The pineal region is defined as the area of the brain bordered superiorly by the splenium of the corpus callosum and the tela choroidea, inferiorly by the quadrigeminal plate and midbrain tectum, anteriorly by the posterior parts of the third ventricle, and posteriorly by the cerebellar vermis as can be nicely shown in a midline sagittal section through the pineal gland and surrounding anatomical structures in an injected fixed human cadaver (Fig. 37.1). The pineal gland itself, as an invagination of the diencephalic ependymal roof between the habenular commissure and the posterior commissure, lies between the superior colliculi and basal to the splenium of the corpus callosum. It has a thin stalk to the epithalamus and developmentally is considered to be a paired structure. The neural connections with adjacent centers are the topic of discussion but have to be clarified. The pineal body itself has an average length of 7.97 mm (range 5.0-12.0 mm) and is 4.25 mm (2.5-7.0 mm) in height and width. It is oval in shape. The suprapineal recess projects posteriorly between the upper surface of the pineal gland and the lower layer of the tela choroidea in the roof. The stalk of the pineal body, from which the gland extends into the quadrigeminal cistern, has a cranial lamina and a caudal lamina. The habenular commissure, which connects the habenulae, crosses the midline over the cranial lamina, and the posterior commissure crosses the caudal lamina. The pineal recess projects posteriorly from the third ventricle into the pineal body between the two laminae. The posterior commissure forms the base of the triangular orifice of the aqueduct of Sylvius; the other two limbs are formed by the central gray matter of the midbrain. The quadrigeminal cistern is the subarachnoid space of the pineal region, and provides protection for the midbrain from the sharp edge of the tentorial notch. The arteries and veins inside the cistern are embedded in the firm arachnoidal septa. The quadrigeminal cistern communicates anteriorly with the cistern of the tela choroidea of the third ventricle, dorsally along the great vein of Galen with the dorsal cistern of the corpus callosum, laterally into the alae, caudally into the superior cistern of the cerebellum, which is formed by the medullary velum and the vermis, and anterodorsally into the ambient cistern. Through the latter cistern, the large arteries, the posterior cerebral artery and its branches, and the superior cerebellar artery approach the dorsal surface of the brainstem along the edge of the tentorium. The posterior border of the quadrigeminal cistern is formed by thickened opalescent arachnoid. Care must be taken when dissecting this area because the vein of Galen and its tributaries lie immediately rostral. The mesencephalon with the pineal body has its arterial blood supply from various sources. Small vessels supplying the parenchyma of the cerebral peduncles and the rest of the midbrain arise from the posterior communicating artery as perforating branches forming an internal or direct system. The vascularization in situ can be shown using neuroendoscopic techniques in injected human cadavers (arteries red, veins blue) and gives an impression of the enormous variety of the vascular structure (Fig. 37.2). All these arteries widely anastomose with each other, which explains the rarity of infarcts in the mesencephalon and the relative tolerance of the midbrain to direct surgical intervention. The pineal body is supplied by the pineal artery, which originates from the medial posterior choroidal artery, arising from the posterior cerebral artery (PCA), and enters the gland through its lateral portion from both sides. The great vein of Galen and its tributaries form a roof-like, dense venous network above the pineal body and the quadrigeminal plate, formed from the internal cerebral veins after they pass posteriorly through the tela choroidea and unite with the basal veins of Rosenthal. Other tributaries of the vein of Galen include the precentral cerebellar vein, internal occipital vein, posterior mesencephalic vein, and posterior ventricular vein. The straight sinus is formed by the joining of the great vein of Galen with the inferior sagittal sinus.

FIGURE 37.1 Midline sagittal section through the pineal region and related structures in a fixed human cadaver, vessels injected in red (arteries) and blue (veins).

FIGURE 37.2 Endoscopic view using a supracerebellar infratentorial approach demonstrating the pineal gland and the collicular plate. Note the variability of the vascularization; veins injected in blue, arteries in red in a nonfixed human cadaver.

(Courtesy of A. Di-Ieva and M. Tschabitscher, Anatomical Institute, Medical University of Vienna, Austria.)

Histology

The normal pineal gland contains pinealocytes derived from amino precursor uptake and decarboxylation (APUD) cells and glial cells (astrocytes). The pineal gland is usually calcified by the age of 16 and appears so on routine computed tomography (CT) scans. Pineal cysts can be found incidentally in magnetic resonance imaging (MRI) studies in about 1.1% to 4.3% and this incidence seems to be higher in females (~2.4%) than in males (~1.5%) (Fig. 37.3). They can be identified in patients of all ages, with an increased prevalence found in older patients and in approximately 25% to 40% of autopsies, albeit many of the pineal cysts are microcystic. Their etiology remains obscure and may be the result of ischemic glial degeneration or of sequestration of the pineal diverticulum. Usually they are benign, non-neoplastic and may contain clear, xanthochromic, sometimes hemorrhagic, fluid. In the majority of cases, they are asymptomatic and may be followed on serial MRIs. Only in very rare cases do they show an enlargement, and may become symptomatic by causing hydrocephalus through aqueductal compression, headache, or gaze paresis, or hypothalamic symptoms. In those unusual situations with neurological symptoms or signs there is an indication to consider neurosurgical intervention.

FIGURE 37.3 Typical cyst of the pineal region incidentally found in routine magnetic resonance imaging (MRI) scan (40-year-old woman). Sagittal plane (A). The cyst is completely unchanged in a follow-up series more than 15 years later (B).

(Courtesy of K. Turetschek, Diagnostic Center Favoriten,Vienna.)

Function

In reptiles, the pineal gland functions as a photoreceptor to change skin color in response to light. In humans, it is involved with hormone secretion for circadian rhythms and is known to have a neurotransmitter secretory function. The pineal gland inhibits gonadal development and regulates menstruation, adrenal function, and thyroid function. It is innervated by sympathetic nerves from the superior cervical ganglion that release norepinephrine to increase the pineal gland’s melatonin secretion. Light stimuli thereby reach the pineal gland from the retina via a polysynaptic pathway and affect the production of the neuroendocrine substance, melatonin. Melatonin, a derivative of serotonin, is essential in regulating circadian rhythms in endocrine gland activity and produces an antigonadal effect through the hypothalamic-hypophyseal axis. The production of melatonin is inhibited by light. Apparently, in many animals the major function of the pineal gland is to regulate the reproductive cycle; in fall and winter when days are short, more melatonin is produced, causing a gonad-suppressing effect. The exact function of the pineal gland in humans remains unclear. Recent studies could prove a diagnostic value of the melatonin profile in case of tumors of the pineal region. These studies showed a dramatically reduced melatonin rhythm in cases of undifferentiated or invasive tumors as well as the absence of melatonin variation as a consequence of pineal distortion after surgery. Also, the evidence for melatonin deficiency is recognized as a predictive factor to prevent post-pinealectomy syndrome. The absence of production of melatonin, as after pinealectomy, causes a “jet-lag-like” syndrome consisting of a complete disturbance of circadian rhythms.

Pathology

Pineal region tumors are rare tumors, with an estimated overall incidence of about 1% of all intracranial tumors (ranging from 0.5% to 1.6% in different studies) and are more common in children (3-8%) than in adults (less than 1%). Also, the incidence of pineal region tumors is higher among the Japanese, at 4-6% of all intracranial tumors. A population-based study calculated the incidence of pineal region tumors at 0.06 to 0.07 per 100,000 persons per year. No significant differences in the incidence between races were noted. Other reports describe the incidence in children younger than 20 years of age to be about 0.061 per 100,000 children per year. They are uncommon tumors and occur in a wide variety of different histological types. Furthermore, many tumors are of mixed cell type. The pathological classification depends on the substrate in the pineal region from which the tumor may arise. There are tumors which arise from the pineal glandular tissue itself, such as pinealocytomas (WHO grade I), pineal parenchymal tumors of intermediate differentiation (WHO grades II or III), pinealoblastomas (WHO grade IV), and papillary tumors of the pineal region. Other tumors arise from the glial cells, such as astrocytomas, oligodrendrogliomas, and glial cysts. Arachnoid cells are the basis for pineal-region meningiomas and non-neoplastic arachnoid cysts. Ependymal cells give rise to ependymomas in this region. Sympathetic nerves serve as a substrate for chemodectomas. Germ cell remnants give rise to germ cell tumors such as germinoma, choriocarcinoma, embryonal carcinoma, endodermal sinus tumor (yolk sac tumor), and teratoma. Lastly, the absence of a blood-brain barrier in the pineal gland makes it a suitable site for hematogenous metastases mostly from breast cancer, stomach cancer, renal cancer, or melanomas (Table 37.1).

TABLE 37.1 Types of Pineal Tumors: 2007 WHO Classification of Tumors of the Central Nervous System

Tumor	Origin	Frequency
Germ Cell Tumors	Rest of germ cells	~60%
Germinoma Mature Teratoma Immature Teratoma Teratoma with Malignant Transformation Yolk sac tumor (endodermal sinus tumor) Embryonal carcinoma Choriocarcinoma
Pineal Parenchymal Tumors	Pineal glandular tissue	~30%
Pineocytoma (WHO grade I) Pineal parenchymal tumor of intermediate differentiation (WHO grade II or III) Pinealoblastoma (WHO grade IV) Papillary tumor of pineal region
Tumors of Supportive and Adjacent Structures		~10%
Astrocytoma Glioma (glioblastoma or oligodendroglioma) Medulloepithelioma	Glial cells
Ependymoma Choroid plexus papilloma	Ependymal lining
Meningioma	Arachnoid cells
Hemangioma Hemangiopericytoma or blastoma Chemodectoma Craniopharyngioma	Vascular cells
Non-neoplastic Tumor-like Conditions		<1%
Arachnoid cyst	Arachnoid cells
Degenerative cysts (pineal cysts)	Glial cells
Cysticercosis	Parasites
Arteriovenous malformations	Vascularization
Cavernomas Aneurysms of the vein of Galen
Metastases	Absence of blood-brain barrier	<0.1%
Lung (most common), breast, stomach, kidney, melanoma

Louis DN, Cavanee WK, Oghaki H. WHO Classification of Tumours of the Central Nervous System, 4th ed: WHO Classification of Tumours v. 1 (IARC WHO Classification of Tumours), World Health Org; 4th edition (May 2007).

Several authors have described different classification systems. The most current classification system for pure pineal parenchymal tumors is from the World Health Organization (WHO) Classification of Tumors of the Central Nervous System edited by Louis and associates and published in 2007.

Germ Cell Tumors

Germ cell tumors derive from pluripotential germ cells and span a wide range of differentiation and malignant characteristics. They constitute a unique class of rare tumors that affect mainly children and adolescents. Predominantly they occur in the midline when they arise in the central nervous system (CNS). Intracranial germ cell tumors, in general, account for 0.4% to 3.4% of intracranial neoplasms. Their average incidence is considered to be 0.1 per 100,000 persons per year. Pineal germ cell tumors occur primarily in males. Germ cell tumors in females are more common in the suprasellar region. Most germ cell tumors of the CNS occur in the first three decades (98%) with a peak in the second decade (65%) between 11 and 20 years. The histogenesis of germ cell tumors is a subject of controversy. For a long time, they have been assumed to represent the neoplastic offspring of primordial germ cells. During the last decade, however, a variety of speculative proposals have been published on this topic. As a result of the etiology, certain observations suggest that gonadotropins play a role in the development or progression of CNS germ cell tumors. These include the predilection with Klinefelter syndrome, a condition characterized by chronically elevated serum levels of gonadotropins. Due to the variety of possible origins, the following entities are distinguished: germinoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumor), choriocarcinoma, mature teratoma, immature teratoma, teratoma with malignant transformation, and mixed germ cell tumors. An accurate histological identification and subclassification of CNS germ cell tumors is critical for current treatment planning and prognostication. In fact, only the germinoma and teratoma are likely to be encountered as pure tumor types.

Germinoma

Pure germinomas (Fig. 37.4A to C) account for 65% to 72% of all intracranial germ cell tumors. These usually occur in the pineal region, although the second most common site is supra- and intrasellar, sometimes also parasellar. Germ cell tumors can be “synchronous,” and can be found both in the the suprasellar region and in the pineal region approximately 10% of the time. In fact, the discovery of a synchronous lesion on MRI is indicative of a germ cell tumor. The germ cell tumors are usually poorly circumscribed, light gray, granular, solid neoplasms that destroy the pineal gland and infiltrate the ventricular system and subarachnoid space early in their course. Hemorrhage into the tumor and necrosis or cystic degeneration are not often found. This tumor is composed of uniform cells resembling primitive germ cells, with large, vesicular nuclei, prominent nucleoli, and a clear, glycogen-rich cytoplasm. Additional features include lymphoid or lymphoplasma cellular infiltrates and, less frequently, scattered syncytiotrophoblastic giant cells (Fig. 37.5A and B).

FIGURE 37.4 Midline sagittal section through the brain, with gross appearance of a germinoma. The tumor is infiltrating the brainstem at the level of the midbrain (A). Frontal section through the brain, gross appearance of a germinoma growing into the ventricle (B). Tumor cells of a germinoma in the postoperative cerebrospinal fluid representing a typical large cell with two prominent nucleoli (MGG [May-Grunwald Giemsa], ×600) (C).

(Courtesy of Q. Koperek, Neuropathological Institute, Medical University of Vienna.)

FIGURE 37.5 Histopathological features of a germinoma with typical lymphocytic infiltrates along fibrovascular septae (H&E, ×200) (A) and immunohistochemistry staining of the cytoplasm and cytoplasmic membrane with placental alkaline phosphatase (PLAP) (×400) (B).

(Courtesy of O. Koperek, Neuropathological Institute, Medical University of Vienna.)

Teratoma

Teratomas (Fig. 37.6A and B) derive from all germ layers and are composed of well-differentiated tissues in an organ-like pattern. These tumors in the pineal region most often affect males. They are usually identified within the first two decades of life but occur more often in much younger children than other germ cell tumors (mostly in children younger than 9 years of age; about 20% occur between the ages of 16 and 18). By definition, the term teratoma can be used only when tumor elements derive from two or three germ layers. These tumors are usually well circumscribed, round or lobulated, and multicystic and compress the surrounding structures. The cystic component of the tumor may be watery, mucoid, or sebaceous. Sometimes bone, cartilage, hair, or teeth are present. Immature tumors are more frequently associated with a malignant course. Histologically, teratomas differentiate along ectodermal, endodermal, and mesodermal lines (e.g., they recapitulate somatic development from the three embryonic germ layers). Mature and immature variants as well as teratomas with malignant transformation must be distinguished from each other.

FIGURE 37.6 Histopathological features of a teratoma of the pineal region with fetal-type glands and embryonic mesenchyme–like stroma (H&E, ×200) (B). Immunohistochemistry out of (A) staining with synaptophysin representing the immature neuronal differentiated appearance (×200) (B).

(Courtesy of Q. Koperek, Neuropathological Institute, Medical University of Vienna.)

Yolk Sac Tumor (Endodermal Sinus Tumor)

The histological appearance of endodermal sinus tumors classically features Schiller-Duval bodies, which resemble the yolk sac or endodermal sinus—an extraembryonic endodermal derivative in lower animals. These bodies are composed of a blood vessel invaginating a space, with both being covered by a layer of cuboidal tumor cells with clear cytoplasm, small dark nuclei, and prominent nucleoli set in a loose, variably cellular and often conspicuously myxoid matrix resembling extraembryonic mesoblasts. Eosinophilic hyaline globules, immunoreactive for α-fetoprotein, are a diagnostic feature. Endodermal sinus tumors are usually highly invasive. Sometimes they can occur within the lateral ventricle, although this seems to be very rare.

Embryonal Carcinoma

This type of germ cell tumor is the least frequently reported and is one that represents a primitive neoplasm consisting of pluripotential large cells that proliferate in cohesive nets and sheets. They form abortive papillae or line irregular, gland-like spaces. The tumor may exceptionally replicate the structure of the early embryo, forming “embryoid bodies” replete with germ disks and miniature amniotic cavities. A high mitotic rate and zones of coagulative necrosis complete the histological picture.

Choriocarcinoma

This type rarely arises extragenitally and is characterized by extraembryonic differentiation along trophoblastic lines. These tumors are characterized by two cell types: uniform cytotrophoblastic cells of medium size, with clear cytoplasm, vesicular nucleus, and distinct cell borders, and syncytiotrophoblastic cells, which are larger and multinucleated. The gross appearance of choriocarcinoma is a granular, reddish brown mass, almost always with hemorrhage and necrosis. As for all other tumors of germ cell origin, choriocarcinoma is usually accompanied by elements of either tumor of this group.

Pineal Parenchymal Tumors

As described in the previous section, these types of tumors constitute the second major group of pineal region tumors, accounting for 20% to 30% of all neoplasms in this location. They are considered to be the true neoplasm of the parenchyma of the pineal gland and are usually sharply delineated, with some formation of capsule and displacement of surrounding structures such as thalamus and midbrain. As a result of the variety of histological origins, the following entities are distinguished: pinealocytomas (WHO grade I), pineal parenchymal tumors of intermediate differentiation (WHO grades II or III), pinealoblastomas (WHO grade IV), and papillary tumors of the pineal region.

Pinealocytoma (WHO Grade I)

Pinealocytomas are defined as slow-growing pineal parenchymal neoplasms. They represent approximately 45% of all tumors with pineal parenchymal origin and occur throughout life, but most frequently in young adults (25-35 years). There is no sex predilection. Macroscopically, these tumors are well circumscribed with a gray-tan, homogeneous or granular cut surface. Degenerative changes, such as hemorrhage and small cystic cavities, can be present. They may disseminate widely along the CSF pathways. The histological appearance is of a well-differentiated neoplasm composed of small, uniform, mature cells resembling pinealocytes (Fig. 37.7A to C). They grow in sheets, but also feature large pinealocytomatous rosettes composed of abundant, delicate tumor cell processes. Pinealocytomas may contain astrocytic or neuronal components or both (so-called ganglioma of the pineal gland). Such tumors are the most benign of the pineal parenchymal neoplasms.

FIGURE 37.7 Histopathological features of a pinealocytoma with characteristic lobular pattern mimicking the structure of the normal pineal gland (H&E, ×200) (A), isomorphic cells with small round nuclei and nucleus-free spaces filled with a fine meshwork of cell processes (neuropils) (H&E, ×400) (B), and immunohistochemistry intensive diffuse staining with synaptophysin (×200) (C).

(Courtesy of Q. Koperek, Neuropathological Institute, Medical University of Vienna.)

Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grade I or II)

This group of true pineal parenchymal tumors represents monomorphous types of lesions characterized by moderately high cellularity, mild nuclear atypia, occasional mitosis, and the absence of large pinealocytomatous rosettes. They occur in approximately 10% of all pineal parenchymal tumors and at all ages with a peak incidence in adulthood. The clinical behavior is variable.

Pinealoblastoma (WHO Grade IV)

This type of tumor (Fig. 37.8A to D) is defined as a highly malignant, primitive embryonal tumor of the pineal gland itself and represents a true primitive neuroectodermal tumor (PNET). Although they are rare intracranial tumors, they constitute approximately 45% of all pineal parenchymal tumors. Usually they occur in the first two decades of life, more often in children, but principally can arise at any age. Some of these tumors may be present during the neonatal period. In larger series, pinealoblastomas are more common in males, with a male-female ratio of 2:1. The tumor usually replaces the tissue of the pineal gland. They are mostly soft, friable, and poorly demarcated and are pink, white, or gray, smooth or granular when cut, sometimes cystic, and frequently hemorrhagic or necrotic. Calcifications are rare and infiltration of the surrounding structures, including the meninges, is common. Constituting the most primitive of pineal parenchymal tumors, pinealoblastomas are composed of patternless sheets of densely packed small cells with round to irregular nuclei and scant cytoplasm. Pinealocytomatous rosettes are lacking, but Homer-Wright and Flexner-Wintersteiner rosettes may be seen. Retinoblastomatous differentiation of pinealoblastomas sometimes occurs and supports the theory of the photoreceptive origin of pineal gland cells. Pinealoblastomas may accompany bilateral retinoblastomas, in which case together they are called trilateral retinoblastoma. Pinealoblastomas sometimes contain melanin pigment. Because of its infiltrating nature into surrounding structures, dissemination in the CSF is not rare: according to the literature, between 8% and 24%. Metastases to bone, lung, and lymph nodes have been reported.

FIGURE 37.8 Frontal section of the brain, with gross appearance of a pinealoblastoma. The tumor is infiltrating the third ventricle (A). Histopathological features of a pinealoblastoma with Flexner-Wintersteiner rosettes (H&E, ×400) (B), typical tumor cells with mitotic activity in the cerebrospinal fluid (MGG, ×600) (C), and high cellularity with numerous mitotic figures (H&E, ×400) (D).

(Courtesy of D. Koperek, Neuropathological Institute, Medical University of Vienna.)

Papillary Tumors of the Pineal Region (Similar to WHO Grade II or III)

This rather newly defined group consists of rare neuroepithelial tumors in adults characterized by a typical papillary structure and epithelial structure. Their biological behavior is variable and shows a similar course to the one of grade II or III tumors. The first description as a distinct entity goes back to 2003. The origin of that group of tumors is specialized ependymal cells from the subcommissural region. Because of that in later years they have been reported as papillary pineocytomas or pineal parenchymal tumors, choroid plexus tumors, and even as ependymomas or papillary meningiomas. The incidence seems extremely rare and representative data are still not available. Worldwide, no more than 100 cases have reported to date in children as well as in adults. In this case no sex predilection could be found. In recent studies with a small patient group tumor progression occurred in more than 70%.

Tumors of Supportive and Adjacent Structures

There are several other tumors that can also be considered pineal parenchymal tumors, such as astrocytomas, ependymomas, or less frequently gliomas (glioblastomas or oligodendrogliomas). Glial cell tumors can also occur in the pineal gland, because astrocytes are normally present there, or may arise from the pluripotential pineal parenchymal cells. However, almost all glial tumors may arise from the glial tissue elements intimately surrounding the pineal gland. Real, true astrocytomas of the pineal gland itself are extremely rare. Tumors of other histological types may also occur as a substrate from the surrounding tissue—for example, choroidus plexus papillomas or medulloepitheliomas. Tumors of mesenchymal origin that may occur include meningiomas, hemangiomas, and hemangiopericytomas or blastomas, which arise mostly from the falx and tentorium near their junction or from the velum interpositum at the roof of the third ventricle. Also reported are exceptionally rare cases of chemodectomas and craniopharyngiomas of the pineal region. Another not-so-well-known entity is malignant solitary fibrous tumors that also may occur in the pineal gland. Solitary fibrous tumors are rare fibroblastic tumors that most commonly arise in the pleura, sometimes in the orbit. In the CNS in general they are extremely rare with around 100 reports in the literature and just a handful from the pineal region.

Non-Neoplastic Tumor-Like Conditions

Sometimes of neurosurgical importance are non-neoplastic tumor-like malformations, for example, arachnoid cysts arising from the arachnoid cells of that region or “degenerative” cysts lined by fibrillary astrocytes (so-called pineal cysts). They occur in 1.1% to 4.3% but may be seen more often, as proved in autopsy series up to 25% to 40%. Cysticercosis and vascular lesions, such as arteriovenous malformations, cavernomas, and aneurysms of the vein of Galen, can also be included, but are very rare.

Metastases to the Pineal Region

The absence of a blood-brain barrier in the pineal gland makes it a susceptible site for hematogenous metastases; however, despite this fact these tumors of the pineal region are surprisingly rare. The most common site of origin for metastases to the pineal region is the lung, followed by the breast and other organs, such as the stomach, kidney, and melanomas.

Signs and Symptoms

The presentation of patients with pineal region tumors relates to the anatomy being affected as well as to the specific tumor histological type. However, the remarkable developments in neuroimaging are helping us to uncover more lesions in the pineal region in patients who have minimal symptoms, and those patients who might not normally be discovered until they became much more symptomatic. If the tumor is large enough to cause clinical symptoms, then these symptoms arise either because of hydrocephalus, local infiltration into surrounding neural structures, or local compression to the adjacent structures.

The most common symptom is Parinaud syndrome. It is present in 50% to 75% of all patients suffering from a pineal region tumor, characterized by its typical ocular movement disorder including paralysis of upward gaze, convergence or retraction nystagmus, and light-near dissociation. Direct pressure of the tumor on the tectum or dilatation of the proximal aqueduct causes the less common sylvian aqueduct syndrome, which includes paralysis of down gaze or horizontal gaze superimposed on Parinaud syndrome. Convergent nystagmus may be present when upward gaze is attempted. The anatomical substrate of these ocular functions is located below the posterior part of the third ventricle and anterior to the aqueduct. Lid retraction (Collier’s sign) is quite rare; it is caused by compression of levator inhibitory fibers in the posterior commissure. Pupils are dilated and respond poorly to light, although they may respond to accommodation.

Almost all patients with severe headaches have hydrocephalus by the time of presentation, causing the typical associated signs and symptoms, vomiting, lethargy, and memory impairment. In infants, one typical sign is also an abnormally increasing head circumference and seizures. In the case of large tumors with invasive characteristics, infiltration of the thalamic region or even the internal capsule can cause contralateral hemihypesthesia or paresthesias and sometimes can also be combined with typical thalamic pain syndromes. Depending on the extent of the invasion, extrapyramidal syndromes as well as different types of movement disorders can occur. Sudden presentation of the “sun-setting” phenomenon, caused by hydrocephalus and Parinaud syndrome, together with decreased mental status, especially in children, may be related to hemorrhage into the pineal tumor (pineal apoplexy) or acute hydrocephalus.

A commonly described endocrine disturbance associated with pineal region tumors is precocious puberty, which occurs in 10% of male patients with these lesions, and has been attributed to several potential causes. One hypothesis connects the development of precocious puberty with ectopic secretion of beta human chorionic gonadotropin by choriocarcinoma or germinoma and thus explains the absence of precocious puberty in girls with pineal region tumors. Another hypothesis links precocious puberty with a mass effect or a synchronous lesion in the region of the posterior diencephalon or infundibulum, which blocks its inhibitory effect on the median eminence of the hypothalamus, thereby augmenting secretion of gonadotropins. This hypothesis explains the association of precocious puberty with other symptoms of hypothalamic dysfunction (e.g., diabetes insipidus and polyphagia). According to a third hypothesis, the growth of a tumor in the pineal region causes a decrease in the secretion by the pineal gland of a substance (or substances) with antigonadotropic effect. If a pineal parenchymal tumor causes hypersecretion of such an agent, isolated hypogonadism may occur.

In the case of drop metastases from the CSF, seeding radiculopathy or myelopathy can occur, sometimes from a nonspecific appearance. Signs and symptoms can occur in very rare cases as a result of hematogenous metastases to several structures outside the CNS. The most typical clinical signs and symptoms are summarized in Table 37.2.

TABLE 37.2 Most Frequent Tumors of the Pineal Region: Typical Characteristics

Diagnostic Studies

Today, the two most important powerful diagnostic tools are laboratory tests including CSF cytological examination (tumor markers) and neuroradiological examinations using MRI and CT. Both are widely available and have great value.

Imaging

Diagnostic tools such as MRI have revolutionized the management of pineal region tumors (Figs. 37.9 to 37.11). The ability to obtain high-resolution images and multidimensional views makes it possible to show tumor location and extension clearly and accurately. Today, ventriculography and pneumencephalography are primarily of historical value. Skull radiography, formerly an important diagnostic study, has fallen into disuse because of its low sensitivity in detecting tumors. The normal pineal gland is seen on plain films as a calcified mass in 60% of the population over 20 years of age and very rarely in children before the age of 6 years. Any calcified pineal gland that is larger than 1 cm in any dimension should be viewed with suspicion. The appearance of a calcified pineal gland in early childhood is usually abnormal, but can, in fact, be physiologically normal in up to 5% of cases.

FIGURE 37.9 Coronal T1-weighted gadolinium-enhanced magnetic resonance imaging (MRI) scan demonstrating an enhancing, demarcated mass lesion in the posterior part of the third ventricle representing a pinealoblastoma (A). Axial (B) and sagittal (C) T2-weighted MRI studies of the same patient.

FIGURE 37.10 Infused magnetic resonance imaging (MRI) scans of a patient presenting a typical meningioma in the pineal region. Sagittal T1-weighted (A), coronal (B), and axial (C).

FIGURE 37.11 Infused T1-weighted magnetic resonance imaging (MRI) scans of a germinoma in the sagittal direction (A) and axial direction (B) compressing the aqueduct, causing obstructive hydrocephalus.

CT superseded all other radiological imaging methods for the detection of pineal region tumors in the early 1980s. Currently, high-resolution CT with or without intravenous contrast administration is used to examine the pineal region, but is often more important for planning the appropriate approach than as a diagnostic tool. Carotid and vertebral arteriography are only occasionally required, often in cases in which preoperative embolization may be considered; superselective angiography, in skilled hands, is used in this region for further endovascular treatment when a vascular tumor is encountered. In some institutions, magnetic resonance (MR) angiography or CT angiography is the angiographic study of choice for noninvasive evaluation. Both modalities provide accurate information on the anatomy of the arteries and veins in the region for surgical planning. Therefore, the current recommendation is to perform a high-resolution MRI examination, in combination with MR angiography and, when appropriate, in addition, CT scans with and without contrast, respectively, with or without CT angiography. Table 37.3 gives an overview and comparison of the neuroradiological appearance of pineal region tumors in correlation to their pineal versus parapineal appearance, signal intensity (heterogeneous versus homogeneous), appearance of hemorrhage, calcification, brain edema or invasion, and contrast enhancement.

Table 37.3 Immunohistochemical Profiles (Tumor Markers) of Tumors of the Pineal Region

Newer, evolving diagnostic tools can provide additional information. MR spectroscopy provides information of biological behavior or activity, MR chemical shift imaging (CSI) may contribute to a more precise differential diagnosis, tensor diffusion-weighted imaging (DWI) assists with defining the functional anatomy in relation to the lesion, and high-field MRI (3 tesla up to 7 tesla) can provide a better understanding of the relationship of the tumor with its surrounding anatomy. Intraoperative MRI-guided neuronavigation has been an immensely useful tool in the approach, trajectory, and surgical planning to the pineal region, despite the midline location of this structure. Image fusion modalities make it possible to get all the radiological information integrated so that the surgeon can integrate the anatomical and functional planning during surgery.

Tumor Markers

Certain pineal region tumors manifest tumor markers in the CSF and blood serum. The identification of markers is important not only for diagnostic purposes, when present, but also for monitoring response to treatment and relapse. However, it should be noted that these markers are not uniformly present in all patients with pineal tumors and their absence does not eliminate the diagnosis of a specific tumor.

The most important and useful markers are α-fetoprotein and β-human chorionic gonadotropin (β-hCG). α-Fetoprotein, a glycoprotein, is normally produced by the yolk sac and the fetal liver, and its production stops by the time of birth. An α-fetoprotein value of less than 5 ng/mL in serum and CSF is considered to be normal. The greatest production of α-fetoprotein can be seen in some cases of yolk sac tumors (endodermal sinus tumors). Embryonal carcinomas and immature teratomas produce α-fetoprotein to a lesser extent, less than 1000 ng/mL. β-Human chorionic gonadotropin, also a glycoprotein, is normally produced by the syncytiotrophoblastic giant cells of placental trophoblastic tissue with a normal value in the serum and CSF of less than 5 mIU/mL. Choriocarcinomas normally produce the highest amount, more than 2000 ng/mL. Mild elevations of less than 770 ng/mL can be seen in some patients with germinomas and embryonal carcinomas. The biological half-life is about 5 days for α-fetoprotein, but less than 24 hours for β-hCG. In general, serum titers tend to show higher positivity than do CSF titers, because the tumor should be in direct contact with the CSF for positive markers.

Human placental lactogen (HPL) is well known as a marker in case of choriocarcinoma and other trophoblastic tumors, mostly in the lung or stomach, but also cervix. In recent studies, placental alkaline phosphatase was reported to be a specific marker for primary intracranial germinomas and is measured with an enzyme-linked immunosorbent assay in the serum as well as in the CSF.

Cytokeratin as a marker can be found in teratomas, yolk sac tumors, embryonal carcinomas, and choriocarcinomas but only with lower serum levels. It seems to be more specific in case of papillary tumors of the pineal region. C-kit functions as a tyrosine kinase receptor and represents a target for small molecule kinase inhibitors, found normally in breast or lung cancers. Sometimes it could be found also in germinomas, but is extremely rare in teratomas without significant correlation between c-kit expression and prognosis. OCT4 has some biological functions and clinical applications as a marker of germ cell neoplasia and seems slightly increased in germinomas and embryonal carcinomas but without clinical significance. Melatonin as a tumor marker may be used in cases of tumors that destroy the pineal gland. The absence of melatonin in serum after surgery thereby indicates complete removal of the pineal gland. Elevation of the polyamines putrescine and spermidine in CSF has been reported in malignant brain tumors of childhood, especially PNETs.

Although the levels of markers in serum and CSF, when present, have been found to be extremely useful in assessing the efficacy of various treatment modalities and tumor recurrence, the tumor markers alone do not yield a definitive histological diagnosis. Furthermore, in a large number of patients these tumor markers are simply absent. Table 37.4 gives a brief overview of the serum and CSF levels occurring in pineal region tumors. Advanced neuroimaging (MRI, MRI spectroscopy, CSI and PET, high-resolution CT) and tumor marker evaluation, when present, improve diagnostic accuracy.

TABLE 37.4 Frequency of Typical Clinical Signs and Symptoms in Pineal Region Tumors

Clinical Sign/Symptom	Frequency
Headache Vomiting Lethargy Memory disturbance Hydrocephalus	Common (~80%)
Nystagmus	Common (~60-70%)
Parinaud’s sign Convergence Accommodation palsy Supranuclear upward glaze	Frequent (~50-75%)
Lid retraction Setting sun sign (Collier’s sign)	Less frequent (~10%)
Endocrine disturbance Precocious puberty (in boys) Hypothalamic dysfunction Diabetes insipidus Polyphagia Isolated hypogonadism

Less frequent (~10%) Radiculopathy or myelopathy Rare Seizures Rare Hemihypesthesia/paresthesia Rare Thalamic pain Rare Extrapyramidal movement disorders Rare

Choice of Treatments

Surgical treatment of pineal region tumors has been a topic of debate, controversy, and intellectual innovation for the past 100 years in neurological surgery. In the beginning of the twentieth century, the lack of technical, anesthetic, and radiological refinements led to uniformly poor surgical results and a surgical mortality rate close to 90%. For decades, the treatment of these tumors was relegated to CSF diversion followed by radiotherapy. Even until the mid-1970s, the therapy of pineal region tumors consisted of ventricular shunting and radiation therapy, with 5-year survival rates as high as 60% to 80% with some histological types of tumors.

Advanced techniques in microneurosurgery, neuroanesthesiology, neuroimaging, and intensive care medicine have enabled modern neurosurgeons to operate on such lesions with more than acceptable outcomes. This has resulted in a much higher cure rate, decreased surgical mortality and morbidity rates, and increased longevity for those patients who have tumor recurrence after therapy. Today, control of hydrocephalus, which is associated with most of the tumors in this region, is no longer a problem and should be carried out routinely either through a shunting procedure or, more often, via endoscopic third ventriculostomy. Even in the case of nonresectable tumors, a safe and efficient histological identification is advised and worth attempting by endoscopic or stereotactic biopsy. This serves as the basis for further adjuvant radiotherapy and chemotherapy in these nonresectable lesions. There is a subset of tumors that lend themselves to resection despite their size and location. In these tumors a radical resection through a variety of approaches should be attempted by surgeons who are experienced with the technical refinements and surgical anatomy in this challenging region.

Stereotactic Procedures

Stereotactic procedures, frame-base or frameless, have become increasingly more advanced and easy to use as a diagnostic tool for tumors that may not be amenable to resection. Most reports concerning this type of procedure indicate that the risks of intervention are minimal. However, caution is advised because the pineal region is surrounded by an important complex of arteries and veins, as described in the earlier section on anatomy. The vessels may be displaced from their normal position for several reasons, such as tumor mass, or hydrocephalus. Also, some tumors, such as pinealoblastomas or choriocarcinomas, are highly vascular. However, the complication rate in stereotactic biopsy of lesions in this location is low, approximately 1.3% mortality rate and 7% morbidity rate in skilled hands according to a large European series. The diagnostic accuracy and specificity is equivalently high (94%), although stereotactic biopsy may fail to disclose the histological heterogeneity of selected tumors due to sampling error, especially in the case of mixed malignant tumors.

Neuroendoscopy and Hydrocephalus

Recent advances in neuroendoscopic techniques have enabled this technology to become a major component of the treatment strategies of pineal region tumors. In most of the cases, endoscopic biopsy can be performed with more than acceptable results, especially for tumors reaching into the posterior part of the third ventricle. There are now case series of pineal region tumors in which the hydrocephalus is treated by an endoscopic third ventriculostomy followed by a pineal region biopsy. The technique of endoscopic third ventriculostomy has proved to be highly effective and has obviated the need for placement of a permanent shunt. Alternatively, hydrocephalus may be controlled with either tumor mass reduction or a CSF diversion procedure such as a ventriculoperitoneal shunt. Patients presenting acutely with hydrocephalus may be treated using neuroendoscopic third ventriculostomy or, if not available, with external ventricular drainage. The ability of pineal cell tumors to metastasize through a diversionary CSF shunt is rare but has been reported. Certain biopsy-proven germ cell tumors can be reduced in size with concomitant resolution of their associated hydrocephalus within a short time following irradiation or chemotherapy.

Surgical Approaches

The efficacy of open microsurgery on pineal region tumors is undisputed in the twenty-first century. The main goal is complete tumor removal with minimal morbidity whenever possible. Even if radical resection cannot be achieved for several reasons, histological verification, maximal cytoreduction, and more often, restoration of CSF pathways may be achieved. For the benign pineal region tumor, surgery alone is often curative. Although about 80% of pediatric tumors are malignant, open surgery is recommended in most adult cases and selected pediatric cases in which resection is considered safe based on the appearance of the lesion by MRI. Radical resection is especially helpful in cases of the malignant nongerminoma germ cell tumors, as the extent of resection influences the prognosis of the patient. Because the pineal region is located in the geometric center of the intracranial cavity, operative approaches from every conceivable angle and direction have been developed (Fig. 37.12). The five most common surgical approaches are as follows:

1. The posterior transcallosal approach pioneered by Dandy

2. The transventricular approach pioneered by Van Wagenen

3. The occipital transtentorial approach pioneered by Foerster and Poppen

4. The infratentorial-supracerebellar approach pioneered by Krause and popularized by Stein

5. The three-quarter prone, operated side down, occipital transtentorial approach described by Ausman

FIGURE 37.12 Schematic drawing of the various operative approaches to the pineal region from every direction.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

Other approaches include the frontal (anterior) ones in which the pineal region is accessed transcallosally or transcortically. The transcallosal transventricular transvelum-interpositum approach by Sano is useful for large pineal tumors with anterior extension into the third ventricle. An alternative frontal approach to reach the pineal region includes the transcortical, subchoroidal approach.

The Posterior Transcallosal Approach

In 1921, Walter Dandy was one of the first to propose this approach to the pineal region. The primary anatomical structures exposed are the splenium of the corpus callosum, internal cerebral veins, basal vein of Rosenthal, vein of Galen, pineal body, posterior commissure, and quadrigeminal plate. Patient position is similar to the position for the classical anterior transcallosal approach. However, a higher angle is required to provide the appropriate trajectory of about 40 degrees. We prefer a semilunar skin incision over the midline. Craniotomy should include the lambdoid at the posterior margin of the bone flap (Fig. 37.13). A semilunar dural flap is elevated to expose the cortical surface of the posterior parietal lobe. Entry point is the interhemispheric fissure (Fig. 37.14). Bridging veins are rare posteriorly but should be preserved, whenever possible. Retraction of the mesial parietal lobe exposes the splenium of the corpus callosum and after splitting the splenium, the internal cerebral veins can be seen as they drain into the vein of Galen. The pineal gland is located inferior to the venous complex (Fig. 37.15). The limitations of this approach include difficulty in visualization of the quadrigeminal plate and cerebellum, and laterally the mesial occipital lobe, and the requirement to split the splenium of the corpus callosum and retract the mesial occipital lobe. Advantages of this approach are the superior access superior to the venous complex (internal cerebral veins) and the ability to visualize these veins in the velum interpositum so that they are not sacrificed. We recommend this approach for tumors spreading above the venous complex and expanding anteriorly into the third ventricle as well as those extending upward into the corpus callosum (Fig. 37.16A-C). It is an approach that still has indications and should be a part of the surgeon’s armamentarium.

FIGURE 37.13 The posterior transcallosal approach. Direction of the approach, skin incision, and position of craniotomy.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.14 Dura opening and entrance into the interhemispheric fissure in an anatomical cadaver.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.15 Approach to pineal region while performing the posterior transcallosal approach, demonstrating the relation from the pineal tumor to the venous system and surrounding structures.

(Modified from Pendl G, editor. Pineal and Midbrain Lesions. Berlin: Springer; 1985.)

FIGURE 37.16 Intraoperative findings in the case of a pinealoblastoma as presented in Figure 37.6. Situation during splitting the splenium of the corpus callosum using a nonstick bipolar forceps (A). Appearance of the tumor located in the posterior part of the third ventricle before resection (B) and after complete tumor removal (C).

The Occipital Transtentorial Approach

This approach was first proposed by Foerster in 1928 and described in detail by Poppen in 1966. Primary anatomical structures exposed are the splenium of the corpus callosum, internal cerebral veins, basal vein of Rosenthal, vein of Galen, precentral cerebellar vermian vein, pineal body, posterior commissure, and quadrigeminal plate. This approach comes from a more lateral direction and we prefer to have the patient in the recumbent, semisitting position with the chin tucked. Skin incision is an inverted L-shaped incision to expose the occipital region. The inion should be clearly exposed and the bone flap is made with its superior margin approximately 1 to 2 cm below the lambdoid suture. The inferior margin is below the inion, thus placing the torcular within the inferior portion of the dural exposure (Fig. 37.17). After opening the dura, the occipital lobe is retracted laterally to expose the posterior incisural edge and its junction with the falx cerebri. After the tentorium is incised, the lateral entry point has been reached and the venous complex can be explored (Fig. 37.18). Sharp dissection of the arachnoid exposes the vein of Galen and the ipsilateral basal vein of Rosenthal. The pineal gland is most clearly visible inferior to the venous complex (Fig. 37.19).

FIGURE 37.17 The occipital transtentorial approach: trajectory of the approach, skin incision, and position of craniotomy.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.18 Dura opening and entrance after incision of the tentorium in an anatomical cadaver.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.19 Pineal region after performing an occipital transtentorial approach presenting the relation of the pineal tumor to the venous system and surrounding structures

(Modified from Pendl G, editor. Pineal and Midbrain Lesions. Berlin: Springer; 1985.)

Limitations of the approach include poor visualization of the internal cerebral veins anteriorly, the quadrigeminal plate inferiorly, the falx cerebri and vein of Galen medially, and the occipital lobe laterally. In addition, it is not uncommon to compress and temporarily affect the visual cortex through the extremes of retraction that are required to lift the occipital lobe. An advantage of this approach is the superb view, both above and below the tentorium. This approach is recommended for tumors growing through the tentorial hiatus with a supra- and infracerebellar extension, and especially in the case of meningiomas (Fig. 37.20A-C). This approach is used in about 20% of the cases in our institution and makes this the second most common approach for dealing with tumors in the pineal region.

FIGURE 37.20 Intraoperative findings in case of a meningioma as presented in Figure 37.7. Photograph before the incision of the tentorium with the tumor in the background (A). Incision of the tentorium, as one of the key steps in performing the approach, (B) and the situation after complete tumor removal. The surrounding tissue is covered with Surgicel (C).

The Infratentorial-Supracerebellar Approach

The infratentorial-supracerebellar approach was first described by Krause in 1913 and then modified and popularized by Stein in 1971. Performing this kind of approach in the sitting position means that gravity assists the cerebellum in falling down from the undersurface of the tentorium. Primary anatomical structures exposed are the cerebellum, cerebellar veins, cerebellar vermian veins, internal cerebellar veins, basal veins of Rosenthal, vein of Galen, pineal body, posterior commissure, quadrigeminal plate, splenium of the corpus callosum, and posterior third ventricle. We prefer the patient to be placed in the sitting position with the head flexed anteriorly. The amount of flexion depends on the relationship of the tumor to the straight sinus. As an alternative position, we recommend the so-called modified concord position that allows the surgeon to sit comfortably behind the patient. One of the main advantages of the concord position is that it decreases the risk of air embolism. One of the disadvantages is that it is sometimes impossible when the tentorium is very steep. The skin incision is made in the midline, and we use either an S-shaped or a straight midline incision. The craniotomy is centered over the external occipital protuberance and includes the torcular herophili at the superior portion of dural exposure (Fig. 37.21). This allows some upward retraction of the sinus complex, decreasing the degree of necessary downward retraction of the cerebellum. In most of the cases it is not necessary to open the foramen magnum to drain the cisterna magnum so that the cerebellum requires very little retraction. The preserved rim of bone inferiorly provides support for the cerebellum, decreasing traction on its superior connecting elements to the brainstem. Arachnoid dissection and division of the superomedial cerebellar bridging veins allow subsequent inferior retraction of the cerebellar hemispheres (Fig. 37.22). In most cases, a very thick arachnoid membrane is found spanning the interval between the cerebellar vermis and the central posterior incisura. After dissection of the arachnoid membrane the venous complex surrounding the pineal gland can be explored (Fig. 37.23). Limitations of the approach are its restriction to the midline and limited extension to the lateral side. The most powerful advantage is the superior access inferior to the venous complex. We recommend this approach in most of the cases (more than 72%) in which the tumors are restricted to the midline and inferior to the venous complex. It also represents a perfect opportunity to use a rigid angled endoscope as an adjuvant during surgery. This so-called endoscope-assisted or endoscope-guided procedure allows not only perfect illumination (which gives the anatomical structures more plasticity), but also enables the surgeon to have a “look around a corner” without even touching any anatomical structure. This helps the surgeon to detect any residual tumor hiding in the recesses of the pineal region, thus increasing the chance for a radical tumor resection (Fig. 37.24A-D).

FIGURE 37.21 The infratentorial-supracerebellar approach: trajectory of the approach, skin incision, and position of craniotomy.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.22 The infratentorial-supracerebellar entry into the pineal region in an anatomical cadaver.

(Modified from Day JD, Koos WT, Matula C, Lang J, editors. Color Atlas of Microneurosurgical Approaches. Stuttgart: Thieme; 1997.)

FIGURE 37.23 Pineal region while performing the infratentorial supracerebellar approach presenting the relation of the pineal tumor to the venous system and surrounding structures.

(Modified from Pendl G, editor. Pineal and Midbrain Lesions. Berlin: Springer; 1985.)

FIGURE 37.24 Intraoperative findings in case of a germinoma as presented in Figure 37.8. Photograph during the opening of the arachnoid membranes in the pineal region with the tumor in the background (A). Appearance of the tumor before resection (B) and after complete tumor removal (C), and endoscope-assisted approach with the view into the third ventricle presenting the intermediate mass, the choroid plexus at the roof, both fornices, and the anterior commissure (D).