The Normal Pineal Gland

The pineal organ (Latin pineale, pine cone), or more appropriately, the pineal gland, first becomes visible in the human during the second fetal month, when a diverticulum and adjacent cellular thickening develop in the roof of the diencephalon. The pineal parenchyma is formed of tubules that are transformed into solid cell masses, separated by connective tissue and nerve twigs. By the middle of the first decade the structure of the pineal approaches that of a mature gland, consisting of pineocytes arranged into lobules separated by delicate connective tissue septa and thin-walled blood vessels. Variable numbers of astrocytes are intimately associated with the pineocytic lobules.

The pineal cells are a specialized type of neuroepithelial cells, closely related to neurons. They lack axons but have one or more elongated cytoplasmic processes, which end chiefly in the perivascular space around capillaries. Ultrastructurally, besides the usual cellular organelles, mammalian pineocytes have granular (dense­cored) vesicles, generally considered to be of a secretory nature. Small numbers of astrocytes are present between the pineal cells. Typical neurons are found rarely in the human pineal, although a ganglion of about 20 nerve cells (Pastori' s ganglion) is present in the tissue at the tip of the gland. Foci of mineralization (acervuli), largely of hydroxy- or carbonate apatite structure. develop from early infancy and increase with age but do not become radiologically demonstrable until the second decade. The adult pineal weighs about 140 mg (100 to 800 mg) and measures 8 to 12 mm in length, 5 to 8 mm in width. and 4 to 5 mm in thickness. Its blood supply is derived from the posterior cerebral arteries via their posterior choroidal branches. In humans. at least some of the blood drains into the junction of the great cerebral veins.

During its phylogenetic development, the pineal has undergone remarkable changes. In fishes and amphibians. it is chiefly a neurosensory photoreceptor organ. In reptiles and birds, the photo­sensory function has gradually been lost and replaced by an exclusively secretory function. The concept of direct derivation of the mammalian neurosecretory pineocyte from the pineal photoreceptor cell of the lower vertebrate is reinforced by the finding of similar organelles in both these cells. The mammalian pineal gland has a neurotransmitter secretory function. Photic stimuli from the retina reach the pineal gland by the way of a polysynaptic pathway, whose final links are postganglionic sympathetic fibers from the superior cervical ganglia.

Most of the research concerned with the biological behaviour of the pineal gland has been performed on animals that show considerable species variation. Most attention has been directed toward melatonin, named for its blanching effect on tadpole skin. Melatonin is synthesized in pineocytes from tryptophan through a series of metabolic reactions, one of which is the formation of serotonin. Serotonin is found in the pineal tissue in concentrations higher than in any other area of the brain. It is subsequently converted to melatonin in two steps. The final reaction is catalyzed by an enzyme, hydroxyindole-O-methyltransferase (HIOMT). The pineal is also rich in noradrenalin and peptides such as arginine vasotocin.

Melatonin in animals is essential in regulating circadian rhythms in endocrine activity, producing an antigonadal effect primarily through the hypothalamic-adenohypophyseal axis. Light inhibits melatonin production. In humans the importance of melatonin is less well defined. It influences sleep cycles and has endocrine, immunoenhancing and oncostatic activity.

Masses in the Pineal Region: Histogenesis, Classification, and General Features

About 0.4 to 1 percent of all intracranial tumors arise from the pineal region. Not only are they rare, but neoplasms of a great variety of histological types can occur and have been described. Some of the tumors arise from the pineal parenchymal cells. others from supportive tissues in and around the gland. The most frequently occurring pineal neoplasm, the germinoma, is derived presumably from misplaced germ cells, which are not a normal component of the pineal. In the past, the name pinealoma was used to designate this most common pineal growth, and the term ectopic pinealoma was used when it was found at other intracranial sites, such as the suprasellar region. As the histological similarity of the pinealoma to a common testicular neoplasm was recognized, the name atypical teratoma was proposed for the pineal tumor, to emphasize its relation to germ cell tumors. Eventually the name germinoma supplanted both previous terms as the similarity among this tumor, the testicular seminoma, and the ovarian dysgerminoma became well established. The classification of pineal neoplasms is based on this concept (Table 1).

Tumors of Germ Cell Origin

The hypotheses of origin, the classification, and considerations of the pathogenesis of this group of neoplasms in the context of extragonadal germ cell tumors have been thoroughly reviewed. These tumors are believed to arise from primordial germ cells that failed to migrate properly during the first few weeks of embryonic development. This explanation also accounts for the location of such neoplasms at other intracranial sites, most often in the suprasellar region, and extracranially in the midline of the body. The spectrum of tumors arising from the pineal site is similar to that of gonadal tumors of germ cell derivation and is outlined in a simplified form in Table -2. The concept of a common germ cell origin of these neoplasms is reinforced by the frequent finding of more than one histologic pattern in the same tumor.

Tumors of all types of germ cell origin occur predominantly in males and are most frequent in the first 3 decades, with a peak in the middle of the second decade, although no age group is totally immune. A similar age distribution exists for this group of neoplasms in the suprasellar region, but at the latter site the sexes are more equally affected.

The germinoma is the most common tumor of germ cell origin arising at the pineal site and accounts for more than 50 percent of all neoplasms at this location. An unusually high occurrence of germinomas is seen in Japan. where their incidence is reported to be 5.6 to 9 percent of all intracranial tumors, and 11 percent if only children are considered. The germinoma is extremely malignant and fast-growing but also highly radiosensitive. With therapy, about two-thirds or more of the patients survive for more than 5 years. Spinal cord metastases have been reported in 14 percent of patients with biopsy-proven germinoma. Extraneural haematogenous and shunt metastases have been reported rarely.

On gross examination the tumor is usually poorly circumscribed. At times the pineal mass is connected with a suprasellar tumor by continuous invasion of the walls of the third ventricle, so that it is not possible to be certain of its site of origin. The cut surface of the tumor is light gray, granular and usually solid. Haemorrhage, necrosis, grossly visible cysts and degeneration may be seen but are uncommon.

Microscopically the germinoma is composed of two cell types. There are islands and trabeculae of large round or polyhedral cells with well-defined cytoplasmic membranes. The cytoplasm may be clear or eosinophilic. The nuclei are prominent, round and rather vesicular, with some coarse peripherally clumped chromatin and one or more prominent nucleoli. Mitoses are variable. The large cells are separated by a fibrovascular stroma, which is infiltrated by lymphocytes, the majority of which have in a few cases been identified as T cells. The presence of inflammatory granulomas, complete with giant cells, is not as common in intracranial germinomas as it is in their extragonadal counterparts. However, if a granuloma is the sole finding of a needle biopsy, multiple sampling is essential to exclude germinoma. Microcysts containing proteinaceous fluid and also liquefaction necrosis have sometimes been described. Other tissue elements, such as glands with columnar epithelium, cartilage, squamous epithelium. and trophoblast, may be present. In about half of intracranial germinomas, immunoreactive syncytiotrophoblastic giant cells may be demonstrated and may be accompanied by an elevation of human chorionic gonadotropin (hCG) levels in cerebrospinal fluid (CSF) or serum. Such a finding does not seem to alter the prognosis.

Other closely related tumors of germ cell origin, the embryonal carcinoma, endodermal sinus tumor, and choriocarcinoma, are also highly malignant and tend to invade locally and to seed throughout the spinal fluid pathways. Rarely, extraneural metastases have been described in all the tumor types. Although mixtures of various elements of germ cell origin, including the germinoma, are often seen, purer forms also may occur. Unlike the germinoma, the tumors in this group are not radiosensitive but do respond to some chemotherapeutic agents. There are no specific features characteristic of each tumor type on gross inspection. Small and large cysts, necrosis, and haemorrhage may be apparent.

The embryonal carcinoma is the most primitive of these tumors. It is composed of cells of cuboidal or columnar epithelium growing in a glandular, tubular, or papillary pattern or in solid sheets. Focal differentiation into extraembryonic or embryonic structures may occur and can be responsible for the expression of alpha fetoprotein (AFP) of hCG in CSF, serum or urine or in tissue sections.

The endodermal sinus tumor, which is probably the most infrequent of this rare group is believed to represent extra­embryonic differentiation of the totipotential cell. Fewer than two dozen such pineal tumors have been reported in the literature. This tumor carries a poor prognosis. Several distinctive histologic patterns are described, consisting of reticular arrangement of primitive epithelial cells, communicating cavities and channels, papillary structures, solid areas and so-called Schiller-Duval bodies. The latter are characterized by the presence of delicate blood vessels surrounded by primitive columnar cells. lying in a space lined by flattened cells. Hyaline, eosinophilic, periodic acid-Schiff (PAS)-positive, diastase-resistant intra- and extracellular globules containing AFP and alpha-1 antitrypsin, respectively, are present and may be demonstrable by immunohistochemistry. Detectable levels of AFP may be measured in the serum, urine and CSF of affected patients.

The choriocarcinoma also is thought to represent extraembryonic differentiation of totipotential cells and most often is a component of another malignant germ cell neoplasm. In a review of 47 previously reported tumors, only 15 did not contain other germ cell components and more than one-third were associated with precocious puberty. This tumor is highly vascular and prone to haemorrhage, and is composed of cords of large, round cytotrophoblastic cells with clear cytoplasm surrounded by multinucleated syncytio­trophoblastic cells. hCG may be demonstrable in CSF, serum or urine or by immunohistochemistry in tissue sections.

The teratoma results from further differentiation of embryonic structures and contains the derivatives of all three germ layers. Like other tumors in this group, the pineal teratomas occur mainly in young males, most often in the first decade. Immature teratomas are more common, behave usually in a malignant manner and may disseminate intracranially.

Mature teratomas are grossly well defined and spherical or lobulated, generally remaining localized while compressing surrounding structures. The cut surface is variegated, and areas of cartilage, bone, or even teeth may be recognizable. Epidermoid or dermoid cysts are frequently seen and may contain fluid, hair, or keratinous material. Isolated instances of rupture of such cysts have been reported, with discharge of irritating materials into the CSF compartment.

Microscopically, any combination of tissue elements from the various germ cell layers may be identified. The presence of immature tissue components does not in itself denote malignancy. The teratomas that behave aggressively usually contain germ cell elements and less commonly may have a carcinomatous or sarcomatous component, such as rhabdomyosarcoma.

Tumors of Pineal Parenchyma

Approximately 20 percent of the pineal tumors are derived from the pineal parenchymal cells. About two-thirds of the affected patients are male. The neoplastic cells appear to possess the ability to differentiate along several lines, so that neurons, astrocytes, retinoblastomatous and sometimes even ectomesenchymal structures may be identified.

The pineal parenchymal neoplasms originate from pineocytes, which are the principal component of the pineal gland. Understanding and classification of these tumors are still evolving: Changes are made slowly as additional cases are observed and studied with modern techniques. The tumors form a spectrum that can be divided into three broad categories. About one-half of the neoplasms are pineoblastomas, and the other half are approximately equally divided between pineal parenchymal tumors with intermediate differentiation (PPT with intermediate differentiation), and pineocytomas. The pineoblastomas are tumors of primitive cells, are malignant, invade locally, and frequently disseminate throughout the spinal fluid pathway. The PPT with intermediate differentiation and the rare mixed pineal parenchymal tumors with elements of both pineoblastoma and pineocytoma are intermediate in frequency of spinal fluid seeding. The pineocytomas are the most differentiated neoplasms, grow slowly, are non­invasive, and remain localized. In view of accumulating data, it would seem appropriate to restrict the term pineocytoma to tumors with large pineocytomatous rosettes (previously thought to represent pineocytomas with neuronal differentiation) and to apply the term PPT with intermediate differentiation to the tumors with transitional cytology, between pineoblastomas and pineocytomas (previously classified as pineocytomas). In a small number of pineal parenchymal neoplasms, additional differentiation into retinoblastomatous structures, mature neurons, astrocytes, and even ectomesenchymal components has been described as outlined in Table-3.

The gross appearance of tumors of pineal parenchymal origin does not permit them to be distinguished from other pineal neoplasms. Although the benign forms remain circumscribed focal masses, the malignant types will invade locally and disseminate widely in the CSF compartment. Necrosis, cysts, and focal haemorrhages are not uncommon. The pineoblastoma is a highly cellular tumor with small, round to oval nuclei, variable numbers of mitoses. and ill-defined, wispy cytoplasm. The tumor resembles the medulloblastoma and Homer Wright rosettes, characterized by a circular arrangement of nuclei around a fibrillary center, may occasionally be seen. Focal haemorrhages and necrosis are frequent. Several additional features may be seen. In a small but well-documented number of cases, retinoblastomatous differentiation is recognized in the form of fleurettes and retinoblastoma (Flexner- Wintersteiner) rosettes. These structures represent abortive attempts at photo­receptor development. The fleurettes are believed to be more advanced and consist of a semicircular arrangement of columnar cells with terminal membranes through which project club-shaped processes. The Flexner-Wintersteiner rosettes are more primitive and are characterized by a circular arrangement of columnar cells with a distinct apical membrane.

Retinoblastomatous differentiation in tumors of pineal origin reflects the evolution of the pineal gland from a neurosensory photoreceptor organ. There is additional evidence of a close relation-ship between some pineal and retinal neoplasms. Some children with bilateral inherited retinoblastoma also develop a pineal tumor, a condition termed trilateral retinoblastoma. The tumor at the pineal site has the appearance of a pineoblastoma with or without retinoblastomatous components.

As in differentiated pineocytoma. glial and ganglionic differentiation has been observed in pineoblastomas. In one of two such tumors, retinoblastomatous features were present as well. More diverse neuroepithelial and ectomesenchymal differentiation has been observed in three pineoblastomas that exhibited combinations of retinoblastomatous, neuroblastic and neuronal elements, melanotic epithelium, striated muscle and cartilage. Such tumors are thought not to represent immature teratomas and the name pineal anlage tumor has been suggested to describe them. Alternatively, a relationship to tumors of ocular medullary epithelium has been proposed.

Isolated cases of pineoblastomas with the mosaic pattern of the developing pineal gland or presence of melanin pigment in pineoblastic cells have also been reported. The PPT with intermediate differentiation is a transitional form between pineoblastoma and pineocytoma. This tumor has a tendency toward lobular arrangement and better-defined cellular cytoplasmic processes, which may be directed toward blood vessel walls. Mitotic figures may or may not be present. Dissemination in CSF pathways is less frequent than in pineoblastoma.

Two mixed tumors with elements of pineocytoma and pineoblastoma have been described and classified with the tumors of intermediate differentiation. Neuronal and rarely astrocytic differentiation may also occur. In one of the two reported cases with astrocytic differentiation, the astrocytic component was malignant. Four pineal parenchymal tumors with a prominent papillary pattern probably belong in the category of PPT with intermediate differentiation. One patient, whose tumor invaded locally, died soon after diagnosis. The other three patients were alive without evidence of tumor dissemination at 3 years, 1.5 years, and 9 months after presentation.

The pineocytoma is composed of cells with small, round, benign-looking nuclei and ill-defined cytoplasm. The cells are arranged in groups and sometimes form large rosettes called pineocytomatous rosettes. Mitotic figures are absent. In a few cases, areas with large rosettes blend with a more variegated pattern of clearly recognizable ganglion cells and astrocytes, resembling a ganglioglioma.

Only limited numbers of pineal parenchymal tumors have been studied ultrastructurally. The tumors exhibit features of mammalian pineocytes and are composed of dark, clear cells with intra­ and extracellular vacuoles. Cytoplasmic organelles include clear and dense core vesicles, vesicle crowned rodlets, microtubules and microtubular sheaves, membranous whorls, fibrous bodies, and heterogeneous cytoplasmic inclusions. Electron microscopy may be useful in determining the degree of differentiation of pineal parenchymal tumors and hence the prognosis they carry. In a study of 17 neoplasms, dendritic processes with microtubules. dense core granules, and clear vesicles were characteristic of the pineocytomas. The dendritic processes were short in tumors with intermediate differentiation and abortive in the 3 pineoblastomas studied.

Experience with tumor markers in diagnosis and monitoring of pineal parenchymal neoplasms has been limited. In addition to assays of melatonin and HIOMT in serum and CSF measurement of another immunoreactive substance, S-antigen, holds promise. S-antigen is a 48-kDa protein found in retinal photoreceptors and pineocytes. It is also present in some pineal parenchymal tumors, retinoblastomas, and medulloblastomas and has been demonstrated in the CSF of a patient with a pineocytoma.

The histologic diagnosis of pineal parenchymal tumors has traditionally depended on the somewhat cumbersome Achucarro­Hortega silver carbonate method modified by DeGirolami and Zvaigzne. Although no specific immunohistochemical stain for pineal parenchymal cells exists, expression of nonspecific enolase and synaptophysin has been demonstrated in pineocytomas. S-antigen reactivity may sometimes be present in pineal parenchymal neoplasms. Astrocytes can be demonstrated with the glial fibrillary acidic stain.

Pineal parenchymal tumors can occur at any age. Pineoblastoma tends to be seen in younger individuals, and pineocytoma in older individuals. The PPT with intermediate differentiation tends to spare infants and young children. In a recent series of 30, the median age of patients with pineoblastoma was 18 years (range, 11 months to 66 years), the median age of patients with PPT with intermediate differentiation was 32 years (range, 8 to 77 years), and the median age of patients with pineocytoma was 36 years (range, 17 to 72 years).

Survival figures for patients with pineal parenchymal tumors are difficult to assess because of their rarity. A variety of therapeutic modalities have been applied, ranging from combinations of surgical procedures that have recently improved remarkably to additional radiation therapy, sometimes combined with chemotherapy. For patients treated after 1950, projected 5-year survival rates from the Mayo Clinic were 58 percent for pineoblastoma and PPT with intermediate differentiation and mixed types, all of which can seed, and 67 percent for the non-disseminating pineocytoma.

Tumors of Glial and Other Cell Origin

A great variety of neoplasms have been reported to have originated in the pineal gland in rare instances. The occasional tumors of glial origin that arise at the pineal site are derived either from astrocytes present normally in the gland or from elements of the intimately related surrounding brain tissues. Astroblastoma, astrocytoma, glioblastoma, ependymoma, oligodendroglioma, choroid plexus papilloma, and medulloepithelioma have been identified. All histologic subtypes of meningioma have also been described. These are thought to arise from the velum interpositum in the roof of the third ventricle, the junction of the falx and tentorium to which they may be attached, or possibly the connective tissue of the pineal gland itself. Other even rarer findings are paraganglioma, hemangiopericytoma, hemangioma, lipoma, and craniopharyngioma. Involvement of the pineal gland by metastases from disseminated malignant neoplasms has been reported infrequently. In one series of autopsies of 130 such patients, pineal tumor was present in five, and only in three was the tumor grossly visible.

Non-Neoplastic Cysts and Masses

Small cysts, usually containing gelatinous material, are seen in up to 40 percent of pineal glands at routine autopsy. Rarely, such cysts become large enough to produce a mass effect. Focal degeneration of the pineal parenchyma or distention of an obliterated portion of the pineal diverticulum has been postulated as their source. In a recent series of 53 patients with non-neoplastic pineal cysts identified with magnetic resonance imaging (MRI), obstructive hydrocephalus was present in five patients, three of whom also had Parinaud's syndrome. Obstruction was seen only with cysts larger than 2 cm in anteroposterior diameter. Most patients were in the third to fourth decade, and there were three times as many women as men. Microscopically, the cysts are composed of an inner layer of astroglial tissue in which Rosenthal fibers may be prominent; a middle layer of normally lobulated pineal parenchyma, often with prominent calcospherites; and an outer layer of thin, discontinuous fibrous tissue. There may be evidence of prior haemorrhage. Proper orientation of the surgical specimen is essential to prevent misdiagnosis of a low-grade astrocytoma or well-differentiated pineal parenchymal neoplasm.

Epidermoid cysts at the pineal site are usually a part of teratoma, although rare instances without a demonstrable teratomatous component are recognized. Other rare lesions at the pineal site include arachnoid cyst, cysticercus lesions, sarcoid without any systemic manifestations, tuberculoma, and syphilitic gumma.

Behaviour and Complications of Pineal Neoplasms

Tumors in the pineal region, like tumors elsewhere, may form a local mass, extend directly to surrounding structures, or metastasize to distal sites. Although in most instances the pineal gland is enlarged or even obliterated by the neoplasm, occasionally there may be only slight change in its size, even while the tumor has spread extensively. Sometimes the pineal gland is spared altogether as the tumor arises in the parapineal region. Usually early in the course of the disease the aqueduct of Sylvius is compressed, with a consequent increase in intracranial pressure. The neoplasm may compress or infiltrate the tectum of the mid­brain, extend into the third ventricle and hypothalamus, and invade infratentorially into the posterior fossa. Dissemination of neoplastic cells throughout the subarachnoid compartment can result in cranial nerve palsies and masses in the distal neuraxis. Extracranial metastases are rare but may occur, usually after surgical intervention. They have been described in tumors of both germ cell and pineal parenchymal cell origin. The tumor disseminates by the haematogenous route, appearing in lungs or other organs. Occasional shunt metastases also have been reported. An uncommon but catastrophic complication is massive haemorrhage into a pineal tumor or cyst, which may be accompanied by subarachnoid extension of the blood.

The importance of arriving at a precise histologic diagnosis of each pineal tumor cannot be emphasized enough, since these tumors differ in their biological behaviour and response to various modes of therapy.