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.


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.


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.


Since pineal region tumors are among the most dangerous intracranial masses to excise, there has been an ongoing debate for at least the last half-century concerning their surgical management. The debate centers on whether it is in the patient's best interest to explore these lesions at the time of their diagnosis, or whether the obstructive hydrocephalus should be treated with a shunt and the posterior third ventricular tumor irradiated without a tissue diagnosis-maneuvers which can be carried out with a low morbidity and mortality rate.

Even though it has been demonstrated repeatedly that it is feasible for highly experienced surgeons to operate on lesions in the posterior third ventricle with a combined morbidity and mortality rate of under 10 percent, whether all patients with a pineal region tumor require surgical intervention remains a matter of judgment. For example, patients in whom cytologic examination of the cerebrospinal fluid shows malignant cells, patients with evidence of either spinal or extraneural metastases, and patients harboring synchronous anterior and posterior third ventricular tumors and in whom a tumor marker is elevated, most likely have a germinoma or other malignant germ cell tumor and may not require direct intervention.

In contrast to these cases, there is a group of patients in whom surgical exploration is mandatory. These are patients previously treated with a shunt and radiation therapy without a tissue diagnosis who present with progressive neurological problems in the presence of a functioning shunt. Such patients have often survived for a period of years, and benign or relatively benign tumors are particularly frequent among this select group. The controversy centers on the posterior third ventricular lesion whose nature cannot be established preoperatively in spite of the best available diagnostic modalities. In centers in Japan and in England these patients are managed on a protocol of local field irradiation followed by assessment by MRI as to whether tumor regression occurs. If this does occur, the patients are subjected to whole-brain or whole-CNS irradiation. Among two groups of patients treated in Tokyo between 1975 and 1988 there was a 73 percent 5-year survival of those with histologically diagnosed germinomas and an 83 percent 5-year survival of those with suspected germinomas, outcomes which the investigators reported to be statistically the same. Patients not responsive to the 20 Gy local field irradiation are approached surgically. Among patients with this group of nongerminomatous tumors, the 5-year survival rate was 28 percent. Hoffman et al. have reported a 45 percent survival among patients with non-germ cell tumors treated with surgery and radiation.

In the reported experience from the Royal Marsden Hospital. 50 patients with pineal tumors were managed with an initial 20 Gy local field irradiation. Responders were then given another 30 Gy to the brain and to the spine. These authors reported an 81 percent 5-year survival rate among patients with histologically diagnosed germinomas who respond to 20 Gy irradiation, 64 percent 5-year survival among those with non-germ cell tumors, and 18 percent 5-year survival among those with malignant teratomas.

The malignant teratomas have a particularly bad prognosis and are those tumors which often present with elevations in the tumor markers and which recur rapidly following irradiation or surgical excision. It is particularly in these tumors and in patients with tumor recurrence that chemotherapeutic approaches seem to have a particular value. Currently cisplatin-based therapy of VP-16 and cisplatin alternating with vincristine, methotrexate, and bleomycin have been used to treat these cases with encouraging results.

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