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Hortegas Research Paper

Pío del Río Hortega and the discovery of the oligodendrocytes

Fernando Pérez-Cerdá,*María Victoria Sánchez-Gómez, and Carlos Matute

Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain

Edited by: Fernando De Castro, Hospital Nacional de Parapléjicos-SESCAM, Spain

Reviewed by: Rafael Lujan, Universidad de Castilla-La Mancha, Spain; James C. Vickers, University of Tasmania, Australia

*Correspondence: Fernando Pérez-Cerdá, Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa 48940, Spain sue.uhe@zerep.odnanref

Author information ►Article notes ►Copyright and License information ►

Received 2015 May 6; Accepted 2015 Jun 25.

Copyright © 2015 Pérez-Cerdá, Sánchez-Gómez and Matute.

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Abstract

Pío del Río Hortega (1882–1945) discovered microglia and oligodendrocytes (OLGs), and after Ramón y Cajal, was the most prominent figure of the Spanish school of neurology. He began his scientific career with Nicolás Achúcarro from whom he learned the use of metallic impregnation techniques suitable to study non-neuronal cells. Later on, he joined Cajal’s laboratory. and Subsequently, he created his own group, where he continued to develop other innovative modifications of silver staining methods that revolutionized the study of glial cells a century ago. He was also interested in neuropathology and became a leading authority on Central Nervous System (CNS) tumors. In parallel to this clinical activity, del Río Hortega rendered the first systematic description of a major polymorphism present in a subtype of macroglial cells that he named as oligodendroglia and later OLGs. He established their ectodermal origin and suggested that they built the myelin sheath of CNS axons, just as Schwann cells did in the periphery. Notably, he also suggested the trophic role of OLGs for neuronal functionality, an idea that has been substantiated in the last few years. Del Río Hortega became internationally recognized and established an important neurohistological school with outstanding pupils from Spain and abroad, which nearly disappeared after his exile due to the Spanish civil war. Yet, the difficulty of metal impregnation methods and their variability in results, delayed for some decades the confirmation of his great insights into oligodendrocyte biology until the development of electron microscopy and immunohistochemistry. This review aims at summarizing the pioneer and essential contributions of del Río Hortega to the current knowledge of oligodendrocyte structure and function, and to provide a hint of the scientific personality of this extraordinary and insufficiently recognized man.

Keywords: Del Río Hortega, myelin sheath, oligodendroglia, oligodendrocyte precursor cell (OPC), Ramón y Cajal

Biographical Sketch of Del Río Hortega

Pío del Río Hortega (1882–1945) was, with the exception of Ramón y Cajal, the most prominent figure of the Spanish school of neurology (Andres-Barquin, 2002; Pasik and Pasik, 2004; De Carlos and Pedraza, 2014). He revolutionized the study of neuroglia by developing and improving metallic impregnation techniques that he applied to the study of the group of non-astrocytic cells. These cells were poorly stained with the methods available at that time, and were known after Ramón y Cajal as the “third element” of Central Nervous System (CNS), neurons and astrocytes being the “first and second element”, respectively (Ramón y Cajal, 1913a). With the staining tools he developed, Del Río Hortega was able to identify two kinds of cells and to unveil their origin: microglia, the true “third element” due to its mesodermic origin; and oligodendroglia, included with astrocytes as second element due to their shared ectodermal origin (Del Río Hortega, 1918, 1920, 1924).

Pío del Río Hortega studied Medicine (1899–1905) and even as a student, he committed himself to follow a career in research which was focused on neurohistology and pathology all his professional life (exhaustively reviewed in Cano-Díaz, 1985; Del Río Hortega, 1986; López-Piñero, 1990). With some delay but with an enormous capacity for sustained hard work, he began his postdoctoral training in 1911, in Nicolás Achúcarro’s laboratory in Madrid (Spain), the year after. Achúcarro was Del Río Hortega’s true mentor and inculcated in him a deep interest in neuroglia before he worked in several European laboratories for short periods. After finally returning to Spain in 1914, he had the opportunity to share scientific interests with Ramón y Cajal, to whom he always felt great admiration, since Cajal’s and Achúcarro’s laboratories were located in the same building though each did independent research. Following closely in Achúcarro footsteps, and stimulated by Cajal’s third element, Del Río Hortega, now working full time in the laboratory, began to search for more stable variations of Cajal’s and Achúcarro’s metallic impregnation methods to study this cell class (reviewed in Castellano-López and González-de Mingo, 1995). In that fertile scientific environment, Del Río Hortega made numerous adjustments to the staining procedures which accounted for more than one hundred variations by the end of his career.

After developing modifications of Achúcarro’s ammoniacal silver method (Del Río Hortega, 1916), Del Río Hortega challenged the accuracy of Ramón y Cajal’s concept about the third element of CNS which grouped non neuronal (first element) and non-astrocytic (second element) cells (Ramón y Cajal, 1913b, 1916; García-Marín et al., 2007). Later, he described his silver carbonate staining technique which was the methodological key to identify two distinct elements: the microglia, the “true third element”, and what he called initially “interfascicular cells” and later oligodendroglia (Del Río Hortega, 1918, 1920, 1921). Ramón y Cajal and others were not convinced particularly regarding the existence of oligodendroglia (reviewed in Pasik and Pasik, 2004). Perhaps, this skepticism delayed the immediate acceptance of these cells, and contributed to a misunderstanding between the two scientists which ended up with the dismissal of Del Río Hortega from Cajal’s laboratory in 1920 and his move to a new one, promoted in some ways by Ramón y Cajal himself. He was aware of Del Río Hortega talent as researcher and although they never worked again together, their relationship improved later on.

Once in his own laboratory, Del Río Hortega continued frantically with his investigations and created an important school with outstanding pupils from Spain and abroad. Among them was Penfield, who greatly supported and replicated the results of Del Río Hortega, and thus, contributed to the international recognition of Del Río Hortega’s discovery of oligodendroglia (Penfield, 1924; Gill and Binder, 2007). This intense activity was favored by the commitment of the Spanish Government of that time to guarantee high standards in science, an atmosphere that helped Del Río Hortega to develop a well equipped Laboratory of Histology and Pathology, as he named it (Andres-Barquin, 2002; De Carlos and Pedraza, 2014). At the same time, Del Río Hortega himself was an active advocate of science both within and outside of the academic circles. Del Río Hortega became internationally recognized for his contributions to the understanding of glia in the healthy nervous system and also in disease, mainly in cerebral tumors. Unfortunately, the Spanish civil war (1936–1939) forced him into exile which interrupted the development of his school, though he strived to keep it alive in the midst of difficulties while working abroad in Oxford and Buenos Aires (reviewed in Cano-Díaz, 1985; López-Piñero, 1990).

Silver Carbonate Staining Method of Del Río Hortega

All along his career, del Río Hortega had a great interest in improving metallic impregnation techniques to advance the characterization of neural cells (reviewed in Castellano-López and González-de Mingo, 1995; Pasik and Pasik, 2004). He developed new modifications to the Achúcarro’s ammoniacal silver staining (Del Río Hortega, 1916), applied Cajal’s formol uranium nitrate and gold chloride sublimate methods (Ramón y Cajal, 1913b, 1916), as well as the Golgi’s method. This array of techniques gave him and those who used them, an almost complete picture of the morphology of the protoplasmic and fibrous astrocytes (FAs), cells known as the second element of the CNS, neurons being the first element. However, these methods did not stain the remaining cell types of the CNS which were termed by Ramón y Cajal as the third element which in his own words was composed solely of “corpuscles without processes” grouping adendritic, apolar dwarf cells that were present in white matter, perineuronally and as perivascular satellites (Ramón y Cajal, 1913a, 1916; García-Marín et al., 2007).

The identification of these cells was possible when Del Río Hortega described a method of using silver carbonate to stain glial cells (Del Río Hortega, 1918) with precise timing of the formalin-ammonium bromide fixative introduced by Ramón y Cajal (1913b). Del Río Hortega never explained how (i.e., a mistake, an intuition, or a test) he happened to introduce lithium carbonate with silver nitrate to precipitate it as silver carbonate (Del Río Hortega, 1918), but it could be said that in the best Cajalian tradition, he doggedly tried modification after modification of methods to selectively stain cell types. His discovery provided Del Río Hortega with a new tool to transform morphological and physiological concepts of the CNS. For the first time, this method clearly distinguished two cells types with distinct cytoplasmic expansions in the previously so-called third element group, which Del Río Hortega termed microglia and oligodendroglia (Del Río Hortega, 1920, 1921). He focused his research efforts on microglia and found its mesodermal origin (the true third element), its surveillance function and phagocytic capacity in pathology in a remarkably precise fashion, which was soon accepted by the scientific community. However, there was still much debate on the existence of oligodendroglia as a distinct CNS cell type, particularly by Ramón y Cajal and others (reviewed in Pasik and Pasik, 2004). It was not until 1924 when the confirmation of oligodendroglia as a variety of neuroglia of ectodermic origin (part of second element as astroglia was) was broadly accepted (Del Río Hortega, 1924; Penfield, 1924; Gill and Binder, 2007).

Contribution of Del Río Hortega to Understanding Oligodendroglia

Del Río Hortega rendered the first systematic description of oligodendrocytes (OLGs) in an article published in 1928 (Del Río Hortega, 1928; Figures ​1, ​2). Nevertheless, the complete story of his discovery had already begun when he described microglia (Del Río Hortega, 1920; Castellano-López and González-de Mingo, 1995; Pasik and Pasik, 2004) as the third element, mentioning the existence of a new cell type of neuroglia, the interfascicular glia, made up by cells showing very fine processes and arranged in groups among axonal tracts. Surely this distinction was only made possible using the new silver carbonate impregnation method developed by him (Del Río Hortega, 1918). In 1921, he named these cells as oligodendroglia or glia with very few processes (Del Río-Hortega, 1921), because they were present not only in white matter but diffusely distributed in all regions of the CNS and commonly grouped next to neurons in gray matter. He was aware that as many other histochemical techniques involving metallic silver impregnations, his silver carbonate method had very specific requirements, which did not, however, guarantee reproducible results in every preparation. Despite the results were very variable in terms of staining, he predicted the relationship of oligodendroglia with myelination, its implication in neuronal trophism, and its ectodermal origin. In fact, one year later (Del Río Hortega, 1922) proposed that these cells were functionally similar to Schwann cells in the CNS and responsible for myelination. However, the demonstration of oligodendroglia as cells that produce and maintain the myelin sheaths that insulate CNS axons had to wait for the introduction of electron microscopy in the 1960s (reviewed in Verkhratsky and Butt, 2007; Butt, 2013). This temporal gap, together with difficulties in oligodendroglia staining until the introduction of immunohistochemical techniques, and that the seminal articles by Del Río Hortega were published in Spanish, made his discovery of oligodendroglia not recognized internationally, as his discovery of microglia was, and restricted to scientists, who were histologists (Castellano-López and González-de Mingo, 1995; Pasik and Pasik, 2004).

Figure 1

Drawings of the cerebral cortex (A) and white matter (B,C) after staining with the Golgi-Hortega method or the silver carbonate procedure by Hortega (inset in A). (A) Notice pyramidal neurons (PN), protoplasmic astrocytes (PA), vessels (V), and type I...

Figure 2

Drawings of the subcortical (A) and spinal cord (B) white matter after staining with the Golgi-Hortega method. (A) Display of oligodendrocytes of the third type with different kind of processes around axons are represented: one has two clear and long...

Del Río Hortega published a thorough review of his discoveries about morphology and functionality of oligodendroglia in 1928 (Del Río Hortega, 1928). By this time he had introduced a new metal impregnation protocol based on the Golgi method, known as Golgi-Hortega technique, which provided detailed information on the morphology of these cells, which he renamed as OLGs. He noted three kinds of OLGs according to their neighboring relationship: interfascicullar (alignment of closely apposed cells in rows along axonal tracts); perineuronal (juxtaposing neuronal soma) and perivascular (abutting blood vessels but lacking contacts; Figures ​1, ​2). He was astonished with the complexity of oligodendrocytic morphology which he profusely illustrated with drawings and photomicrographs in a review (Del Río Hortega, 1928). Accordingly, he tried to classify OLGs according to their soma size and shape, number and characteristics (orientation) of cellular processes, their distribution within CNS, manner of interaction with axons and size of the axons with which they were associated. As a consequence of this analysis, he grouped OLGs into four subtypes (I to IV), while recognizing the absence of clear boundaries among them.

Type I OLGs or Robertson’s OLGs, are named so because this type was probably the only one observed by Robertson (Robertson, 1899), have small rounded cell body (15–20 μm diameter) and a high number (from 5 to 20 or more) of very fine processes emerging in multiple directions and towards axons that are usually thinly myelinated. They are present in gray (nearly all perineuronal OLGs are of the first type) and white matter (frequently arranged in interfascicular series; Figures ​1, ​2).

Type II OLGs or Cajal’s OLGs, named as a tribute to him, are only present in white matter. They are polygonal or cuboidal in shape (20–40 μm) with fewer and thicker processes than type I OLGs, which are directed to axons and attached to them longitudinally (Figure ​1B).

Type III OLGs or Paladino’s OLGs because Paladino, although associated with many misinterpretations, had intuited that myelin had a neuroglial origin (Paladino, 1892). Theseare also less abundant than types I and II. They are present in white matter with thick myelinated fibers (as brain stem and spinal cord) and are distinguished by one to four processes emanating from a bulky cell body and directed toward axons (Figure ​2).

Type IV OLGs or Schwannoid OLGs, due to their similarity in appearance, are very elongated cells with flattened somata, and found adhered and extended mono or bipolarly to medium or large thickness axons in white matter of brainstem and spinal cord (Figure ​2B).

This classification was not made for purely descriptive purposes. In fact, he also made a synthesis about the morphological and physiological knowledge of OLGs creating the concept of neurogliona (Del Río Hortega, 1942), by suggesting that OLGs have a close association with neurons and attributing to them hypothetically mechanical, trophic and myelinogenic functions. Although many observations along his scientific career supported the formation of myelin by OLGs, either directly or by supplying axons with needed materials, he was cautious enough not to consider them as definitive. This conclusion could be regarded as an example reflecting his high standards of scientific reasoning and intuition (Cano-Díaz, 1985; López-Piñero, 1990; Castellano-López and González-de Mingo, 1995; Andres-Barquin, 2002; Pasik and Pasik, 2004; Gill and Binder, 2007).

Scientific Legacy of Del Río Hortega on Oligodendrocyte Knowledge

The oligodendrocyte phenotypic diversity proposed by Del Río Hortega was initially neglected, but it has been later on confirmed by electron microscopy, intracellular dye injection, immunohistochemistry and more recently with genetic tools (Butt, 2013). This could be due to the fact that his studies were made mainly in gyrencephalic brains while current consensus about OLGs has been mainly obtained from lysencephalic ones. Indeed, Del Río Hortega’s contribution to the field has been often overlooked and reference to his pioneer ideas are not included in recent relevant papers (for example: Nishiyama et al., 2014; Dumas et al., 2015; Zeisel et al., 2015). This oblivion is unfair since we learned from his discoveries that OLG phenotypes are related to the number of axons myelinated per OLG and the diameters of fibers they myelinate. As a result of that finding, we now classify OLGs in two distinct phenotypes defined by the caliber of the axon they myelinate, i.e., below and above of 2–4 μm of diameter which correspond to Del Río Hortega’s types I/II and III/IV (Verkhratsky and Butt, 2007; Butt, 2013). In addition, although he did not specifically mention it, he did suggest that there was a direct relationship between the axon caliber and the internodal length (i.e., the length between two nodes of Ranvier, the unmyelinated axonal gap where action potentials are generated), as well as with the width of the myelin sheath.

As of today, it is not clear how OLG polymorphism impacts the thickness and width of the myelin sheath and the functioning of the myelinated axons. In addition, recent evidence about axonal metabolic support provided by OLGs (Morrison et al., 2013; Saab et al., 2013) could be related to the concept of neurogliona suggested by Del Río Hortega (1942). It is outstanding that, as with Ramón y Cajal, he related morphology to function usingmicroscopy and neurohistological preparations impregnated with innovative and specific staining methods exclusively. This reveals an enormous capacity for hard work, deep observational abilities and exceptional artistic skills.

Current data show a population of adult oligodendrocyte progenitor cells, called NG2-glia or polydendrocytes, which provide a pool of slowly proliferating cells that generate OLGs throughout life (Nishiyama, 2013; Nishiyama et al., 2014). Del Río Hortega already observed this cell population in white matter (Del Río Hortega, 1928). He described it as a cell type with ambiguous character sharing with OLGs the size and shape of soma, but differing from them by the number and characteristics of its expansions: very numerous, not very long, dichotomized at acute angles several times with a semiprotoplasmic appearance similar to that of astrocytes which display a crown-like shape though its diameter is much smaller. He named them as dwarf astrocytes (DA) and although he did not propose a particular biological significance for those cells, they could possibly correspond to polydendrocytes, whose morphological descriptions are very similar (See Figure ​1C). We now know that OLGs are not the only fate of polydendrocytes, particularly during development since they can differentiate into astrocytes (Nishiyama, 2013; Nishiyama et al., 2014).

Another exciting OLG type described by Del Río Hortega was the perineuronal one whose soma lie apposed to neuronal soma (Del Río Hortega, 1928). They are non-myelinating cells and although their role is not clear, they could provide neurotrophic and metabolic support for neurons as he suggested, an idea that others extended to pathology showing that they could produce myelin in response to demyelination (Nishiyama et al., 2014).

Del Río Hortega observations and interpretations have been instrumental to contemporary neurobiology. He anticipated concepts that were dormant during decades, due in part to the neurocentric view of the CNS, and of the view that astrocytes are the relevant glial cells in the understanding of physiology of CNS and its pathology. More recently, the interest in OLGs has had a renaissance with the increasing attention to translational research on demyelinating diseases, and ultimately, provide justice to the pioneer contributions to our knowledge of oligodendroglia made possible by Del Río Hortega. It would be difficult to imagine a coherent story of OLGs without recognizing his contributions.

Molecular Epilog

Historically, OLGs have been classified using location and morphology, as started by Del Río Hortega (1928), in combination afterwards with molecular markers (reviewed in Butt, 2013). Although the majority of OLGs in any one category tend to look alike (see Figures ​1, ​2), very recently the analysis of the RNAs expressed in these brain cells (Zeisel et al., 2015) has revealed the possibility of classifying OLGs into a half-dozen classes according to progressive changes in previously known and novel gene expression markers along OLG differentiation. The harmonization of morphological and genetic criteria to classify OLGs remains to be done, and reveals the complexity of oligodendroglia. All in all, this open question reveals that the knowledge of the OLG network organization, pioneered by Del Río Hortega almost a century ago, is still an open question which needs further exploration.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Work in our laboratory is funded by CIBERNED, Gobierno Vasco (EJ/GV) and MINECO (SAF2013-45084-R). We thank MM Panicker for reading the manuscript.

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Introduction

I am satisfied to be able to summarize the contribution of Pío del Río Hortega to the field of neuropathology, in particular, tumors of the central nervous system. As a pathologist, I am keenly aware of the classifications of central nervous system tumors and can now provide a context for many of the contributions of Dr. Pío del Río Hortega.

As stated in other sections of this monograph, Río de Hortega was an illustrious character, both at the human level and at the scientific level. A self-taught man with an extraordinary knowledge of laboratory techniques, he was a leading scientific figure in the cities where he worked. The combination of expertise, dedication, and an undeniable persistence and capacity for work, together with considerable talent, led him to make key discoveries in the history of neuroscience, including microglia and oligodendroglia (as described in other chapters of this Special research Topic; see Pérez-Cerdá et al., 2015; Tremblay et al., 2015).

His techniques, especially the silver carbonate staining method, enabled him to work on tumors of the central nervous system and develop his highly practical classification (Polak, 1947; Llombart Rodríguez, 1965; Obrador, 1965).

Historical Context

The first descriptions of brain tumors date from the period of Virchow, who described gliomas arising from neuroglial cells. Virchow made a distinction between myxoglioma, gliosarcoma, glioma durum, and glioma hemorrhagicum, which are composed of glial cells that sometimes contained fibers. Virchow's pioneering comparison of neoplastic cells with normal brain tissue laid down the scientific foundations for all subsequent classifications of tumors of the central nervous system. The main studies at the end of the nineteenth century and beginning of the twentieth century were performed by Simon (1874), who described spider cell glioma, and Tooth and Conheim, who reported that tumors arose from embryonic remnants.

Between 1900 and 1950, the various classifications of central nervous system tumors led to decades of confusion over terminology. The more notable studies of the period were by Ribbert (1910, 1918) who speculated about the histogenesis and etiology of glioma, particularly in his paper on spongioblastoma and glioma (“Über das Spongioblastoma und das Gliom” [On spongioblastoma and glioma]). Some authors feel that this study had a negative effect on the classifications of glioma that were produced during the following 20 years. In his study, which was based on theoretical deductions, Ribbert concluded that differentiated glial areas can never return to a lower grade of differentiation and that gliomas, glioblastomas, and spongioblastomas would therefore necessarily have to be explained by the presence of embryonic remnants whose growth had stopped at various stages of differentiation. According to this hypothesis, Ribbert believed that tumors stemmed from embryonic stages and not from changes occurring in the most differentiated cells. Nevertheless, Ribbert paved the way for the cytological study of tumors and for more specific studies based on impregnation methods, of which Río Hortega was a major proponent. The histogenetic and embryological approach adopted by Ribbert was modified by the cellular approach espoused mainly by Río Hortega. The contributions of the French school (Lhermitte and Dumas, 1916; Cornil, 1924; Roussy and Oberling, 1932) around the 1920 made it possible to distinguish between fibrillary astrocytoma, four subgroups of non-fibrillary glioma (round, spindle-shaped, polymorphic, and ameboid cells), glioblastoma, and spongioblastoma. The classification included ependymomas with choroid plexus tumors, which were separate from the other gliomas. The histogenetic approach was maintained in the studies by Globus and Strauss (1925) and in those of Bailey and Cushing (1926), where a distinction is made between various histogenetic cell types in glioma. The authors recognize the considerable internal heterogeneity of these tumors, to the extent that their classification placed considerable emphasis on the predominant cell type. The same authors performed an exhaustive study of brain tumors based on morphologic characteristics and on correlations with the patient's prognosis after surgery (Bailey, 1924; Bailey and Bucy, 1929). Their classification developed from the concept that tumor cells could arise from a medullary epithelium parent cell, which could differentiate into other glial, neural, or choroid cells. These cells could then differentiate even further. In theory, tumors could develop at each of these phases of differentiation. This period saw the first description of oligodendromas and cerebellar medulloblastomas. Although these tumors had been described as sarcomas or neuroblastomas by other authors, Bailey and Cushing (1925) have the merit of separating them from neuroblastoma based on their gross appearance, origin, form of growth, and spread along the spinal cord.

The 1926 classification of Bailey and Cushing is similar to the present one. It distinguished between tumors of the central nervous parenchyma, as follows:

(1) Astrocytoma (grades I–IV), pilocytic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, choroid plexus papilloma, pinealoma, colloid cyst, and medulloblastoma.

(2) Meningeal tumors: meningioma, malignant meningioma, meningeal sarcoma, and meningiomatosis.

(3) Tumors of the cranial pairs: neurinoma.

(4) Tumors of the pituitary gland: adenoma, invasive adenoma, carcinoma, and craniopharyngioma.

(5) Vascular tumors: hemangioblastoma.

(6) Embryonal tumors: dermoid cysts and teratomas.

This classification had an enormous impact on neuroscience and neurosurgery, although it was criticized by several authors, mainly Scherer, who stressed the lack of correlation between clinical and pathological aspects in several tumors and the fact that a very high number of tumors (up to 30%) could not be classified following the authors' criteria. In parallel, authors such as Cushing focused on clinical classifications that described tumors with a favorable prognosis, for example cerebellar astrocytoma, which they stressed was different from cerebral astrocytoma, despite the histogenetic similarity between the two. Using data from studies of the child brain, the authors described non-recurring cystic tumors that were well-defined in terms of growth stage and whose classification was highly relevant at the time. This distinction was not based merely on histogenetic and cytologic principles, but on clinical, histopathologic, and clinical data. Important as well the contributions of Penfield (1931).

The publications and lectures of Río Hortega during the 1930s played a major role in promoting histogenetic classification, largely thanks to very accurate silver staining techniques. Most authors from this period and thereafter felt that his classification contained the most exhaustive collection of images until then. Río Hortega's classification was not based on clinical findings or anatomical site, but on morphological and histogenetic data.

Tumors of the Central Nervous System: the Contribution of Río Hortega

During the initial stage of his training, Río Hortega analyzed brain tumors in four studies. One of these was his doctoral thesis (“Causas y Anatomía Patológica de los Tumores de Encéfalo” [Causes and Histopathology of Brain Tumors]), which he defended under the direction of his tutor, Leopoldo López García, between the years 1911 and 1912.

Río Hortega wrote papers on the histopathology of carcinomas and of the nervous system in patients with brain tumors (1911a), the pathophysiology of brain tumors (1911b), and abnormalities of nerve tissue and general symptoms of brain tumors (Río-Hortega, 1911a,b, 1912, 1914a,b,c; Río-Hortega and y Costero, 1928; Río-Hortega and y Álvarez Cascos, 1930).

During the following phase of his training, Río Hortega performed a study of subcutaneous giant cell glioma, the results of which were published in 1926 (Río-Hortega, 1926). The third phase (1928–1936) saw the appearance of his most important contributions to the field of neuro-oncology. In 1930, he published a series of monographs analyzing the cytologic and histogenetic characteristics of specific tumor groups, beginning with a detailed consideration of meningeal exotheliomas, which he discussed and included in the differential diagnosis of what was then known as Cushing meningioma. He described variations of meningioma, such as xanthomatous tumors and fascicular tumors, which have been reported sporadically by other authors. The examination of these histopathologic forms led him to propose three major patterns: (a) a predominantly syncytial pattern; (b) a pattern based on fibrillary differentiation of cytoplasm that tended to arrange itself in plaques and bundles; and (c) a pattern involving more epithelioid and lobulated morphological differentiation. Similarly, he described the formation of acervuli and psammoma bodies in meningioma, the pineal gland, and the colloid plexus (Río-Hortega, 1930c).

The year 1932 saw the publication of the major study “La estructura y sistematización de los gliomas y paragliomas” [Structure and systematization of gliomas and paragliomas], which, with more than 260 pages and 200 images, was the fruit of the techniques that Río Hortega had been developing using mainly silver carbonate staining (Río-Hortega, 1932, 1933a,b).

He performed the study using his in-depth knowledge of the histology of the glia and brain and had to seek the help of neurosurgeons and other pathologists to compile a sufficiently large series of brain tumor samples for study and classification. The French neurosurgeon Clovis Vincent was of inestimable help during this period.

The results, which were based on neuroembryological data, pointed to four potential evolutionary pathways of the primitive medullary epithelium (neuroblasts, glioblasts, pineoblasts, and choroideoblasts). Given the considerably heterogeneous nature of brain tumors, Río Hortega thought that it was important to classify them into histologic types with common embryological findings. Therefore, he tried to define two large groups of tumors, with emphasis on histological and embryological lineage. The first group comprised gliomas and the second paragliomas, which included all those tumors formed by immature or mature elements of the nervous system and tumors arising from choroidal folds and the pineal gland.

His systematic typing of the gliomas according to the degree of maturity of the cell components or the degree of differentiation enabled him to define the following entities (Río-Hortega and y Jiménez de Asúa, 1921; Río-Hortega, 1930a,b, 1932, 1933a,b; Pineda et al., 1962; Diaz, 1985) (Figure 1):

(1) Embryonal glioblastoma or spongioblastoma.

(2) Heteromorphic glioblastoma.

(3) Isomorphic glioblastoma (Figures 2, 3).

(4) Astroblastoma.

(5) Astrocytoma (Figure 4).

(6) Oligodendroglioma, with a distinction between oligodendrocytomas and oligodendroblastomas (Figure 5).

(7) Glioepitheliomas, which included ependymal tumors (ependymocytoma and ependymoblastoma).

Figure 1. Morphological evolution of the cells that are derived from the neural epithelium in the central nervous system (taken from Río-Hortega, 1933a).

Figure 3. Another example of isomorphic glioblastoma with wave-like arrangement of glioblasts (taken from Río-Hortega, 1933a).

The classification of paragliomas included neuroma from neuroblasts (neuroblastoma), neurocytoma, pineal tumors (pinealcytoma, pineoblastoma), and choroid plexus tumors, which he termed chorioepitheliomas (Figure 6).

At the International Cancer Congress on the Scientific and Social Fight Against Cancer held in Madrid in 1933, he provided a more extensive summary of his classification in a lecture based on 287 pages of text (315 pages including the bibliography) and 248 images.

The classification, which to a certain extent complemented those proposed by Roussy and Overling and especially that proposed by Bailey and Cushing, differed in major areas, some of which are worthy of mention. Río Hortega's classification was based on the cytologic and embryologic characteristics of tumor cells, irrespective of their location, and therefore included tumors such as cerebellar medulloblastoma alongside tumors with a blastic lineage from within the brain. This distinction between medulloblastomas and other neuroblastic or primitive tumors was controversial at the time and continues to be so today.

In his lecture, Río Hortega stressed the need for international harmonization of the nomenclature applied to tumors of the nervous system, as also proposed by Roussy and Overling. The groups he suggested in the lecture were as follows:

(1) Tumors arising from choroidal folds, the pineal valve, and homologous evaginations of the diencephalon that develop in the embryo.

(2) Tumors arising in the parenchyma of the brain and spinal cord and visual system, which is a prolongation of the brain.

(3) Tumors arising in the sympathetic nervous system, but not all those that develop from sympathogonia.

(4) Tumors arising in the nerve roots and in the peripheral nerves from interstitial cells or parenchymatous cells, depending on the interpretation of neoplastic elements (Figure 7).

(5) Tumors arising in the meninges owing to proliferation of cells or to new vascular formations (Figure 8).

(6) Tumors arising from hyperplasia in the parenchyma of the pituitary gland and from dislocated epidermal germ cells and invaginations of the Rathke pouch.

Figure 8. Meningeal exothelioma. The disordered cells are forming clusters and concentric layers or acervuli (taken from Río-Hortega, 1933a).

The fourth stage of Río Hortega's life (1936–1945), which was spent in exile, saw the publication of several papers on the nervous system (see below) (Río-Hortega, 1940a,b,c, 1941a,b, 1942, 1943).

In 1940, after his stay in Oxford, he performed a study on tumors of the optic nerve. During the same year, once he had settled in Argentina, he published a study on neuroblastomas, in which he concluded that there were no nervous system tumors with bipotential cells that were able to progress to neuroblasts or glioblasts and that most of the so-called medulloblastomas should be termed neuroblastomas, which is the term that corresponds to their lineage. His approach was considered scientific in terms of its embryological interpretation.

This interpretation remains controversial today. The embryological approach did not take histopathological characteristics into account. In addition, the neuroblastoma group included tumors that developed from other precursors, namely, medulloblasts, which develop in the molecular layer of the cerebellum.

His paper entitled “Del glioepitelioma al glioblastoma isomorfo” [From glioepithelioma to isomorphic glioblastoma], which was published in 1941, discussed and criticized the use of the term ependymoma—suggested by Bailey and Cushing—for tumors associated with the ependymal wall.

In 1943, Río Hortega (Río-Hortega et al., 1943) performed a cytological study of neurofibromas (also known as lemmocytomas), in which he described the histologic characteristics of the tumors and the elements that characterize them. He made an in-depth examination of the constitution of these tumors, discussed the identification of the main elements of Schwann cells and the embryonic origin thereof, and examined the specific differentiation of multiple neurofibromas and neurinomas (solitary schwannomas). His findings remain in force today.

He added new pathological information after previous papers (Cushing, 1917; Kernohan et al., 1931; Kernohan and Ody, 1932; Scherer, 1933).

In 1944, Río Hortega reported the results of an extensive study on oligodendrogliomas, which he classed as a gliomatous ectodermal variety characterized by small cells with a spherical nucleus (Río-Hortega, 1944a,b). His description of the nucleus as “very round” continues to be of use today in the diagnosis of oligodendrogliomas. Similarly, he observed that oligodendrocytes tend to be arranged in dense or diffuse patterns and never in perivascular patterns. Río Hortega established three cytological types of oligodendroglioma: (a) those whose cells have a spherical nucleus surrounded by a characteristic light halo and wrapped in a small layer of protoplasm that projects a varying number of fine and long appendages; (b) a more infrequent type of oligodendroglioma, which is formed by large neoplastic oligodendrocytes; and (c) a type that includes tumors with a non-uniform structure. As Río Hortega pointed out, the neoplastic oligodendrocyte evolves morphologically to the extent that it takes on the characteristics of an astrocytoma.

The year 1944 is also notable for Río Hortega's cytological study of tumors of the optic chiasm and nerve. The tumors described at this level that can be classed as gliomas, which were similar to brain tumors, with a moderately expansive or infiltrative character. The several cell types that can be identified for tumors of the optic nerve and chiasm include the following: (1) cells with small, round nuclei; (2) cells with bipolar, spindle-shaped, and long nuclei; (3) cells with a tripolar cytoplasm and thick prolongations; (4) cells with multipolar cytoplasm and fibroid and undulating prolongations; (5) cells with multipolar cytoplasm that invade the vasculature. Río Hortega reached the conclusion, albeit indefinite, that there are two basic neoplastic types in the formations he studied: one characterized by long elements (Schwann oligodendrocytes) and another defined by multipolar elements that give it the appearance of astrocytes (Ortiz de Picon, 1983).

Classification of Central Nervous System Tumors After Río Hortega

Current classifications of nervous system tumors are mixed, based on cytological and histogenetic criteria, as well as on histopathological variants that are of clinical and prognostic importance.

The main studies published after Río Hortega include that of Kernohan and Sayre (1952), Miller et al. (1952) who began to grade gliomas by establishing a correlation between microscopy findings, degree of malignancy, and prognosis.

In 1965, Zülch stressed the importance of other factors, such as patient survival, and included the concept of clinical malignancy (Zülch, 1965). Finally, the first classification of the World Health Organization was published in 1979 (Zülch, 1979) and classified tumors as follows:

(1) Tumors of neuroepithelial tissue, including astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, pinealcytoma, medulloblastoma, gangliocytoma, ganglioglioma, and neuroblastoma.

(2) Meningeal tumors, such as meningioma and meningeal sarcoma.

(3) Tumors of nerve sheath cells, such as neurinoma and neurofibroma.

(4) Primary cerebral lymphoma.

(5) Tumors arising in blood vessels, such as hemangioblastoma.

(6) Germ cell tumors, such as germinoma and teratoma.

(7) Metastatic tumors.

(8) Malformative tumors and tumor-like lesions, such as craniopharyngioma, epidermoid cyst, dermoid cyst, and colloid cyst of the third ventricle.

(9) Local extensions from regional tumors, such as glomus jugulare tumor and chordoma.

(10) Tumors of the anterior pituitary, such as pituitary adenoma.

(11) Unclassified tumors.

This classification serves as the basis for the subsequent editions of the World Health Organization classification until the year 2007 and the subgroups that are currently being incorporated. The most notable new additions are as follows:

(1) Variants of grade 1 astrocytomas, such as fibrillary, protoplasmic, and gemistocytic astrocytoma.

(2) Pilocytic astrocytoma as an independent entity.

(3) Subependymal giant cell astrocytoma.

(4) Astroblastoma.

(5) Anaplastic (malignant) astrocytoma.

A distinction is also made between oligodendroglial tumors and oligoastrocytic tumors [oligoastrocytomas and anaplastic (malignant) oligodendrogliomas].

Within the ependymal tumors and colloid plexus tumors, it is important to distinguish between variants of ependymomas, such as myxopapillary ependymoma, papillary ependymoma, subependymoma, and anaplastic ependymoma. At the level of the colloid plexus, we must distinguish between colloid plexus papilloma and colloid plexus carcinoma.

The neuronal tumors include variants such as gangliocytoma, ganglioglioma, ganglioneuroblastoma, gangliocytoma, anaplastic (malignant) ganglioglioma, and neuroblastoma.

Among the poorly differentiated and embryonal tumors it is important to identify glioblastoma (with its two subvariants, glioblastoma with a sarcomatous component and giant cell glioblastoma), medulloblastoma, medulloepithelioma, primitive polar spongioblastoma, and gliomatosis cerebri.

The classification covers tumors of the meningeal and related tissues, such as meningioma, with at least 11 morphological variants depending on the predominance of the Schwann, angiomatous, and papillary component. Similarly, the anaplastic (malignant) variant of meningioma is a distinct entity.

The classification still includes vascular tumors (e.g., hemangioblastoma and a malignant variant known as monstrocellular carcinoma), primary malignant lymphoma, and several variants of germ cell tumors. The previously cited group of malformative tumors and tumor-like lesions is extended to include enterogenic cysts, lipoma, hypothalamic neuronal hamartoma, nasal glial heterotopia (nasal glioma), as well as various vascular malformations (capillary telangiectasia, arteriovenous malformations, and Sturge-Weber disease).

The 2007 classification continues to include new entities, mainly anatomical-clinical conditions where it is very important to distinguish between gliomas with a high and low degrees of malignancy based on cytological criteria. The new types of low-grade glioma described include angiocentric gliomas, which are variants of glioneuronal tumors (e.g., rosette-forming or papillary tumors), and cytological variants of tumors of the anterior pituitary (e.g., pituicytoma and spindle cell oncocytoma). We can also distinguish between pilocytic tumors and their pilomyxoid variants, which have a poorer clinical prognosis (Louis et al., 2007).

In the coming years, it will be necessary to add the molecular abnormalities underlying the transformation and malignancy of these tumors. Our knowledge is expected to increase thanks to amplification of genes such as EGFR in glioblastoma, loss of alleles on chromosomes 1p and 19p in oligodendroglioma, and mutations in genes such as in p53 and IDH1 in low-grade astrocytoma that progresses to malignant astrocytoma. Intra- and inter-tumoral heterogeneity could be understood as resulting from cancer stem cells and the accumulation of various molecular abnormalities.

As has occurred with other types of tumor, especially lymphoma, whose classifications have for decades been based merely on morphological or clinical criteria, a joint approach to classification is probably the most suitable for clinical practice. Cytological abnormalities, location, and histopathological characteristics could facilitate a more in-depth study of the various types of tumor. It is important to remember that the major objective of any classification is that the information it provides be of use in clinical practice. Only thus can the patient receive the best and most personalized treatment possible.

Author Contributions

The author confirms being the sole contributor of this work and approved it for publication.

Funding

Fondo de Investigaciones Sanitarias (11/00185), Redes Temáticas de Investigación Cooperativa en Salud (Ref. RD06/0020/1020).

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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