CrossRef] [PubMed]
34. Kanamori, M.; Takami, H.; Yamaguchi, S.; Sasayama, T.; Yoshimoto, K.; Tominaga, T.; Inoue, A.; Ikeda, N.; Kambe, A.; Kumabe,
T.; et al. So-called “bifocal tumors” with diabetes insipidus and negative tumor markers: Are they all germinoma? Neuro Oncol.
2020, 20, noaa199. [CrossRef]
35. Li, B.; Lv, W.; Li, C.; Yang, J.; Chen, J.; Feng, J.; Chen, L.; Ma, Z.; Li, Y.; Wang, J.; et al. Comparison between craniospinal irradiation
and limited-field radiation in patients with non-metastatic bifocal germinoma. Cancer Res. Treat. 2020, 52, 1050–1058. [CrossRef]
[PubMed]
36. Tan, G.C.; Sallapan, S.; Haworth, K.; Finlay, J.; Boue, D.R.; Pierson, C.R. CNS germinoma with extensive calcification: An unusual
histologic finding. Malays. J. Pathol. 2019, 41, 71–73.
37. Tong, T.; Zhenwei, Y.; Xiaoyuan, F. MRI and 1H-MRS on diagnosis of pineal region tumors. Clin. Imaging. 2012, 36, 702–709.
[CrossRef] [PubMed]
38. Reiter, R.J.; Tan, D.X.; Kim, S.J.; Cruz, M.H. Delivery of pineal melatonin to the brain and SCN: Role of canaliculi, cerebrospinal
fluid, tanycytes and Virchow-Robin perivascular spaces. Brain Struct Funct. 2014, 219, 1873–1887. [CrossRef]
39. Murai, Y.; Kobayashi, S.; Mizunari, T.; Ohaki, Y.; Adachi, K.; Teramoto, A. Spontaneous regression of a germinoma in the pineal
body after placement of a ventriculoperitoneal shunt. J. Neurosurg. 2000, 93, 884–886. [CrossRef]
40. Awa, R.; Campos, F.; Arita, K.; Sugiyama, K.; Tominaga, A.; Kurisu, K.; Yamasaki, F.; Karki, P.; Tokimura, H.; Fukukura, Y.;
et al. Neuroimaging diagnosis of pineal region tumors-quest for pathognomonic finding of germinoma. Neuroradiology 2014, 56,
525–534. [CrossRef]
41. Reis, F.; Faria, A.V.; Zanardi, V.A.; Menezes, J.R.; Cendes, F.; Queiroz, L.S. Neuroimaging in pineal tumors. J. Neuroimaging. 2006,
16, 52–58. [CrossRef]
42. Nagaishi, M.; Suzuki, R.; Tanaka, Y.; Hoya, K.; Narita, Y.; Shinomiya, A.; Shibui, S.; Hyodo, A. Pure germinoma of the pineal
gland with synchronous spinal dissemination—Case report. Neurol. Med. Chir. 2010, 50, 505–508. [CrossRef]
43. Ogawa, K.; Shikama, N.; Toita, T.; Nakamura, K.; Uno, T.; Onishi, H.; Itami, J.; Kakinohana, Y.; Kinjo, T.; Yoshii, Y.; et al. Long-term
results of radiotherapy for intracranial germinoma: A multi-institutional retrospective review of 126 patients. Int. J. Radiat. Oncol.
Biol. Phys. 2004, 58, 705–713. [CrossRef]
44. Ronchi, A.; Cozzolino, I.; Montella, M.; Panarese, I.; Zito Marino, F.; Rossetti, S.; Chieffi, P.; Accardo, M.; Facchini, G.; Franco, R.
Extragonadal germ cell tumors: Not just a matter of location. A review about clinical, molecular and pathological features. Cancer
Med. 2019, 8, 6832–6840. [CrossRef]
45. Schoenfeld, G.O.; Amdur, R.J.; Schmalfuss, I.M.; Morris, C.G.; Keole, S.R.; Mendenhall, W.M.; Marcus, R.B., Jr. Low-dose
prophylactic craniospinal radiotherapy for intracranial germinoma. Int. J. Radiat. Oncol. Biol. Phys. 2006, 65, 481–485. [CrossRef]
46. Causil, L.D.; Ames, R.; Puac, P.; Castillo, M. Adult brain tumors and pseudotumors: Interesting (Bizarre) cases. Neuroimaging Clin.
N. Am. 2016, 26, 667–689. [CrossRef] [PubMed]
47. Shinoda, J.; Sakai, N.; Yano, H.; Hattori, T.; Ohkuma, A.; Sakaguchi, H. Prognostic factors and therapeutic problems of primary
intracranial choriocarcinoma/germ-cell tumors with high levels of HCG. J. Neurooncol. 2004, 66, 225–240. [CrossRef]
48. Jiang, T.; Raynald; Yang, H.; Zhang, W.; Li, C. Predictive factors of overall survival in primary intracranial pure choriocarcinoma.
J. Clin. Neurosci. 2019, 61, 93–101. [CrossRef]
49. Lv, X.F.; Qiu, Y.W.; Zhang, X.L.; Han, L.J.; Qiu, S.J.; Xiong, W.; Wen, G.; Zhang, Y.Z.; Zhang, J. Primary intracranial choriocarcinoma:
MR imaging findings. AJNR Am. J. Neuroradiol. 2010, 31, 1994–1998. [CrossRef]
50. Qi, S.T.; Zhang, H.; Song, Y.; Zhang, J.L. Tumor cells forming sinusoids connected to vasculature are involved in hemorrhage of
pineal choriocarcinoma. J. Neurooncol. 2014, 119, 159–167. [CrossRef] [PubMed]
51. Sato, K.; Takeuchi, H.; Kubota, T. Pathology of intracranial germ cell tumors. Prog. Neurol. Surg. 2009, 23, 59–75. [CrossRef]
52. Patil, A.S.; Menon, G.; Easwer, H.V.; Nair, S. Extraventricular neurocytoma, a comprehensive review. Acta Neurochir. 2014, 156,
349–354. [CrossRef] [PubMed]
53. Rodriguez, F.J.; Mota, R.A.; Scheithauer, B.W.; Giannini, C.; Blair, H.; New, K.C.; Wu, K.J.; Dickson, D.W.; Jenkins, R.B. Interphase
cytogenetics for 1p19q and t(1;19)(q10;p10) may distinguish prognostically relevant subgroups in extraventricular neurocytoma.
Brain Pathol. 2009, 19, 623–629. [CrossRef]
Cancers 2021, 13, 1547 16 of 18

54. Peterson, C.M.; Buckley, C.; Holley, S.; Menias, C.O. Teratomas: A multimodality review. Curr. Probl. Diagn. Radiol. 2012, 41,
210–219. [CrossRef] [PubMed]
55. Sandow, B.A.; Dory, C.E.; Aguiar, M.A.; Abuhamad, A.Z. Best cases from the AFIP: Congenital intracranial teratoma. Radiographics
2004, 24, 1165–1170. [CrossRef]
56. Smith, A.B.; Rushing, E.J.; Smirniotopoulos, J.G. From the archives of the AFIP: Lesions of the pineal region: Radiologic-pathologic
correlation. Radiographics 2010, 30, 2001–2020. [CrossRef] [PubMed]
57. Cuccia, F.; Mortellaro, G.; Cespuglio, D.; Valenti, V.; DE Gregorio, G.; Quartuccio, E.; Blasi, L.; Francaviglia, N.; Gallo, C.; Lo Casto,
A.; et al. A case report of adult pineoblastoma occurring in a pregnant woman. Anticancer Res. 2019, 39, 2627–2631. [CrossRef]
58. Jouvet, A.; Saint-Pierre, G.; Fauchon, F.; Privat, K.; Bouffet, E.; Ruchoux, M.M.; Chauveinc, L.; Fèvre-Montange, M. Pineal
parenchymal tumors: A correlation of histological features with prognosis in 66 cases. Brain Pathol. 2000, 10, 49–60. [CrossRef]
59. Jing, Y.; Deng, W.; Zhang, H.; Jiang, Y.; Dong, Z.; Fan, F.; Sun, P. Development and validation of a prognostic nomogram to predict
cancer-specific survival in adult patients with pineoblastoma. Front. Oncol. 2020, 10, 1021, Erratum in Front. Oncol. 2020, 10,
594049. [CrossRef]
60. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.;
Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: A summary.
Acta Neuropathol. 2016, 131, 803–820. [CrossRef]
61. Lancia, A.; Becherini, C.; Detti, B.; Bottero, M.; Baki, M.; Cancelli, A.; Ferlosio, A.; Scoccianti, S.; Sun, R.; Livi, L.; et al.
Radiotherapy for papillary tumor of the pineal region: A systematic review of the literature. Clin. Neurol. Neurosurg. 2020, 190,
105646. [CrossRef] [PubMed]
62. Mallick, S.; Benson, R.; Rath, G.K. Patterns of care and survival outcomes in patients with pineal parenchymal tumor of
intermediate differentiation: An individual patient data analysis. Radiother. Oncol. 2016, 121, 204–208. [CrossRef] [PubMed]
63. Rousselle, C.; des Portes, V.; Berlier, P.; Mottolese, C. Pineal region tumors: Clinical symptoms and syndromes. Neurochirurgie
2015, 61, 106–112. [CrossRef] [PubMed]
64. Leston, J.; Mottolese, C.; Champier, J.; Jouvet, A.; Brun, J.; Sindou, M.; Chazot, G.; Claustrat, B.; Fèvre-Montange, M. Contribution
of the daily melatonin profile to diagnosis of tumors of the pineal region. J. Neurooncol. 2009, 93, 387–394. [CrossRef]
65. Su, S.C.; Hsieh, M.J.; Yang, W.E.; Chung, W.H.; Reiter, R.J.; Yang, S.F. Cancer metastasis: Mechanisms of inhibition by melatonin. J.
Pineal Res. 2017, 62. [CrossRef]
66. Chatterjee, D.; Lath, K.; Singla, N.; Kumar, N.; Radotra, B.D. Pathologic prognostic factors of pineal parenchymal tumor of
intermediate differentiation. Appl. Immunohistochem. Mol. Morphol. 2019, 27, 210–215. [CrossRef]
67. Freeman, D.; Guillaume, D.; Bell, W.R.; Chen, C.C. Devascularization of a hemorrhagic pineocytoma by laser thermal ablation
followed by endoscopic resection: A proof-of-principle case report. World Neurosurg. 2020, 139, 583–587. [CrossRef]
68. Almahariq, F.; Raguz, M.; Romic, D.; Dlaka, D.; Oreskovic, D.; Sesar, P.; Chudy, D. A biphasic tumor in posterior cranial fossa and
the pineal region in young adult. Surg. Neurol. Int. 2020, 11, 64. [CrossRef] [PubMed]
69. Dumrongpisutikul, N.; Intrapiromkul, J.; Yousem, D.M. Distinguishing between germinomas and pineal cell tumors on MR
imaging. AJNR Am. J. Neuroradiol. 2012, 33, 550–555. [CrossRef]
70. O’Connell, K.; Crimmins, D.; Power, S.; Ligon, K.L.; Cryan, J.; Beausang, A. Pineal apoplexy due to pleomorphic variant
pineocytoma. Clin. Neuropathol. 2019, 38, 253–255. [CrossRef] [PubMed]
71. Blakeley, J.O.; Grossman, S.A. Management of pineal region tumors. Curr. Treat. Options Oncol. 2006, 7, 505–516. [CrossRef]
72. Cardenas, R.; Javalkar, V.; Haydel, J.; Wadhwa, R.; Fowler, M.; Scheithauer, B.; Nanda, A. Papillary tumor of pineal region:
Prolonged control rate after gamma knife radiosurgery—A case report and review of literature. Neurol. India 2010, 58, 471–476.
[CrossRef]
73. Liu, A.P.Y.; Gudenas, B.; Lin, T.; Orr, B.A.; Klimo, P., Jr.; Kumar, R.; Bouffet, E.; Gururangan, S.; Crawford, J.R.; Kellie, S.J.;
et al. Risk-adapted therapy and biological heterogeneity in pineoblastoma: Integrated clinico-pathological analysis from the
prospective, multi-center SJMB03 and SJYC07 trials. Acta Neuropathol. 2020, 139, 259–271. [CrossRef]
74. Liu, A.P.Y.; Priesterbach-Ackley, L.P.; Orr, B.A.; Li, B.K.; Gudenas, B.; Reddingius, R.E.; Suñol, M.; Lavarino, C.E.; Olaciregui,
N.G.; Santa-María López, V.; et al. WNT-activated embryonal tumors of the pineal region: Ectopic medulloblastomas or a novel
pineoblastoma subgroup? Acta Neuropathol. 2020, 140, 595–597. [CrossRef] [PubMed]
75. De Jong, M.C.; Kors, W.A.; de Graaf, P.; Castelijns, J.A.; Kivelä, T.; Moll, A.C. Trilateral retinoblastoma: A systematic review and
meta-analysis. Lancet Oncol. 2014, 15, 1157–1167. [CrossRef]
76. Charafe-Jauffret, E.; Lehmann, G.; Fauchon, F.; Michiels, J.F.; Paquis, P.; Maraninchi, D.; Hassoun, J. Vertebral metastases from
pineoblastoma. Arch. Pathol. Lab. Med. 2001, 125, 939–943. [CrossRef] [PubMed]
77. Fraser, G.; Rampling, R.; Smith, C.; Nicoll, J.; Stephen, M. Long-term survival following extra-neural metastasis from a pineoblas-
toma. J. Neurooncol. 2000, 48, 141–144. [CrossRef]
78. Golbin, D.; Nikitin, K.V.; Konovalov, A.N.; Pitskhelauri, D.I.; Shishkina, L.V.; Golanov, A.V.; Cherekaev, V.A.; Kobiakov, G.L.;
Absalyamova, O.V.; Lasunin, N.; et al. Intraosseous metastasizing of pineoblastoma into the anterior skull base, calvarial bones,
and vertebrae. Cureus 2015, 7, e437. [CrossRef] [PubMed]
79. Huo, X.L.; Wang, B.; Zhang, G.J.; Ma, J.P.; Wang, L.; Zhang, L.W.; Xu, X.Y.; Li, X.J.; Li, H.; Li, D.; et al. Adverse factors of treatment
response and overall survival in pediatric and adult patients with pineoblastoma. Cancer Manag. Res. 2020, 12, 7343–7351.
[CrossRef]
Cancers 2021, 13, 1547 17 of 18

80. Tian, Y.; Liu, R.; Qin, J.; Wang, J.; Ma, Z.; Gong, J.; Li, C. Retrospective analysis of the clinical characteristics, therapeutic aspects,
and prognostic factors of 18 cases of childhood pineoblastoma. World Neurosurg. 2018, 116, e162–e168. [CrossRef]
81. Blessing, M.M.; Alexandrescu, S. Embryonal tumors of the central nervous system: An update. Surg. Pathol. Clin. 2020, 13,
235–247. [CrossRef] [PubMed]
82. Lee, J.C.; Mazor, T.; Lao, R.; Wan, E.; Diallo, A.B.; Hill, N.S.; Thangaraj, N.; Wendelsdorf, K.; Samuel, D.; Kline, C.N.; et al. Recurrent
KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal
tumor of intermediate differentiation (PPTID) from pineoblastoma. Acta Neuropathol. 2019, 137, 851–854. [CrossRef]
83. Choque-Velasquez, J.; Raj, R.; Hernesniemi, J. One burr-hole craniotomy: Supracerebellar infratentorial paramedian approach in
Helsinki Neurosurgery. Surg. Neurol. Int. 2018, 9, 162. [CrossRef]
84. Fèvre Montange, M.; Vasiljevic, A.; Champier, J.; Jouvet, A. Papillary tumor of the pineal region: Histopathological characterization
and review of the literature. Neurochirurgie 2015, 61, 138–142. [CrossRef] [PubMed]
85. Alkhotani, A.; Bilbao, J.M.; Mainprize, T.G. A 49 year-old woman with a pineal mass. Brain Pathol. 2014, 24, 191–192. [CrossRef]
86. Boco, T.; Aalaei, S.; Musacchio, M.; Byrne, R.; Cochran, E. Papillary tumor of the pineal region. Neuropathology 2008, 28, 87–92.
[CrossRef] [PubMed]
87. Hua, X.; Yang, P.; Zhang, M.; Zhao, Y.; Wang, B. Papillary tumor of the pineal region: A case report and review of the literature.
Exp. Ther. Med. 2015, 10, 1375–1379. [CrossRef]
88. Kaloshi, G.; Rroji, A.; Lame, A.; Leka, L.; Haxhihyseni, E.; Vreto, G.; Petrela, M. Natural history of papillary tumor of the pineal
region: New insights on biological explanation. J. Neurooncol. 2010, 100, 487–488. [CrossRef]
89. Poulgrain, K.; Gurgo, R.; Winter, C.; Ong, B.; Lau, Q. Papillary tumour of the pineal region. J. Clin. Neurosci. 2011, 18, 1007–1017.
[CrossRef] [PubMed]
90. Fernández-Mateos, C.; Martinez, R.; Vaquero, J. Long-term follow-up after radiosurgery of papillary tumor of pineal region: 2
case reports and review of literature. World Neurosurg. 2018, 116, 190–193. [CrossRef]
91. Shibahara, J.; Todo, T.; Morita, A.; Mori, H.; Aoki, S.; Fukayama, M. Papillary neuroepithelial tumor of the pineal region. A case
report. Acta Neuropathol. 2004, 108, 337–340. [CrossRef]
92. Braun, M.; Tomasik, B.; Bieńkowski, M.; Wiśniewski, K.; Kupnicka, D.J.; Jaskólski, D.; Papierz, W.; Fijuth, J.; Kordek, R. Recurrent
pineocytomalike papillary tumor of the pineal region: A case report and literature review. World Neurosurg. 2018, 120, 1–14.
[CrossRef]
93. Fèvre-Montange, M.; Hasselblatt, M.; Figarella-Branger, D.; Chauveinc, L.; Champier, J.; Saint-Pierre, G.; Taillandier, L.; Coulon,
A.; Paulus, W.; Fauchon, F.; et al. Prognosis and histopathologic features in papillary tumors of the pineal region: A retrospective
multicenter study of 31 cases. J. Neuropathol. Exp. Neurol. 2006, 65, 1004–1011. [CrossRef]
94. Matyja, E.; Grajkowska, W.; Nauman, P.; Bonicki, W. Histopathological patterns of papillary tumour of the pineal region. Folia
Neuropathol. 2011, 49, 181–190. [PubMed]
95. Nakamura, H.; Makino, K.; Kochi, M.; Nakazato, Y.; Kuratsu, J. Successful treatment of neoadjuvant therapy for papillary tumor
of the pineal region. Brain Tumor Pathol. 2009, 26, 73–77. [CrossRef]
96. Koziarski, A.; Grala, B.; Skrobowska, E. Papillary tumor of the pineal region. Report of two cases and literature review. Neurol.
Neurochir. Pol. 2014, 48, 356–362. [CrossRef]
97. Vandergriff, C.; Opatowsky, M.; O’Rourke, B.; Layton, K. Papillary tumor of the pineal region. Proc. Bayl. Univ. Med. Cent. 2012,
25, 78–79. [CrossRef] [PubMed]
98. Gutenberg, A.; Brandis, A.; Hong, B.; Gunawan, B.; Enders, C.; Schaefer, I.M.; Burger, R.; Ostertag, H.; Gaab, M.; Krauss, J.K.;
et al. Common molecular cytogenetic pathway in papillary tumors of the pineal region (PTPR). Brain Pathol. 2011, 21, 672–677.
[CrossRef]
99. Kamamoto, D.; Sasaki, H.; Ohara, K.; Mizutani, K.; Yoshida, K. A case of papillary tumor of the pineal region with a long clinical
history: Molecular characterization and therapeutic consideration with review of the literature. Brain Tumor Pathol. 2016, 33,
271–275. [CrossRef]
100. Edson, M.A.; Fuller, G.N.; Allen, P.K.; Levine, N.B.; Ghia, A.J.; Mahajan, A.; Brown, P.D.; DeMonte, F.; Li, J. Outcomes after
surgery and radiotherapy for papillary tumor of the pineal region. World Neurosurg. 2015, 84, 76–81. [CrossRef]
101. Bando, T.; Ueno, Y.; Shinoda, N.; Imai, Y.; Ichikawa, K.; Kuramoto, Y.; Kuroyama, T.; Shimo, D.; Mikami, K.; Hori, S.; et al.
Therapeutic strategy for pineal parenchymal tumor of intermediate differentiation (PPTID): Case report of PPTID with malignant
transformation to pineocytoma with leptomeningeal dissemination 6 years after surgery. J. Neurosurg. 2018, 1–7. [CrossRef]
102. Choque-Velasquez, J.; Resendiz-Nieves, J.C.; Jahromi, B.R.; Colasanti, R.; Raj, R.; Tynninen, O.; Collan, J.; Hernesniemi, J. Pineal
parenchymal tumors of intermediate differentiation: A long-term follow-up study in Helsinki Neurosurgery. World Neurosurg.
2019, 122, e729–e739. [CrossRef] [PubMed]
103. Wu, X.; Wang, W.; Lai, X.; Zhou, Y.; Zhou, X.; Li, J.; Liang, Y.; Zhu, X.; Ren, X.; Ding, Y.; et al. CD24 and PRAME are novel grading
and prognostic indicators for pineal parenchymal tumors of intermediate differentiation. Am. J. Surg. Pathol. 2020, 44, 11–20.
[CrossRef] [PubMed]
104. Fomchenko, E.I.; Erson-Omay, E.Z.; Kundishora, A.J.; Hong, C.S.; Daniel, A.A.; Allocco, A.; Duy, P.Q.; Darbinyan, A.; Marks,
A.M.; DiLuna, M.L.; et al. Genomic alterations underlying spinal metastases in pediatric H3K27M-mutant pineal parenchymal
tumor of intermediate differentiation: Case report. J. Neurosurg. Pediatr. 2019, 25, 1–10. [CrossRef]
Cancers 2021, 13, 1547 18 of 18

105. Scheithauer, B.W.; Fuller, G.N.; VandenBerg, S.R. The 2007 WHO classification of tumors of the nervous system: Controversies in
surgical neuropathology. Brain Pathol. 2008, 18, 307–316, Erratum in Brain Pathol. 2008, 18, 640. [CrossRef] [PubMed]
106. Fauchon, F.; Jouvet, A.; Paquis, P.; Saint-Pierre, G.; Mottolese, C.; Ben Hassel, M.; Chauveinc, L.; Sichez, J.P.; Philippon, J.;
Schlienger, M.; et al. Parenchymal pineal tumors: A clinicopathological study of 76 cases. Int. J. Radiat. Oncol. Biol. Phys. 2000, 46,
959–968. [CrossRef]
107. Tsumanuma, I.; Tanaka, R.; Washiyama, K. Clinicopathological study of pineal parenchymal tumors: Correlation between
histopathological features, proliferative potential, and prognosis. Brain Tumor Pathol. 1999, 16, 61–68. [CrossRef] [PubMed]
108. Nam, J.Y.; Gilbert, A.; Cachia, D.; Mandel, J.; Fuller, G.N.; Penas-Prado, M.; de Groot, J.; Kamiya-Matsuoka, C. Pineal parenchymal
tumor of intermediate differentiation: A single-institution experience. Neurooncol. Pract. 2020, 7, 613–619. [CrossRef]
109. Amato-Watkins, A.C.; Lammie, A.; Hayhurst, C.; Leach, P. Pineal parenchymal tumours of intermediate differentiation—An
evidence-based review of a new pathological entity. Br. J. Neurosurg. 2016, 30, 11–15. [CrossRef] [PubMed]
110. Abdallah, M.A.; Shahid, M.; Ellithi, M.; Yeddi, A.; Cunningham, A.; Askeland, R.; Dodin, J. Pulmonary adenocarcinoma
presenting as a pineal gland mass with obstructive hydrocephalus. Ochsner J. 2020, 20, 232–235. [CrossRef] [PubMed]
111. Hogan, E.; Almira-Suarez, I.; Li, S.; Collins, S.P.; Jean, W.C. Clinical management of prostate cancer metastasis to pineal gland:
Case report and review of literature. World Neurosurg. 2019, 122, 464–468. [CrossRef] [PubMed]
112. Ji, J.; Gu, C.; Zhang, M.; Zhang, H.; Wang, H.; Qu, Y.; Ren, M.; Ning, W.; Yu, C. Pineal region metastasis with intraventricular
seeding: A case report and literature review. Medicine 2019, 98, e16652. [CrossRef]
113. Mitsumasa, A.; Shinya, N.; Motoki, O.; Hirotaka, K.; Tadashi, K. Diplopia presenting in a case of pineal metastasis of pulmonary
sarcomatoid carcinoma refractory to treatment. Asian J. Neurosurg. 2020, 15, 449–454. [CrossRef]
114. Blas Jhon, L.; Sánchez-Fayos, P.; Martín Relloso, M.J.; Calero Barón, D.; Porres Cubero, J.C. Primitive neuroectodermal tumor of
the esophagus with metastasis in the pineal gland. Endosc. Int. Open 2019, 7, E1163–E1165. [CrossRef]
115. Al-Holou, W.N.; Terman, S.W.; Kilburg, C.; Garton, H.J.; Muraszko, K.M.; Chandler, W.F.; Ibrahim, M.; Maher, C.O. Prevalence
and natural history of pineal cysts in adults. J. Neurosurg. 2011, 115, 1106–1114. [CrossRef]
116. Bosnjak, J.; Budisić, M.; Azman, D.; Strineka, M.; Crnjaković, M.; Demarin, V. Pineal gland cysts–an overview. Acta Clin. Croat.
2009, 48, 355–358.
117. Choque-Velasquez, J.; Colasanti, R.; Baluszek, S.; Resendiz-Nieves, J.; Muhammad, S.; Ludtka, C.; Hernesniemi, J. Systematic
review of pineal cysts surgery in pediatric patients. Childs Nerv. Syst. 2020, 36, 2927–2938. [CrossRef]
118. Gokce, E.; Beyhan, M. Evaluation of pineal cysts with magnetic resonance imaging. World J. Radiol. 2018, 10, 65–77. [CrossRef]
[PubMed]
119. Kim, E.; Kwon, S.M. Pineal cyst apoplexy: A rare complication of common entity. Brain Tumor Res. Treat. 2020, 8, 66–70. [CrossRef]
120. Nevins, E.J.; Das, K.; Bhojak, M.; Pinto, R.S.; Hoque, M.N.; Jenkinson, M.D.; Chavredakis, E. Incidental pineal cysts: Is surveillance
necessary? World Neurosurg. 2016, 90, 96–102. [CrossRef] [PubMed]
121. Taraszewska, A.; Matyja, E.; Koszewski, W.; Zaczyński, A.; Bardadin, K.; Czernicki, Z. Asymptomatic and symptomatic glial
cysts of the pineal gland. Folia Neuropathol. 2008, 46, 186–195. [PubMed]
122. Storey, M.; Lilimpakis, K.; Grandal, N.S.; Rajaraman, C.; Achawal, S.; Hussain, M. Pineal cyst surveillance in adults—A review of
10 years’ experience. Br. J. Neurosurg. 2020, 34, 565–568. [CrossRef]
123. Choy, W.; Kim, W.; Spasic, M.; Voth, B.; Yew, A.; Yang, I. Pineal cyst: A review of clinical and radiological features. Neurosurg.
Clin. N. Am. 2011, 22, 341–351. [CrossRef]
124. Májovský, M.; Řezáčová, L.; Sumová, A.; Pospíšilová, L.; Netuka, D.; Bradáč, O.; Beneš, V. Melatonin and cortisol secretion profile
in patients with pineal cyst before and after pineal cyst resection. J. Clin. Neurosci. 2017, 39, 155–163. [CrossRef] [PubMed]
125. Barboriak, D.P.; Lee, L.; Provenzale, J.M. Serial MR imaging of pineal cysts: Implications for natural history and follow-up. AJR
Am. J. Roentgenol. 2001, 176, 737–743. [CrossRef] [PubMed]
126. Asundi, A.; Tampieri, D.; Melançon, D.; Del Maestro, R.; Petrecca, K.; Cortes, M.D. Pineal apoplexy: Imaging diagnosis and
follow-up of three new cases. Can. J. Neurol. Sci. 2011, 38, 931–933. [CrossRef]
127. Bruno, F.; Arrigoni, F.; Maggialetti, N.; Natella, R.; Reginelli, A.; Di Cesare, E.; Brunese, L.; Giovagnoni, A.; Masciocchi, C.;
Splendiani, A.; et al. Neuroimaging in emergency: A review of possible role of pineal gland disease. Gland Surg. 2019, 8, 133–140.
[CrossRef] [PubMed]