Pediatric Neuro-Oncology: A Historical Perspective


Pediatric Neuro-Oncology: A Historical Perspective

James Tait Goodrich

Cancer has been called “the emperor of all maladies” by Siddhartha Mukherjee, a well-known oncologist.1 This chapter discusses the development of the field of pediatric neuro-oncology and introduces a historical perspective on the cursed malady called cancer. Pediatric neuro-oncology has only recently become a recognized field, as it has existed for less than 100 years. Review of the earlier historical literature reveals little understanding of what composed a cancer or a tumor. What we call tumors now were variously categorized as fungus, swellings, growths, ulcerations, and other terms. Subsequent chapters in this volume discuss modern treatments of cancer. This chapter focuses on the general views and historical medical and surgical treatment of cancers of the central nervous system (CNS) up to the first quarter of the 20th century. This review is general in scope, giving a perspective on how far we have come in the treatment of pediatric neurooncological lesions and showing how much further we have yet to go.

The earliest recordings of cancer have been dated to Imhotep (fl. 27th century BC, 2655–2600) ( Fig. 1.1 ), a polymath, skilled in architecture and engineering, and one of the earliest physicians of the Egyptian dynasties. Imhotep′s status was raised to that of a deity, which was rare for a commoner, and he became a god of medicine and healing. Though still subjected to conjecture, to Imhotep we owe the earliest known written medical literature—the Edwin Smith (1832–1906) papyrus that dates from 1700 BC, a copy of text believed to have been written at least a thousand years earlier.2 The papyrus is over 15 feet in length and incomplete, as the final 15 inches remain blank, suggesting that the amanuensis stopped before completing the project. Although the text is unsigned, the writings are thought to originate with Imhotep. This early papyrus discusses, in very general terms, various swellings, growths, and fungi. Imhotep detailed a case of a fungating breast lesion (Case 45), likely a case of breast cancer for which he noted there was no hope for a cure. Some of these lesions were likely of cancerous origin, but the concept of what we call a cancer did not develop until the 19th century, when cellular pathological studies were introduced. Of historical note in this papyrus is the first use of the word brain. The author also describes the dural coverings and arachnoid membrane along with the underlying spinal fluid. A second papyrus dates from 1552 BC called the Ebers Papyrus, acquired by Georg Ebers in Thebes in 1872, and in it a case of a large tumor of the limb is described. Interestingly, the author admonishes against surgery, as it might prove to be fatal. The Hammurabi (ca. 1750 BC) code of “a limb for a limb” dictated that the surgeon would lose his hand if the patient died.

A review of the early Greek literature, in particular the writings of Hippocrates (460–370 BC) reveals several interesting and thorough clinical observations, though only a few writings exist of what might be called oncological description.3 Hippocrates does provide what appear to be descriptions of breast cancers, cancer of the rectum and uterus, and skin and stomach lesions. Treatments offered in the form of surgical excision or medical therapies were minimal at best, as these lesions were almost always considered fatal. Following the Asclepiads philosophy, bed side care and comfort to the patient in the final days were the best and usually the only treatments offered in this period; holistic, herbal, and homeopathic medical care remained the norm until innovations of the 20th century.

The concept of the disease process now known as cancer dates from the early Hippocratic schools ( Fig. 1.2 ). The word cancer was derived from carcinos meaning “crab,” a term used medically to describe chronic ulcerations and swellings and any eating types of sores; in retrospect, these lesions were most likely tumors of malignant origin.4,5 Celsus (25 BC to 50 AD), the great medical encyclopedist, translated the word carcinos into “cancer” and introduced the term carcinoma. 6 Celsus described several cancerous-type lesions, mostly involving the breast, skin, nose, and lips, and rarely recommended surgery (which typically included only caustic medicants or a red-hot cautery application). Galen of Pergamon (130–200 AD), the great Alexandrian surgeon, brought us “oncos” to describe a tumor or swelling. Galen also developed the humoral theory and its effect on the development of cancer.7 According to this theory, cancerous lesions developed as a result of a buildup of “black bile,” one of the four humors, which solidified and formed lesions. Treatment involved the administration of purgatives to dissolve the collection, and when that failed the lesion was excised. Such was Galen′s influence on medicine; this humoral view of cancer was to remain the dominant theme of medical oncology for over 1,600 years. The general use of the word cancer as a medical descriptive to describe a disease began to appear regularly in the English literature in the early 17th century when it replaced the term canker 5 ( Fig. 1.3 ).

The period of late antiquity (~ 600–1000 AD) shows medicine to be heavily under the influence of the Arabic-speaking schools of medicine. The Arabic schools and their educators were great codifiers of the earlier Greek and Latin writings, with virtually all the existing manuscripts being translated into Arabic and thus forming the then-current corpus of medical texts. Considering that these educators were compilers and not innovators, it is not surprising that a review of the Arabic literature shows little in the way of new advances in medical or surgical treatments. However, there are in these writings some interesting perspectives as to surgical treatment of oncological diseases. Avicenna (980–1037 AD) ( Figs. 1.4, 1.5 ) wrote in his great Canon of Medicine descriptions of cancer invasion, destruction of adjoining tissues, loss of sensation, use of the affected part, and the eventual death secondary to widespread disease.8 Albucasis (1013–1106), one of the most elite of Arabic/Islamic surgeons, wrote on the surgical excision of cancerous lesions.9,10 These cancerous lesions had to be at an accessible site, such as the breast or on a limb, and for such sites he recommended a complete excision. Albucasis′s surgical excision technique involved a circular cauterization with a hot iron, so that the lesion was literally burned out; the edges of the cancerous lesion were allowed to ulcerate. For an advanced lesion he appropriately recommended no surgical treatment. Medical management of cancerous lesions followed the Galenic paradigm of purgatives and bleeding to remove the “sequestered black bile.” At no point in these early writings, whether from the Greek, Latin, or Arabic-speaking Islamic schools, are there any recommendations for operating on the brain for cancerous lesions. Except for the rare case of head trauma, there are almost no recommendations for opening the dura and excising an intracranial lesion. The risk of hemorrhage, cerebrospinal fluid leaks, and infections led to an almost 100% mortality, so it was the very rare surgeon who would even consider an operation on the brain.

a, b (a) Imhotep lived in Egypt during the reign of Pharaoh Zoser of the Third Dynasty. As a great architect and the prime minister of the Pharaoh, he was responsible for the construction of the first pyramid (the tomb of Zoser at Saqqaral) and one of the first Egyptian temples built of stone. These temples that he built came to be used as places of healing, and some 2,000 years after his death, Egyptians deified him as the god of medicine. The sculpture of this piece was done by Doris Appel (1904–1995) of Lynn, MA, who produced a series of limited production pieces on figures in the history of medicine. (b) A leaf in hieroglyphics from the Edwin Smith papyrus. The original now resides in the New York Academy of Medicine.
A bust of Hippocrates surrounded by early printed works from the Hippocratic/Galenic era of medicine.
Title page from a collected works of Galen of Pergamon. So influential were these writings that they have been constantly reprinted and re-translated from the time of his dead in 200 AD right up to recent times. This title page comes from an eight-volume collected works published in Venice, Italy, in 1575.7
A manuscript leaf from an 18th-century manuscript depicting Avicenna applying a red-hot cautery to a lesion, likely a fungating cancer of the chest wall. (From the author′s collection.)

In reviewing the Medieval and Renaissance medical literature, no further innovations came to light for the treatment of any of the oncological disorders. Galen′s treatment of bloodletting and the use of purgatives remained the then-current form of medical treatment.11 Tumors or swellings, that is, cancers, were treated only if they were accessible. Tumors of the breast, limbs, rectum, and uterus were typically accessible and thus could be considered for surgical resection. Reviewing the literature on “resection” reveals some crude and barbaric treatments. Initially, surgeons performed the surgical excision with initially red-hot cautery; that is, they burned out the lesion. Later, with the innovations of 16th-century European surgeons, surgery entailed excising lesions with sharp knives, the use of burning hot cautery finally being discarded. Medical treatment still involved bloodletting and the use of purgatives to break up and move along the sequestered black bile, as the views of the 2nd century AD Galen′s humoral theory remained in force some 14 centuries later.

A modern reproduction of Avicenna (in yellow) attending to a patient with an abdominal lesion. (From the author′s collection.)
A 16th-century scene of a surgeon at work (right page) and examples of early knives and surgical instruments (left page), ca. 2nd century AD, Roman origin. (From the author′s collection.)

The period of the Renaissance was a critical time in medicine and surgery, and it brought in particular the introduction of “hands-on” anatomic dissection. Physicians and surgeons, moving away from the previously entrenched medieval dogma, realized that to understand internal human anatomy one needed to do hands-on anatomic dissections, a teaching technique that had been virtually dead for religious and secular reasons since before the time of antiquity. In Italy, the great schools of medicine such as Padua and Bologna developed anatomic theaters and performed routine dissections of executed criminals. Under great personages such as Andreas Vesalius (1519–1564) and Jacopus Berengario da Carpi (1470–1550), dissections became a routine part of the medical school curriculum.1214 The popular technique during the Middle Ages was for the surgeon or physician to sit at a lectern reading Galenic text while a prosector did the dissection following the details of Galen′s written anatomy ( Fig. 1.6 ). Unfortunately, much of Galen′s anatomy was based on animal dissection rather than human. A review of the 16th-century surgical texts, however, still shows a very heavy influence of the Galenic humoral theories, and again cancerous lesions were removed only if they were accessible and fairly discrete. Considering that this was in the pre-antisepsis and pre-anesthesia era (concepts not introduced until the mid-19th century), these must have been extraordinarily painful procedures with a high incidence of disfiguration and death due to infection and generalized sepsis.

In the 17th century there appeared several surgical manuals with excellent anatomic and surgical illustrations showing techniques for removal of superficial cancerous lesions; the approach to, and understanding of, cancerous lesions within the brain was not even to be attempted until the 19th century. Some examples of the early surgical techniques are given to provide a short overview of what our early surgical brethrens offered in the way of treatment. Medical treatment consisted still of only purgatives, caustics, and bloodletting.

Johannes Scultetus (1595–1645) provided one of best-illustrated surgical manuals of the 17th century.15 Several examples are given of surgical excisions of cancerous lesions, particularly of the breast. In this pre-antisepsis and pre-anesthesia era, the then prevalent techniques of burning out, cauterizing, or sharply excising lesions must have been a horrendous experience for both the patient and the surgeon. Postoperative treatment followed Galenic humoral theory in that the patient would be given foul-tasting emetics and purgatives, with venous bleeding then applied—all of this done in an effort to keep the four humors in balance. One can only imagine the high morbidity and mortality associated with these rather coarse and brutal, by today′s standards, techniques ( Fig. 1.7 ).

Henri Francois Le Dran (1685–1770), a leading figure in the early French school of medicine, provided a new and innovative view of cancer when he introduced the concept that cancer began as a local disease and then later spread via the lymphatic chain to lymph nodes and then into the general circulation. This revolutionary view led to the concept of metastasis and theories on how it might occur. As a result of these new and novel observation, Le Dran was among the first to argue for early surgery to prevent later metastasis. He also argued against the use of caustic pastes and purgatives; rather, he felt that surgery was the better option.16,17

Giovanni Battista Morgagni (1682–1771) published in his 79th year, a most remarkable work on the “seat and causes of diseases”—De Sedibus et Causis Morborum (1761).18,19 This work was a culmination of a lifetime of work using autopsy material and clinically correlating autopsy findings with the medical history, a very common experience today but virtually unheard of in the 18th century. Morgagni′s work contains some 70 letters reviewing over 700 cases. Several different cancers are reviewed, including those involving the breast, stomach, rectum, and pancreas. Unfortunately, Morgagni had no concept of cancer origins or its pathology; he did, however, provide some very interesting and early examples of cancerous lesions and then speculated on the cancer′s effect on the patient′s outcome ( Fig. 1.8 ).

Matthew Baillie (1761–1823), a prominent London physician and leader in the English school of medicine, contributed to the pathological studies of diseases. He published his pathological findings in a now landmark work called The Morbid Anatomy of Some of the Most Important Parts of the Human Body (1793).20 His pathology atlas was followed by a series of fascicles published from 1799 to 1802 entitled A Series of Engravings Accompanied with Explanations, Which Are Intended to Illustrated the Morbid Anatomy of Some of the Most Important Parts of the Human Body.21 In Baillie′s atlas we have the first appearance of illustrated specimens showing different tumors affecting the skull, brain, and the dura mater. The drawings where of the highest caliber and reflected for the first time some, albeit minimal, understanding of cancerous lesions. Baillie provided here one of the earliest illustrations of a meningioma ( Fig. 1.9 ).

The development of a scientific approach to oncological surgery has been historically a late phenomenon and occurred in the same period with the works and writings of the great English surgeon John Hunter (1728–1793). Hunter is considered the father of “modern” surgery, with few individuals being as productive in the field of original surgical research. He offered some interesting views on cancer that were published after his death in his Lectures on the Principles of Surgery (1839).22 Hunter felt there were three conditions that influenced the development of cancer: age, heredity, and perhaps climate. From his clinical observations it was apparent to Hunter that the age in which cancers occurred was from 40 to 60 years; pediatric lesions were not discussed. Hunter also noted that the earlier the cancer appeared (the example used was breast cancer), the worse the outcome. The cancers described by Hunter were typically solid lesions of the breast, uterus, lips, nose, pancreas, and other sites. Hunter appeared not to have an understanding of, or at least did not describe, cancers that we now know as leukemias or lymphomas. Hunter also appreciated the fact that if lymph nodes were involved, that meant that the cancer had spread and that cure was unlikely. If the lesion was well circumscribed and mobile, then the lesion was easily removed and Hunter felt the patient was curable ( Fig. 1.10a,b ).

Astley Paston Cooper (1768–1841), a pupil of Hunter′s, carried on the great Hunterian tradition of surgery combining surgical research and anatomic dissections. At St. Thomas Hospital of London, Cooper developed an intense interest in anatomic dissections, which he carried out on a regular basis. This work led to an incredible foundation of knowledge in both surgical anatomy and surgical pathology. His studies under Hunter further refined his skills at anatomic dissection. Appreciation of his skilled dissections led to his appointment as lecturer in surgery and anatomy at St. Thomas′s, and later elected surgeon at Guy′s Hospital in 1800. Using Hunterian principles of anatomy and physiology, he continued to develop his surgical practice. Cooper was very much interested in diseases of the breast and in particular cancer of the breast. Cooper summarized his findings in a book on diseases of the breast, which is now a landmark classic in the history surgery.23 Cooper′s learning technique of starting with several anatomic dissections and then combining these findings with his clinical and surgical experiences enabled him to develop some of the earliest, and yet seemingly “modern,” technical advances in the surgical treatment (i.e., excision) of localized cancer lesions.

From the extraordinary school of English surgeons also came Charles Bell (1774–1842), who is remembered for several original contributions to surgery and in particular the differentiation of the physiological functions of motor and sensory cranial nerves. Germane to this chapter is an illustration of Bell′s showing the earliest illustrated example of a cerebellopontine angle tumor; this illustration appeared in Bell′s 1830 book, The Nervous System of the Human Body, 2nd edition.24 Bell described a cerebellopontine angle tumor arising from the trigeminal nerve in which the patient had developed severe facial pain. Although the case is described as a postmortem finding, it is nevertheless one of the earliest examples of a clinical finding of a facial pain being associated with the pathological finding of an intracranial tumor ( Fig. 1.10c ).

John Abercrombie (1780–1844), Lord-Rector of Marischal College, Aberdeen, Scotland, published the first work devoted solely to pathological disorders of the brain and spine, albeit a work with many misconceptions about the origins of tumors and the pathological processes of the brain and spinal cord. He had previously published several articles on neuropathology in the Edinburgh Medical and Surgical Journal and then summarized these findings in a monograph entitled Pathological and Practical Researches on Diseases of the Brain and Spinal Cord published in 1828.25 In this work of 476 pages are over 150 case reports, with no illustrations, describing various pathological conditions of the brain, spinal cord, and peripheral nerves. In the third and fourth sections of this book are some of the earliest gross pathological descriptions of tumors and mass lesions involving the brain and spinal cord. Abercrombie noted that, clinically, masses in the head could cause “long-continued severe headaches,” headaches that typically occurred in the morning and were exacerbated by motion. With severe headaches could also occur impairment or loss of vision. Vomiting and convulsions were also detailed and described as part of the clinical picture of a brain tumor. Clinical findings such as hemiplegia were recorded. Of particular note was the fact that Abercrombie provided some of the first clinical and pathological descriptions of tumors of the spinal cord. Abercrombie′s clinical descriptions included tumors, cysts, abscesses, and tuberculomas of the spinal cord. He also pointed out that these tumors anatomically could arise from both from within and external to the spinal cord. The final section of his book is an appendix in which Abercrombie noted that tumors and other pathological conditions also occurred in nerves. He described softening, discoloration, swelling, shrinking, and compression of nerves by tumors. This volume by Abercrombie is considered by most writers to be the earliest definitive work (albeit with many inaccuracies) to discuss tumors and cancers of the brain and spinal cord.

(a) Title page from Scultetus′s work on surgery, a work that was so popular that it underwent several editions and translations. The illustration shows a patient with a large fungating lesion arising from the left cheek region. The surgeon placed a ligature around the base of the lesion and tied it down, and thereby amputated the lesion. The two assistants to the side are there to restrain the patient from moving during the procedure.15 (b) An illustration from Scultetus′s surgical work demonstrating a 17th-century surgical technique for removing a cancerous lesion of the breast in an awake patient with only a minimum of anesthesia, usually narcotics and alcohol. (c) Scultetus′s technique for trephining the skull.15
a, b (a) Frontispiece and title page from Morgagni′s magnum opus in which are described for the first time a pathological basis for disease and in particular oncological disorders.18 (b) Title page from the first English translations of Morgagni′s Seats and Causes of Diseases.19

In the early part of the 19th century there appeared several excellent pathological atlases with beautifully illustrated engravings of lesions of the brain and spinal cord. The first neuropathology atlas of note was by Robert Hooper (1773–1835), who published a remarkable work entitled The Morbid Anatomy of the Human Brain; Illustrated by Coloured Engravings of the Most Frequent and Important Organic Diseases, to Which that Viscus Is Subject. 26 Hooper was a London practitioner and he was also interested in pathology, and his work was based on his 4,000-plus autopsies performed at the St. Marylebone Infirmary over a 30-year period. In this work, along with descriptions of hemorrhage and abscess, are some of the earliest descriptive examples of tumors of the brain that Hooper described as “cephaloma,” “chondroma,” “osteoma,” “melanoma,” and other terms. Tumors are described as circumscribed, meaning those that “so blended with the surrounding cerebral substance they could not be easily traced.” Terms like soft, hard, solid, and cystic where used to characteristically describe tumors. Hooper also recognized the single versus multilocular nature of cysts, although it is not always clear whether he was discussing tumors or abscesses. Tumors such as gliomas and meningiomas are easily ascertained from his gross descriptions. Microscopic descriptions were not provided. Interestingly, the text contains no clinical descriptions, just descriptions of gross morphology and pathology of the human brain. Hooper was also the first to illustrate an example of multiple sclerosis ( Figs. 1.11, 1.12 ).

(a) Title page from Baillie′s first fascicle of The Morbid Anatomy of the Human Body. Each of the fascicles dealt with a region of the human body, and the fascicle dealing with the brain provides some of the first illustrations of morbid anatomy involving the skull, brain, and dura mater.21 (b) Baillie′s illustration of a series of skull lesions. It is not clear whether these are secondary to tumors or to an infectious process. The lower lesion is likely a meningioma of the skull base.21 (c) The upper image is the floor of the fourth ventricle with an exophytic lesion arising from the floor. The lesion has been sectioned in the lower left images. The lesions to the right labeled “Fig. 2” are small dura-based meningiomas.21 (d) The upper image labeled “Fig. 1” is a cross section of a dura-based lesion. The image below shows a series of dura-based meningiomas that come from the dura over the convexity.21
(a) An oil painting of John Hunter in the collection of the Royal College of Surgeon (London, England) done at the height of his career. (b) John Hunter was an early investigator in the concept of organ and tissue transplantation. In this pathology specimen Hunter transplanted a tooth into the comb of a rooster that survived and became vascularized. (c) One of the earliest illustrations of a brain tumor, in this case a tumor arising from Meckel′s cave, which Charles Bell described as giving the patient severe facial pain. The finding was a postmortem one and likely a trigeminal neuroma. The trigeminal nerve and ganglion can be seen arising from the pons, just medial to the tumor.24 (Courtesy of the Hunterian Pathological Collection of Royal College of Surgeons, London, England.)

Robert Carswell (1793–1857) was the first professor of pathology at University College Hospital in London, taking that position in 1828.27 Ten years later (1838) this artist-pathologist published an atlas entitled Pathological Anatomy: Illustrations of the Elementary Forms of Disease, in which he included a large number of examples of neuropathological lesions such as metastatic melanoma (melanosis) and other carcinomas of the brain.28 Carswell was an accomplished artist in both watercolors and etching, and provided the over 2,000 watercolor plates (“my coloured delineations”) of these different pathological processes. He was able to offer only his “visual” view of these tumors as the underlying cellular pathologies had not yet been worked out. To make the images completely accurate, Carswell engraved them on stone (lithography) for printing. According to Sir William Osler, “these illustrations have, for artistic merit and for fidelity, never been surpassed, while the matter represents the highest point which the science of morbid anatomy had reached before the introduction of the microscope.”29

a, b (a) A page from Hooper′s landmark work on the morbid anatomy of the brain, with some of the earliest illustrated pathological drawings of diseases and tumors of the brain.26 (b) A hand-colored illustration by Hooper showing a “cystic” lesion of the right inferior temporal lobe. Clinical details were not provided on this patient.26

One of the most beautifully illustrated neuropathology atlases to come out in this period was by Richard Bright (1789–1858). Bright′s atlas on diseases of the brain and spinal cord was issued as the second volume of his two-volume work. The atlas was published in 1831 and titled Diseases of the Brain and Nervous System, under the general title of Reports of Medical Cases.30 Although Bright is best remembered for his description of glomerulonephritis (Bright′s disease), he also provided several original graphic and clinical descriptions of diseases of the CNS. Within this volume are 25 elegant colored plates along with over 200 autopsied cases of neuropathological diseases. Bright categorized these conditions into five pathological phenomena: (1) inflammation and febrile illness; (2) mass lesions causing surrounding pressure, hemorrhage, or stroke; (3) concussion from outside phenomena; (4) irritation; and (5) deficient blood circulation leading to insufficient blood supply. It appears that the first illustrated example of a pediatric pontine glioma with obstructive hydrocephalus is illustrated and provided with a clinical description. Bright also provided several other interesting clinical histories of patients with brain lesions. He noted that patients with increased intracranial pressure could develop paresis and eventually lapse into coma. Cases were described in which were premorbid clinical findings of screaming, agitation, and convulsions. Clinical complaints of headaches (typically dull), tinnitus, visual loss, loss of consciousness, and eventually coma were outlined in his clinical histories. Case CLXIV (p. 349) is a typical example where he describes a “tumour in the brain” in a man who initially presented with a headache and then numbness of the right arm. This progressed to a complete right hemiplegia, loss of speech, and eventually death on his 26th day of hospitalization. Bright did the autopsy and found a lesion in the left cerebral hemisphere. He illustrated the gross anatomic findings of this patient in this work. Despite these elegant findings, clinicians had to wait more than 30 years before Paul Broca (1824–1880) and Carl Wernicke (1848–1905) were to make the definitive anatomic and clinical association of the left hemisphere lesions with expressive (Broca′s) and receptive (Wernicke′s) aphasia.31,32 To Richard Bright we owe an extraordinary debt of gratitude for a work that was clinically quite advanced and to this day still contains some of the most beautifully illustrated examples of brain lesions ever published ( Fig. 1.13 ).

The first half of the 19th century was a prolific period for the publication of atlases and textbooks demonstrating various pathological processes. In the area of pediatric neuro-oncology, another strikingly beautiful atlas was published in Paris by Jean Cruveilhier (1791–1874) entitled Anatomie pathologique du corps humain (1829–1842).33 Cruveilhier was the first professor of pathological anatomy at the Paris School of Medicine. He was also affiliated with the Salpêtrière, an interesting institution at this time as it was originally built as a hospital, but historians now describe it as more of a prison for female destitutes and incurables. By 1822 it was a “grand asylum of human misery” containing 3,900 incurables, 800 insane people, and 360 sick people.34 To this hospital Cruveilhier was proudly attached (or so he states in his preface!), and from this institution came his abundant autopsy material. This clinical material appeared in this atlas, which was issued in a series of fascicles dealing with all parts of the human body. Of interest to this chapter are several illustrated examples of meningiomas, cerebellopontine angle tumors, and epidermoid tumors (tumeurs perlée), along with several spinal cord pathological specimens. The exquisite watercolor illustrations only rarely have been exceeded in their accurate graphic details. This pathology atlas has remained a benchmark to which all other pathological atlases are compared ( Fig. 1.14 ).

a, b (a) A hand-colored illustration by Hooper showing a series of brain lesions, including a dura-based meningioma (upper left), an intrinsic cortical lesion (upper right), and an abscess of the sagittal sinus (bottom).26 (b) A hand-colored illustration by Hooper showing a dura-based lesion that he described as “fungous tumor of the dura,” likely a meningioma.26

A work important in the incunabula period of neuropathology, one without any illustrations, was that by a Frenchman by the name of Claude Francois Lallemand (1790–1853). As an intern at the Hôtel Dieu he had seen a great deal of pathology, and it was his goal to classify this material in a useful medical handbook. To do this, he issued a three-volume work (1820–1825) of over 1,500 pages entitled Recherches anatomico-pathologiques sur l′encéphale et ses dépendences.35 It was Lallemand′s goal to present a work that classified diseases of the brain solely on pathological grounds. To do this, he was influenced by Morgagni′s presenting a series of clinical cases with autopsied material to further document the clinical history. Germane to this chapter are the numerous early descriptions of brain tumors that Lallemand described as fibrous, fibrocartilaginous, cartilaginous, or osseous. This work predates the use of microscopic investigations, so these techniques were not yet available. Despite the lack of microscopic detail, this remains an important work, completed in the pre–cerebral localization era. With the works of Bright, Cruveilhier, and Lallemand, we see the origins of thought underlying an understanding of the pathology and clinical details of brain tumors along with some elegant pathological illustrations.

Disorders of the spinal cord were also being brought to the attention of clinicians. An early example was the work by Charles Prosper Ollivier d′Angers (1796–1845), an anatomist, pathologist, and clinician, who published a monograph entitled De la moelle épinière et de ses maladies.36 The author had felt that disorders of the spinal cord were often ignored at autopsy, and it was his intention to correct this oversight. He presented 65 cases with two interesting illustrated examples. Breaking these cases down, he classified spinal disorders under several headings, including congenital malformations, atrophy, trauma, compression, commotion, induration, tumors (tissus morbides développés), among others. Of importance to this chapter is the earliest illustrated example of a spinal root tumor. This tumor originated from the first thoracic spinal root, causing 2 years of severe pain to the patient, who eventually committed suicide. At autopsy the tumor was found to be soft and solid, and containing a concentric arrangement of fibers on cross section; it is likely that this tumor was what we would call a schwannoma or neurofibroma. d′Angers is also remembered for describing and coining the term syringomyelia 37 ( Fig. 1.15 ).

(a) Title page from volume II of Bright′s Medical Reports, in which he details several cases of brain tumors and in particular a pontine glioma.30 (b) Bright′s illustration of a hemisphere lesion that had bled and contained “fungating” material.30 (c) Bright′s description of a diffusing infiltrating tumor of the pons, likely a low-grade glioma. Bright′s describes a “morbid enlargement of the Pons Varolii, involving the third, fourth, fifth, sixth, seventh, and eighth pair of nerves, all of which were soft, and somewhat indistinctly seen.” (From legend of plate 11.)30 (d) In this illustration of a brain lesion, Bright notes that he has made the cut just off the midline (of the pons). The pons has been replaced with a diffusing infiltrating tumor, findings that now would most likely be consistent with a pontine. Clearly present is diffuse infiltrating pattern in which the “whiter matter” [sic] has been disrupted. Bright also noted the small hemorrhages that have been elegantly detailed in this illustration.30
(a) Illustrations of “fungating” tumors arising from the dura, eroding bone, and with surrounding hyperostosis and erosion through the skull. These are dura-based lesions and represent what we now call meningiomas.33 (b) The earliest known illustrated lesion of what we would now call an olfactory groove meningioma (top two images). The lower images are an example of convexity dura-based meningiomas with expansion and displacement into the underlying brain.33 (c) Cruveilhier and Richard Bright were among the first to illustrate intrinsic lesions of the brainstem. Illustrated here is a large exophytic lesion, which is distorting and expanding the pons Varolio.33 (d) In this illustration Cruveilhier has done a sagittal cut through the pons and mesencephalon. A diffusely infiltrating lesion is detailed along with small punctate hemorrhages.33 (e) One of Cruveilhier′s most memorable illustrations, in this case an epidermoid tumor infiltrating throughout the brainstem. He described the tumor as having a “pearl-like” (tumeur perlée) appearance.33 (f) Cruveilhier also had an interest in spinal cord pathology, and here provides one of the earliest known illustrations of a spinal cord tumor that had hemorrhaged. Cruveilhier detailed the devastating consequences of these types of bleeds.33

Modern histological pathology as we know it now began its development in the 19th century. With the work of Xavier Bichat (1771–1802), the science of histology was inaugurated; his studies revealed that organs do not exist solely as basic units but rather are made up of tissues.38 This was further elaborated in the writings of Matthias I. Schleiden (1804–1881) and Theodor Schwann (1810–1882), who elaborated the cellular theory.39 These new concepts were applied to cellular disease by the great German pathologist Rudolf Virchow (1821–1902), who postulated the fundamental concept of Omnis cellula e cellula (“each cell comes from a cell”).40 The importance of this work can scarcely be overstated; it is not only the cornerstone but also the very foundation of cellular pathology. Virchow′s theory that the seat of disease as well as any developed tissue could be traced back to the cell prompted his dictum Omnis cellula e cellula to be added to William Harvey′s (1578–1657) Omne vivum ex ovo (“every living thing from an egg”). From this viewpoint came the new concept that from the cell can come both normal and abnormal (i.e., cancerous processes). Virchow published some 35 papers on neuropathology including several on tumors of the brain and congenital anomalies. These new concepts firmly put to rest the age-old doctrine of the humoral theory that had been in existence since the 2nd century AD when first postulated by Galen of Pergamon ( Fig. 1.16 ).

These new findings and concepts prompted several innovative investigations of the CNS. A prominent figure from this period and one best remembered for some of the earliest accurate neurologic contributions was Jean Marie Charcot (1825–1893). Charcot assumed the chair of pathological anatomy at the Faculty of Medicine in Paris in 1872 and went on to have one of the most productive careers of any figure in the history of medicine. Charcot believed very strongly in the postmortem examination, and, using some very simple staining techniques, he described several neurologic diseases including amyotrophic lateral sclerosis, bulbar paralysis, multiple sclerosis, tabes dorsalis, and several of the muscular dystrophies.41 Continuing the recently developed views of abnormal pathology underlying disease, Charcot provided several accurate descriptions of pathological processes involving the CNS.

There were several prominent physicians in the latter half of the 19th century who contributed to the then-evolving views of cancer of the nervous system. Space limitations preclude a full discussion of all the personages involved, but several do merit mention. Alois Alzheimer (1864–1915) was the founder of the Munich school of neuropathology. He is remembered eponymically for his work on the organic mental diseases of arteriosclerosis and premature senility. Alzheimer′s talent for illustrating lesions is evident throughout his work, and his profusely illustrated works contain some of the earliest and finest examples of cancerous lesions of the brain.42 Contemporary with Alzheimer was Franz Nissl (1860–1919) of Heidelberg, a pioneer in the techniques of histopathology, without which little understanding of what is normal versus abnormal in the brain could be understood. Nissl devised several histological stains that he then used to delineate various pathological processes within the CNS. In 1904 Alzheimer and Nissl published a remarkable six-volume work entitled Histologische und histopathologische Arbeiten über dis Grosshirnrinde. In this work are detailed some of the earliest and finest examples of pathological processes of the brain.43 The German schools were exceptionally productive at this time, with techniques and stains for study of the CNS being developed by Alfons Maria Jakob (1884–1931), Max Bielchowsky (1869–1940), Carl Weigert (1845–1904), and Walter Spielmeyer (1879–1935). With the rapid introduction of the microscope into neuropathology and of special stains that reveal both normal and abnormal pathology, the CNS was now being examined for a better understanding of what cancers of the brain and spine entail.

a, b (a) A contemporary engraving of C.P. Ollivier d′Angers (1796–1845). (From the author′s collection.) (b) Illustration from C.P. Ollivier d′Angers′s book on the spine showing a lesion of the spinal nerve root (T1), likely representing a neurofibroma or schwannoma.36

With the introduction of anesthesia in the 1840s, of anti-sepsis in the 1860s, and cerebral localization in 1870s, the medical team could now put a patient asleep for painless surgery and remove a pathological lesion with a markedly reduced risk of infection. Even the brain lesions could be more accurately located, in part due to the recently developed concepts of cerebral localization. Using a neurologic examination and localization of lesion by pathological findings gave the clinician the ability make a preoperative determination of where the lesions might be localized and thereby direct the surgeon where to operate. Now nearly 150 years later, computers are taking over this task, with image-guided frameless surgical systems. Soon the surgeon will be relegated to merely data entering—plugging in positioning coordinates while computers and robots complete the task.

In the 19th century surgeons were becoming more adventurous, having developed a better understanding of the etiology and subsequent removal of cancerous lesions. But having said this, the surgical morbidity and mortality remained exceptionally high. Fundamental to reducing operative morbidity and mortality was the innovative work of Joseph Lister (1827–1912),44,45 who continued the fine English tradition of surgery and made one of the greatest advances to surgery ever—the introduction of antiseptic technique. The control of infection and its reduction has led to profound changes in surgical technique and dramatically improved postsurgical outcome. Surgical mortality has dropped from 19th century rates that were as high as 95% to as low as 1% now with markedly reduced rates of infection. One cannot underestimate the profound effect the Listerian antiseptic techniques had on surgery; without this contribution it was almost always a hopeless situation when it came to surgery of brain or spinal tumors ( Fig. 1.17 ).

These recent developments of anesthesia, antisepsis, and cerebral localization had a dramatic influence on the practice of surgery and in particular neurosurgery. These new techniques were to encourage the Scottish surgeon William Macewen (1848–1924) to undertake a surgery on July 27, 1879, that successfully removed a dural-based lesion.46 Macewen was a surgeon and lecturer in surgery at the Royal Infirmary, Glasgow, Scotland, and surgeon to the Hospital for Sick Children in Glasgow. The patient was a 14-year-old girl who had presented with a supraorbital periosteal tumor a year previously, which had been removed. She re-presented with progressive headaches, swelling over the eye, and seizures involving her right side. Macewen applied a large trephine over the lesion and found under the skull a dural-based lesion that he was able to remove completely. The patient rapidly recovered and returned to normal health. When Macewen published his landmark book in 1888, he had operated on 21 cerebral cases with 18 recoveries and only three deaths—a dramatic reduction in both morbidity and mortality.45,46

(a) A cabinet photograph of Rudolf Virchow taken in his early twenties, at the beginning of a brilliant career. (b) An early photograph of Virchow′s pathology laboratory at the Institute of Pathology at the Charité Hospital, Berlin, Germany. Virchow amassed a huge collection of specimens, both human and animals, that he spent a lifetime cataloging and using in developing his cellular theory. Unfortunately, in the two world wars, many of the specimens were lost or destroyed. (c) The lecture room at the Institute of Pathology, Charité Hospital. Virchow is at the lectern addressing a large international audience—a common sight in the latter half of his career. Physicians and scientists traveled from around the world to hear his views. (Courtesy of the Institute of Pathology, Charité Hospital, Berlin, Germany.)

Another landmark case in neurosurgery also occurred in England, in 1884. For the first time an intraparenchymal brain tumor was removed by surgery. Rickman John Godlee (1849–1925), a general surgeon and a nephew of Joseph Lister, undertook the surgery after having quickly adopted Lister′s techniques of antiseptic surgery. Godlee was able to remove a lesion that had been diagnosed and localized by A. Hughes Bennett (1848–1901), a neurologist. This is the first case where the recent introduction of cerebral localization principles and a neurologic examination were used to localize a lesion that caused specific alterations in motor or sensory functions.47,48 The case involved a 25-year-old man named Henderson who, for 3 years, had had a succession of focal motor seizures. They started as seizures of the left face and progressed down the arm and leg. Six months prior to surgery, he presented with weakness of the arm. An eye examination done just prior to surgery revealed papilledema and hemorrhages. In addition, the patient had developed severe headaches and vomiting. On November 25, 1884, at the Hospital for Epilepsy and Paralysis (now known as Maida Vale Hospital, Regent′s Park, London), a trephination was done over the fissure of Rolando (localized by Bennett); Godlee then made a cortical incision, and a tumor was found at the depth of ⅛ inch. The tumor was encapsulated and enucleated piecemeal and found to be a glioma. Unfortunately, the patient died a month later of meningitis complications, an interesting irony considering the recent progress in antisepsis surgery ( Fig. 1.18 ).

(a) An albumin print or “cabinet card” of Joseph Lister at about the age of 50. (b) Lister detailed his principles of “antiseptic” surgery in several papers. In the beginning, these principles were met with a great deal of resistance. It was not until the 1890s that surgeons routinely washed their hands, and in some cases wore sterile gowns and created a sterile field.45 (c) Illustrated here are two “carbolic” sprayers introduced by Lister to “spray” the operating room prior to the start of surgery, part of his principles of “antiseptic” surgery.

Furthering this theme of collaboration between a surgeon and a neurologist led another English surgeon, Victor A.H. Horsley (1857–1916), to successfully removed a spinal cord tumor in 1888. The patient had been worked up and diagnosed by William Gowers (1845–1915), a prominent London neurologist.49 Gowers′s patient had presented with a slow but progressive loss of motor function in his lower extremities. Gowers was able to localize a level for the lesion in the spine and point Horsley to the right surgical level. Horsley performed a laminectomy at the surgical site and removed the tumor. The patient did well and made uneventful postoperative recovery. These innovative individuals laid the foundation work not only for neurosurgery but also for modern neuro-oncology ( Fig. 1.19 ).

The first textbook to reflect modern views of neuropathology and brain tumors was written and illustrated by Byrom Bramwell (1847–1931) and first published in 1888.50 Bramwell graduated from the University of Edinburgh in 1869 and first entered into private practice with his father and later joined the Royal Infirmary of Edinburgh as physician and pathologist. He is remembered as superb clinician and expert diagnostician, along with also being a popular teacher with large, well-attended classes. Early on he developed a vested interest in diseases of the nervous system, and he published two books on the nervous system that are now classics. The first book, published in 1882, addressed diseases of the spinal cord.51 The second book, published in 1888, addressed intracranial tumors50 and immediately became a classic standard work of the 19th century. This work appeared just shortly after the classic cerebral localization studies of Char-cot, Broca, Ferrier, and others. Aggressive investigations in the 1870s and 1880s had localized various neurologic functions to specific areas of the brain. Bramwell carried these studies even further by noting the clinical effects of pathological brain tumors and their disruption of neurologic function, which he offered as further evidence of regional brain function. Bramwell was also the first to describe the effects of pituitary tumors on the hypothalamus, and he was an early advocate of neurosurgery; he was quite excited about the surgical efforts of Victor Horsley and William Macewen. From a case report came Bramwell′s following poignant observations:

The brilliant results which Macewen has obtained in cerebral surgery, and which Victor Horsley has recently published, seem to prove that the expectations which Hughes Bennett formed when he first advocated the operation were well founded. And, thanks to antisepsis, the dangers of trephining are now so slight, that in all cases of intracranial tumour in which substantial improvement is not obtained by the administration of iodide of potassium (early chemotherapy? [author′s comment]), the possibility of removing the new growth by operative procedure must be carefully considered.51(p. 249)

A case report by Bennett and Godlee on the first successful surgical removal of an intraparenchymal brain tumor. The tumor was localized by a neurologist, A.H. Bennett, and then removed by a general surgeon, R.J. Godlee.49
A landmark paper in neuro-oncology and neurosurgery in which a successful collaboration between a surgeon and a neurologist led to the diagnosis, surgical location, and then removal of a spinal cord tumor. The patient did well.50

Bramwell then goes on to outline what he felt were the most important conditions for successful operative interference:

1. Successful localization of the tumour…. 2. The tumour must be assessible…. 3. The tumour must be single and of such a pathological character as to permit of complete enucleation or removal…. In the case of multiple tumours, such as secondary deposits of cancer or melanotic sarcoma, operative measures for the removal of the tumour are of course quite out of the question. Hence the great importance of exact diagnosis, not only as regards the position of the tumour, but also as regards the pathological character of the new growth.51(pp. 249250)

In retrospect these are clearly very prophetic comments made at the beginning of the modern era of neurosurgery, neuropathology, and neuro-oncology ( Fig. 1.20 ).

(a) Title page from the first American edition of Bramwell′s work on intracranial tumors.50 (b) An intraparenchymal brain tumor, after tumor resection, most likely a glioblastoma multiforme, described as a gliosarcomatous lesion in Bramwell′s monograph on brain tumors.50 (c) Title page from Bramwell′s early work on diseases of the spinal cord along with descriptions of spinal cord tumors.52
(a) Photograph of Cushing (bending over patient) seeing a postoperative patient at the Brigham Hospital. He is surrounded by his staff and some visiting faculty. (From the author′s collection.) (b) Title page from the first monograph to provide an early and detailed classification of brain tumors based on their histogenetic correlation by P. Bailey and H. Cushing.54 (c) A schematic of the proposed classification of brain tumors based on histogenesis of the cell type.55

The foundation of our present-day classification of brain tumors was started by the pioneering American neurosurgeon Harvey Cushing (1870–1939), who began the classification of brain tumors first with his pioneering clinical and surgical work on tumors of the pituitary gland.52 Further neuropathological and neurooncological studies were provided in his monograph on acoustic nerve tumors published in 1917.53 For neurooncologists, the landmark studies done by Cushing, in collaboration with P. Bailey (1892–1973), on classifications of tumors of the CNS set the benchmark.54 Essential in any clinical treatment is an understanding of the underlying pathology, its characteristics, and it growth patterns; with these types of foundation studies, clinicians have been able to develop protocols to treat various tumors and other oncological diseases. Bailey and Cushing′s classification of brain tumors was clearly the first real effort to develop protocols, following up Bramwell′s original work that laid an important foundation for neuro-oncology ( Fig. 1.21 ).

A Nobel Prize–winning technical achievement was accomplished in the 1890s, a technique that revolutionized the concept of how we deal with brain tumors—the addition of the “Röntgen Ray” to clinical armamentarium.55 At the end of the 19th century, nervous system was assessable only by direct examination, which in many cases led to dire outcomes and consequences. A dramatic change occurred in medicine with Röntgen′s discovery of the X-ray. For the first time internal structures of the human body could be visualized by noninvasive techniques. For clinicians, Röntgen′s work was further refined with serendipitous finding of William H. Luckett (1872–1929), who had studied a patient with a frontal skull fracture and spontaneous pneumoencephaly.56 On the X-ray Luckett immediately recognized that the air within the ventricles provided a contrast to see internal structures and thereby could possibly outline underlying pathology. Walter Dandy (1886–1946), a neurosurgeon, and Kenneth D. Blackfan (1883–1947), a pediatrician, took this investigation one step further and introduced the ventriculogram/ventriculography/encephalography techniques, which involved introducing air into the subarachnoid space by a lumbar puncture.5761 Dandy and Blackfan originally designed these studies to better understand the mechanism and pathology of hydrocephalus. These techniques evolved into a diagnostic test for intracranial tumors and other pathologies, and became the diagnostic standard for CNS examinations until the later introduction of computed tomography (CT) and then magnetic resonance imaging (MRI). By analyzing very subtle shifts and deformations on the pneumoencephalogram, the surgeon, for the first time, could better localize the abnormal pathology, a huge advance in tumor surgery ( Fig. 1.22 ).

a, b (a) A “pneumoencephalogram” from one of Dandy and Blackfan′s studies. This technique is rarely used now; my last case was in 1982 when I assisted one of my attendings at the New York Neurological Institute. These studies have been replaced by CT and MRI along with several other advanced imaging paradigms.59 (From the author′s collection.) (b) One of the early models of a CT scanner created by Sir Geodfrey N. Hounsfield. This was one of the great scientific inventions of the 20th century. The contribution of this technology to medicine has been immeasurable! (On exhibit at the Science and Technology Museum, London, England.)

Believing that the brain remained a “dark continent,” Antonio Caetano de Egas Moniz (1874–1955), a Portuguese physician and statesman, developed and perfected a technique of introducing a nontoxic contrast dye into the arteries62; by introducing a contrast medium, clinicians could now “visualize” brain vessels on X-ray. Moniz′s book on arteriography, which contained 189 arteriograms, was published in 1931, and it laid the foundation of modern arteriography.63 Moniz provided yet another seminal leap in the discovery and treatment of intracranial and spinal pathology. Moniz was awarded the Nobel Prize in 1949, not for this work but for his studies on the surgical treatment of psychiatric disorders by frontal lobotomy.

One of the single greatest contributions to the diagnosis and treatment of brain lesions was the introduction of the computed tomography by Godfrey N. Hounsfield (1919–2004).64 He came up with the concept of the CT scanner from an idea he developed that one could determine what was inside a box by taking a series of X-rays/gamma rays at various angles.65 Using a computer, he then analyzed each of the X-ray angles and developed a “slice,” or tomogram. Summing together these slices with mathematical algorisms led to computed tomography. The original experiment took 9 days to complete, but he quickly got that down to 5 minutes, and now modern machines compile these images in a matter of seconds.

In a grand rounds lecture given during my residency, Houns-field described how he took his first CT prototype and used it on formaldehyde-fixed human brain. He later tried this on a fresh cow brain, and then he conducted a CT on himself. The first clinical CT was done at Morley Hospital, Wimbledon, England, on October 1, 1971. I vividly remember this lecture and the first electromagnetic interference (EMI) scan that I saw at the New York Neurological Institute—a small Polaroid image with very little contrast! Hounsfield was awarded the Nobel Prize in Medicine in 1979 for this work, the first engineer to receive a Nobel Prize in the category of medicine. This technique of CT, along with MRI, has revolutionized how we look at the brain and other internal structures. Although radiology is never pathology, there is no question that these techniques have clearly enhanced our ability to treat patients with oncological disorders by using noninvasive techniques.65

Computers have had an enormous impact on medicine and science. From CT and MRI to image-guided frameless brain surgery, these machines are integral to our lives as physicians and surgeons. A breathtaking achievement is discussed in the following quotation, which clearly details how far and how fast we have come from the introduction of the CT scanner in the 1970s:

If you want to see real nanotechnology in action, check out Intel′s Penryn computer chip. It contains some 820 million transistors each with features just a few tens of nanometers across. These transistors are so small that more than 2 million can fit on the period at the end of this sentence. A device inside each one flips an electrical switch on and off as many as 300 billion times a second. In the time it takes for one such flip, light travels less than half a centimeter.66

We have come a long way from the first mechanical computer constructed by Charles Babbage (1791–1871) using the “0” and “1” concept. The machine would have been able to do only the simplest of calculations, and it occupies a large floor space and stands nearly five feet in height. Babbage is now considered the “father of the computer.” This machine is now exhibited at the London Science Museum.67


Cancer remains “the emperor of all maladies,”1 but we have come a long way from Imhotep, who could offer no cure for cancer. In reviewing history from antiquity to the 19th century, there was clearly little to be offered for the treatment of cancer. In fact, the treatments offered were barbaric: bleeding, purging, cathartics, and hot cautery! We have seen dramatic changes in pediatric neuro-oncology in the past 150 years, and many significant medical and surgical advances have been made. The cell was discovered, anesthesia and antisepsis were introduced, and, thanks to the pioneering work of Cushing, Horsley, and others, the brain and spine were no longer forbidden territory for the surgeons. However, the “cure” of pediatric neurooncological lesions remains not in the hands of surgeons but in the hands of the oncologists and scientists. Modern technology makes it much easier now to locate pathological lesions. Surgeons can remove them and provide tissue for a pathological diagnosis, but the final cure resides in turning off that malignant cell, eliminating its immortality, and in turn stabilizing the cellular system. Much has been contributed to these efforts, and the subsequent chapters in this book discuss these most important neurooncological advances and techniques ( Fig. 1.23 ).


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Jun 28, 2020 | Posted by in NEUROLOGY | Comments Off on Pediatric Neuro-Oncology: A Historical Perspective
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