NEUROBLASTOMATA: WITH A STUDY OF A CASE ILLUS- TRATING TIIE THREE TYPES THAT ARISE FROM THE SYMPATHETIC SYSTEM.* H. R. WAHL, M.D. (From the Pathological Laboratories of Western Reserve University and Lakeside Hospital, Cleveland, Ohio.) SYNOPSIS. I. INTRODUCTION. II. REVIEW OF THE LYrERATURE: (a) Ganglioneuromata; (b) embryology of the sympathetic system; (c) malignant neuroblastomata; (d) chromaffine tumors; (e) discussion of the tables of the cases: I. Table I., ganglioneuromata. 2. Table II., malignant neuroblastomata. 3. Table III., chromaffine tumors. III. REPORT OF A CASE: (a) Clinical history; (a) post-mortem examination; (c) the tumor tissue: i. Macroscopical description. 2. Microscopical description. A - Differentiated nerve tissues (ganglioneuroma). B -Undifferentiated nerve tissues (malignant neuroblas- toma). C - Chromaffine tissues (paraganglioma). (d) Summary; (e) anatomical diagnosis. IV. DIscusSION: (a) Relation of the tumor to the sympathetic system; (b) differentiated nerve tissue elements (ganglioneuroma); (c) cystoid forma- tions; (d) myeloid tissue; (e) undifferentiated nerve tissue elements (malignant neuroblastoma); (f) vascular changes; (g) nature of the tumor tissue as a whole and its relation to nerve tumors in general; (h) nomenclature; (i) diagnosis. V. SUMMARY AND CONCLUSION. INTRODUCTION.- It is becoming recognized, especially in the last four or five years, that the most highly differentiated tissue of the body - the nerve tissue - may and does fre- quently undergo blastomatous change. True nerve tumors, i.e., growths consisting of specific nerve tissue elements, may * Received for publication Feb. 25, I914. (205) 206 WAHL. occur in any part of the nervous structure, but by far the greater number of them have their origin in the sympathetic system. These tumors may be either benign or malignant, and though they often differ widely in their structure, behavior, and occurrence, yet they are closely related onto- genetically. Both the benign and malignant forms are most frequent and best illustrated in the sympathetic system. The former includes the ganglioneuromata and the chro- maffine tumors, in both of which the cells are more or less highly differentiated -depending on the rapidity of their growth and their location. The latter is represented in the central nervous system by the gliomata. Outside of the rentral nervous system, this form was not generally recog- nized until the last four or five years. It originates in a blastomatous change of undifferentiated and embryonic nerve cells. In the peripheral ganglia it forms what Marchand has termed the neurocytoma. In the sympathetic system, where almost all of the reported cases, especially the more malignant ones, have been found, often associated with the adrenal gland, it is composed of the embryonic formative cells (" Bildungszellen") of the sympathetic system. The development of the present knowledge concerning these true nerve tumors is outlined in a very brief review of the literature. REVIEW OF THE LITERATURE: (a) Ganglioneuromata. - The term neuroma was first used by Odier, in I803, to designate " deep-seated tumors which are characterized by painful swellings of the nerve involved." Later, it was employed more loosely, being applied to any tumor in rela- tion to a nerve, and indicated an overgrowth of the connec- tive tissue sheaths of the nerve. Then it became entirely a clinical term regardless of whether the tumor to which it was applied was an inflammatory swelling, a metastatic growth, or a new formation of nerve tissue, and it was not until I863 that the pathology of neuromata was placed on a histologi- cal rather than a clinical basis. In this year Virchow cleared up the confused status of the neuromata and made a sharp NEUROBLASTOMATA. 207 distinction between the true and the false forms. Accord- ingly, the true neuromata arise in the nerve tissue, and are composed essentially of nerve elements. The false neuromata have their origin in the interstitial connective tissue of the nerves. Virchow sub-divided the true neuromata into: (i) the neuroma gangliocellulare, containing newly formed ganglion cells; (2) the neuroma fibrillare amyelini- cum, consisting chiefly of non-medullated nerve fibers; and (3) the neuroma fibrillare myelinicum, composed mainly of medullated fibers. He also pointed out that undoubtedly the nervous nature of many neuromata had been overlooked, because the non-myelinated fibers were mistaken for connec- tive tissue fibers, and many of the ganglion cells and nerve fibers had disappeared through pressure atrophy and degeneration, and had been replaced by fibrous tissue. While Virchow admitted the possibility, he did not believe that a true neuroma containing proliferating ganglion cells had been carefully described and proved to be such without question. Gunzberg in I847 reported such a case, but Virchow did not consider his description sufficiently com- plete or convincing to warrant his diagnosis. The first well authenticated case of a ganglioneuroma was that reported by Loretz in I870. This was followed by Axel Key's case in i879 and Weichselbaum's ganglioneuroma in adrenal gland in I88I. No cases were reported for the next eighteen years until I 897, when Busse and Borst each described a typical ganglioneuroma. From this time on similar tumors were reported with gradually increasing frequency. The following year Chiari and Knauss each reported a case. The latter gave the first careful descrip- tion of multiple neuromata situated in the subcutaneous tissues all over the body. Knauss believed that all of the tumors of his case bore a direct relation to the blood vessels, and that they were derived from the sympathetic cells embedded in the sympathetic plexus about these vessels. He maintained that most, if not all, true neuromata had their origin in the sympathetic system, a view also held by 208 WAHL. Czerny, and suggested that many multiple neuromata con- taining only newly-formed nerve fibers probably had gan- glion cells that either were overlooked or had gone to pieces in some stage of their development. In I9OI Beneke reported two cases of considerable inter- est. The tumor in his first case was a retroperitoneal pelvic growth, containing nerve fibers and ganglion cells that varied in size from that of small lymphocytes to fully developed large ganglion cells. Beneke believed that all of the nerve elements - sheath cells, ganglion cells, and nerve fibers- were actively proliferating. He also pointed out that the ganglion cells had no specific functional activity, because the fibers had no end organs. Furthermore, he maintained that in pathological new growths of nerve tissue a true new formation of fibers can arise only in relation to the ganglion cells. Beneke's second tumor is interesting in that it illus- trates the malignant transformation of a ganglioneuroma with metastases into the surrounding lymph glands. The tumor enclosed the aorta and metastasized into the surround- ing lymph glands. Many of the ganglion cells were scarcely recognizable, being large, irregular and more or less packed with nuclei, giving the appearance of multinucleated giant cells. Typical and atypical ganglion cells were present in the metastases. Beneke pointed out that in the metastases the cells have acquired an epithelioid tendency to line the alveolar framework, and that the ganglioneuromata were associated only with the sympathetic system, and were due to an embryonic fault, i.e., displaced cell rest. The first true neuroma of the central nervous system was probably that described by Worcestor in I9OI. The author believed that the ganglion cells in his tumor arose from small round cells with very little cytoplasm and a nucleus so rich in chromatin that no structure could be made out. He regarded these small cells as having an indifferent character, and as being capable of developing into nerve cells or glial cells. In I907, Oberndorfer, in describing a case of a ganglioneu- roma involving the adrenal gland, emphasized the intimate !EROBLASTOMATA. 209 association of the ganglioneuromata with the sympathetic system, maintaining that with a true new formation of nerve fibers there must also be newly formed ganglion cells and that every true neuroma must of necessity be a ganglioneu- roma. In the same year Falk from a brief review of the liter- ature concluded that in all cases there was a growth of nerve fibers and ganglion cells as well as glial cells and sheath cells; that most cases occurred in individuals under thirty years of age; and that the size of the tumor bore an inverse ratio to the age of the host. He also pointed out that with but two exceptions (Haenel and Axel Key) all the tumors arise in the sympathetic system. He did not believe that there was a ganglion cell for each nerve fiber, explaining the great preponderance of nerve fibers over the ganglion cells in three ways: (a) The nerve fibers represent the product of all genera- tions of ganglion cells that had existed and gone to pieces since the growth began; (b) a new growth of nerve fibers long after the ganglion cells have degenerated, and lastly (c) the development of nerve fibers from the sheath cells. He is thus the first of many workers on nerve tumors to support the cell chain theory of the origin of peripheral nerve fibers. He described many nerve fibers as arising from the cells of the sheath of Schwann through the continuous growth and differentiation of the protoplasm of the latter. In I908 Verocay described the case of a man with an endothelioma of the dura, many subcutaneous neurofibro- mata, several true neuromata involving spinal nerves, gliomata in the brain stem and a true neuroma arising in the trunk of the sympathetic system. He pointed out that multiple nerve tumors (the so-called neurofibromata) are not made up of connective tissue, but of true neurogenous tissue formed by nerve fiber cells (sheath cells) or by correspond- ing cells so altered that they are unable to produce the nor- mal elements of nerve tissue.