Early descriptions of the pineal gland

The pineal gland has been the subject of human inquiry for thousands of years. The name itself is derived from the Latin word, pinealis, with pinea meaning pinecone, a reference to the shape of the gland because it hangs from the posterior roof of the third ventricle. It has also been referred to as the epiphysis (“that which grows on something”) as well as the konareion (meaning in Greek, “the cone of the pine tree”). In much of the Latin literature, it has been referred to as turbo, corpus turbinatus, glandula turbinate, glandula piniformis, glandula conoides, conariumm, penis cerebri, corpus pineale, and virga cerebri. In the German literature, it is referred to as Zirbel and Zirbeldrüse.

Interest in the pineal gland can be traced as far back as ancient China during the reign of the Yellow Emperor (2697–2597 bc ). In the ancient Hindu scriptures, the Vedas , a collection of religious teachings of ancient India, the pineal gland was 1 of the 7 chakra points, or centers of vital energy. Specifically, the pineal gland was considered the “supreme or crown chakra…the ultimate center of spiritual force.”

The Greek physician and philosopher, Aelius Galenus (130–200 ad ), better known as Galen of Pergamon ( Fig. 1 ), credits Herophilus (325–280 bc ) as the first to discover the pineal gland. Herophilus, a Greek physician at the University of Alexandria in Egypt, is considered the first person to have systematically performed scientific dissections of cadavers, recording his findings in 9 volumes. Herophilus asserted that the pineal gland was a valve or sphincter controlling the flow of pneuma from the third to the fourth ventricles. Pneuma was considered the fine substance derived from air and responsible for thought ( psycikon , in Greek) and organic movement.

Galen; lithograph by Pierre Roche Vigneron (Paris: Lith de Gregoire et Deneux, approximately 1865).

( Courtesy of History of Medicine Division, National Library of Medicine.)

Galen himself did not entertain such respect for the pineal gland, considering it merely a supporting structure for the deep venous structures/internal cerebral veins. In his writings, he scoffs at Herophilus’ ideas on the pineal gland :

The notion that the pineal body is what regulates the passage of the pneuma is the opinion of those who are ignorant of the action of the vermiform epiphysis [vermis superior cerebelli] and who give more than due credit to this gland.

Galen found Herophilus’ hypothesis of the pineal gland’s function as a valve to control flow of pneuma laughable. In the eighth book of his anatomic works, De Usu Partim (On The Usefulness of the Parts of the Body) , he asserts that the external nature of the gland with respect to the interventricular space meant it could have no such role. Galen advocated that it was the vermis of the cerebellum that regulated the passage of pneuma from the third to the fourth ventricle. Galen’s view went unchallenged throughout the Medieval Period. Not until the fifteenth century was the pineal gland re-examined. During the Renaissance, Andreas Vesalius (1514–1564), the father of modern anatomy, topographically mapped the pineal gland and discussed the relevant anatomy in De Humani Corporis Fabrica, Libri Septem (On the Fabric of the Human Body) , first published in 1543. In regards to possible pineal function, he agreed with Galen’s viewpoint of the insignificance of the gland due to its exterior location. During the same time, Niccolò Massa (1485–1569), an Italian anatomist, in 1536 proved that the ventricles were not filled with pneuma but with liquor cerebro-spinalis, or the cerebrospinal fluid.

The Pineal Gland—The Seat of the Soul?

In the seventeenth century the French logician and philosopher, René Descartes (1596–1650) ( Fig. 2 ), a contemporary of Vesalius, studied and wrote extensively on the pineal gland. Descartes, although widely known for his work in mathematics and philosophy, was no stranger to human anatomy. To the pineal gland he gave the unique distinction of “the seat of man’s soul.” The first description of the pineal in his works is documented in Dioptrics (1637) as a small gland (or the conarion ) in the middle of the ventricles, the seat of the sensus communis (the general faculty of the senses). He maintained the pineal gland was the organ that allowed the res cogitans (spirit or anima) to maintain contact with the res extensa (the material body ). In his Les Passions de l’Âme (The Passions of the Soul) , from 1649, he writes, “Although the soul is joined with the entire body, there is one part of the body [the pineal] in which it exercises its function more than elsewhere…”

René Descartes; oil painting by Frans Hals, 1649; in the Louvre, Paris.

( Courtesy of Cliché Musées Nationaux, Paris.)

In Descartes’ philosophy, the pineal body was the medium between the soul and the body. Descartes argued that the pineal gland served as a filter that accumulated espirits animaux (animal spirits) from the blood. This spirit was then distributed through tiny pores in the ventricular walls to nerves attached to motor nerves based on the movement of the pineal gland. Information received from the eyes and optic nerves was passed along to the pineal gland along the ventricular pores and used as input corresponding to resultant pineal gland motor output ( Fig. 3 ). In L’ Homme (Treatise of Man) , he explains his reasoning for why the pineal is the seat of the soul. He believed it was the only structure in the entire brain that was not duplicated. He notes that the pineal is small, light, and easily movable and even though the other gland (ie, the pituitary) is also small and undivided, it is immobile and located outside the brain. Using the same analogy, he said that Galen’s vermian appendage was not a suitable candidate because it had 2 halves.

( A ) René Descartes’ L’Homme (Treatise of Man) . Published in 1664, posthumously, by Descartes’ self-appointed literary executor, Claude Clerselier. ( B ) A drawing from René Descartes’ L’Homme , showing the pineal gland (H) as the link between visual stimuli and resulting action.

( Courtesy of Historical Collections & Services, Claude Moore Health Sciences Library, University of Virginia.)

Other scientists of the Renaissance also held unique views on pineal function. François Magendie (1783–1855), a French physiologist, advocated that the pineal gland itself acts like a tampon, designed to expand or shrink and in this way close off or open the aqueduct of Sylvius. Gunz (1753) attributed dementia to impeding flow of the spirits caused by the pineal body.

By the early to mid-nineteenth century, the relatively new field of comparative anatomy was emerging. Scientists compared structures in the human body with those found in various classes of the animal kingdom, including vertebrates and nonvertebrates. Ahlborn and Rabl-Rückhardt (1839–1906), both accomplished comparative anatomists, pointed out the similarity between the nonmammalian pineal gland and the primary optic vesicles. Other scientists, including De Graaf and Korschelt and Spencer, described the reptilian and amphibian epiphysis as a unique photosensory organ, whose function regressed and became vestigial in mammals.

Its role as a third eye in nonmammals sparked an immense scientific output on its possible role in humans but also led to an important role in religious thought. An example of this is from Helena Blavatsky (1831–1891), the founder of theosophy. She advocated the ancient Hindu concept of the third eye of Shiva, the ambaka, through which communication in humans is done. For Madame Blavatsky, humans received this divine inspiration not through a figurative third eye but literally through the pineal gland itself. It was an “organ of spiritual vision.”

Greater understanding of the pineal was made with the advancement in the field of microscopic histology. Kölliker in 1888 demonstrated that the pineal gland was mainly composed of 2 type of cells—the small round cells and the multipolar nerve cells with the compact bundle of nerve cells. Perhaps the greatest leap forward in understanding the pineal gland came from Studnicka in first decade of the twentieth century. He pushed forward the hypothesis that the pineal body had glandular function based on the activity of its nonmammalian well-developed counterpart. Within the mammalian pineal gland, he distinguished the pinealocyte from the neuroglial cells, suggesting that the vesicles and granules present within the pinealocyte hinted at their secretory activity. Studnicka’s claims were taken with all the more seriousness once the first case reports emerged at the end of the nineteenth century, suggesting a relation between a boy with a pinealoma and precocious puberty. Cajal thought that the nerve fibers in the pineal body are sympathetic and the body itself a vascular gland. Marburg, during the first decade of the twentieth century, advanced the principle of the pineal gland regulating hormonal cycles. Having coined the term, pubertas praecox (precocious puberty), he explained that this occurred due to hypopinealism or destruction of pineal glandular tissue by a tumor, such as a pinealoma. Likewise, Marburg hypothesized that hyperpinealism resulted in slow and incomplete development of the reproductive organs. Other researchers even touted the use of pineal gland extract for antigonadotropic purposes.

This view, however, was largely discounted in the 1930s and 1940s, as researchers understood more about the structure and function of the hypothalamus. It was observed that pinealomas affected sexual development not intrinsically but through mechanical force on specific hypothalamic centers. In the 1940s further research continued with Bargmann’s landmark article describing the anatomy and histology of the pineal gland as well as commenting on external and internal factors, which could induce changes in pineal function. Specifically, and importantly, he mentioned the need for further research for the influence of light on pineal secretions. Bargmann also suggested the pineal to not only have hormonal input and output but also neural input and output.

During World War II (1940s), with the advent of the electron microscope, the mammalian pineal gland was confirmed as having neurosecretory cells, named pinealocytes, and supporting glial cells. The visualization of the endoplasmic reticulum and dense core vesicles also revealed more about the pineal’s secretory functions.

Pineal tumors

The understanding of the pineal gland’s function over time was tied in a large part to the pathology encountered and reported in the literature.

Charles Drelincourt (1633–1697), a French physician, was the first to report a case of pineal tumor in the seventeenth century. As reported by Magnet in a book published in Geneva in 1717, Drelincourt encountered a 20-year-old woman with a hardened pineal gland found the size of “a fowl’s egg.”

Giovanni Battista Morgagni (1682–1771), an Italian anatomist and the father of modern anatomic pathology, also recorded cases of various patients with enlarged pineal glands. In his famous compendium of pathology, The Seats and Causes of Disease , published in 1761, he went into a discussion on the calcified pineal gland and reported on a patient with a calcified gland the size of an egg.

Gilbert Blane (1749–1834), a Scottish physician, was the first in the English-speaking to report a pineal tumor. He served as physician of the British fleet for more than 35 years and was known for his efforts in instituting the mandatory use of lemon juice to prevent scurvy. He reported on a pineal tumor in a 36-year-old naval officer. The tumor was found to press down on the cerebellum, resulting in excruciating pain and eventual delirium.

Throughout the nineteenth century, other case reports emerged on tumors of the pineal region but little could be reported in regards to histology because microscopic tissue examination had yet to be perfected. Only gross pathology could be described, resulting in various inaccurate names given to pineal tumors, including adenomas, carcinomas, sarcoma, and gliomas.

In 1883, the French ophthalmologist, Henri Parinaud (1844–1905), described a syndrome characterized by supranuclear paralysis of vertical gaze seen in 10 of his patients. He was unable, however, to accurately pinpoint the anatomic location responsible for the syndrome. Parinaud syndrome is thought to be caused by the compression of the mesencephalic tectum by an enlarging pineal mass.

The first pineal tumor correctly identified and studied was the teratoma. Karl Weigert (1845–1904), a German pathologist from Breslau, is credited with correctly identifying its gross and microscopic histology. In 1875, Weigert reported on a 14-year-old boy with a pineal teratoma, which histologically consisted of squamous and columnar epithelium along with hair and skin.

In 1896, Richard Gutzeit first commented on a possible relationship between the pineal teratoma and endocrine abnormalities. In his dissertation for his Doctor of Medicine degree, he described a 7-year-old boy with unusually large and developmentally mature external genitalia and a concurrent pineal teratoma. In 1899, 2 further articles reported on the peculiar association between precocious puberty and pineal teratomas. The second article was presented at a Pathologic Society of London meeting.

By 1909, the relationship between precocious puberty and pineal tumors, in particular the teratoma, was established. Two articles were crucial in this regard. Lothar von Frankl-Hochwart (1872–1914), a distinguished neurologist from Vienna, presented a case report of a pineal teratoma and thoroughly discussed its relation with precocious puberty. In 1910, Giovanni Pellizzi of Pisa, Italy, reported on precocious genital development with a pineal tumor, which came to be referred to as Pellizzi syndrome, in a 2-part article in an Italian journal. Not only was precocious puberty described in relation to pineal teratomas but also hypogonadism discussed. The first case report discussing this was by Max Neumann of Karlsruhe in 1901.

In the late nineteenth and early twentieth centuries, terms for pineal tumors had been borrowed from histologic variants of tumors they resembled in other parts of the body. Knud H. Krabbe (1885–1965), a Danish neurologist from Copenhagen, in his landmark thesis, Histologic Studies of the Pineal Body , published in 1912, was the first to use the word the word, pinealoma . His extensive study and dissection of more than 400 human postmortem pineal glands led him to conclude that the normal gland was composed of essentially 2 cell lines—special pineal cells and neuroglial cells. In general, the term pinealoma was intended to be used for a generic pineal mass. The technical limitations of the era led many scientists to falsely conclude the tumors were all of pineal parenchymal origin.

Gilbert Horrax (1887–1957), an American neurosurgeon, and Percival Bailey (1892–1973), an American neuropathologist, neurosurgeon, and psychiatrist, in 1925 subdivided pineal tumors into 2 groups. Their first group had 11 cases of a tumor cell type that resembled the adult pineal parenchymal cells. This group was entitled, pinealomas, as Krabbe had proposed. The second group consisted of 2 cases of teratomas. The following year Bailey and Harvey Cushing (1869–1939) subdivided the first group into pineoblastomas and pinealomas. They observed that the pinealoblastoma resembled a cerebellar medulloblastoma, a tumor they first described 2 years previously in 1924. Pinealoblastomas were described as rapidly growing tumors of the pineal body consisting of primitive glial cells or spongioblasts. Pinealomas, in contrast, were described as made of large spherical cells with processes ending in bulbs. The newly named pinealoblastoma was quickly accepted by other pathologists, including Russell and Rubinstein and Ziilch.

The second tumor, pinealoma, however, had controversy surrounding its exact classification and histopathologic structure. Bailey had originally described the tumor as composed of neoplastic pineal parenchymal cells and lymphoid cells in a fibrovascular stroma.

Joseph Globus (1885–1952) of Mount Sinai Hospital, New York, agreed with Bailey but asserted the lymphoid cells were also neoplastic. He considered the tumor an “autochthonous teratoid of bidermal origin.” In a differing point of view, Dorothy H. Russell of London Hospital felt the tumors were atypical teratomas —a term once used to describe testicular teratomas. Nathan B. Friedman of the US Armed Forces Institute of Pathology in Washington, DC, agreed with Russell. He was convinced that histopathologically the tumor was similar if not identical to the seminoma of the testes, dysgerminoma of the ovaries, and extragonadal germinomas. For this group of similar tumors, whether they were genital or extragenital in location, he coined the term, germinoma . Thus, for more than 30 years the term pinealoma was used for the most common pineal tumor, today known as the germinoma.

Eventually, by the 1970s, it had been documented that all varieties of germ cell tumors had the potential to be found in the pineal region. Although germinomas and teratomas are the most prevalent, choriocarcinoma, yolk sac tumor, and embryonal carcinoma have all been found.

The term, pinealoma, was found to cause confusion and after Friedman introduced the term, germinoma, pinealoma fell out of favor. A new term was needed to describe well-differentiated pineal parenchymal tumors. In 1933, the term, pineocytoma , was conferred on a “better differentiated pinealocytic tumor” by Pio del Rio-Hortega (1882–1945) of Buenos Aires. By 1959, Russell and Rubinstein adopted pineocytoma for a “differentiated pineal parenchymal neoplasm” in their textbook. They also explicitly demonstrated the relationship between rosette formations and pineocytomas. Later, other investigators went further and differentiated pineocytomas into 2 categories, including a pure, monomorphic variant composed of confluent pineocytomatous rosettes and the more common mixed pineocytomas with pineocytomatous rosettes and “neoplastic ganglion and glial cells.”

Russell and Rubinstein’s textbook, Pathology of Tumors of the Nervous System , became the standard for the classification of pineal tumors. They divided pineal masses into 4 broad categories: tumors of germ cell origin (germinomas and teratomas), tumors of pineal parenchymal cells (pineoblastomas and pineocytomas), tumors of glial and other cell origin, and non-neoplastic cysts and masses.

Pineal tumors

The understanding of the pineal gland’s function over time was tied in a large part to the pathology encountered and reported in the literature.

Charles Drelincourt (1633–1697), a French physician, was the first to report a case of pineal tumor in the seventeenth century. As reported by Magnet in a book published in Geneva in 1717, Drelincourt encountered a 20-year-old woman with a hardened pineal gland found the size of “a fowl’s egg.”

Giovanni Battista Morgagni (1682–1771), an Italian anatomist and the father of modern anatomic pathology, also recorded cases of various patients with enlarged pineal glands. In his famous compendium of pathology, The Seats and Causes of Disease , published in 1761, he went into a discussion on the calcified pineal gland and reported on a patient with a calcified gland the size of an egg.

Gilbert Blane (1749–1834), a Scottish physician, was the first in the English-speaking to report a pineal tumor. He served as physician of the British fleet for more than 35 years and was known for his efforts in instituting the mandatory use of lemon juice to prevent scurvy. He reported on a pineal tumor in a 36-year-old naval officer. The tumor was found to press down on the cerebellum, resulting in excruciating pain and eventual delirium.

Throughout the nineteenth century, other case reports emerged on tumors of the pineal region but little could be reported in regards to histology because microscopic tissue examination had yet to be perfected. Only gross pathology could be described, resulting in various inaccurate names given to pineal tumors, including adenomas, carcinomas, sarcoma, and gliomas.

In 1883, the French ophthalmologist, Henri Parinaud (1844–1905), described a syndrome characterized by supranuclear paralysis of vertical gaze seen in 10 of his patients. He was unable, however, to accurately pinpoint the anatomic location responsible for the syndrome. Parinaud syndrome is thought to be caused by the compression of the mesencephalic tectum by an enlarging pineal mass.

The first pineal tumor correctly identified and studied was the teratoma. Karl Weigert (1845–1904), a German pathologist from Breslau, is credited with correctly identifying its gross and microscopic histology. In 1875, Weigert reported on a 14-year-old boy with a pineal teratoma, which histologically consisted of squamous and columnar epithelium along with hair and skin.

In 1896, Richard Gutzeit first commented on a possible relationship between the pineal teratoma and endocrine abnormalities. In his dissertation for his Doctor of Medicine degree, he described a 7-year-old boy with unusually large and developmentally mature external genitalia and a concurrent pineal teratoma. In 1899, 2 further articles reported on the peculiar association between precocious puberty and pineal teratomas. The second article was presented at a Pathologic Society of London meeting.

By 1909, the relationship between precocious puberty and pineal tumors, in particular the teratoma, was established. Two articles were crucial in this regard. Lothar von Frankl-Hochwart (1872–1914), a distinguished neurologist from Vienna, presented a case report of a pineal teratoma and thoroughly discussed its relation with precocious puberty. In 1910, Giovanni Pellizzi of Pisa, Italy, reported on precocious genital development with a pineal tumor, which came to be referred to as Pellizzi syndrome, in a 2-part article in an Italian journal. Not only was precocious puberty described in relation to pineal teratomas but also hypogonadism discussed. The first case report discussing this was by Max Neumann of Karlsruhe in 1901.

In the late nineteenth and early twentieth centuries, terms for pineal tumors had been borrowed from histologic variants of tumors they resembled in other parts of the body. Knud H. Krabbe (1885–1965), a Danish neurologist from Copenhagen, in his landmark thesis, Histologic Studies of the Pineal Body , published in 1912, was the first to use the word the word, pinealoma . His extensive study and dissection of more than 400 human postmortem pineal glands led him to conclude that the normal gland was composed of essentially 2 cell lines—special pineal cells and neuroglial cells. In general, the term pinealoma was intended to be used for a generic pineal mass. The technical limitations of the era led many scientists to falsely conclude the tumors were all of pineal parenchymal origin.

Gilbert Horrax (1887–1957), an American neurosurgeon, and Percival Bailey (1892–1973), an American neuropathologist, neurosurgeon, and psychiatrist, in 1925 subdivided pineal tumors into 2 groups. Their first group had 11 cases of a tumor cell type that resembled the adult pineal parenchymal cells. This group was entitled, pinealomas, as Krabbe had proposed. The second group consisted of 2 cases of teratomas. The following year Bailey and Harvey Cushing (1869–1939) subdivided the first group into pineoblastomas and pinealomas. They observed that the pinealoblastoma resembled a cerebellar medulloblastoma, a tumor they first described 2 years previously in 1924. Pinealoblastomas were described as rapidly growing tumors of the pineal body consisting of primitive glial cells or spongioblasts. Pinealomas, in contrast, were described as made of large spherical cells with processes ending in bulbs. The newly named pinealoblastoma was quickly accepted by other pathologists, including Russell and Rubinstein and Ziilch.

The second tumor, pinealoma, however, had controversy surrounding its exact classification and histopathologic structure. Bailey had originally described the tumor as composed of neoplastic pineal parenchymal cells and lymphoid cells in a fibrovascular stroma.

Joseph Globus (1885–1952) of Mount Sinai Hospital, New York, agreed with Bailey but asserted the lymphoid cells were also neoplastic. He considered the tumor an “autochthonous teratoid of bidermal origin.” In a differing point of view, Dorothy H. Russell of London Hospital felt the tumors were atypical teratomas —a term once used to describe testicular teratomas. Nathan B. Friedman of the US Armed Forces Institute of Pathology in Washington, DC, agreed with Russell. He was convinced that histopathologically the tumor was similar if not identical to the seminoma of the testes, dysgerminoma of the ovaries, and extragonadal germinomas. For this group of similar tumors, whether they were genital or extragenital in location, he coined the term, germinoma . Thus, for more than 30 years the term pinealoma was used for the most common pineal tumor, today known as the germinoma.

Eventually, by the 1970s, it had been documented that all varieties of germ cell tumors had the potential to be found in the pineal region. Although germinomas and teratomas are the most prevalent, choriocarcinoma, yolk sac tumor, and embryonal carcinoma have all been found.

The term, pinealoma, was found to cause confusion and after Friedman introduced the term, germinoma, pinealoma fell out of favor. A new term was needed to describe well-differentiated pineal parenchymal tumors. In 1933, the term, pineocytoma , was conferred on a “better differentiated pinealocytic tumor” by Pio del Rio-Hortega (1882–1945) of Buenos Aires. By 1959, Russell and Rubinstein adopted pineocytoma for a “differentiated pineal parenchymal neoplasm” in their textbook. They also explicitly demonstrated the relationship between rosette formations and pineocytomas. Later, other investigators went further and differentiated pineocytomas into 2 categories, including a pure, monomorphic variant composed of confluent pineocytomatous rosettes and the more common mixed pineocytomas with pineocytomatous rosettes and “neoplastic ganglion and glial cells.”

Russell and Rubinstein’s textbook, Pathology of Tumors of the Nervous System , became the standard for the classification of pineal tumors. They divided pineal masses into 4 broad categories: tumors of germ cell origin (germinomas and teratomas), tumors of pineal parenchymal cells (pineoblastomas and pineocytomas), tumors of glial and other cell origin, and non-neoplastic cysts and masses.