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Symptoms and Signs
Pineal tumors are a
heterogeneous group of mass lesions originating in or located adjacent to the
pineal gland. Neoplasms in this region cause symptoms when they compress or
invade local structures or are disseminated beyond the confines of the tumor.
When these tumors occlude the cerebral aqueduct, obstructive hydrocephalus with
intracranial hypertension occurs; if the superior colliculus and pretectal area
are involved, characteristic eye signs develop, which may include impairment of
upward gaze and abnormalities of the pupil, paralysis or spasm of convergence
and nystagmus retractorius. This sylvian aqueduct syndrome is indicative of a
periaqueductal lesion. Parinaud's syndrome, the paralysis of upward gaze alone,
is often and incorrectly used as synonymous with the sylvian aqueduct syndrome.
The anatomic substrate underlying these functions is located just anterior to
the aqueduct and below the posterior part of the third ventricle. Downward gaze.
which also may be impaired in these patients, has its localization caudal to
that of upward gaze in the brain stem. Compression or invasion of the cerebellum
results in dysmetria, hypotonia and intention tremor. There may be altered
consciousness due to intracranial hypertension or direct invasion of the brain
stem by tumor. Malignant pineal tumors may metastasize to the spinal cord or
cauda equina or to structures outside the nervous system. These metastases may
also pass through the shunts inserted to treat intracranial hypertension. Less
common symptoms, occurring in less than 10 percent of male patients with pineal
tumors are precocious puberty or delayed onset of sexual maturation. Even less
common is the occurrence of pineal apoplexy, in which a patient undergoes sudden
neurological deterioration secondary to intratumoral hemorrhage and sudden
expansion in the size of the posterior third ventricular tumor.
Pathology
The lesions in the posterior
third ventricle represent a diverse group of tumors; however, the crucial
differentiation prognostically is between those lesions which are benign and
those which are malignant. Approximately 10 percent of lesions in this area are
truly benign, including pineal cysts, lipomas. arteriovenous malformations and
aneurysms, pineocytomas. and meningiomas. Another 10 percent of tumors are
relatively benign lesions. including low-grade gliomas and dermoids. The
remaining 80 percent of pineal region neoplasms are highly malignant lesions.
These include the germ cell tumors typified by the atypical teratoma (pineal
germinoma) and also represented by the choriocarcinoma, endodermal sinus tumor.
embryonal carcinoma. and malignant teratoma: and the non-germ cell malignancies
such as pineoblastoma, glioblastoma, metastatic tumor and sarcoma.
Associated Lesions
The suprasellar germinomas are
included in this family of neoplasms. These are a subgroup of tumors,
histologically identical to the pineal germinoma, which arise in or beneath the
anterior part of the third ventricle. Germinomas represent a distinct pathologic
entity arising from germ cells that originate from yolk-sac endoderm, migrate
widely and settle in the gonadal ridges of the embryo. Normally, the nongonadal
cells disappear from these sites; a failure of these cells to involute in the
retroperitoneum, sacrococcygeal region, mediastinum, cerebral hemisphere or
pineal or suprasellar region forms the cellular basis for an identical group of
tumors which occasionally arise at these diverse locations. Many suprasellar
germinomas represent an anterior extension of a pineal germinoma: however,
suprasellar germinomas have been shown to exist free of pineal involvement.
Kageyama and Belsky categorized
these suprasellar tumors. The type 1 suprasellar germinoma is a metastatic tumor
from the pineal region which invades the floor of the third ventricle,
hypophysis and optic pathways. The symptoms are usually caused initially by
hypothalamic and chiasmatic involvement. In one study, germ cell tumors with
synchronous lesions in the pineal and suprasellar regions constituted 12.8
percent of germ cell tumors in a brain tumor registry. Type 2 germinomas are
those which arise within the third ventricle and produce an obstructive
hydrocephalus early in the disease: later findings are indicative of invasion of
the hypothalamus, pituitary and optic pathways. Type 3 germinomas are those
which originate in the region of the optic chiasmal region, grow outside the
ventricular system, and only late in the disease invade the third ventricle and
hypothalamus.
When there is suprasellar involvement, the patient may
present with a triad of findings including diabetes insipidus, visual defects
and endocrine dysfunction. Diabetes insipidus is the most common manifestation
of these tumors and may precede the development of other findings by years. The
abnormalities of the visual system encountered include reduction in visual
acuity, often in conjunction with optic atrophy. There are isolated reports of
extraocular paralysis or severe exophthalmos due to infiltration of the tumor
into the optic chiasm, nerves and orbit. Papilledema may not be evident, even in
the presence of severe intracranial hypertension, because of the associated
optic atrophy. Visual field studies may demonstrate bitemporal inferior
scotomas, indicating a lesion on the dorsum of the chiasm. Macular fiber
involvement by tumor growing into the posterior and superior part of the chiasm,
associated with a bitemporal inferior scotomatous defect, is particularly
characteristic of this tumor. Hypopituitarism is the third most common finding,
after diabetes insipidus and visual abnormalities, and is often associated with
growth arrest when the tumor occurs before puberty or with hypogonadism and
amenorrhea when it occurs in older patients. Pathologic obesity, neurogenic
hypernatremia, hyperphagia with amnesia, abnormalities in temperature
regulation, and excessive somnolence are uncommon manifestations reported in
conjunction with these lesions. Elevated intracranial pressure is seen in tumors
arising by extension from pineal region neoplasms. Suprasellar germinomas may
also metastasize throughout the neuraxis and outside the nervous system.
The occurrence of multiple tumors involving the nervous
system occurs not only with synchronous germ cell tumors presenting in the
pineal and suprasellar regions, but may be seen with the trilateral
retinoblastoma in which a patient with an intraocular retinoblastoma or
bilateral intraocular retinoblastomas presents with either a pineal,
suprasellar, or parasellar retinoblastoma. In a report from the Wills Eye
Hospital, this phenomenon was seen in seven (3 percent) of 245 consecutive cases
of retinoblastoma, and five of these seven patients died of the intracranial
disease.
Molecular genetic studies have shown that transgenic mice
expressing the large T-antigen of the simian virus 40 (SV 40) under the control
of the Moloney murine sarcoma virus (MSV) enhancer and the SV 40 promoter,
develop heritable midline brain and ocular neoplasms with the features of a
trilateral retinoblastoma. In these systems there is controversy about whether
the pineal tumors arise from the subependymal cells of the cerebral aqueduct or
are the result of the neoplastic transformation of pineal parenchymal cells.
Diagnosis
Computed tomography (CT) of the head with enhancement
indicates the size and position of the lesion; whether there is a calcific,
cystic, or hemorrhagic component; the degree of hydrocephalus; and whether there
is evidence of subependymal extension or extension into the lateral ventricles
or the suprasellar region. The suprasellar extension from a posterior third
ventricular mass may be quite subtle and may require serial thin CT sections for
detection, especially of subependymal enhancement. The suprasellar germinomas
may show obliteration of the suprasellar cistern, irregular margins, moderate
enhancement by contrast material and tumor infiltration of the walls of the
third ventricle and both lateral ventricles. There may also be extension into
the orbit and expansion of the optic nerves or chiasm caused by tumor
infiltration.
Germinomas appear on CT as high-density homogeneous lesions
with intense contrast enhancement. Teratomas are often multilocular,
heterogeneous appearing masses containing lipid areas. However, there are no
pathognomonic CT features which allow differentiation among the various tumor
types found in this region.
Magnetic resonance imaging (MRI) with enhancement provides
exquisite anatomic detail, outlining the lesion, the cerebrospinal fluid (CSF)
pathways, and the venous anatomy around the vein of Galen. Also, MRI can aid in
the detection of tumor seeding to other parts of the nervous system. However, as
with CT, the MRI characteristics of pineal region tumors are usually
nonspecific.
Cytologic examination of the cerebrospinal fluid is
important, because the presence of malignant cells may establish the nature and
extent of the lesion. Seeding of the cerebrospinal fluid is a particularly
characteristic feature of the germinomas, although this property is also
exhibited by an occasional pineoblastoma and glioblastoma. Among brain tumors,
the medulloblastomas have the highest incidence of malignant cells in the
cerebrospinal fluid, 61.9 percent; however, the incidence of this phenomenon in
patients with malignant pineal tumors is not known. There are reports of this
occurrence in up to 60 percent of cases examined serially, especially when the
sensitivity of the cerebrospinal fluid examination is improved by the use of
millipore-filtered CSF tissue culture techniques.
The MR or catheter angiographic examination of the
intracranial arterial and venous vasculature allows identification of aneurysms
of the posterior cerebral artery. arteriovenous malformations, abnormalities of
the vein of Galen, and meningiomas. Although germinomas are vascular, it is
unusual for them to contain neovascularity demonstrable by angiography, whereas
embryonal carcinoma and teratocarcinoma show tumor vessels, and the presence of
such tumor vascularity is suggestive of these malignant tumors. In addition,
angiography provides important preoperative information about the relation of
the internal cerebral veins, vein of Galen, basal veins of Rosenthal and
precentral cerebellar vein to the mass lesion, information which can be
important in planning the surgical approach.
In the presence of either a pineal region tumor or
synchronous lesions in the anterior and posterior third ventricle, MRI
examination of the entire spine is also carried out to identify asymptomatic
spinal metastases or assess the response of such lesions to therapy. In the
absence of an obstructive hydrocephalus, one also samples CSF for malignant
cells. The presence of malignant cells in the CSF is of major diagnostic and
therapeutic importance, particularly since one cannot determine with a high
degree of accuracy the nature of an isolated posterior third ventricular mass on
the basis of current radiographic studies alone.
The patient with a posterior
third ventricular tumor requires as part of the investigation a careful
assessment of endocrine function. Diabetes insipidus is the most common
endocrine abnormality associated with pineal tumors; when present, it is
probably due to anterior third ventricular extension of the neoplasm. Such cases
are often overlooked. The physician should be suspicious and should undertake
appropriate provocative tests. Tests of anterior pituitary function are also
part of the investigation, to exclude adrenocorticotropic hormone deficiency and
secondary, possibly life-threatening, adrenocortical insufficiency.
Abnormalities of sexual maturation require that the levels of luteinizing
hormone, follicle-stimulating hormone, testosterone. prolactin, growth hormone
and melatonin of the cerebrospinal fluid and serum be surveyed.
Neuro-ophthalmologic examination
is mandatory in search of the defects seen in conjunction with these lesions and
to provide evidence of the extent of the tumor involvement - which may not be
apparent from the other studies - as well as a baseline for comparison after
treatment.
Immunoassay of serum, CSF and
tumor cyst fluid for alpha fetoprotein (AFP) and the beta chain of human
chorionic gonadotropin (hCG) may allow the diagnosis of an intracranial germ
cell tumor (e.g. germinoma, teratocarcinoma, choriocarcinoma, or embryonal
carcinoma). The AFP level may be elevated in endodermal sinus tumors. and the
hCG-beta level is characteristically elevated in choriocarcinoma. Elevations of
both of these tumor markers are seen with malignant teratomas and with
undifferentiated germ cell tumors. In addition, the plasma level of these tumor
markers correlates with tumor growth and regression and may be used to assess
the response to therapy.
The S-antigen, a 48 kilodalton
protein also called "arrestin," is found in the retina and pineal. S-antigen
reactivity has been detected in the preoperative CSF of one patient with a
pineocytoma, and subsequently the tumor specimens were shown to have S-antigen
immunoreactive cells. The same patient also had high levels of CSF melatonin. In
experimental studies utilizing transgenic mice expressing the large T-antigen of
SV 40, the large T-antigen was found exclusively in nuclei of cells containing
S-antigen immunoreactivity in their cytoplasm, and these cells composed the
neoplasm of one pineal region.
