THE AMERICAN JOURNAL OF CANCER A Continuation of The Journal of Cancer Research

VOLUMEXXXIV NOVEMBER,1938 NUMBER3

STRUCTURAL DEVELOPMENT IN GLIOMAS

H. J. SCHERER, M.D. (Frorn the Dtparlrnent of Pathology, Bzrnge Institute, Antwerp, Belgium)

In a morphological study of tumors the purely cytological characteristics, the neoplastic structures formed by the tumor cells, the gross aspects of growth and extension of the tumor, the stages of architectural and cellular development may each be especially considered. Most tumors are classified by their structural characteristics; thus one speaks of adenocarcinoma, scir- rhous carcinoma, alveolar carcinoma, etc. Gliomas, on the contrary, since the work of Bailey and Cushing (2), are classified essentially on the basis of cytologic or even histogenetic characteristics. Recently investigators have become interested in the study of the develop- mental stages of neoplastic structures and the laws regulating their evolution. Ewing (8) has insisted upon the importance of studying “ developmental stages, variations in structures, age, rate of growth and local reactions” in tumors. W. Fischer and his pupils have presented, for the first time, a series of investigations on the laws governing structural development in certain adenocarcinomas (3, 5, 7, 9, 11, 19). For several years we have made a systematic study of the structural evolu- tion of the gliomas (22, 23, 24, 25, 26). This group of tumors, because of the enormous structural variability found even in a single neoplasm, presents a fascinating problem. Our research has had a double purpose: first, to analyze the laws governing structural development in gliomas; second, to attempt the application of these rules of growth to tumors in general. Because gliomas grow in an organ in which the tissue structures are both variable and highly differentiated, they are especially favorable for a study of the influence of preexisting structures on the architectural evolution of the tumor. This is our first attempt to bring together our observations as a whole. At present we are concerned with a description of the structures seen in gliomas and their development both in and of themselves and as they are modified by preexisting tissues. The application of these observations to future classifica- tion of gliomas, the study of the causes of the variations observed in the differ- 333 334 H. J. SCHERER ent gliomas, and the genetic relation between the glial reactions and glioma growth must be the object of further research.

MATERIALAND METHODS This work is based upon the microscopic study of 100 gliomas, including the entire tumor and surrounding structures, by means of large celloidin sec- tions taken in many different planes. This method approximates an incom- plete serial section study of the tumor and adjacent tissue. All the gliomas were from autopsy material since we believe it is necessary to examine the entire brain. The celloidin sections were stained by the Nissl, van Gieson and Achucarro methods. Smaller portions of the tumors were examined in both frozen sections and paraffin embedded sections which, in specific instances,

FIG. 1. PRECOCIOUS PERISEURAL STRUCTURES FORMINGCAPSULES ABOUT NERVE CELLS. CASE 6/36 NISSL

were stained with hemalum-eosin, Mallory, Spielmeyer, Holzer, Bielschowsky, Cajal gold sublimate or scharlach as the occasion demanded. The sections were cut at 20 p to demonstrate clearly the architecture of the tumors.

A. SECONDARYSTRUCTURES

The term " secondary structures " is used to designate all those structures formed by the cells of the glioma which depend on the preexisting tissue ele- ments. These structural characteristics may be recognized even after com- plete destruction of the tissue elements by the tumor cells. Some of the secondary structures resemble in localization and form corresponding reactive formations. (1) Perineural and Ncuronophagic Growth: It is frequently observed that, as a glioma begins to invade the cortex or other mass of gray substance, the first manifestation of the neoplastic process is a collection of glioma cells about all or a great many of the nerve cells (Figs. 1 and 2). This we call perineural growth. Sometimes the neoplastic cells may be seen for a con- STRUCTURAL DEVELOPMENT IN CLIOMAS 335 siderable distance along the dendrites, particularly the apical dendrites of the pyramidal cells of the cortex. This picture may occur in a cortex otherwise relatively free of glioma cells (" precocious perineural growth," see Scherer, 24) or in a cortex already heavily infiltrated with tumor cells (" late perineural growth "). These cells are identical with the other tumor cells found in the region (Figs. 1, 2 and 3) and this, plus the great regularity of the phenomenon, easily distinguishes the process from a " satellitosis " or reactive neurono- phagia. If the collection of tumor cells replaces the nerve cells after their destruc- tion, we speak of the process as neuronophagic growth. In this case the groups of tumor cells may closely resemble the nerve cells in form and dis- tribution. This may occur in the isocortex and allocortex, in the brain stem, thalamus, and corpus striatum, as well as at other levels. In areas having a

FIG. 2. PRECOCIOUSPERIXEITRAL STRUCTURES FORMED BY MONSTROUSGLIOMATOUS CELLS REPL4rING TIIE Nt,itVE Ck1.I.S AND THEIRDEHnRITES. CASE 128/35. NISSL characteristic architectural pattern, such as the cortex, or the corpus striaturn the resemblance of the collections of the glioma cells to the normal architecture is striking (Fig. 4). This phenomenon has been observed as an occasional process in isolated cases by Storch (28), Landau (13), Stumpf (30), Ranke (18), Bielschowsky (4) and von Santha (2 1 ) , but was first described as a frequent form of glioma growth by Scherer in 1936 (24). (2) Surface Growth: Surface growth, first described by Storch in 1899 (28), consists in a more or less thick layer of gliomatous cells in the molecular layer of the cortex (Fig. 9) above a glioma of the white matter which does not involve the cortex generally. We have observed this phenomenon rarely on the internal surface of the brain, in the form of an extensive subependymal growth. This secondary structure corresponds to reactional surface gliosis but, like other secondary growths, is differentiated by the neoplastic character 3 36 H. J. SCEIERER of the cells. These glial borders, at first very thin, become progressively thicker and remain recognizable by their greater cellular density even after the whole cortex is markedly invaded by the glioma. (3) Perivascular Growth: In this mode of development, first described by Scherer (1937) as a frequent form of early growth, there is an arrangement

FIG. 3. LATEPERISEUR.\L ASD PERIVASCULAR STRL-CTURES IN A COKrEX ALREADYC0MPI.ETEI.Y ISVADEDHY THE TUMOR.CASE 150/35. NWL of the glioma cells outside the Virchow-Robin spaces (Figs. 3 and 4) about many of the preexisting vessels in a situation corresponding to a reactive peri- vascular gliosis. It may be differentiated from a true perivascular gliosis by the character of the cells, the regularity of the process, the predilection for small vessels of capillary and precapillary size, the sharply limited external borders and, in many cases, by the tendency to develop concentrically ar- ranged layers of cells (Fig. 3). Like the perineural growth, the perivascular growth may be seen at some distance from the compact tumor in areas other- wise totally free of tumor cells (precocious form). On the other hand, this characteristic structure may persist after the tumor cells are already fairly dense (Fig. 3). This phenomenon is much more frequent in the cortex and in the corpus striatum than in the white substance. The cellular nature of the perivascular cuffs varies with the cellular character of the rest of the tumor. (41 Pcrijasciczilar Grouith: Perifascicular growth is in accord with the observation of Strobe (29) that “ the gliomatous growth follows the paths of the preexisting nerves.” It is much less frequently seen, however, than was formerly supposed. It is observed most frequently in the deep portions of the centrum ovale at the interdigitation of radiations of the corpus callosum and the internal capsule, in the internal capsule itself, and in the cerebral peduncle. The tumor cells occupy the interfascicular spaces, following the STRUCTURAL DEVELOPMENT IN GLIOMAS 337 surface of the thick nerve bundles, without invading the bundles themselves. The resulting picture resembles a network made up of elongated, round, or ovoid links depending on the direction in which the section is cut (Fig. 5). (5) Zntrafascicular Growth: Growth within the bundles of nerve fibers, leaving intact their distribution, direction, and decussations (Fig. 6), was first

FIG. 4. PRECOrlOUS PLRIVAS(.ULAR 4ND PtRlStUR,\L STRUCTURES lh' TIlE PUTAMEN, IMITATISC PERFECTLYTIIE NORMALAHWITLCTURE OF THE CORPL~SSTRIATUM. CASE 204/35. NISSL

FIG.5. TYPICALPLRIFASTICULAR STRZK TLTRES, CUT TRASSVERSELY.CASE 75/35. NISSL described by Scherer (25) in 1936. The picture thus produced resembles " central neurinoma '' or spongioblastoma unipolare (Cox, 6). We believe this type of growth to be a simple secondary structure which is rather infre- quently seen, but may occur under favorable conditions in entirely different cytological types of glionia. Once developed, it maintains its characteristic 338 H. J. SCHERER

FIG. 6. INTRAFASCIC171.AR GROwlH IN A GLIOBLASTOMA MULTIPORMEGAXCLIOIDES IN THE ISTERNAL CAPS1TI.E. CASE 64/37. NISSL The tumor imitates perfectly the normal fasciculation and stops exactly at the border of the caudate nucleus (above). Under the higher magnification (below) the cells are seen to have as- sumed an elongated form.

appearance even when the area has become densely invaded by tumor cells (Fig. 6). It occurs most frequently in spongioblastoma multiforme and the most beautiful examples are seen in the internal capsule, corona radiata. (6) Zrrterfibrillary Growth: Essentially the same as intrafascicular growth, interfibrillary growth is quite different in appearance, consisting of long col- STRUCTURAL DEVELOPMENT IN GLIOMAS 339

FIG. 7. I’YPICAL INTERFIBRILLARY GROWTII,IN THE INTERNAL CAPSULE. CASE 21/37. NISSL

FIG.8. DIFFUSEGLIOBLASTOMA, SIIOWINC IN PLACESA GROWTHPURELY IN THE WHITESUBSTANCE, RESPECTINGTIIE CORTEX, AND IN OTIIER PLACES A PURELY INTRACORTICAL GROWTH RESPECTINGTIIE WHITESUBSTANCE. CASE 75/35. NISSL umns of gliomatous tumor cells perfectly parallel and equidistant from each other and following the course of nerve fibers (Fig. 7). It is a more rare type than either perifascicular or intrafascicular growth and we have observed it only in the internal capsule. In the areas of the cortex, which normally possess a marked radial striation, one occasionally sees radial striations of gliomatous cells (Scherer, 25). This cortical form, also rare, may possibly be considered as a form of interfibrillary growth. (7) White and Gray Matter Growth: The fact that many gliomas are limited to the white matter and in their growth stop short of the cortex or 3 40 H. J. SCHERER nuclei has long been known. We have (23) described the great frequency of this form of growth as well as the opposite phenomenon, namely a systematic intracortical form of growth without invasion of the white matter. The in- tracortical growth is certainly much more rare than the growth limited to the white matter and is never found in pure form. It is seen locally in gliomas which in other situations present a predominant growth in the white matter and even stop short of the cortex. Fig. 8 shows an extensive glioblastoma which clearly illustrates this phenomenon. As these forms of growth depend

Ftc:. 9. COMRINATION OF PRECOUIOCS SIII’ERFIUIAL, PERIVASCULAR, AID PERINEURAL STRIJCTLIRKS. CASE 27/57. VAN GlESOS The perineural growth is seen only in the deep layers of the cortex. entirely upon pre-existing structures they fit well into the classification of secondary structures. (8) ComOinations of Secondary Structures: In many glioblastomas certain constant combinations of different secondary structures are encountered. The most frequent is a combination of perivascular, neuronophagic, and surface growth (Fig. 9). Indeed, neuronophagic growth hardly ever appears without being accompanied in the same area by perivascular and superficial growth. Superficial and perivascular growth, on the contrary, may be seen without accompanying neuronophagic growth. The combination of these three types is much more frequent than their isolated occurrence. Less frequently there is seen a combination of intrafascicular growth with perineural and perivascu- STRUCTURAL DEVELOPMENT IN GLIOMAS 341 lar structures. This occurs at the level of the striatum where, in the myeli- nated striations, the intrafascicular structure may be seen, while in the gray matter, on the contrary, a neuronophagic and perivascular growth is present.

B. AMORPHOUSARRANGEMENT OF CLIOMA CELLS When the cells of a neoplasm fail to show any characteristic architecture we speak of an amorphous arrangement of cells. The lymphosarcoma is an

FIG. 10. CANALICULARPROPER STRUCTURES IN AN EPENDVMOMA.CASE 52/37. NISSL example par excellence of such an arrangement, with uniform cells regularly distributed. Such a structure is characteristic of many gliomas, especially typical astrocytomas, medulloblastomas, and oligodendrocytomas. Transfor- mation from an amorphous condition to secondary structural growth is some- times seen in astrocytomas in areas of dedifferentiation. Glioblastomas appear amorphous at times in a transitional stage, after the disappearance of secondary structures and before the appearance of proper structures.

C. PROPERSTRUCTURES The term proper structures may be used to designate all those structures in a glioma which do not depend on preexisting tissue but are an expression of the intrinsic architectural potentialities of the tumor cells. These are the structures which have been carefully studied in the past by Bailey and Cushing (2), Hortega ( 12), Penfield ( 17), Roussy and Oberling (20). Although these forms are so numerous and variable that a schematic presentation is difficult, they may be classified in five principal groups. (1) Canalicular or glandular structures (Fig. 10). These consist of tubes in which the lumen is lined by cells resembling epithelium. In the literature these structures have been most commonly described in ependymomas and in neuroepitheliomas, 342 H. J. SCHERER

(2) True papillary structures (Fig. 11) in which the formations of glial cells cover, more or less regularly, extensions of mesenchymal stroma. Such a true polypoid form as seen in Fig. 11 is rare, but the perivascular crown (the “ perivascular pseudo-rosette ” form of Bailey, or the “ gliovascular system ” of Hortega) which develops about vessels of the tumor proper is not uncom- mon in neoplasms of an expansive type of growth (ependymomas). Ordi- narily this cannot be confused with the secondary perivascular structures of gliomas of the infiltrative type. ‘The latter consist of a collection of tumor cells about preexisting vessels. The distinction may be difficult in the so- called astroblastoma of Bailey and Bucy (1). According to our experience, however, the perivascular arrangement in astroblastomas appears to be a secondary structure.

FIG. 11. PAPILLARYPROPER STRUCTURES. CASE 84/36. NISSL

(3) The irregularly intertwined fascicular form resembling a so-called “ fibrosarcoma.” This develops as a late stage in glioblastomas (Fig. 12) and is independent of preexisting fiber fasciculation, as it is found preferentially in the cortex or subcortical regions, where there are no such interwoven fibers. Elsewhere fascicular proper structures appear only long after destruction of the preexisting structures, and their complex intermingling is much more irregular than that seen in our intrafascicular secondary structures. A con- fusion between the two is impossible. These forms are independent of the mesenchymal tissue, which frequently becomes very prominent in the late stages of glioblastomas. They may be differentiated by stain for collagen and re ticulin. (4) Symplastic formations, consisting of collections of tumor cells occur- ring as spheres, bands, or whorls. Although they are rare as compared to the fascicular structures mentioned above, they appear in bizarre arrangements in widely different locations, in the white matter a5 well as the gray, in the advanced stages of various gliomatous tumors, Figs. 13 and 16 show ex- amples of this structure. STRUCTURAL DEVELOPMENT IN GLIOMAS 343

F~Gs.12 AND 13. FASCICULARPROPER STRUCTURES IN THE CORTEXAND SUBCORTICALWHITE MATTER (ABOVE)AND SYMPLASTICPROPER STRUCTURES IN THE CORTEX(BELOW). CASES 131/35 AND 6/36. hTISSL

(5) We may have an arrangement of nuclei in heaps, more or less volu- minous, in bands or in palisade formations (Fig. 17) which have a certain regularity. The localization and distribution of these formations and the stages at which they arise in the tumor permit easy differentiation from cer- tain secondary structures which they may resemble. 314 H. J. SCHERER D. TERTIARYSTRUCTURES By tertiary structures we mean certain formations which are brought about by the interaction of the glioma with the proliferating mesenchymal tissue of the tumor. In this group we do not include the angioplastic formations (22) characteristic of certain gliomas, for these generally remain fairly limited from the surrounding gliomatous tissue and as a result are distinctly recognizable. We consider only the more or less massive proliferation of mesenchymal fibers which develops in the living gliomatous tissue or which organizes necrotic areas. The first type, the most frequent especially in the advanced stages of cortical gliomatosis, results from an invasion of the glioma by meningeal connective tissue. A definite fasciculated appearance (Fig. 14) is seen which may be differentiated from secondary or proper fasciculated structures by appropriate staining methods. Connective-tissue organization of necrosis in gliomas is rather rare. When it does occur, the cicatricial fibrous tissue may be invaded by glioma cells. Structures may then be seen which resemble the architectural appearance of scirrhous carcinoma, such as narrow columns of tumor cells in densely com- pact and hyalinized connective tissue (Fig. 15 ) . The so-called " carcinoma- tous " structures in gliomas, mentioned by Singer and Seiler (27), are ac- cording to our experience seen only in these areas of cicatrical mesenchymal tissue.

E. EVOLUTIONARYSTAGES OF GLIOMASTRUCTURES Our systematic studies of a large collection of gliomas have shown that in the majority of cases the structures are not at all stable but in their evo- lution pass through stages which follow certain laws and have a tendency to repeat themselves. In this study we have been able to distinguish four modes of structural development. ( 1) There are gliomas which form only proper structures both at the be- ginning and throughout their development. These are tumors which have an expansive type of growth and do not infiltrate the presxisting nervous tissue. This fact alone excludes the possibility of the development of secondary structures. The best example of this type is found in tumors of the epen- dymoma group. These tumors have a relatively stable structure and are comparatively rare (3 per cent) in our material. (2) A second group of gliomas, of essentially infiltrating type, show from the beginning an amorphous structure without the development of proper or secondary structures even though the pregxisting tissue invaded by the tumor is readily visible and apparently unchanged. The best example of this group is the typical astrocytoma. Because the preexisting structures are preserved the failure of development of secondary structures is explicable only by some intrinsic factors in the glioma growth process itself. (3) In a third type of glioma, growing in an infiltrative fashion, the zone of growth presents with great regularity a structural evolution of three stages (Figs. 16 and 17). First are seen variable secondary structures, followed by an amorphous cell arrangement and finally by the appearance of different STRUCTURAL DEVELOPMENT IN CLIOMAS 34s proper structures. This succession of structures is regular and of frequent occurrence in the growth zone of tumors showing little differentiation and gen- erally classified as glioblastomas. The invasion of the cerebral cortex, for example, occurs in the following manner: first a certain number of tumor cells are seen dispersed in a cortex (Fig. 16~and 17~)in which the architecture is still perfectly recognizable. The outer contour is preserved or even accen- tuated by the surface growth, and the molecular layer is recognizable by the absence of nerve cells or neuronophagic glioma cell collections. The archi- tecture of layers I1 to VI remains clearly visible either because the nerve cells are well preserved or because they have been replaced by tumor cells which

FIGS. 14 AND 15. TERTIARYFAsciru1.w STR1.CTL’RES Ih’ THE CORTEX (LEFT)AND TERTIARYSTRUC- TURES WIT11 A CARCISOXIATOUS APPEARANCE IS A CLIOBLASTOMA(RIGHT). CASES 298/34 ASD 1238/32. NISSL form neuronophagic collections. Dense growth of glioma cells finally replaces the cortical architecture by a completely amorphous formation. The molecu- lar layer, the zones of superficial growth, the perineural or perivascular struc- tures, the cortical layers are no longer visible. Only the contour of the con- volutions remains preserved for a long time (Fig. 17c). Finally, after in- vasion extends into the meninges (Fig. 16~),even this line of surface contour disappears and frequently proper structures appear at the same time in the amorphous masses of the intracortical neoplastic cells. Fig. 16 shows these stages of evolution of cortical invasion in a glioma which produced curious symplastic structures (Fig. 13). More frequently fascicular structures or nuclear collections or palisades (Fig. 17~)are observed. Finally the archi- tecture becomes more complex due to the evolution of tertiary structures pro- voked by the mesenchymal tissue. This process which we have described in the cortex occurs in essentially the same order in other portions of the brain. FIG.16. THREESTAGES IN TIIE CORTIC’AL GROWTH OF A GLIOMA, TIIE SAME MAGNIFICATIONAND THE SAME SECTION. CASE 6/36. NISSL A. Perineural structures. B. Amorphous structure with disappearance of the perineural struc- tures and invasion of the meninges. C. Symplastic proper structures (see Fig. 13).

346 STRUCTURAL DEVELOPMENT IN CLIOMAS 347

Secondary structures are more prominent in the gray matter than in the white matter because of the great richness of its preexisting architecture, This type of structural evolution is, according to our experience, by far the most frequent. In many instances the final stages are not attained. Death may intervene, or regressive changes such as necrosis and organization may appear in the amorphous stage before the development of proper struc- tures. If, however, all portions of such a tumor are examined, areas which clearly demonstrate this evolution will almost always be encountered. The rapidity with which one stage follows the other and the persistence of sec- ondary structures are extremely variable in different tumors. Frequently the development of proper structures is only vaguely recognized by a certain f asciculation. (4) There is a fourth type of glioma, which destroys preexisting struc- tures so rapidly that there is no framework for the development of secondary structures. In these forms the amorphous cellular arrangement appears early and may or may not be followed by proper structures. The medulloblastoma is the typical example of this type of development, but it is occasionally seen in certain glioblastomas. This group is quite different from group 2, in which the amorphous character exists in spite of the preservation of preexisting tissue.

DISCUSSION The systematic study of the glioma architecture and of its development has shown the great frequency of secondary structures, which are glioma cell structures essentially influenced by the architecture of the preexisting tissue. The perineural, perivascular, and surface structures are each found in about 35 per cent of our 100 cases. If we exclude those tumors showing an expansive type of growth (ependymonias) and those showing a primary amorphous structure (medulloblastomas, pure astrocytomas, and certain forms of glio- blastoma), the percentage increases to over 50. The secondary structures of the white substance (perifascicular, intrafascicular, and interfibrillary ) are less frequent, being seen in only about 10 per cent of the cases. Since these structures are only stages in development, these percentages must be con- sidered as minimal and as giving merely an indication of distribution. As opposed to the great frequency of the various secondary structures, the proper structures are much more rare. We have encountered tubular forma- tions in only 4 per cent, true papillary structures in 6 per cent, and syniplastic structures in 7 per cent. Fasciculated proper structures, palisading, and ar- rangements in small groups are more frequent, but do not occur in more than about 25 per cent. Furthermore, these structures are usually restricted to circumscribed areas of the tumor. The secondary structures, on the contrary (principally perineural and perivascular structures), tend to be widely dis- tributed. We must conclude that the architecture of gliomas depends much more fre- quently on the preexisting tissue than on inherent architectural potentialities of the glioma cells themselves. This helps to explain the great structural variations in different parts of the same glioma. It is an essential character- istic of all secondary structures that they change in different areas depending 348 H. J. SCHERER on the architecture of the locality invaded. It can be seen, then, why tumors having a strictly expansive type of growth and following only the lines of their proper architectural potentiality show a more uniform structure. The fact that amorphous cellular arrangement is seen from the beginning in certain tumors (astrocytomas), even with preservation of preexisting tissue, proves that the formation of secondary structures is also a special expres- sion of the structural potentialities of the neoplasm. Tumors may be seen with no secondary structures; in some, secondary structures are rudimentary or short lived; in others secondary structures occur late and only in the coni- pact parts of the glioma, and in still another group the secondary structures are the first manifestations of the neoplastic process in a given area. These differences in architectural behavior must also be an expression of the essential biological characteristics of the neoplasm. Since the biological behavior of a tumor is capable of changing at any moment, in a tunior having generally the amorphous structure of a typical astrocytoma there may be one small area with dedifferentiated cells showing the formation of secondary structures. As the structural evolution of gliomas is an expression of their essential biological differences, this must be taken into consideration in any future classification of gliomas. The architectural development should be given the same weight as differences in localization, manner of extension and celluiar form. In the future, a classification based upon cellular differences alone will not be satisfactory, especially since the differences in structural behavior in no wise coincide with the cytological differences. Identical secondary struc- tures, especially perineural and perivascular, may be formed by glioma cells which differ greatly morphologically. On the contrary, growth respecting the preexisting fasciculation provokes elongated tumor cells, while in other areas of the same neoplasm the cells have an entirely different shape. Our studies have shown that a progressive evolution of structures (and cellular forms) is the rule in the majority of gliomas having an infiltrative type of growth. This statement is of considerable practical importance since the few earlier investigations dealing with progressive changes in tissue character in gliomas (Tooth, 31; Globus, 10; RIiiller, 16) give the impression that such evolution is exceptional. We must now consider it not as an exception but rather as the general rule. We have already called attention to the resemblance of certain secondary structures in gliomas to corresponding glial reactions. Thus, for example, perineural growth corresponds to reactive neuronophagia, and perivascular and superficial growth to reactive perivascular and superficial gliosis. These resemblances, however, do not indicate the cause or the genesis of these sec- ondary structures. At present, two possibilities suggest themselves, Either there is a neoplastic transformation of the presxisting glial cells (for example, the satellites of nerve cells, and perivascular and marginal glial cells), or a selective migration of tumor cells toward these respective preexisting struc- tures. Secondary structures developing in the white matter always depend on fasciculation and so may easily be explained on mechanical grounds. A mechanical explanation for perineural, perivascular, and superficial structures does not appear possible. FIG. 17. STAGES IS TIIE CORTIC'AI. GROWTI1 OF A GLIOHLASTOMA, THE SAME SECTION AND THE SAME MAGNIFICATION. CASE340/.56. NISSL A. Perineural structures with conservation of the molecular layer. B. More dense perineural growth, disappearance of the molecular layer. C. Amorphous structure. D. Appearance of proper structures in palisades and in irregular nuclear masses. 349 3 50 H. J. SCHERER

Finally, we must briefly compare our statements on the development of structures in gliomas, as given in this report, to similar studies on other types of tumors. Unfortunately, systematic investigations of this question hardly exist. The investigations of the school of W. Fischer have demonstrated that the architectural formation of certain adenocarcinomas and their metastases is entirely independent of the types of tissue invaded (Dabelstein, 7). On the other hand, the observations of Masson and Oberling (15) have shown that liver metastases of primary carcinomas of the breast may imitate per- fectly the preexisting trabecular structure of the liver. Here the cancer cells create tissue structures resembling closely those of the organ destroyed. These two different observations indicate the principle that the architecture of carcinomas may be dominated at one time by the proper structural tendency of the carcinoma tissue itself and at another time by the secondary structures, in the sense that we have described for gliomas. We seem to be dealing with essential biological differences which may be found in tumors having widely different histogeneses.

SUMMARYAND CONCLUSIONS (1) A systematic study of the structural evolution in 100 gliomas has been made, by means of large celloidin sections taken in multiple planes and in- cluding the whole tumor with its surrounding tissue. (2) Glioma structures depend upon the preexisting nervous structures (secondary structures) or upon primary architectural properties inherent in the glioma cells (proper structures). The structure of a glioma may be in- fluenced, also, by connective tissue which invades the tumor (tertiary struc- tures). When the cells of the glioma are uniformly and evenly distributed, the structure is described as amorphous. (3) The following secondary structures are described: perineural or neu- ronophagic growth, perivascular growth, superficial growth, perifascicular, in- trafascicular and interfibrillary growth, and elective growth in gray and white matter. (4) The proper structures are classified as canalicular, papillary, fas- cicular, and syniplastic structures, and ribbon and palisade formations. (5) The secondary structures play a much more important r61e in the architecture of most gliomas than do the proper structures. Certain rare gliomas, having a strictly expansive type of growth (ependymomas) do not develop secondary structures. Infiltrating gliomas do not always develop secondary structures, sometimes because of the extremely rapid destruction of the preexisting tissue (medulloblastonias, certain glioblastomas) , but certain other infiltrating tumors remain amorphous in spite of the perfect conservation of the preexisting tissue (typical astrocytomas). (6) Three stages of structural evolution are encountered in the majority of gliomas. Various secondary structures are first formed, followed by an amorphous arrangement and finally by the various proper structures. (7) There are marked differences in the structural development of gliomas. These variations must be considered as an expression of the fundamental biological differences of the tumors themselves, and must be taken into con- STRUCTURAL DEVELOPMENT IN GLIOMAS 351 sideration in any future classification together with localization, mode of extension, and cellular appearance. (8) Gliomatous structures differ in the same tumor depending upon the area invaded (different secondary structures) and upon the age of the tumor (different stages of the structural evolution). Stable structures in gliomas are rather rare. (9) At present differences between gliomas in respect to structural evolu- tion are unexplained. The etiology of the curious secondary structures is also unknown. (10) A review of the literature suggests that carcinomas also show dif- ferences of structural development in the sense that either proper structures or secondary structures may appear to predominate. This suggests that there are broad and general laws which determine the morphological evolution of all neoplasms.

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