CANCER RESEARCH

VOLUME 25 FEBRUARY 1965 NUMBER 2

Nineteenth Century Foundations of Cancer Research Advances in Tumor Pathology, Nomenclature, and Theories of Oncogenesis'

VICTOR A. TRI0L0 (McArdle Laboratory, University of Wi8consin, The Medical School, Madison, Wisconsin)

SUMMARY This review discusses morphologic, taxonomic, pathophysiologic, and etiologic advances in nineteenth century oncology. Progress in research on human neo plastic diseases is examined with reference to the origins of experimental research on cancer and related diseases, described in a previous report. A critical bibliography accompanies the discussion.

CONTENTS Introduction 76 Connective Tissue Theory g4 Academic Impetus 76 Epithelial Theory 88 Peyrilhe 76 Endothelial Theory 89 Morgagni 76 Modern Foundations of Systematic Oncology 90 English, Scottish, and Irish Schools 76 Epithelial Tumors 91 Society for Investigating the Nature and Cure of Endothelial Tumors 91 Cancer 76 Connective Tissue Tumors 92 Early Surgical Research on Cancer 77 Etiologic Considerations 92 Later Trends in Tumor Pathology 78 Neoplastic Blastemas 92 French School 78 Traumatic and Irritative Stimuli 93 Beginnings in Pathologic Anatomy 78 Senile Disposition 93 Vitalist Movement 79 Interface Antagonism 94 Advances in Tumor Histology 79 Embryonic Rests 94 Consequences of Histogenic Research 80 Tissue Tension 95 Etiologic Currents 81 Anaplasia 96 German, Austrian, and Swiss Schools 82 Conclusious Precursors 82 Tumor Morphology 96 Blastema Theory 82 Cell Biology 97 Tumor Cells 82 Tumor Stromas 83 Inherent Susceptibility 97 Tumor Nomenclature 84 Environmental Carcinogenesis 97 Cellular Pathology 84 Research on Human Cancer and Exierimental Tu mor Pathology 97 ‘This work was supported by grant 5T4 CA 5002 of the Na- Addendum 97 tional Institutes of Health, USPHS. Received for publication October 8, 1964. References 98 75

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 76 Cancer Research Vol. 25, February 1965

INTRODUCTION Thus, theories of oncogenesis, especialiy before 1850, fre “Cancerresearch, or oncology, is not a science in itself quently had to be reconciled to more general pathologic but the simultaneous and frequently coordinated activity theories ; for example, the “humoralist―versusthe “solidist― of many independent scientific disciplines. . . . All these controversy. Views on the local development of cancer approaches have been directed toward the common aim of have similar historical roots : this thesis was defended by the elucidation and control of the neoplastic transforma Gendronas early as 1700 (Cancer, 9: 645—47,1956),yet the tion and like all applied sciences are nourished, sustained, dialogue between the “localists―and the “constitutional and invigorated by fundamental advances and discoveries ists―persisted well into the nineteenth century (110). In in these and related fields. They did not start from the dications of circumspect attitudes in the field of neoplastic same chronologic point, but each, as its usefulness became diseases mark several other significant precedents in the evident, joined the group which may be called the oncologic eighteenth century. sciences (J. P. Greenstein, Biochemistry of Cancer [162]).― ACADEMIC IMPETUs This report will outline the formation and early progress of several of the above implicated research trends within the Peyrilhe.—Although neoplastic diseases have occupied a principal clinical schools of the nineteenth century : (a) the prominent place in medical thought from ancient times, English, Scottish, and Irish Schools; (b) the French School; interest in the subject began to intensify among medical and (c) the German, Austrian, and Swiss Schools. The writers during the eighteenth century (475, 1 : 119—122). specific objectives encompass (a) a summary of salient Additional evidence of this circumstance appears in the research developments, including a key to the critical stress given cancer research by scientific societies of the literature,2 in the formative years of modem oncology, and period. For example, the French Royal Academy of Sur (b) a review of precedents in pre-modern oncology which gery in 1732 and the Lyon Acoxkmy of Scieiwe in 1773 promoted the realization of experimental programs (405). offered prizes for original essays on the question, “Whatis Crucial research issues will be given emphasis in the text Cancer?― (115). The latter prize was awarded to the and footnotes. surgeon-chemist Bernard Peyrilhe in whose work (1774 The organization into geographic divisions, specifically [306; also 307]) appears the first recorded cancer experi regional schools, does not imply separate modes of thought ment, the inoculation of a dog with cancer fluid from hu and influence : the schools were mostly interdependent. mans; this is described fully by Woglom (474). Peyrllhe's Nevertheless, by virtue of a common tongue, each school study ranks among the earliest to differentiate malignant comprised a unique forum of ideas through its professional growths from hyperplasias and benign lesions. For similar societies and prints. Close professional ties also tended to observations contemporary with those of Peyrilhe see preserve the regional character of research in the nine Astruc (20) and le Dran (113). teenth century. Virchow and Remak were students of Morgagni.—In 1761 the Paduan anatomist Giovanni Johannes Muller, and Virchow, in turn, educated a sue Battista Morgagni published, On the Sites and Causes of ceeding generation of gifted domestic and foreign workers. Disease (274), in which he laid the foundations of patho There are several significant exceptions to this rule ; for logic anatomy on the organ level. Morgagni's work per example, Hermann Lebert (originally Lewy) was a student mitted an advance in cancer research by strengthening the of many masters and an investigator of truly international conception of cancer as a local disease through descriptions proportions. Proper names, professional descriptives, and from numerous autopsies of neoplasms at various sites. locations cited in the text are authorized from biographical Morgagni distinguished malignant neoplasms from benign data in Ackerknecht (2), Wolff (475), Fielding H. Garri swellings—aneurysms, strumas, gummas, exostoses, stea son's, An Introduction to the HIIstOry of Medi@,ine (4th ed., tomas, etc. This represented a first step toward the later Philadelphia and London: Saunders, 1929), and Haber establishment of a sound taxonomic framework for neo.. ling, W., Hübotter,F., and Vierordt, H., Eds. Biograph plastic diseases. isches Lexikon der hervorrangenden Arzte alter Zeiten und ENGLISH, SCOTTISH, AND IRISH SCHOOLS Völker(2nd. ed., Berlin u. Wien: Urban & Schwarzen @@@ Tii@ SocIE@rrFOR NATURE Ctm@i berg, 1929—34). OF CANCER Problems in nineteenth century oncology did not stand apart from a well established corpus of medical dogma. The first cooperative venture in oncology was promoted by a group of English clinicians who organized themselves 2 Behla's 1901 bibliography (35) lists approximately 5500 items, mostly from the 1880—1900period. Numerous titles appear in into a professional society about 1802. This movement the first series of the Surgeon-General's Index-Catalogue under was given impetus by the work of John Hunter, a student Cancer (Vol. 5: 664—669,1881), Tumors (Vol. 14: 861—896,1893), of Percival Pott the discoverer of ‘chimney-sweeps' cancer. and under other subject headings. Schmidt's Jahrbuch for 1892 Hunter (1786 [206]) suggested that tumors, although prod contains a critical review by Beneke (36) of the work on cancer ucts of lymph secretions, were structurally comparable to from 1886to 1891,and a review by Hauser on the carcinoma litera ture from 1891 to 1898 appears in the Centralblatt füraligemeine normal organ formations, a novel interpretation of the Pathologie und pathokgische Anatomie (1898 [182)). For con prevailing lymph theory of cancer to which Hunter sub temporary guides to the older and newer cancer literature the scribed. His students and associates, Everard Home reader should consult Oatfield (1950 [294)) and Donohue (1960 (surgery and anatomy), Matthew Baillie (pathology and [hiD. Juraj Körbler'sGeschichteder Krebslcrankheit(405, p. 4, anatomy), John Pearson (surgery and clinical medicine), n. 1) will be withheld from publication due to a lack of support through subscriptions. Inquiries on the future status of this work John Abernethy (surgery), and Thomas Denman (mid should be addressed to Verlag Palm & Enke, Erlangen, Germany. wifery), all members of the cancer society, explored the

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0Lo—Foundations of Cancer Research 77

new avenues suggested by Hunter's conclusion (1, 106, the dissemination of cancer through the circulation. 202, 301). Other observations on the morphology of tumors were The English cancer society aroused contemporary inter reported by the pathologist Thomas Hodgkin (1829) est in cancer by issuing among medical practitioners a [196}) who advanced a cystic theory of tumor genesis questionnaire (1802) published with a glossary in 1806 which proposed that the production of neoplasms occurred (316). The brochure covered the following aspects: (a) through simple or multiple cysts of unknown character. diagnostic signs of cancer; (b) nature of the precancerous This hypothesis was criticized by contemporary authors state; (c) relationship between cancer and other diseases; (e.g., Waishe [457, p. 43]) for its etiologic inadequacy. (d) hereditary origins of cancer (e) infectious nature of One of the most comprehensive tumor surveys of the cancer; (J) local and constitutional predisposition to middle period was issued by the Irish pathologist Walter cancer; (g) climatic and other geographical influences on Hayle Waishe who published (1844 [457], 1846 [458]) a susceptibility or resistance to cancer; (h) susceptibility of tumor nosology in which he correlated previously reported animals to cancers; and (i) spontaneous cures in cancer. data on gross anatomy with microscopic findings on tumors Appended commentaries to these questions urged im described by Muller (1838 [280]). Walshe assembled proved clinical observations and diagnostic technics. A these results into a tumor nomenclature comprising three reply to the queries was published by the Dublin surgeon types of cancer: (a) encephaloid ; (b) scirrhus; and (c) Richard Carmichael (1809 [76]) who deemphasized sus colloid. The encephaloid group included Abernethy's pected hereditary and infective influences; Carmichael medullary sarcoma, the fungus hematodes, and other stressed the constitutional source of cancer in ternis of an known varieties of ‘soft'cancer. The scirrhus group in iron oxide deficiency. eluded Abernethy's pancreatic and carcinomatous sar coma, and other previously reported ‘hard'cancers. The EARLY SURGICAL RESEARCH ON CANCER colloid, a new category, included neoplasms which will be mentioned in connection with the research of Cruveilhier William Hey (surgery) published in 1803 (191) a series and Muller. of observations on vascular tumors which he designated Walshe disclaimed contemporary theories which speci fungus hematodes. Tumors of this type were first de fled trauma, heredity, and chronic inflammation as local, scribed imperfectly as spongoid inflammation by the Glas excitory causes of tumors—although he believed that irri gow surgeon John Burns (1800 [73]), but their relationship tation could induce a predisposition to cancer—by suggest to infiltrating cancers of muscle, bone, and blood vessels ing as etiologic alternatives the ‘perverision' of nutritive and was explored more thoroughly by the Edinburgh surgeon secretory activities at the intervascular interstices of all James Wardrop (1809 [4611). Abernethy (1804 [1]), at organized tissues. This view followed the humoral ap tempting a classification of tumors according to anatomic proach (313 ; 457, p. 54) ; however, Waishe's ideas indicate structure, described eight types of ‘sacroma':(a) common the new trend toward empirical analyses of tumor struc vascular or organized; (b) adipose; (c) pancreas tissue-like; ture. (d) cystic; (e) mastoid or mammary; (J) tuberculated; (g) In 1849 John Hughes Bennett (39) published data medullary (identical to the fungus hematodes and later supporting contemporary arguments for structural distinc identified as a milt-like tumor by Monro (1811 [273]); and tions among epithelial neoplasms; i.e., between cancers and (h) carcinomatous sarcoma. Samuel Young, in 1813, first cancroids as proposed by Lebert in 1845 (233). Bennett related scirrhus (carcinoma scirrhosum) and encephaloid admitted that cancroids possessed a ‘cancerous nature' (carcinoma spongiosum) as species of the genus cancer or but not a ‘cancerous structure'; thus he was unable to carcinoma (457, p. 3). endorse Lebert's hypothesis on the existence of a path Hunter's tradition was continued in the work of Home ognomonic cancer cell, a conception advanced simulta who was one of the earliest investigators to employ the neously by Hannover in 1843 (167, 168). Bennett, who achromatic microscope in tumor research. In his well held that cancer represented one of many clinically dis ifiustrated treatise (1830 [203]) Home indicated homoge tinct species of destructive growth, contributed to the nous, spherical globules, which he assumed were equiv existing confusion in tumor taxonomy by introducing alent to lymph corpuscles, as the structural elements of several artificial distinctions into the cancroid neoplastic tissues. Sir Astley Paston Cooper (Surgery), nomenclature—i.e., ‘epithelial-cancroid.' He enlarged through microscopic research, distinguished benign an alleged category of ‘filamentous' or ‘fibrous'can growths and inflammatory hyperplasias, particularly of croids to include (a) sarcomatous, (b) desmoid, (c) the mammae (1829 [85]) and testes (1830 [86]), from scir chondroid, and (d) neuromatous varieties. rhoid and other true neoplasms. The pathologist RObert John Zachariah Laurence (1858 [232]) upheld Lebert's Carswell, by 1838 (77, 78), examined the structure of sev specific cell concept by distinguishing a unique cell type in eral widely distributed cancers (i.e., ‘scirrhoma' and epithelial tumors, and he supported the claims for Han ‘encephaloma'), and he was among the first to suggest nover's epithelioma as a local disease distinct from cancer. a At this time dogs were thought to be the only species subject Between 1847 and 1852 the problem was reviewed by the to cancer (see [291, p. 1671). The frequent occurrence of mam surgical pathologist Sir James Paget, who greatly assisted mary tumors (venereal sarcomas?) in dogs was noted by Car the work of bringing order to the systematics of neoplastic michael (1809 [76, p. 481]). For a review of the English Cancer diseases. In agreement with Virchow, Paget (1853 [299]) Society and a reproduction of their report see Michael B. Shimkin, Thirteen Questions: Some Historical Outlines for Cancer Research, challenged the alleged distinctions between cancroids, J. Nat. Can. Inst., 19: 295—315,1957. epitheliomas, and epithelial cancer by including all within

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 78 Cancer Research Vol. 25, February 1965

the same generic category. Moreover, Paget contributed through irritative influences—a view which adhered to to Virchow's creation of the modern concept of sarcoma Cohnheim's and Virchow's theories. Conflicting opinions by relating description of ‘flbro-cellular,‘‘flbro-nucleated,' were aired at an extended debate before the Pathologit@al and ‘recurrent-fibroid'tumors as a single category, each Society of London, March 7th to April 21st, 1874, (110) in member of which showed slight structural variations. which Morgan, Arnott, and others defended the bocalistic Paget included in this category the ‘fibro-plastic' tumors theory, whereas Sir William Jenner, Paget, and Simon of Lebert (1845) for which he substituted the term ‘mye upheld arguments for the constitutional theory. bid.' In 1884 the surgeon Sir William Savory (369) reviewed the localist and constitutionalist controversy with reference LATER TRENDS IN TUMOR PATHOLOGY to newer concepts on hereditary and infectious influences The impact of more circumspect views resulting from in cancer. He emphasized that the character of cancer research activities in France and Germany, also influenced in its later stages could differ markedly from its mode of the course of English laboratory programs after 1860. origins; thus, local beginnings and ultimate constitutional For example, in 1850 the surgeon Sir John Simon (382) manifestations were not incompatible assumptions. defined cancer as a neoplasm arising under the pressure of Moreover Savory stressed that the role of cells as “im some ‘mysterious'constitutional necessity: by 1878 Simon, mature forms demonstrating pronounced growth lability― “reflectingonthe present state and prospect of our knowl be especially considered in tumor pathology. Although edge of cancer―(383, p. 222), suggested (a) heredity, (b) the cancer cell resembled embryonic substance in its physi irritative stimuli, and (c) infective processes as primary cal character, it differed from the latter in its vital attri causative factors. At the same time he urged the im butes and life history—―inthe almost, if not quite com mediate application to the cancer problem of chemical plete absence of change of structure or of endowment―— and microbiologic technics. a distinctionof importanceforthe considerationsoftumor The scope of the new research is apparent in the work of taxonomists. In the last analysis, Savory (369, p. 38) the Cambridge anatomist Charles Creighton who reported conceded that, “beforewe shall ever be able to answer (1874—1876[95—97])that secondary and tertiary cancers the question of why or how do tumours form. . .we must were not simple offshoots of the parent growth but were be able to solve the problem of normal growth and de autochthonous to the site at which they occurred and re velopment.― suited from a ‘contact-influence' imparted by the primary The tenor of English cancer research in the 1880's and tissues to the host tissues. Creighton subsequently (1879 1890's, beyond the parasite theory (405, pp. 5—8),generally [98]) suggested that epithelium infiltrating the surrounding followed lines suggested by theories on the organic origins stroma resembled an infective process through which were of cancer, through (a) irritative stimulus in experimental established autonomous, though reactive (with connective situations (Power, 1893 [315]) or industrial situations tissue elements) pockets of alveolar cells. This conclusion (Spencer, 1890 [388], Marshall, 1891 [2631),(b) through the bridged contemporary views, spearheaded by Biliroth, dislocation of embryonic cells (Spencer-Wells, 1888 [389]) or Thiersch, and Waldeyer, on inherent neoplastic altera atypia@@lcellformations (Marshall, 1889 [262]), and (c) tions in normal tissues. It was also suggestive of early through a cometitutional or inherited susceptibility (J. ideas on the induction of tissue alterations in cancer Williams, 1880 [471], W. Williams, 1884 [472], Snow, 1885 through a pathogenic principle (W. Muller, 1871 [283]). [384], Butlin, 1887 [74], Woodhead, 1888 [477], Snow, 1893 The idea that epithelioma originated through a prolifera [385]). tive stimulus in epithelium which had migrated into the FRENCH SCHOOL connective tissue was similarly supported by Henry Arnott (1872 [18]). Histologic transformations in epi BEGINNINGS IN PATHoLOGIC ANATOMY thelioma were investigated by George Thin (1876 [402]) The practice of pathologic anatomy instituted by Mor who concluded, in agreement with Kiebs, that epithelial gagni was perpetuated in France by the anatomist-physiol growth in cancer occurred through an ‘apposition'of ogist Marie-François-Xavier Bichat who laid the founda lymph-cells and preexisting epithelium. The relation of tions for histologic research in his Anatomie générale(1801 lymphatic tissues in tumor genesis was further studied by [41]). In this work Bichat distinguished stroma and George Hoggan (1878 [201]). parenchyma in rudimentary terms, the former of which he Belief in the constitutional (diathesis) nature of cancer designated a ‘cellularsystem' common to all tumors. was upheld by Paget (1853 [299, @:791—795])who argued Bichat's crude ideas on cancer were substantially imple for hereditary transmission. In 1887 Paget (300) ex mented (404) by the internist Réné-Théophile-Hyacinthe panded this view by suggesting that two coexisting condi Laennec who classed cancers among the heterologousadven tions were necessary for the production of cancer: (a) a titious tissues—tissues which did not have normal organ specific ‘morbid'material, perhaps a microbe or virus, counterparts but were dv novo productions of pathologic which was disseminated through the vascular system ; and processes (1812 [225], also [34]). He listed as representa (b) a hereditary predisposition towards the reception of this tives of this type (a) tubercles, (b) scirrhus, (c) encephaloid neoplastic impetus. The doctrine of the local origins of or cerebriform cancers, and (d) melanomas. Laennec cancer was defended by the surgeon Campbell de Morgan (1815 [227]) related encephaboid tumors to the fungus (1872 [275]) who specified that cancer developed through hematodes, medullary sarcoma, and other ‘soft'cancers. isolated aggregates of anomalous enbryonic cells, derived He alsoadvancedthe ideaof neoplasticgrowthas a degen from neighboring tissues, given a proliferative impetus erative process of tissues (226).

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TrtIoLo—Foundations of Cancer Research 79

Priority for the identification of heterologous tissues was causes in the various pathways of irritation culminating in claimed by the surgeon Guillaume Dupuytren (271) who is inflammation. credited (411) withone ofthe earlier experimental attempts A modification of Broussais' hypothesis was advanced by to prove the infectiousness of cancer by feeding and inocu the pathologist Grabiel Andral (1829 [9]) who defined bating animals with fragments of malignant tissues from cancer not as a specific structural lesion but as a product of humans. A similar experiment was performed by Alibert nutritive alterations and aberrant secretory activities (des in 1806 (7). The pathologist Jean Cruveilhier extended ignated collectively as lesions of nutrition and secretion) to Laennec's plan of differentiation by devising (1816 [100]) a which inflammation was a contributing factor. According tumor classification based upon pathologic alterations in to Andral, cancer was a terminal event, manifesting itself neoplastic tissues. This development, although it pre as eroding, infiltrating ulcers, common to a wide variety of ceded application of the achromatic microscope to the nutritive and secretory derangements. He specified the problem, was a decisive follow-up to Morgagni's de source of cancer ‘morbidity' as an organized, coagulated scriptions of pathologic changes in diseased organs. mass of flbrin in the blood stream. This assumption un Cruveilhier defined cancer as a malignant degeneration, as derlay other vitalistic theories of this era, and Andral's generalized as inflammation, affecting all tissues, and he views were reflected in Waishe's humoralism. The excita identified two principal types: (a) scirrhus; and (b) car lion theory was given a more practical form by the anato cinoma (viz. encephaboides). However, he believed the mist Gilbert Breschet and the surgeon Guillaume-Marie only difference between these forms stemmed from the AndréFerrus (1822 [61]) who attempted to correlate the relative amounts of ‘cancer-juice'occurring in each. Colloid clinical appearances of cancer with the effects of irritation cancer, first described by Cruveilhier, was distinguished by and inflammation; however, they rejected the nihilism of him from other neoplastic types since it contained no Broussais by adopting the localistic emphasis upon the ‘cancer-juice.' By specifying ‘cancer-juice'asthe common early surgical excision of tumors. denominator of cancers Cruveilhier's views not only sup The Strasbourg pathologic anatomist Johann Georg ported the humoral theory (3, p. 117), but also approached Christian Friedrich Lobstein extended the hypothetical the pathognomonic concept of cancer (475, 1: 108). consequences of Broussais' doctrine by combining it with Although Cruveilhier inclined towards humoralism, Andral's ‘blood'theoryof cancer formation and other ideas Laennec's solidistic outlook was adopted by two internists, mostly appropriated from Laennec. Lobstein (1829 [240]) Gaspard-Laurent Bayle and Jean-Bruno Cayol (1812 [33]) proposed that all lesions resulted from a ‘plasticlymph,' who investigated the clinical manifestations of cancers and which, under the influence of a misdirected vital or ‘plastic' diseases which superficially resembled them; i.e., mammary force, became organized through coagulation and trans carcinoma and mastitis, ulcerating skin cancers (long formation into adventitious (heterologous) formations. known as Not me tangere) and intractable ulcerations. Lobstein designated this process as heteroplasz@z,and he They distinguished scirrhus growths from fibroid lesions, distinguished it from the natural (honwopla@tic)capacity of cartilaginous and fibrocartilaginous tumors, and melanotic the organism to preserve its original form through regen growths. Encephaboid or cerebriform cancers were distin erative and other growth phenomena. Among the hetero guished from the lesions of tuberculosis and scrofula at plastic tissues, which were deposited in organ interstices various sites. Their diagnoses prompted Bayle and Cayol, displacing normal tissues (Laennec's definition for degen in disagreement with Laennec, to argue for the constitu eration), Lobstein classed (a) scirrho-cancerous, (b) fungus tional nature of cancer, a conclusion apparently demanded medullary (viz. Abernethy's ‘sacroma'),and (c) melanotic by the appearances of cachexia and frequent recurrences. growths. Lobstein's theory was adopted by Astley Cooper and other investigators of the period. Tui@ VITALIST MOVEMENT A countercurrent in the French Clinical School pro ADVANCES IN TUMOR HISTOLOGY ceeded from the views of the internist François-Joseph Laennec (227, pp. 169—170)attempted to improve his Victor Broussais who opposed the solidism of Laennec by descriptions of neoplasms by observing macroscopically adopting a stheni.c doctrine of pathology. The idea that thin tissue slices, but work in this direction was limited by cancer was a manifestation of changes in the constitutional imperfections in existing lenses for microscopes. Eight ‘tone'or vigor through alterations in the organisms in eenth century attempts at microscopic examinations, such herent irritability, had been suggested by two English as by Muys (cited by Louis, 1774 [245]), added few details authors (Fearon, 1786 [133] and Nisbet, 1800 [291]). to a knowledge of tumor structure. In 1824 an achro Broussais (1821 [66]) reworked this assumption into the matic microscope, one of the earliest of its kind, was con hypothesis that neoplastic growth resulted from chronic structed for Silligues who presented the instrument to the Paris Academy of Science (475, 1 : 325). Achromatic inflammation inducing tissue damage through excessive microscopes were first applied to the study of plant and excitation. Broussais supposed that except for super animal tissues by Raspail (1827 [320]) and later by Brown ficially localized instances, cancer, as a generalized conse (1833 [67]), Schleiden (1838 [370]), and Schwann (1839 quence of inflammation, was incurable, but he also believed [377]). These events are part of the history of the Cell that it occurred infrequently since the disease was re Doctrine. The simultaneous application of the achro stricted to a single (inflammatory) mode of origin. Unlike matic microscope to the tumor problem by Johannes Laennec and Bayle and Cayol who defined malignant Muller (1838 [280]) constitutes one of the major advances growth as an alteration sui gensris, Broussais sought its in nineteenth century cancer research. The availability,

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 80 Cancer Research Vol. 25, February 1965

especially after 1860, of reliable fixatives and dyes (e.g., tumors, subscribed to the prevalent blastema theory—the aniline series) for histologic research constitutes another assumption that cells grew out of amorphous matricial or major development (see Epithelial Theory). vascular fluid elements. Although the Belgian histopathologist Gottlieb Gluge At mid-century, French investigators, working largely (1837 [154]), using achromatic lenses, reported the ap within the framework of the blastema theory, pursued the pearances of fluids from encephaloid tumors, the work of tumor. differentiation problem usually on the basis of the histopathologist and clinician Hermann Lebert more homeomorphic and heteromorphic separations (Cruveilhier, closely approaches Muller's examination of neoplastic 1849—1864 [101], Broca, 1866—1869 [64]). Lebert's ‘fibro tissues. Lebert (1845 [233]) described the form and plastic' tumors were becoming recognized by Robin (1849 dimensions of a unique cancer cell which he assumed as the [347]), Nélaton(1860 [286])—who described a ‘myoplaxic' characteristic element of all malignant growths, and he variety—and others, as types of sarcoma. Together with assigned this specific cell type to tumors of a heteromorphic Velpeau, the distinctions between cancroids and ‘true'can category (comparable to the heterologous and heteroplastic cers were critically examined by Kuss (1845 [222])—who series of Laennec and Lobstein), including the encephaloid, was among the first to relate the microscopic appearances scirrhus, and related forms. Tumors without this atypical of alleged epithelial tumors (cancroids) and ‘true'cancers element he classed as benign or Iwmeomorphic growths —by Michon (1848 [270]), and by d'Hôtel (1855 [204]). (comparable to the homologous and homeoplastic series of Michel (1857 [269]) and Demonchy (1867 [105]) regarded Laennec and Lobstein), which encompassed diverse va cancroids as true (glandular) epitheliomas. These events rieties such asepithelial, fibrous, fibroplastic (sarcomatous), coincided with other investigations on the cellular struc and cystic tumors. ture of epidermal tumors (Mayor, 1846 [266], Dupuy, Lebert established a subcategory of homeomorphic 1855 [116], Offier, 1856 [295], Heurtaux, 1860 [190]), tumors, the pseudocancers or cancroids, including ulcerating although the idea of cancroids as unique cutaneous lesions surface cancers, which otherwise bore a structural resem was not entirely overthrown by 1860. blance to true cancers except that they lacked the specific, distinguishing cell of the latter—namely, a cell having a CONSEQUENCES OF HISTOGENIC RESEARCH distinctive cytologic character. As a consequence of his As early as 1840 Muller's discoveries were made known contention he was forced to deny that cancroids possessed to French medical circles (Mandi [257]). However, the malignant properties. Lebert's work, continued in later consequences of this new knowledge and its climax in the publications (1850 [234], 1851 [235]), advanced the first Cellular Pathology was with few exceptions confronted in claims for distinctions in cancer on the cytologic level France by attitudes still attuned to the blastema theory. Laennec first distinguished cancer on the hietologic level Various workers (Lortet, 1861 [242]) accepted Virchow's following in the wake of newer pronouncements on the contention that cancroids and other cancers originated Cell Theory. He arrived at his conclusions from micro from undifferentiated elements of the connective tissues. scopic and physical diagnoses, and in a special work on In contrast, Michel (269, pp. 315—339)presented original malignant diseases (1851 [236]) Lebert separated cancers arguments not only against the specific nature of cancroids, from cancroids in the various organs, designating the but also conclusions approaching Remak's that carcinoma encephaloid as a prototype of the former. was of exclusive epithelial origins. More typical of the Lebert's specific cell concept was taken up by other period is the work of Robin and his collaborators (1853— French authors of the times (Sédifiot,1846 [379], 1865 [241, 258, 348—355])on mammary cancers (hetero.. Robin, 1848 [346]), but it was opposed by the Parisian ade,wmas). Robin traced the source of ‘heteroadenomas' surgeon Alfred-Armand-Louis-Marie Velpeau (1854 [409]) to an infiltration and hypertrophy of epithelium. He sug who, through extensive microscopic diagnoses of neoplastic gested that although the structure of ‘heteroadenoma' was tissues, was unable to identify a ‘specific' cancer cell. analogousto that of normal glandular epitheium, the neo Valpeau also denied any distinction between cancroids and plasm possessed neither the strict appearances nor the same ‘true'cancers by stressing that the former possessed the mode of origins as natural acinar tissues. Robin spoke of fundamental properties of the latter—the capacity to in the pathognomonic character of cancer cells and nuclei, and filtrate and metastasize. Moreover, Velpeau cited the of a unique form and arrangement of tissue constituents in universal disagreement among microscopists not only on mammary cancers. Although his ideas were credited by issue of the specific cell but on the entire micrographic later authors (Herrmann and Lesur, 1885 [187, p. 112]) as a record in oncology. For example, Lebert's report (1852— confirmation of the epithelial theory, they were too largely 1853 [2371) on ‘adventitious fibroplastic' neoplasms was phrased in terms of the specific cell doctrine and the thrown into open controversy (Marjolin, 1852—1853[261], theory of heteromorphic tissues to bring this view into Follin, 1852—1853[139]). Follin (1854 [140]) argued for sharp focus. the pathognomonic significance in cancer of atypical nuclei, Following Robin, Cornil (1865 [90]) attempted to nucleoli, and other nuclear inclusions, all of which corn demonstrate that the nuclei of acinar cells in tumors be bined to form the distinctive cell character, and he desig came isolated from the connective tissues in the prolifera nated this form as nuclear cancer. Courty (1851 [93]) tion of neoplasms. Although Cornil (1864 [87—89]), suggested a pathognomonic caudated cancer cell, resem Ranvier (1866 [319]), Demonchy (1867 [105]), and others blingsquamousepithelialcells, which evolved from preexist recognized the exact character of epithelial proliferation ing embryonal (cancer) constituents, whereas Broca (1852 in cancer they were unable to relinquish entirely the opin [63]), noting the highly diverse structural appearances of ion that epithelial growth originated in the connective tis

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TrtloLo—Foundations of Cancer Research 81

sues, and this attitude continued into later times (Lan Ledoux-Lebard also cited a successful experiment by cereaux, 1875 [228], Labbé and Coyne, 1876 [223], Klencke (?) who inoculated a stallion with melanoma Chambard, 1880 [79]). Conversely, Michel was followed fluids from a mare. Within four months Klencke allegedly by Laboulbène (1879 [224]) who, in the light of newer observed the growth of a melanoma at the implantation German research, rejected the role of connective tissues in site. On the basis of these two results Ledoux-Lebard the formation of cancer. (1885) concluded that only implantations among animals In the wake of more complete knowledge (by 1885) of of the same species would provide the key to success in tumor histogenesis there evolved a new concept of the transplantation research.) A position intermediate be neoplastic cell. This concept, entirely removed from the tween the diathesis and localistic views was adopted by specific cell doctrine, was framed in terms of omni@cellul,a e Téaffier(1836 [398]) who considered cancer a local disease cellula ejusdem naturae (all cells are derived from cells of the rooted in various unfavorable constitutional circumstances same nature). For example, the Lyon pathologist, Louis —heredity, menstrual irregularities, physical conditioning, Bard, from 1885 to 1895 (24—30),advanced the view that etc. undifferentiated precursors of cancer, in the strict sense of The diagnosis and curability of cancer was debated by Cohnheim's embryonic cell and Virchow's connective tis many high ranking clinicians before the Imperial Academy sue cell, were nebulous conceptions. Onthe contrary, cellu ofMedicine at Paris (1854—1855[108,109]). The localiste, lar specificity was endowed through differentiation of the under Velpeau, were opposed by the constitutionalists under ancestral type, and both normal and neoplastic cells re the surgeon César-AlphonseRobert who argued for Le tamed their primordial racial traits (theory of atavism). bert's hypothesis. Among other topics the practical value The neoplastic cell was distinguished through its capacity of microscopic diagnoses of neoplastic tissues, specifically for deviations from a reproductive norm, and Bard em form, structure, and pathognomonic significance of cancer ployed this viewpoint (referred to again later) in a tumor cells, nuclei and nucleoli, wasdiscussed. Asa consequence, classification based upon simple (fibro ; epithelio; adeno the clinical microscopist and chemist Henri-Marie Dela epithelio ; sarco ; neuro ; lympho) and complex (angio ; lym fond presented original cytologic research which severely pho-angio) formations. Other tumor classifications resem damaged the specific cell concept. bling Bard's appeared in France about the same time Delafond's comparative micrometric data on neoplastic (Cornil and Ranvier, 1884 [92]), and the systematics of tissues from humans and animals (Chart I) led to the fol epithelial tumors was given more detailed consideration lowing conclusions, translated from the French (1855, 109, by Malherbe (1885 [256]) and especially by Fabre pp. 403—405):(a) Normal cells, apart from the embryonic, Domergue (1898 [132]). are entirely analogous in microscopic appearances to so called cancer cells. It is impossible employing the best ETI0L0GIC CURRENTS microscopes, that is instruments with resolutions of 500 to The nihilism of Broussais appeared in the thinking of 600 diameters, to distinguish between these species. (b) Lebert who (234, 236) held that cancer originated through In their primordial states, fibroplastic, epithelial and can a humoral diathesis overlying some hereditary predisposi cer cells show no marked dissimilarities as to form, nuclei, tion; moreover, Lebert viewed the frequent recidivism nucleoli, or chemical character. (c) If, later, these three associated with cancer as proof of its incurability. How types—particularly fibroplastic and cancer cells—show ever, he continued to argue for the local and benign charac dissimilarities in form, volume, nuclei and nucleoli, these ter of homeomorphic tumors such as cancroids. The differences comport with the natural degree of density, diathesis doctrine was opposed by Velpeau (1854 [409]) fibrousness, softness, or pulpiness of the tumor; micro who maintained that cancers arose from local influences metric measurements on fibroplastic, scirrhus, and en trauma, mechanical insult, contact infection—as well as cephaloid cells decisively verify this contention. (d) Free through hereditary predisposition. To test the hypothe or bound states, form, volume, chemical reactions, and the sis that cancer was contagious Velpeau, in collaboration variable, fluctuating characteristics of nuclei and nucleoli with Follin and Lebert, injected human cancer fluids into a of the so-called cancer cell are of sufficiently marked char dog. This procedure allegedly resulted in the production acter to permit positive distinctions between it and the of small visceral tumors (409, p. 545). (Other attempts to fibroplastic cell. (e) Chemical reactions do not provide the transplant fragments and fluids of human cancer into means whereby distinctions between epithelial, fibro animals have been cited. The results of these trials were plastic, or cancer cells may be adduced. (f) A plentiful reviewed in 1867 by Henocque (186) and by Ledoux number of facts already gathered by skillful microscopists Lebard in 1885 (238, pp. 428-435). Among the unsuccess and surgeons adept at experimentation demonstrate that ful attempts following Dupuytren's are those of Tanchou true cancers possess no specific cell, inasmuch as tumors (1842 [397], Quinquaud (1868 [317], Hyvert (1872 [207]), diagnosed certainly as noncancerous present the same cel and others. Henocque (186, p. 707) and Ledoux-Lebard lular aspects as cancerous tumors. (g) Equally undeniable @ (238, pp. 432—433) referred to one successful result by and numerous facts prove that epithelial as well as fibro Goujon (1867 [159, 160]), who, after a series of inoculations plastic tumors are true cancers capable of rapid multipli of human cancer into various animals, succeeded at trans cation in situ or at distant sites. (h) These facts demon planting a fragment of epithelial cancer from one guinea strate that the blastema, the morbid principle of cancer, pig to another. After fifteen days Goujon is reported to exists as some amorphous entity which eludes our present have found an almond-sized nodule at the implantation methods of investigation, and that it is independent for site. Extensive metastases to the viscera were also found. the most part of fibroplastic, epithelial, and those cells

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 82 Cancer Research Vol. 25, February 1965

Tableaucomparatif des mesures micrométriquesmoyennesdes cellules simples et multiples des tumeurs ,@Thro-.plastique,squirrheuse et encephaloIde de l'homme et des animaux domestiques. @[email protected]@ HO@IMES. DIAMETRE. —DIAMETRE.

SIMPLES ou multiples. DES D@ DES DES DES DES NOTAUI.Ffbro.pLastlque. -CELLULES. @. NOYLUX. NUCLEOLES.ANIMAUX.CELLULES.

mm. ... Simples o.oi o.®@ O.OOi.2 0.01 a o@ 0.004 0001 a OOI.@ Cancersqulrrbeux. . Id. o.oi a 02 0.005 0.001 0.01 a 03 0.9645 0.0019 Cano@@encéphalolde. Id . . 0@03a04 0006 0.0025 0.02 1 04 0.011 0.002.5 @ Pibro-plaitique.. . . Multiples ou mere.. 0.05 1 06men.0.001 003 0001.2 1 0.001.5 0.04 a 05 0.001 1 006 O.001.5 I 0.002

@ @canc&::i . . . . . ‘:mm. I [email protected]@mm.0.04 à 06mm.0. 002Ã!mm. 0.002,4 a 0.002.@

CHART1.—Anexample of micrometric research data on cancer and related diseases published in 1854 by Delafond (109). The data show mean measurements on cellular, nuclear, and nucleolar dimensions for human and animal (?) tissues (X600 diameters). The significance of this research is discussed in the text.

improperly designated as cancerous. Delafond's counter gist Phillip Franz von Walther (Bonn), the former of whom attack was directed at Lebert (1851, 236, p. 30) who sug (1816 [297]) presented thorough macroscopic descriptions gested that the mean diameter of the cancer cell ranged of gastric (alveolar or colloid) cancer. Walther (1820 between 0.01 and 0.05 mm, except that in encephaloid [459]) devised a classification for tumors which paralled tumors cell nuclei infrequently exceeded 0.05 to 0.08 mm Laennec's, and the gross separation of neoplasms among and were impossible to distinguish from normal cell nuclei. four varieties, (a) soft (Markschwamm), (b) hard (scirrhus), In such cases the nucleoli of encephaloid tumor cells ap (c) pigmented (melanotic),and (d) vascular (Blutechwamm) peared defective. continued in the sources of German clinical pathology In later years clinical research on cancer reinforced by through the 1830's (460). the Cellular Pathology (of which Bard's theory is a case in point) broadened the etiologic perspective. The labora BLASTEMA THEORY tory output resulting from these developments encorn Tumor cells.—The significance of the microscopic investi passes research on (a) the exact histogenic patterns of gations (1838 [280]) of the versatile genius Johannes malignant tissues (Desfosses, 1881 [107], Ménétrier,1888 Muller (Bonn and Berlin) has already been indicated. [268], (b) the nature of cancer-cell division (Cornil, 1891 MUller noted the predominance of connective tissue in [91], Borrel, 1890—1892 [56, 57], Fabre-Domergue, 1892 scirrhus and he differentiated the stroma of adenoid tumors [131]), as well as (c) views consonant with Cohnheim's and from their parenchyma which he found to exist as a con other theories of tumorigenesis (Cornil, 1865 [90], Cris glomeration of irregular-shaped cells. Muller detected tiani, 1887 [99], Fabre-Domergue, 1898 [132, pp. 286—299]). within these cellularaggregates, nuclei, granules, fat bodies, and other inclusions. The occurrence of ‘racquet-shaped' GERMAN, AUSTRIAN, AND SWISS SCHOOLS or caudated cells was also noted by Muller who assumed these to be primordial elements in fiber formation and not PREcURsoRs specific cancer cells, the presence of which he was unable Before the discoveries of Muller there were few original to establish. With this evidence Muller tried to correlate opinions on cancer within the German areas. For ex clinical symptoms with microscopic appearances in ding ample, at Gottingen the surgeon August-Gottlieb Richter noses of cancers. (344) in an early 1800 work merely separated ulcerating Muller's results, a part of which were reported as early cancers from scirrhus tumors and he followed the conven as 1836 (279), prompted him to reject the Laennecean con tional humoral diethesis theory. The Mainz surgeon cept of heterologous tissues and to adopt a cellular basis for Carl Wenzel (1815 [469]) distinguished scirrhus from other tumor taxonomy. He distinguished according to cell indurated growths; he thought (469, p. 96) that extensive type, (a) fibrous or scirrhus cancer, (b) reticular cancer, (c) irritation culminating in chronic inflammation led eventu alveolar or colloid cancer, and (e) hyaline cancer@ Muller ally to the eruption of carcinoma, in indurated tissues. also studied the structure of cartilage tumors (echondroma), Johann Nepomuk Rust, a Vienna surgeon and a partisan adipose tumors (ciwlesteatonvi), and cystoid tumors (cysto of the localistic theory, argued (1811 [364]) for the existence sarcoma) among others. He attempted unsuccessfully to of an as yet undetermined etiologic moment in the gene broaden his method of tumor differentiation through siB of tumors. efforts to determine solubility differences of neoplastic Among early promoters of pathologic anatomy were the tissue constituents exposed to boiling water and caustic pathologist Adolf Wilhelm Otto (Breslau) and the patholo reagents.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0Lo—Foundations of Cancer Research 83

(Chemical research on tumors was simultaneously pur believed that the capacity for autonomous growth also sued. As early as 1790 Adair Crawford (94) reported characterized cancer cells. chemical observations on the substance of cancer, specifi At Halle the pathologic anatomist Julius Vogel (1845 cally the eliminationof sulfurandammoniasubstances from [438]) hypothesized that tumor formations occurred degenerating tumor tissues and their fluids, to which he through an amorphous blastema or cytoblastema, essentially attached etiologic significance. Routine analyses of tu exuded blood plasma, which became organized into cells mors appeared in the earlier nineteenth century literature under the specific influences of its histologic and chemical (e.g., Bostock, 1806 [59]). Among these was the 1820 milieu. Vogel, who paid particular attention to chemical treatise of Maunoir (264) in which the author, utilizing alterations in tumor production, held that each tissue contemporary technics of extraction and sublimation, grew from a blastema which corresponded to its type, and analyzed with indecisive results the composition of the that a similar correspondence existed in the proliferation of fungus hematodes. Midcentury chemical research on can tumor tissues. This assumption, the so-called law of cer was typified by analyses for organic constituents, such analogous blastema.s, resembled Lobstein's theory of tissue as appear in Lobstein's 1829 work (240, 1 : 403) in which heteromorphisin, except that Vogel's conception took into quantitative data for albumins, gelatins, fibrins, and fatty account the results of the newly formulated Cell Doctrine matter in scirrhus tissues were tabulated. Broca (1852 Together with the search for morphologic distinctions 163, p. 489]) exposed cancer cells to water, alcohol, tincture in tumor cells, Vogel's and similar viewpoints stimulated of iodine, acetic acid, nitric acid, ammonia, ether, and other the search for chemical peculiarities in alleged germinal reagents; he concluded that the walls of these cells had a elements. For example, Friedrich Fuhrer (1852 [149, pp. composition which differed from that of their nuclei. 222—224]),a supporter of the specific cell concept, under Delafond (1855 [109, p. 401]), through similar experiments, took chemical investigations on the “undifferentiatedbut noted that Broca's conclusion also held for pus cells, epi highly plastic tissue builder―—blood plasma—from which thelial cells, fibroplastic and cancer cells.) he separated three specific varieties of blastema, (a) an Muller assumed that tumors grew from separate ger albuminous, (b) a chondrinous, and (c) a gelatinous, each minal elements within the parenchyma. This idea reflects of which occasioned the formation of specific tumors. the blastema theory which was broadly developed in The chemical nature of tumor cells, predetermined in their Germany after 1840. Proponents of this theory, from anlage, eventuated in a distinctive tumor tissue—fibrous, which the specific cell concept emerged, suggested the exist chondrinous, glutinous (mucus), etc. At Vienna the ence of a unique germinal layer, the ‘cancerblastema,' surgeon Franz Schuh (1851 [373]) proposed that organized through which all autonomous new growths evolved. new growths (pseudoplasmata) each differing from another Concomitant with early developments on the blastema according to its physiologic (i.e., nutritional) circum theory, the Danish anatomist Adolph Hannover (1843- stances, grew out of blood-derived blastemas. In the case 1852 [167—169])first described a characteristic element, the of cancer melanodes Schuh pointed to the formative in ‘cellular cancrosa,' of malignant growths (cancers) which fluences of transformed blood constituents, a conclusion he distinguished from epithelial tumors (epitheliomas) arrived at from chemical studies on melanomas which he lacking the element. Hannover assumed that the specific found to be composed of hematins, iron and phosphorus cancer cell passed into the general circulation and gave rise salts, fats, and fibrous matter. Similar investigations on to distant islets of new growth, a novel view of metastases the role of blood in the production of tumors were simul foreshadowed by observations of secondary deposits in taneously carried out by the physiologic chemist Johann cancer previously reported by the French internist Joseph Florian Heller (475, 1: 164). Claude-Anthelm Récamier (1829 [321]). This conception was challenged by the followers of Additional microscopic data on tumors was accumulated Cruveilhier who denied that extravasated blood possessed by the Giessen anatomist Carl Bruch (1847 [68]) who the power to form organic matter. Only blood in the placed still greater emphasis upon the specific form and vessels—the venous capillaries according to Cruveilhier development of cancer cells. Bruch argued that tumors and Carswell—was able to give rise to tumors. Accord formed endogenously from cell nuclei or elements destined ingly, the Berlin clinical surgeon Bernhard von Langen to become nuclei. According to Bruch, the cancer cell beck (1840 [229]) studied the formation of cancer masses nucleus—actually nests of nuclei within a ‘mother-cell'—- in the veins. In order to test the hypothesis that cancer and the atypical appearances of these nuclei in their repro cells were independently viable, Langenbeck administered ductive performances constituted the pathognomonic fea intravenous injections of human cancer fragments and tures of malignant growth. Mother cells, which Bruch fluids to dogs and rabbits, and he reported the subsequent considered to be analogous to embryonal cells since both appearance of nodules in the lungs of one dog. This, to gether with similar reports already described, strengthened existed as undifferentiated primitive types, never divided, contemporary impressions on the dissemination of cancer but existed as secondary productions. Their enclosed, through metastases and its contagious character. resting nuclei, and occasionally free-nuclei, broke forth Tumor stromas.—Another group of workers also attuned and became dispersed among the parenchymal tissue where to the blastema principle sought to differentiate tumors they secreted a cell body which reproduced itself into suc according to the morphologic and histogenic dissimilarities ceeding generations of cells. As a feature of this process, of their stromas. The Vienna internist Josef Engel (1846 in contrast to normal cell@ cancer cells were distinguishable [127]) was among the first to suggest this view, and he was by their very elaborate cytologic appearances. Bruch followed by Virchow (1847 [412]) who also stressed the

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 84 Cancer Research Vol. 25, February 1965

morphogenesis of tumor stromas from the connective 1840's and 1850's on the structure of tumors of epidermal tissues. One of the earliest to report in detail on the origins (Ecker, 1844-1845 [122, 123], Bärensprung, 1848 structural and developmental peculiarities of various [31], Frerichs, 1846—1849[141,144], Bruch, 1849 [69—71]@ cancerstromas,to each of whichheattachedpathognomonic Virchow,1849—1855[414,415,424,426],Reinhardt,1851 significance, was the Vienna pathologic anatomist Karl [325], Bidder, 1852 [42], Foerster, 1858 [137], Reese!, 1858 Rokitansky (1852 [357]). Rokitansky rounded out these [332], Wagner, 1859 [447]) which promoted a gradual results by special studies on the pathogenesis of villous expansion of Hannover's narrow conception of epithe (adenoid) cancer (1852 [358]), alveolar cancer (1852 [359]), lioma, arrived at through his limited study of squamous and mammary cystosarcoma (1853 [360]), a neoplasm cell tumors. This research also foreshadowed a complete variously known as the chronic mammary tumor of Cooper breakdown of the artificial distinctions between cancroids and the mammary glandular tumor of Paget. and cancers. Thus, Virchow (1855 [424]) confirmed Tumor nomenclature.—The appearance of new attitudes Velpeau's conclusion that both possessed equivalent in taxonomic oncology is evidenced by Muller's work, and capacities for metastases and infiltration. this also is part of the pattern of improved knowledge made possible by the blastema theory. Virchow's early CELLULAR PATHOLOGY opinions on tumor pathology (1847 [412]) show a transi The beginnings of the Cellular Pathology are found in the tion from archaic Laennecean concepts to the more new emphasis after 1845 on endogenous cell formation. original outlook : he differentiated among cancers having The multitalented pathologist Rudolph Virchow (Wuertz ‘cellular'origins, among cancers having ‘fibrous'origins, burg, later Berlin), as early as 1847 (412, p. 133), con and among pigmented and vascular cancers. (Later sidered it possible that cancer originated not from ‘free authors adopted similar schemes of classification. For blastema'—from the intercellular plastic lymph—but from example, August Foerster (1868 [138]) arranged cancers the blastema within pre-existing cells. In a subsequent into the following categories, (a) carcinoma fibrosum report Virchow (1851 [420]), starting from the assumption (‘fibrous'cancer), (b) carcinoma medullare (‘cellular' that “anew cell develops within an existing cell,―out cancer), (c) carcinoma telangiectodes, a designation for lined a breeding-space theory which specified that new cell vascular cancers popular among authors of the period, and formation occurred under the influence of the nucleus (d) carcinoma melanodes or pigmented cancer.) Schuh within hollows of the mother cell. By 1855 Virchow (425) (1851 [373]) distinguished benign or homeoplastic tumors had essentially formulated the conception, the details of comprising warty (epidermal), fibrous, fatty, chondrous, which comprise his 1858 treatise on the Cellular Pathology osteous, vascular, and muscular growths from various (428), that the cell was the focal point of vital phenomena cancers. Bone tumors were thoroughly described by in health and disease. Muller (1843 [281]) and Gerlach (1847—1851[150, 152]). Although many prominent investigators (Remak, Vogt, Rokitansky (1846 [356]) described neoplasms in every Kölliker, and Reichert) joined Virchow in opposing the known tissue. idea of free cell formation, the actual starting point for the Pending more complete histologic data within the total Cellular Pathology—recognition of cell multiplication advance of oncologic research after 1840, the tumor no through division—was a research outcome of the early menclature was beset with numerous arbitrary distinctions. 1850's even though the process had been observed in the For example, the histologist Jacob Henle (1845 [184, 185]) 1840's. For example, in 1841 Remak examined the mul described a variety of medullary cancer which he des tiplication through division of blood cells in avian and ignated as siphonoma, although he considered it to be mammalian embryos. In 1845 he observed the same similar to Rokitansky's villous cancer. Villous cancer, phenomena in muscle tissues of frog larvae, and by 1851 the highly vascularized appearance of which was noted by Remak presented numerous data that every embryonic Gerlach (1851 [151]) through examinations of bladder cell multiplied by division (1852 [328, p. 49], and 1855 cancers of this type, was considered by Virchow (1847 [331]). He simultaneously extended the same conclusion [412]) to be identical to cystic cancer, first described by to connective tissue cells (1852 [329]). With reference to Rokitansky (1846 [356, 1: 356—357])asa cystic, alveolar the earliest work on tumors, Virchow (1857 [427, p. 91]) growth occurring in the gastrointestinal and urogenital cited the 1843 observation by Guensburg and Breuer of systems. Alveolar cancer, was given a variety of names; division in cancroid cells, leading to Guensburg's con among others, gelatiniform or gum cancer (Hodgkin), clusion (1848 [163]) that all cells were generated endog gelatinoma, cancer areolaire gekitinforme (Cruveilhier), enously through the partition of their nuclei. At Berlin carcinoma alveolare (Muller), carcinoma colloides (Vogel), the adept microscopist Robert Remak, on the basis of and alveolãreGallertgeschwulst (Frerichs, 1847 [143, p. 56]). initial research in embryology and histology, concluded The promise of improved identifications of epithelial (1852 [328], 1854 [330]) that germinal cells multiplied neoplasms was afforded by the continuing controversy on through nuclear division to form not only embryonal cells cancroids or epithelioma versus cancers or carcinoma. in animals but all normal and malignant tissues as well. The Berlin internist Friedrich Theodor Frerichs (1847 Virchow's actual role in these events appears to be neg [142, p. 10]) distinguished the cancer cell as one having, ligible (2, p. 76). “atailed and irregularly asteriated form,―and the oc Connective tissue theory.—Following in the footsteps of currence of other specific forms were advanced by Führer Muller and ROkitanSky, Virchow assumed that the con (1852 [149, p. 189]), and Foerster (1852—1855[135,136]). nective tissues played an essential role in the formation of This work is part of the expanding research through the tumors. He suggested in 1855 (426, p. 415) that hetero

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TrtloLo—Foundations of Cancer Research 85

plastic4 neoplasms, including ‘epidermoidal'5 growths determined by practical needs, including in his survey of such as cancroids, originated in the connective tissues. true neoplasms the lesions of tuberculosis, syphilis, and This conclusion, largely derived from various earlier leprosy (2, p. 99). (Die krankhaften Geschwalste which observations by Virchow (see 1853 [422]) on the differ predated the era of microbiology represented a catch-all entiation of cells within the connective ss@ was sup for every new tissue formation which presented diagnostic ported by similar reports (Pohi, 1855 [312], Senftleben, difficulties. For example, the inflammatory processes of 1858 [380], Neumann, 1861 [287], Weber, 1864 [462]). It chronic infection were still poorly understood.) More also appeared to be warranted from investigations made over, the work was never completed. Virchow's lectures by Virchow (1850 [416]), adding to evidence already ac on cancer (carcinoma) were not published, and it is crued by Lobstein, on the formation of tumors with corn surmised that his doubts concerning the connective tissue bined tissues and on tissue transformations in tumors. theory underlay this omission (2, p. 98; 130). The connective tissue theory immediately gained numerous Virchow (431, 1 : 16—32) separated tumors into two adherents among German investigators in the 1860's. major categories: the homeoplastic and the heteroplastic. A The connective tissue theory was opposed sirnultane tumor differing widely from its matrix-tissue in texture ously by Remak who held that carcinomas and cancroids (heteroplasm) was not rigidly adventitious, nor invariably were of exclusive epithelial origins. Beginning with malignant. Virchow used the term to indicate that in Hannover (1843 [167]), the work of Ecker (1844—1845 normal circumstances tissues like that of the tumor (a) [122, 123], Foerster (1858 [137]), and Virchow himself, had never occurred at the site in question (heterotopism), or led to a clearer recognition of characteristic cell types (i.e., (b) never occurred at the particular stage of development squamous, cylinder, or columnar-cell) in cancers. An in reached at the time in question (heterochronism), or (c) direct argument for the epithelial origins of epitheliomas never reached the particular size in question (hetero was stated by Remak (1843—1852[326—328])through his metrism). In one setting a tumor might be ‘hetero embryologic evidence for the existence of three primary plastic' and harmless whereas in another setting the tumor germ layers; evidence for these was also furnished by His could be ‘homeoplastic'and destructive. (1865 [193]). As early as 1852—1854Remak (328—330) After presenting a review of the histogenesis and patho proposed that normal as well as neoplastic epithelial genesis of neoplasms, Virchow discussed (431, pp. 102— tissues were derived from a separate germinal element. 127) a basis for tumor taxonomy according to generic type; However, Virchow's authority hindered the acceptance of viz., (a) through extravasated, transudated or exuded, (b) this “extravagant hypothesis,― as Remak's view came to through secreted, and (c) through proliferative origins. be known, until the work of Thiersch and Waldeyer de Among the first two classes, designated collectively as manded its consideration. cystical tumors, Virchow grouped hematomata (431, pp. By 1862—1863Virchow's ideas on the cellular pathology 128—154),hygromata (hydrocele, hydromeningocele cere of tumors were sufficiently crystallized to permit the bralis and spinalis) (431, pp. 155—210), and follicular presentation of an extensive treatment of the subject as a cysts (atheromata and hydatids) (431, pp. 211—286). The series of lectures incorporated into his treatise, Die third category comprised the proliferative tumors or krankhaften GeschurüLste(431). This study bridged many pseudoplasms which occurred as histoid, organoid, tera older and newer perspectives in oncology. Virchow toid, or combined forms. passed beyond the criteria of benignity versus malignancy The fibromata (431, pp. 287—363)comprised nodular to include the anatomic and generic relations of tumors in and papillary growths including the diffuse fibromatoses his taxonomic viewpoint. However, he depended largely (elephantiasis). Combinations of fibroid and other tissue upon the provisory and arbitrary attitudes on tumors as types such as ‘epitheloid'(cancroid) were known to exist, as

4 This is not synonymous with the term used by Laennec and well as the occurrences of fibroid transformations into other authors to distinguish adventitious (malignant) from homol sarcomata. These heteromorphic forms, not uncommonly ogous (benign) tumors. Virchow's use will be discussed in the found in bone tumors, were the heteroplastic fibromas. text. Virchow next discussed hyperplastic, heteroplastic, and 5 Among his conclusions on epithelial tumors Virchow (1850 [4151, 1855 [4261) noted the recurrence of epidermoid (epitheloidal) multiple lipomata (431, pp. 364—395), followed by a cells in ‘cancroids'and of alveolar cell clusters in ‘carcinomas.' review of the so-called mucous tissue tumors or myxomata (His distinction of two species of cancer, cancroids, and carcino (431, pp. 396—434). Chondromata and osteomata were mas, persisted in the later literature.) This remained part of given detailed treatment in other chapters (431, pp. 435— Virchow's justification for omflis cellula e cellula within the frame 536, also 2: 1—105).@Virchow (431, 2: 106—169) dis work of the connective tissue theory. 6 Virchow was among the first to discover cells in the canaliculi tinguished the psammomata or ‘sand'tumors from the of bone (see 1850 [4171),and he demonstrated the transformation true sarcoma; gliomata and melanomata were also dis of chondroid into osteoid cells especially in rachitic specimens in cussed in this section. which the process remained unobscured by extensive calcification The keystone of Virchow's tumor treatise is the chapter (see1851[4191,1853[4231). He was thus led to conclude (see [412, p. 135J) that ossification, when it proceeded not from cartilage on sarcoma (431, 2: 170—384). Sarcoma comprised a but from the membranes, was the direct result of connective tissue variety of histoid tumors which usually but not always cell transformation. The analogous appearances of cartilaginous evolved from distinct fibroplastic species such as fibroma, and periosteal bone growth confirmed his opinion (see [419, p. chondroma, osteoma, glioma, etc. Virchow distinguished 1561)that bone, cartilage and connectivetissue cells were related morphologically. Active cell differentiation in the connective six major varieties, (a) fibrosarcoina, (b) myxosarcoma, (c) tissues such as occurred in bone formations gave analogic support gliosarcoma, (d) melanosarcoma, (e) chondrosarcoma, and to the connective tissue theory of cancer. (I) osteosarcoma,aswellas a numberof lessspecific,local

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 86 Cancer Research Vol.25,February1965 varieties (e.g., medullary sarcoma). Sarcoma corre blood dyscrasias and related subjects are beyond the scope sponded histologically to the common cellular appearances of this report. A partial bibliography of the topic for the of normal connective tissues; as spindle-cell, round-cell interested reader is included in Table lB. and star-cell forms. Spindle-cells greatly resembled im mature muscle and nerve elements. (Biliroth (1860 [47, EPITHELIAL THEORY p. 85]) had suggested from his study of medullary sarcoma An early countercurrent to the connective tissue theory that round-cell sarcoma, except for the absence of the already has been mentioned in connection with Remak's characteristic alveolar structure, might be easily confused and Michel's research. Substantial evidence for the with carcinoma.) Sarcoma typically metastasized opposing view was furnished in 1865 by the Erlangen (also through the circulation especially to the lungs and liver Leipzig) surgeon Carl Thiersch (399) whose investigations but rarely to the lymph glands. Virchow concludes on the epithelial origins of epidermal cancers was corn Volume 2 with chapters on leukemias, lymphomas, and municated to the Congress for Research in the Natural lymphosarcomas (431, 2: 555—756). He is well known for Sciences at Speyer in 1861 (475, 1: 222). Thiersch his research on leukemia, a disease which he is the first acknowledged Rernak's three germ-layer principle as the to have named (1847 [413], 1853 [421]). The history of groundwork for the epithelial theory.

TABLE lÀ EPITHELIAL (ORGAN0ID) TUMORS; TUMORS DERIVED FROM MESOBLAST, EPIBLAST AND HYPOBLAST Based in part on Ziegler's classification (1885[480,1: 235—261]).

Type Comment

A. Adenoma A neoplasm constructed after the type of a secreting gland. 1. Cystadenoma (multilocu A nonmalignant ovarian adenoma, extensively proliferative, in the composition of which cysts are lar cystoma) prominent ; occasionally found as papilliferous cystadenomas. 2. Destructive adenoma (ad A highly malignant adenoma, as contrasted with the more localized adenomas of the sweat or seba enocarcinoma) ceous glands, of the alimentary canal. (A functional rather than a morphologic distinction.)

B. Carcinoma A neoplasm essentially distinguished by epithelial multiplication, and not agreeing, or agreeing imperfectly, with a glandular type. 1. Squamous epithelial can A warty and nodular tumor of the skin, characterized by the occurrence of large epithelial nests, cer (epithelioma; cutane made up of large multiform squamous cells which often appear cornified (epitheUal pearl8) ; known Ous cancroid) as horny or corneous cancroids. Cells derived from the superficial epidermis, also the epithelia of the hair follicles and sebaceous glands. 2. Cylindrical epithelial A soft nodulated tumor, usually of the mucous membranes, arising from the columnar glandular cancer epithelium ; occasionally assumes the appearance of cell-nests as gigantic acini, described as adenocarcinoma (distinct from the term employed for the destructive adenomas). 3. Simple carcinoma A neoplasm usually originating in a gland, and forming a rather firm nodulated tumor having a coarse fibrous network, containing alveoli of various sizes and shapes filled with masses of epithe hal cells. 4. Medullary (encephaloid) A neoplasm having abundant cells and a scanty, delicate stroma, the tissue of which may undergo cancer progressive softening and liquifaction, and from which a milky fluid (cancer juice) may be ex pressed. Resembles soft adenoma and sarcoma. 5. Scirrhus A neoplasm in which the cell-groups are small and scanty and the stroma coarse and dense. Re sembles the hard, firm fibromas, and is not sharply divided from simple cancer. The cancer cells often undergo fatty degeneration and are absorbed, leaving a fibrous, cicatricial-like stroma. 6. Colloid (gelatinous ; alve A tumor occurring as a definite formation or a diffuse infiltration, characterized by a translucent olar) cancer parenchyma (opaque, jelly-like cell-nests giving a glassy appearance) resulting from mucoid or colloid changes affecting the cancer cells. (These changes were studied by Robin, (1853 [3481), Wagner (1860 [448], 1862 [450]), and Schultz (1865 [374]).) 7. Carcinoma myxomatodes A neoplasm which assumes a gelatinous texture in consequence of mucoid changes affecting the stroma. (Metaplasia of the fibrous tissue is often associated with a simultaneous mucoid de generation of the cancer cells.) Occasional loss of cell structure through destruction of the con nective tissue cells of the stroma. Occurs at the same sites as colloid cancer. 8. Cylindroma carcinoma A rare neoplasm characterized by the formation of homogenous spherules within the cell nests. todes Cells, compressed by the spherules into slender trabeculae, assume the appearance of an anas tomosing network. To distinguish it from the sarcomatous variety, it is designated as carcinoma tOdeS. 9. Giant-celled (myeloid) A tumor in which the cancer cells attain enormous size, and become transparent as if through the cancer imbibition of fluids. 10. Melanocarcinoma A gray, brown or black pigmented cancer—rarer than melanotic sarcoma—with pigment diffused in the cancer cells as well as in the stroma.

C. Complex or mixed cancers Combinations of adenoma and carcinoma with other neoplastic formations, resembling simple car cinomas in their general relations.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0L0—Foundations of Cancer Research 87

TABLE lB CONNECTIVE TISSUE (HISTOID) TUMORS; TUMORS DERIVED EXCLUSIVELY FROM MESOBLAST Based in part on Ziegler's classification (1885, [480, 1: 199—235]).

Type Comment

A. Fibroma A fibrous tumor. Existing as combined forms (e.g.,myxofibroma) (Recklinghausen 1882[323]).

B. Myxoma An edematous (mucus) tumor. 1. Myxofibroma A tumor of combined mucus and fibrous tissues, (Koester, 1881 [218], Rumler, 1881 [363]). 2. Myxolipoma A tumor of combined mucus and adipose appearances (Virchow, 1865 [430], Waldeyer, 1865 [452]).

C. Lipoma An adipose tumor. Existing as combined forms (e.g., myxolipoma).

D. Glioma Neuroglia or ganglion cell (?) tumors (Klebs, 1877 [210]).

E. Chondroma (Echondroma) A cartilage tumor. 1. Osseous echondroma A cartilage tumor involving bone (Virchow, 1875 [432]).

F. Osteoma A diffuse and extensive overgrowth in bone (hyperostosis) ; a circumscribed interior bony growth (enostosis) ; An independent osteoma remote from bone (hyperplastic osteoma) (Muller, 1858 [278]). Also existing as combined forms (e.g., osseous echondroma).

G. Angioma A vascular tumor. 1. Simple angioma Simple erectile vascular formation (naevus, hemorrhoid, etc.) (Monod, 1873 [272]). 2. Cavernous angioma An erectile vascular tumor in which the tubular form of the vessel is obliterated. 3. Racemose aneurism, racemose Pathologic alterations of a vascular territory; not true neoplasms. varices 4. Lymphatic angioma An erectile formation of the lymphatic system comparable to haemic varieties as simple lymphangioma, lymphatic telangiectasis, and cavernous lymphangioma (Anger, 1867 [10], Gyorgjevié,1871[165],Arnstein, 1872[19],Wegner,1877[465],Nieden, 1882[290]).

H. Myoma Tumors of newformed muscle fibers, not unlike fibroma. 1. Leiomyoma (levicellular myoma) If fibrous tissue preponderates, the tumor appears as fibromyoma (i.e., uterine fibroids) (Bristowe, 1853 [62]). 2. Rhabdomyoma An unusual tumor rarely composed of striated fibers. Appears in cellular sarcomas as spindle cell forms with striated characteristics (myosarcomata) (Eberth, 1872 [121]), Marchand, 1873 [259], Brodowski, 1876 [65], Kocher and Langhans, 1878 [215]).

I . Neuroma A tumor principally composed of newformed nerve fibers (Verneuil, 1861 [410],Bruns, 1870 [72], Perls, 1873 [305], Czerny, 1874 [103], Recklinghausen, 1882 [323]).

J. Lymphoma A growth (lymphadenoma or lymphosarcoma) not strictly a tumor, but a hyperplasia of the tissue proper to lymphatic glands—lymphadenoid (or adenoid) tissue. Relatable to leukemias and Hodgkin's disease (Lücke, 1866 [249], Langhans, 1872 [231], Mosler, 1872 [276]).

K. Sarcoma A tumor of the connective tissues in which the cellular constituents predominate over the intercellular substance. Resemble immature connective tissues, comparable to embryonic forms. Existing as combined forms (e.g., fibrosarcoma). 1. Round-cell sarcoma A tumor form common to connective tissues of the locomotive and skeletal systems and lymphatic glands (lymphosarcoma) . Related forms : large round-celled alveolar sarcoma and giant-celled or myeloid sarcoma. 2. Spindle-cell sarcoma A tumor form with ramifiedmultiform (pyramidal, prismatic, stellate, and irregular) cells; i.e. ,fibrosarcoma. a. Alveolar sarcoma Sarcoma in which the cell formations resemble epithelial cells or aggregates. (1) Plexiform angiosarcoma An alveolar formation of the vessels of the brain, lymphatic glands, etc., in which the ad (endothelioma) ventitia is invested with endothelial cells (perithelium)(Neumann, 1872[289],Kolaczek, 1878 [219, 220], Maurer, 1879 [265]). A comprehensive review of lymphangiomas, with corn plete bibliography, is presented by Glockner (1897 [153]). (2) Cholesteatoma An endothelioma (?) of the pia mater which contains pearly bodies imparting a lustrous appearance, and made up of laminated layers of squamous or tubular cells (pearly tumors) (Lucae, 1873 [248], Wendt, 1873 [467, 468]). b. Cylindroma A formation in which sarcornatous tissues undergo partial hyaline or mucoid degenera tion, or when sarcomatous and myxornatous formations combine. The term cylindroma is also applied to tumors of another species in which epithelial cells are involved. It en compasses certain endotheliomas (i.e., myxosarcoma and angiosarcoma myxoma@odes).

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 88 Cancer Research Vol. 25, February 1965

TABLE lB—Continued

Type Comment

(1) Myxosarcoma Combined sarcomatous and mucus tissue tumor composed of ramified and anastomosing cells in addition to a mucoid basis-substance possesses distinctive texture. (2) Angiosarcoma myxomatodes A variety of the myxosarcomatous cylindroma in which the mucoid change is chiefly con fined to the vessels, and in which the formation of new vessels is an essential feature. Myxomatodes implies partially degenerate sarcomas in which isolated hyaline spheres appear among the cells. c. Melanosarcoma Malignant sarcomata which contain deposits of black or brown pigment, randomly dis tributed (Recklinghausen, 1882 [323]). d. Psammoma Sarcomatous, fibrous or myxomatous tumors originating in the brain and its membranes and containing chalky concretions (sand tumors). Certain species are relatable to endo thelioma (Wiedemann, 1865 [470], Maier, 1866 [253], Steudener, 1870 [391].) e. Chloroma Cellular tumors giving the appearances of a light green or dirty brownish-green tint. The growths occur chiefly in the periosteum of the skull. Known to various workers as green cancer. (Balfour, 1835 [21], Durand-Fardel, 1836 [117],Aran, 1854 [11], Dressier, 1866 [114], Huber, 1878 [205]).

L. Mixed tumors (not referred to above) A tumor of combined cartilage and bone tissues (cf. osseus echondroma). 1. Osteoid chondroma (osteochon droma) 2. Osteosarcoma A tumor of combined sarcoma and bone tissues.

This system essentially is the first modern epithelial and connective tissue tumor classification. It represents a synthesis of earlier nineteenth century research in taxonomic oncology, and should be consulted by the reader who wishes a point of reference to topics discussed in the text. The bibliographic items specify key research papers in each category.

Thiersch's advance was the result of newly devised ZUrich, then Vienna—whose earlier investigations in technics and circumspect analyses. He attempted to oncology (1859 [45], 1860 [46, 48]) led him into Virchow's correlate his microscopic findings for normal cutaneous camp. Bifiroth cited the substantial amount of collateral and epithelioma tissues; viz. from differentially stained evidence thus far gained in favor of the epithelial theory. serial sections prepared through the use of an improvised Nevertheless, Biliroth pointed out that Thiersch's data microtome-like device incorporating a watch-makers saw, appeared to apply only to a limited number of circum as well as through the use of newly discovered dyes and stances. It would be inappropriate and incorrect, fixatives. He also traced the infiltration of cancer in Biliroth concluded, to extend his arguments to all struc injected specimens. Thiersch tabulated clinical data on tures involving epithelial tissues, especially in view of 102 cases of skin cancer from which his histologic materials Virchow's weighty testimony to the contrary. For were obtained. His results are recorded as well in a series example, how could the epithelial theory account for of illustrations. epithelial tumors in organs which obviously lacked Thiersch established that epidermal tumors were firmly cutaneous tissues—brain, genital glands, etc.? More and intricately bound with the connective tissues and that over, primary cancer was known to exist in the tibia and reproduction of their parenchymal elements was usually lower jaw, and the possibility of similar occurrences in attended by active stromic growth; however, the specific lymphatic tissues still remained. In the last analysis character of these proliferations remained distinct. This common, simple cancer was essentially a formation of the confirmed the idea that ectoderm was deposited as one of connective tissues. the earliest embryonal layers, even though it differentiated Despite his objections Billroth's opinions were by no into many apparently dissimilar tissues (knowledge of means an uncritical vehicle of Virchow's hypothesis. In which had been advanced by Kölliker (1863 [221]) and a paper published simultaneously with the critique of others). Thiersch was able to follow these growth events Thiersch, Biiroth (1866 [51]) advanced his own views on in the neoplastic alteration, as stated in his conclusions the anatomy and histogenesis of adenoma and epithelial translated from the German: (a) the stroma, although it cancer. For example, glandular (mammary) cancer, sustains epithelial growth in a variety of ways, is not the which Billroth separated into acinar and tubular varieties, germinal basis of this growth in health or in disease, (b) appeared to stem from a destructive impingement of epithelium possesses its own germinal identity and is the proliferating connective tissue cells upon an actively pro source of distinct formations in health and disease, and liferating adenoid substanceY This view made conces (c) it is necessary to alter the thesis omnie cellula e cellula 7 Yet Wolff (475, 1: 232, footnote) refers to a thesis, (De vero to omnie cellula e cellula ejusdem generis. By extending carcinomate epitheliali ac nonnula de Epith4iis, Halle, 1865), by this research to the subcutaneous glandular (malphigian) Brunn, in which was reproduced a letter from Billroth to the layers, the same conclusions were applicable to carcinoma. pathologist Georg Eduard Rindfleisch. Biliroth, in his communi Thiersch's work had no resounding impact on medical cation, referred to a mammary carcinoma preparation which ap peared to have exclusiveacinar-cell origins, an observation which thought. A critical review of his results was published so astonished him that he was sending the specimen to Rindfleisch in 1866 by the Surgeon Theodor Biliroth (50),—active at for additional study.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0L0—Foundations of Cancer Research 89

sions to the epithelial theory yet preserved the funda of some irritative, fluid stimulus, an idea similar to that mentals of Virchow's concept. By stressing an adhesion proposed by Virchow. If this type of influence were of epitheial and connective tissues in the neoplastic proc operative, Billroth conceded, it should have a specific ess, Bilroth also voiced a presentiment of the endothelial effect, and act in conjunction with cells. The likelihood of theory. (Biliroth (1866 [51, p. 861]) noted Thiersch's contact influences in carcinogenesis would also suggest the reference to a ‘false'epitheliumof organ linings and spaces, presence of an unknown infective agent. Biliroth con corresponding to an intermediate tissue, which under cluded that the problem might be resolved through im pathologic stimuli altered to connective tissue appearances, plantation and inoculation studies in animals of the same possibly as a result of contact influences. He also cited species (e.g., melanomas in horses, carcinomas and sar His' (1865 @194])description of a middle-germ layer which comas in dogs) since implantations crossing species lines the latter had named endothelium. Biliroth suggested thus far had proven fruitless. He recommended its that endothelium as well as connective tissue might give prosecution to the veterinary laboratories (50, pp. 855— rise to a specific series of new growths.) 857.) The epithelial theory was sustained by Naunyn's (1866 The cancer stroma, the origins of which were traceable [284]) observations on the generative role of epithelial to proliferations in the connective tissue regions about the cells, essentially those of the bile duct, in the formation of acii, was also examined by Waldeyer who confirmed a primary cancers of the liver. Naunyn concluded that number of Rokitansky's observations. Waldeyer stressed cells of the parenchyma did not contribute to this phase of that the changing appearances of evolving and evolved neoplastic growth—a pronouncement of controversial stromas, as well as the diverse forms and arrangements of consequences (134, 304). At the same time the theory cells of the same stock accounted for many of the dif was decisively strengthened by the Berlin anatomist ficulties in the earlier carcinoma literature. Lastly, as Wilhelm Waldeyer (1867 [453]) whose research indicated Thiersch had demonstrated, the distinction between the epithelial origins of all cancers. Waldeyer reviewed cancers and cancroids was no longer tenable. the status of the epithelial theory, concluding (453, pp. 472—475) that it appeared to be upheld by Robin and ENDOTHELIAL THEORY Cornil through their conception of the generatio spontanea (autogenesis) of cancer whereas in Germany Virchow's Despite the accumulation of supporting evidence for the hypothesis was still favored by prominent workers (e.g., Thiersch-Waldeyer interpretation (Lotzbeck, 1868 [244], C. 0. Weber, Foester,Biiroth, Wyss (1866 [478]), Rind Czerny, 1869 [102], Leontowitsch, 1869 [239], Sachs, 1869 fieisch (1867 [345, pp. 82—100]),Klebs (1867 [209]), [366], Eberth, 1869 [120], Berthold, 1869 [40], Hirschberg, Langhans (1867 [230]). 1870 [192], Hoffman, 1870 [198], W. MUller, 1871 [283], Waldeyer (working with primary cancers of the breast) Doutrelepont, 1871 [112], Knoll, 1872 [213], Péréwerseff, distinguished two proliferative events; the intralobular or 1874 [302]), another theory was beginning to crystallize periacinar and interlobular or acinar. Intralobular from the discovery of a ‘false'epithelium, the middle-germ proliferations occurred as an introductory phase terminat layer (motor germinal layer) of Remak, or endothelium. ing in an indurated stroma, and coincided with the onset of In 1856 Billroth (44, p. 55 ; 49, pp. 52—53)suggested that acinar proliferations within the matricial capsule. The vascular tissues through degenerative transtormations into occurrence within the acini of distinctive ‘cancer-formers' hyaline plugs participated in the formation of certain accounted for the production of the disease through re cancroids which he designated as cylindromas. These gressive alterations which obliterated the normal con ‘bulb'or ‘knob'shaped combination tumors were subse figuration of cells. Waldeyer detected similar processes quently studied by a number of investigators (54, 146, in stomach, kidney, ovary, and uterus preparations. In 147, 161 (pp. 184—193),250, 252, 267, 288, 403, 439, 449), agreement with Thiersch he noted the same result in the and the Strasbourg (also Koenigsberg and Wuerzburg) malphigian net, sebaceous and sweat glands, and in many pathologist Friedrich Daniel von Recklinghausen (1864 other areas susceptible to carcinoma. [322, p. 71]) first implicated the lymph vessels in the Waldeyer opposed the idea that metastases occurred development of orbital tumors of this type which he through some ‘infectious dyscrasia.' Only two direct eferred to as myxosarconias. modes of transmission apparently existed : (a) through the In 1867 Recklinghausen's student Karl Koester (216), continuity or contiguity of organ structures; and, of greater through a study of cylindromas of the lower jaw and orbit, significance, (b) by means of embolie transfer through the substantiated Recklinghausen's contention by proposing blood and other fluid passages. Whereas primary that lymph endothelium through cellular metamorphoses carcinoma occurred only in regions layered with genuine gave rise to hyaline (colloid) masses which became re epithelium, secondary growths were direct offshoots of constituted into the cylindrical cancers; subsequently, the parent. The cancer cell insofar as it was transported Koester (1869 [217]) allegedly traced the development of carcinoma from the endothelium of the lymph spaces. to a suitable site represented a ‘parasitic germ' (entozo enkeime) capable of unlimited sell-propagation. (Thiersch His conclusions were upheld by similar reports on the accounted for cancers of the lymph glands through a lymphatic and vascular origins of cylindromas by Pagen process of cell transplantation. Bilroth ultimately sup stecher (1869 [298]) and Birch-Hirschfeld (1871 [53]), the ported the transplantation theory which he renamed an latter of whom suggested the designation angioma mucosum embolus theory. Nevertheless, Bifiroth did not discard proliferum for this group, and on lymph-adenomas of the @ the assumption that metastases were the possible products pleura and other regions by Ernst Wagner (1871 [451]).

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 90 Cancer Research Vol. 25, February 1965

Camillo Golgi, in 1869 (156, 157), first applied the term mother. This event was thought by Friedreich to result endothelioma to psammomas of the dura. from infectious matter in the circulating blood. Waldeyer The evidence accumulated by Recklinghausen and (454, pp. 83—84; 144—146) argued that speculations on some Koester for the endothelial origins of cancer, supported by infective ‘virus'were reminiscent of the discredited specific similar studies (Ruztizky, 1874 [365], Rajewski, 1876 cell concept. He insisted that the epithelial infection [318]), paralleled other results pointing to the forma theory promoted through the cell motility work of Carmalt tion of cancer from cells of mesodermal origin as muscle and others reinforced the belief in cancer cell propagation (Popper, 1865 [314], Karl Otto Weber, 1867 [464], R. through metastases, a phenomenon also established in Volkmann, 1870 [440]), cartilage (Karl Otto Weber, 1866 clinical observations; e.g., Reinecke's report (1870 [324]) [463]), vessel linings and capillaries (Steudener, 1868 on the inoculation of cancer through punctures in pen [390], Arndt, 1870 [12], Gussenbauer, 1872 [164], Vajda, tonitis accompanied by carcinoma. 1873 [408]), and from leukocytes (Classen, 1870 [80], Another argument raised against the endothelial theory Rollett, 1871 [361]). Once again Virchow's arguments for resulted from research on epithelial tissue regeneration by the ‘heteroplastic' origins of epithelial tumors appeared to Cleland (1868 [81]), Heller (1869 [183]), Wadsworth and be sustained. Nevertheless, the controversy was ef Eberth (1870 [446]), Hoffmann (1870 [200]), Lott (1871 fectively offset by adherents of the epithelial theory who [243]), and others. This work indicated that damaged countered with fresh evidence. epithelium regenerated through mitotic activity along its In Waldeyer's laboratory Carmalt (1872 [75]), using intact edges. Waldeyer (454, p. 80) received these thin sections of freshly extirpated carcinoma which he reports as solid collateral testimony for the epithelial shook in silver solution, discovered a dissociation of cancer theory. cells from the underlying endothelium which was left in In later years Virchow deemphasized his connective tact as a silvered layer. Carmalt thus concluded that tissue theory (1888 [435, p. 18]; 1893 [436, p. 5]), yet it endothelium was not necessarily the seat of cancer forma remained part of his views on metaplasia (1884 [434]), and tion. Furthermore, Carmalt (75, pp. 486-487) was the traces of it occurred in his outlook upon neoplastic dis originator of a culture technic illustrating the amoeboidal eases as late as 1900 (437). He also saw a partial vindica movement of cancer cells8 which (a) by contributing to the tion for his beliefs in the endothelial theory. so-called epithelial infection theory bolstered the Thiersch Waldeyer conception of metastases, and (b) supported the MODERN FOUNDATIONS OF HI5T0GENIc ONCOLOGY epithelial theory in conjunction with tissue regeneration Overwhelming proof for the epithelial theory was studies. brought to bear by Waldeyer in newer, more extensive The phenomenon of cell motility with respect to cancer studies on the pathogenesis of carcinoma (1872 [454, 455]). had also come under investigation by Classen (1870 [80]) Through a 5-year study of 203 cases of cancer Waldeyer and other workers who postulated the participation of separated cancers having similar modes of development leukocytes in the formation of cancer (Sick, 1864 [381], among five categories : (a) cancers of the outer skin, true Klebs, 1867 [209], Schuppel, 1868 [376]). (These views epitheliomas and adenomas including the ulcus rodens,9 were consonant with the prevalent Waller-Cohnheim (b) cancer of cylinder-cell epithelium, of which the alveolar leukocyte emigration doctrine of inflammation.) This cancers were types, (c) cancers of the acini, a group which amoeboidal effect was investigated further by Rollett (1871 included as combined forms the fibrocarcinomas, cysto [361]), but Biesiadecki (1867 [43]) showed that migratory sarcomas, and many other previously described tumors of white blood cells occurred commonly and without sig the mammae, (d) hepatic and renal cancers, stemming from nificance among epithelial cells of the outer skin. atypical proliferations of the duct linings, (e) ovarian, Wilhelm Muller (1871 [283]) proposed that cancer cell testicular, and cerebral cancers, a category comprising many infectivity stemmed from an undertermined ‘virus,'and tumors of endothelial origin such as the cylindromas. Friedreich (1866 [148]) reported the occurrence of metas Representatives of these in the mesentenies and pia mater tases to a fetus from a primary growth borne by the were designated by Waldeyer as plexiform angiosarcomas.'°

8 Cell motility had been observed by Hoffmann (1868 [199]) as a Ulcus rodens (cf. basal-cell carcinoma) was long known to a consequence of contractile phenomena in frog cornea epithelium. physicians as Noli me tangere. Bayle and Cayol termed this It was subsequently studied by Heller (1869 [183]) in connection neoplasm ulcère cancéreuse. Lebert, who believed that it with cell division in frog tissues. Similar observations were re lacked the specific cancer cell, designated it ulcèrecancroide. In ported by Stricker and his associates in 1870 (see 293, 393). In 1827 Jacob first referred to it as ulcus rodens, and Paget continued the light of this research, Carmalt, in the course of excising a car to describe it as rodent ulcer. Rokitansky and Broca first sug cinoma, collected a quantity of blood from the coagulum of which gested that it was a growth of epidermoidal origin, and Thiersch, he obtained drops of serum which were combined with particles following this view, classified it as a type of epithelial cancer scraped from the host tumor. This preparation was examined (475, 1: 211—212). microscopically under incubation (40°-42°C.),through which 10 Arnold (1870 [13]) first described a myxosarcoma teleangiec cancer cell movement was readily exposed. In more recent times todes cysticum of the pia mater which Waldeyer (454, p. 137, foot various modification of Carmalt's technic have been applied, note 3) considered an excellent example of plexiform angiosarcoma, especially by Hanes and Lambert (1912 [166]), in a study of iso a lesion relating the appearances of sarcoma and tumors of the lated fibroblasts from rodent tumors, and by Ross Harrison (1910 vascular tissues. This was a type entirely comparable to glioma [176]) in research on the in vitro culture of nerve fibers. Other and psammoma. Furthermore, Waldeyer (454,pp. 148—149,foot forerunners of the modern science of tissue culture (405, p. 22, note 1) related the tumors described by Koester and Reckling footnote 17) devised similar methods which, after 1900, gradually hausen to the species of ‘medullary' lymphar&gioma described by gave way to improved technics (i.e., defined media, balanced salt Pagenstecher (1869 [298]). Waldeyer viewed these interrelation solutions, etc.) stemming from experimental physiology, em ships as the taxonomic bridge between endothelial tumors and bryology, and microbiology. epithelial tumors.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TiuoLo—Foundations of Cancer Research 91

Cancers in organs lacking epithelial tissues unless they Benign varieties, higher in the evolutionary scale, having existed at epithelial tissue junctures were exclusively diverted much of their growth potential into tissue forma secondary productions, an idea contested by Karl Sudhoff tion, represented maturated species. Bard then adapted (1875 [396]) and others. The endothelial theory, Wal this theory to Waldeyer's views on taxonomy : he dis deyer concluded, in no way invalidated the fundamental tinguished (a) epithelial skin tumors, and (b) glandular conditions of the epithelial theory. epithelial tumors on the basis of maturated and un Subsequent research in histogenic oncology will be maturated representatives within each category. Other summarized according to the topics, (a) epithelial tumors, workers preferred straight-forward histologic classifica (b) endothelial tumors, and (c) connective tissue tumors. tions; e.g., Herbert Snow (1893 [385, pp. 28—30]),who Epithelial tumors.—Pathology texts of the 1870 era separated epithelial tumors into the following groups : (a) (TJbie and Wagner, 1868 [407], Rindfleisch, 1869 [345] epitheliomas (skin cancers), (b) carcinomas (acinar-cell Maier, 1871 [254]), still beset by conflicting research cancer), (c) cylindromas (tubular-cell cancer), (d) rodent results, remained uncertain as to the origins of carcinoma. ulcer (follicular-cell cancer), (e) lymphocarcinomas (lymph Waldeyer's view continued to be disputed through the vessel cancer), and (1) blastoma (cancer of vestigial 1870's. For example, Schultz (1874 [375]) challenged structures, comparable to teratoma). The systematics of Waldeyer's critical definition of carcinoma as an ‘atypical epithelial tumors reached its most complex development epithelial formation― by proposing instead that the so with Fabre-Domergue (1898 [132, pp. 40—SO]).This called desmoid carcinoma (actually, lymphosarcoma) was situation led authors such as Hansemann (1896 [174]) an atypical connective tissue formation. Nevertheless, and Lubarsch (1901 [247, p. 229]) to urge a new considera newer investigations (Wolffberg, 1874 [476], Friedländer, tion of Virchow's less complicated nomenclature. Bard's 1877 [145], Malassez, 1877 [255], Hauser, 1883 [177], attitudes are consonant with theories on the organic Schuchardt, 1885 [372], Herrmann and Lesur, 1885 [187]) origins of cancer which are treated in connection with upheld and extended the epithelial theory. After 1900 Cohnheim, Ribbert, and others. Table lÀ presents in most pathologists followed Jacob Orth (1904 [296]) in synopsis a taxonomic review of epithelial tumors in vogue qualifying epitheliomas as tumors having both epithelial about 1885. cell types and origins. Orth distinguished benign epithe Endothelial tumors.—Waldeyer, though at variance with liomas as lesions remaining within the growth-potential of Koester on the origins of carcinoma, acknowledged separ normal epithelium and malignant epitheliomas as lesions able (though relational)'° taxonomic positions for epithelial transcending this potential. According to Orth, all and endothelial tumors. Through the 1870's and 1880's adenomas were by definition epitheiomas and all malig reports of lymphangiomas and similar formations fre nant epitheliomas were by definition cancers. quently appeared (Perls, 1872 [305], Schottelius, 1874 Waldeyer, who grossly classified epithelial tumors as (a) [371], Bostroem, 1876 [601, Neelson, 1882 [285], Baum surface (cutaneous) and (b) deep-seated (parenchymatous) garten, 1882 [32], Lubarsch, 1888 [246]). However, new varieties, was sustained by other authors such as Alberts research results in embryology, accumulated as early as (1887 [5]) who also insisted that the specific histogenic 1870 (Goette, 1869 [155], Bambeke, 1870 [23]), and character of cancers merited them a special taxonomic especially as a consequence of the later work of Balfour status. Many systems of classification were suggested (1880 [22]) and Oscar Hertwig (1882 [188]), clarified the through the 1880—1900 period, a late example of which is endothelioma issue. These investigations demonstrated that by Borst (1902 [58]) who separated epithelial tumors that mesoderm formation proceeded from the juncture of into (a) maturated forms—papillomas, adenomas, cystad ectoderm and endoderm at the primitive groove; also, that enomas — and (b) unmaturated forms — carcinomas. it split subsequently into a double layer—an outer region Many of these tumor classifications, of which Borst's is which joined with ectoderm to form the somatopleure and an example, incorporated Virchow's principle of hetertopy an inner zone which joined with endoderm to form the as implied in Orth's above-outlined view. This idea was spksnchnopleure. The formation of mesenchyme through extensively reworked in the 1880's as previously mentioned the fusion of infiltrating mesodermal cells with epithelium in reference to Bard's work. According to Bard adult also was revealed by these studies. By 1885 it became cells, which no longer retained the growth magnitude of possible for the investigator to think of two rather than embryonic cells, having expended it on the tissue organiza three (Remak-His) primary germ layers. tion, possessed a minimal growth capacity. Referring this In the light of this research, Cornil and Ranvier, 1884 conception to the neoplastic series Bard distinguished [92, 1: 365—374]claimedthat endothelium was meaningful malignant forms as unmaturated growths—as tissues re only within the context of epithelial formations. His maining in the lower stages of development thereby re (1882 [1951) advanced the idea of epiblastic, mesoblastic, taming their primitive tendency toward hyperplasia. and hypoblastic tissue formations as phases of development from the archiblasteme as contrasted with development 11 This is the principal premise of the epithelial theory. The from the parablasteme involving tissues usually identified specific cell concept attempted to define cancer as a unique mor phologic entity; as a cell presenting unvarying earmarks. The as endothelial. This concept was elaborated further by epithelial theory specified that all cancer cells were atypical ver Waldeyer (1883 [456, p. 61]), and Klebs (1889 [211]) sions of normal epithelial cells ; not the particular cell but rather proposed that it be adapted to tumor systematics; viz., the behavior of the group as distinguished through unusual or archiblastemie and parablastemic series. (These concep excessive mitotic figures, aberrant configurations, etc., constituted tions advanced toward improved attitudes on germ layer the morphologic peculiarity of cancer. This not only became the new basis for microscopic diagnoses, but also oriented cancer differentiation in pathologic situations; e.g., see Klaatsch, research toward functional considerations. 1899 [208], Marchand, 1899 [260].)

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 92 Cancer Research Vol. 25, February 1965

i'sIany modifications in the nomenclature of endothelial of alveolar sarcoma, suggested they be categorized as (a) tumors were simultaneously advanced. For example, the perithelioma, (b) endothelionia (intra) vawulare, and (c) Berlin histopathologist David von Hansemann (1897 endothelioma lymphaticum containing the subgroup, [175]) held that (a) endothelium and epithelium (angio en4othelioma perivasculare. The question of endothelial epithelium) of the vascular and lymphatic vessels, and (b) tumors remained a prominent research problem in oncology endothelium and perithelium of the pleuroperitoneal through the early 1900's. linings, pia mater, and similar structures, were morpho Connective tiesue tumors.—The later history of research genically synonymous. on connective tissue tumors consisted in large part of Another segment of workers led by Rudolf Volkmann building upon Virchow's foundations (1850 [418]). Ad (1895 [445, pp. 12—61])insisted that cancer and endo ditional histogenic data on sarcoma were gathered by thelioma were in no sense embryologically synonymous, Biiroth and Czerny (1869 [52]), Sokolow (1873 [387]), although from the standpoint of gross morphology Tillmanns (1873 [400]), Steudener (1874 [392]), Ziegler similarities between them existed. Neoplasms of the (1878 [479]), Ackermann (1883 [4]), and others. Much endothelium were related rather to the connective tissues; of this work involved detailed descriptions of special in the opinion of Volkmann classification of these tumors varieties (Gottschalk, 1894 [158], Pick, 1894—1895 [309— should proceed from this assumption. The similarities 311]). which appeared to exist between endothelioma and sar A firm basis for the classification of connective tissue coma, as in the case of Ackermann's (1883 [4, p. 2008]) tumors was established by Virchow in Die krankhaften so-called ‘interfascicular' endotheliomas of the serous GeSChWÜlSte(431, 1: 128—286) through his division of cavities, strengthened this argument. Moreover, Rozin proliferative neoplasms into two major categories; (a) sky (1896 [362]) reported a transformation of connective histoid tumors built from tissues of the matrices, and (b) tissues to endothelium in ovarian endotheliomas, but this organoid tumors built from elements superimposed on circumstance was doubted by Herz (1899 [189, pp. 462— tissues of the matrices and showing complex and variegated 463]) and other workers. Volkmann's thesis nevertheless characteristics. Cohnheim (1880 [83]) argued that this tended to undermine Koester's theory which continued system advanced morphologic distinctions at the expense to be defended by Mulert (1897 [277]), Glockner (1897 of physiologic distinctions: he proposed the establishment [1531)andothers. of a class of (a) connective tissue types to include fibromas, A related problem for which a solution also pended in lipomas, myxomas, chondromas, osteomas, angiomas, volved the category of tumors which passed under the lymphomas, sarcomas, and mixed forms (a group com arbitrary designation of cylindroma. Earlier authors parable to Waldeyer's desinoid tumors—melanoma, were unable to agree on whether cylindromas were myxoma, echondroma, odontoma, glioma, psammoma cancroids, sarcomas, or endothelion-ias. Waldeyer (454, and sarcoma; a class of (b) muscle tissue types to include p. 132) brought them into connection with perithelial myoma laeuicelluiare and striocellulare; and a class of (c) tumors or the plexiform angiosarcomas. The alveolar ap nerve tissue types to include neuromas and gliomas. pearance of certain cylindromas as well as their occasional Cohnheim's system, with its emphasis upon functional round or spindle-cell appearances, was first described by distinctions, was subsequently adopted and extended by Sattler (1874 [368, p. 98]) who inferred that cylindroma other authors. For example, Borst (1902 [58, 1: 100—509]) was a formation of the adventitial tissues (sarcoma also applied his idea of maturated versus unmaturated carcinomatosum). Etwesky (1877 [129]) investigated the formations to connective tissue tumors. He grouped processes of hyaline or mucoid degeneration of the fibrous benign growths into Cohnheim's category (a), and malig stroma or the adventitia of the vessels in the formation of nant growths into Cohnheim's category (b) including the these growths and he suggested that they be classified destructive sarcomas. Delbet (1896 [104]) followed these according to (a) pure forms existing as plexiform sarcomas general views by distinguishing (a) tumors predicated and as angwnia mucosum proliferum, and (b) mixed forms upon the paradigm of adult tissues, including many harm existing as plexiform angiosarcomas and combinations of less histoid neoplasms, and (b) tumors predicated upon the angioma mucosum proliferum with other new growths. paradigm of embryonic tissues including malignant Despite the intensive research on endothelial tumors by sarcoma. Table 1 B presents, in synopsis, a taxonomic 1900 (475, 1: 287—307)opinions on how to classify them review of endothelial and connective tissue tumors in still differed widely. Hansemann who later thought of vogue about 1885. them as genuine epithelial formations at first suggested (1896 [173]) they be classified within the formal categories, E@rioi@oGIC CoNsIDErt@rioNs (a) sarcoma, (b) carcinoma, (c) carcinoma sarcomatodes, Neoplastic blastemas.—Research on the formation of and (d) adenoma—each suffixed by endOthelüsleto denote cancer from atypical blastemas through chemical altera the generic character of the group. Another classification tions (e.g., Führer,1852 [149, pp. 222—224])tended to sus for endothelial tumors having a specific stroma was also tam the cancer dyscrasia etiology during the blastema proposed by Hansemann : i.e., (a) cylindroma or si era. Thus, Engel (1841—1844 [124—126])and Rokitansky phonoma, (b) myoma, (c) chondroma, (d) scirrhus, and (1846 [356]) attributed the anomalies of neoplastic (e) mixed tumors capable of transformation into sarcoma ‘texture' (stromas) to a blood crasis involving meta or carcinoma. Other authors preferred more homogenous morphoses of the blastema. Nevertheless, Rokitansky classifications. For example, Amann (1894 [8]), who in (356, 1: 334—335)did not discount the possible local origins agreement with Sattler considered endotheliomas a variety of benign tumors, of which he considered sarcoma an

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TR1OL0—Foundations of Cancer Research 93

example, through mechanical insult or infection. The Congress of the German Surgical Association at which the diathesis doctrine was promulgated simultaneously in Leipzig surgeon Richard von Volkmann (441—443) Germany by investigators such as Frerichs (1847 [142, p. presented three case histories on scrotal cancers in workers 7]; 1849 [144, p. 12]). However, Frerichs (1846 [141, pp. of the coal-tar and paraffin industries. These observa 688—690]) indicated that distinctive clinical manifesta tions were simultaneously supplemented by Esmarch (441, tions in carcinoma (and tuberculosis) pointed to the p. 6) and Langenbeck (441, pp. 6—7)both of whom sub possibility of localized formations of neoplastic pseudo stantiated claims for a statistically higher frequency of plasmata, and that dyscrasia was superimposed in later oral cancers among tobacco smokers and chewers. In stages. 1880 Tillmanns (401) examined the ‘tobaccohypothesis' Traumatic and irritative stimuli.—In his tumor lectures with the conclusion that smoke tar distilates, particularly Virchow (431, 1: 41-43, 51, 57—71)proposed a generalized phenol and similar agents isolated by E. Ludwig (1877 basis for the generation of neoplastic diseases through [251]), occasioned a neoplastic impetus entirely comparable miasmic organic influences; he also assumed a constitu to creosote, naphthalene, and other industrial by-products. tional predisposition through heredity. However, he had These events are a prelude to the discovery of various already become convinced that tumors resulted to a large industrial carcinogens by 1900, and coincide with the extent from local phenomena, through irritative or trau refinement of clinical observations on the role of trauma matic stimuli (431, pp. 72—101;2, pp. 76, 101). The idea in tumor induction (Volkmann, 1889 [444]). that a local event usually preceded the onset of diathesis Senile disposition.—That trauma and related effects had entered his thinking as early as 1850 (416, p. 135) at gave only a partial answer to the question of etiology was which time he suggested the insinuation of irritative generally admitted by 1870. Thiersch and Tillmanns thus stimuli in the formation of tumors. (The localized oc specified that mechanical or chemical influences on the currence of cartilage tumors as a result of inflammation production of cancer only acted by virtue of a predisposi and irritation was suggested by von Helmsbach-Meckel in tion rooted in some biologic irregularity. Creighton 1856 [267, pp. 62, 78].) (1874 [95, p. 111]) argued that contemporary research as This view was more fully expounded by Virchow in an yet had failed to pin-point the essential character of neo 1858 paper on Irritation and Irritability (429) in which he plastic growth: proposed that the specific ‘cause'ofcancer proceeded from “Thereis nothing in the explanation of the histogenesis of both the nature of the irritative effect and predisposition the growth [cancer] given by Professor Waldeyer to show wherein of tissues toward this effect. Thus, mechanical and it differs from a mere hyperplasia. Other pathologists, again, chemical stimuli were known to induce local eruptions of such as Professor Virchow, have been led in the absence of such new growth in susceptible tissues; according to Virchow an explanation to assign the origin of the epithelial-like cells of (429, p. 45) : “Howelseis it possible to account for the oc the tumor to an ‘epithelial-infection'of the connective tissue, re currence of the so-called epidermoidal and epithelial jecting, as it were, the strong evidence of epithelial origin for cancer—cancroid—preponderantly at sites most exposed the sake of being able to account for the hyperplasia of the to mechanical insult; namely, the orifices, the surfaces of growth.― skin, the confines of passages, the lip, the edges of the To fill this gap several hypotheses were advanced, tongue, the contact point of esophagous and bronchus, the among the earlier of which is Thiersch's 1865 theory (399, cardia and pylorus, the anus, the orificium externum uteri, pp. 78—86)of senile disposition or growth energy imbalance. the eye lids, and the turbinates of the nose. . .; moreover, Thiersch conceded that it was necessary to look beyond the why does cancroid remain so long stationary where it oc prelusory hyperplasia to find an explanation for neoplasia. curs if it is not a malady of local origins?― He inferred from his anatomic evidence that aging brought Together with the related problem of trauma, the con about senile, regressive alterations of the connective cept of an irritative impetus toward cancer existed as a tissues. Moreover, it appeared that a predisposition strong current in oncologic thought long before Virchow's toward cutaneous cancers in the aged proceeded from pronouncement (475, @:125—141). Only in the last two epithelial hypertrophy following involution of the stroma. decades of the nineteenth century did the irritation hypoth Thiersch suggested that skin cancers were the ultimate esis achieve somewhat of an empirical basis from the products of a disturbance in the histogenic energy equilib laboratory viewpoint (405, pp. 14—15). However, the rum between epithelium and stroma. In the face of irritation hypothesis was sustained through an earlier diminished stromic resistance, actively proliferating recognition of specific environmental stimuli in the epithelium established a zone of new growth, continually production of cancer. pressing its advantage against the stroma, forming the The frequent occurrence of lip cancers among pipe nucleus of a neoplasm. smokers was first noted by Soemmerring (1795 [386]), and Thiersch's deemphasis of the stroma in cancer formation similar observations, in which the injurious effects of was opposed by Virchow's disciples (Hoeber (1875 [197])). tobacco were also suggested, were subsequently reported in Adherents of the epithelial theory were not unanimous in studies on labial cancroids (Lortet, 1865 [242, pp. 52— support of Thiersch's theory since the concept of senile 54]). For example, Thiersch (1865 [399, pp. 190—193]) disposition did not appear to be universally applicable. implicated tobacco smoke and juices in the alteration of For example, Waldeyer (1867 [453, p. 520]) concluded that lip tissues cuhninating in cancer, and he compared this out the production of epithelium, contrasted with the inter come to scrotal cancers through soot injury in chimney stitial connective tissue, often tended to diminish with sweeps. Similar issues were raised in 1874 at the third advancing age (e.g., in glandular atrophy) ; in this case the

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 94 Cancer Research Vol.25,February1965 epithelial structures tended to lose their proliferative vigor Embryonic rests.—The idea of an undifferentiated and become subjected to a replacement fibrosis through germinal layer as a source of cancer was first suggested increased activity of the connective tissue. A further during the blastema era; thus, J. Muller (1838 [280]) repudiation of Thiersch's theory was issued by Waldeyer in postulated an anomalous germ cell (seminum morbi) as the his 1872 work (454, pp. 153—154). root of carcinoma. A succeeding generation of anatomists Interface antagoniem.—A hypothesis proposed by the (e.g., Péréwerseff,1874[303]), under Virchow's influence, Bonn anatomist Franz Boll in 1876 (55) sought to rec continued to stress the plastic, embryonal character of the oncile conflicting views on the growth energy imbalance connective tissue stratum as the seat of neoplastic growth. etiology of cancer. Boll approached the problem of neo This view also became a prominent feature of theories such plastic growth through attitudes stimulated by Remak's as Boll's. reform of embryology. Since each of the three tissue One of the first investigators to rework this idea into a theories of cancer argued from their own limited and major hypothesis was the Breslau pathologist Julius static viewpoints, Boll thought it imperative to refer any Cohnheim. Cohnheim argued that some defect or problem of growth, as a dynamic process from inception to irregularity originating in the embryonal anlage became involution, to the first details of embryogeny. Retracing the focal point of tumor formation. His observation Remak's footsteps, he studied lung differentiation in the 8- (1875 [82]) of a congenital striated muscle sarcoma of the to 11-day chick embryo, concluding (a) that the develop kidneys—a myosarcoma striocellulare, grouped by Virchow ment of lung proceeded through an appositive conflict among the teratomas—led him to assume that the tumor between germinating endothelial connective tissues and grew out of muscle germ cells separated from the renal germinating epithelium, and (b) that the elaboration of primordia. Subsequently, he framed this view into a normal lung was not the result of a unilateral growth theory (1880 [83,pp. 634—654])whichwidely influenced the principle but rather a compromise between two dissimilar contemporary outlook on tumor genesis. Cohuheim's though reciprocally determined principles. theory specified that an overproduction of cells frequently Boll claimed that surface organs (e.g., glands) developed occurred in organ morphogenesis. An excess of cells de by virtue of a similar ‘boundary conflict' (Grenzkrieg) be tached some time between differentiation of the germinal tween the connective tissues of vascular origins and the layers and completion of the organ primordia was capable epithelial parts. At a formative period this interface of emerging as a new growth by virtue of the embryonal antagonism yielded normal structures; a resumption of capacity for proliferation or bioplastic energy within these interface antagonism at the period of involution yielded cells. pathologic counterparts—cancroids. Local irritants gave Cohnheim's theory of atypical tissue formation from the the signal for a renewal of the conflict. Boll distinguished embryonal anlage, or embryonic rest hypothesis, was (a) constant, (b) periodic, and (c) single irritative stimuli, generally favored by the weight of strong clinical evidence. of which only the last two were etiologically significant in The numerous occurrences of congenital and early post cancroid formation. Irritants imparted an impulse natal tumors had long been recognized.'2 For example, toward hypertrophy within the vascularized matricial malignancies stemming from both local malformations tissues, thus upsetting the delicate growth balance such as nevi and warts, as well as from more generalized predetermined in the embryonic life of the organ. The organic irregularities appeared to be attributable to this neoplastic moment depended upon the quality of the cause. Newer additions to knowledge of a hereditary formative, irritative influence. predisposition toward cancer (475, 1 : 357—361) also con By taking into account newer results in clinical research formed, though more indirectly, to Cohnheim's explana on cancer Boll's theory had a positive aspect. Its argu tion. A more decisive argument was that tumor cells mentative consistency surpassed many hitherto proposed commonly gave the appearances of undifferentiated hypotheses. Nevertheless, his conclusions were opposed embryonal types. Furthermore, the apparently ac by Friedländer (1877 [145, pp. 39-44]) who insisted that celerated proliferative behavior of artificially implanted Boll's emphasis upon a dual action of epithelial and embryonal tissues (405, p. 14) suggested that every tumor embryonal connective tissues violated the principle of had a similar foundation. The theory was compatible cancer as an atypical epithelial formation, especially in the with the embolus idea of metastases; Cohnheim (1877 light of newer implantation research. (Nevertheless, [84]) gathered experimental evidence to show that de Friedländer [145, p. 57] conceded that little pathologic tached, growing tissues distributed through the vascular significance could be attached to atypical epithelial transport became the foci of new growths at distant sites. proliferation of itself; this expressed an already latent (In 1896 Pianese (308) urged recognition as a co-founder realization that some functional basis for atypical epithelial of the theory of embryonic rests for the surgeon F. Durante proliferation must be sought.―) Virchow (1880 [433, pp. on the basis of the latter's research on the structure of 192—193])opposed Boll's reference to the connective tissue birthmarks. This work was allegedly reported a year germ layer (vascular matrix) as a “tissuereverted to a before Cohnheim's 1875 publication (82). Durante (1894 condition wholly analogous to the embryonal;― he claimed [119]), about 1872, observed the rapid eruption of two that this expressed nothing more than his own idea of an sarcomas from dermoidal nevi submitted to surgical treat ‘undifferentiated granulation tissue' as the starting point for cancer. Virchow also critized Boll's emphasis upon an 12 Nineteenth century research in this field is too extensive to be considered here. It is fully covered by Wolff (475, 1: 333—368) ‘embryonal mysticism' in place of a straightforward who discusses various phases of the teratoma problem with refer anatomic approach. ence to Cohnheim's theory.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0L0—Foundations of Cancer Research 95

ment. The assumption that these structures possessed a currence of neoplasms at the orifices might be explained latent capacity for malignant tumor production led him as complications in the embryogenesis of these structures, to investigate the histogenesis of nevoid neoplasms. The resulting in the laying down of atypical germinal elements. following is an excerpt of Durante's conclusions as trans However, it was thought necessary by many investigators lated from the Italian (119, p. 35) : “Thisresearch per to look beyond the growth potential of germinal tissues nutted me to firmly assume that malignant tumors were for the causes of neoplasia. generated in the species of birthmarks which possess Tissue tension.—Beginning in 1894 the histopathologist congenital connective and epithelial tissue elements. I Hugo Ribbert (Zurich) communicated a series of reports presented my thoughts upon my embryologic and terato (334, 335, 337—343)inwhich he attempted to answer 5ev logic studies, as well as my observations upon the develop eral objections to Cohnheim's hypothesis by presenting a mental and anatomico-pathologic course of several organs more circumspect analysis of tumor pathogenesis. Rib at the period of puberty, and all other relevant questions, bert proceeded from the assumption that regular tissue in a small memoire on the structure of birthmarks pub growth was determined by the coordinated and balanced lished on the 26th of May 1874 in Palasciano's Archives, development of its cellular components. If the cell be in which I arrived at the following conclusion: ‘Elements came partly or completely detached at some point in the which have retained their anatomic embryonal characters correct sequential development of the tissue it continued in the adult organism, or have regained them through to proliferate in a variety of ways differing from the growth some chemico-physiologic deviation, represent, in my norm; the extent of the withdrawal of the cell from its opinion, the generative elements of every tumor variety typical relationships (expressed as tissue tension) became and specifically those of a malignant nature. Such the standard by which a growth deviation, culminating in elements may remain enclosed within matured tissues for a tumor, was to be gauged. Ribbert (1895 [336]) at many years, giving no indication of their presence, until tempted to summon evidence for the occurrence of ab an irritation—a simple stimulus suffices—rekindles their normal growth pursuant the release of tissue tension vital cellular activities just as heat initiates activity within through the alleged experimental production of enchondro elements of the germinal macule of fowl's eggs. . . . In sis in a rabbit. fact, if we briefly consider just how complicated are the Ribbert's theory actually was subsumed in a growth disposition of tissues which concur in the organic composi principle outlined in 1880 by the Leipzig pathologic ana tion of an epithelial cancer, we must at least admit that tomist Carl Weigert (466). Weigert suggested that nor the genesis of cancer, at some determined point in the mal growth was a biologic expression reciprocally ex organism, derives from a reproduction of internal em changed among tissues to preserve or restore an equitable bryonal activities incorporated in the cell which possesses space-matter relationship. The natural increase of cells the requisite anatomico-physiologic apparatus necessary under a variety of circumstances—abundance or depletion to their manifestation'.―3) of nutrients, aging, etc.—was essentially geared to the An objection to Cohnheim's hypothesis was raised by usual status quo of their appropriate environment, al Samuel (1879 [367]), and later by Hauser (1890 [178]), though as in the case of regenerating tissues overcompen each of whom pointed out that it did not relate well to the sation (hyperplasia) might be expected. Pathologic formation of carcinoma from the standpoint of the growth as marked by excessive cellular proliferation occur epithelial theory. Virchow (1880 [433, pp. 189—190]) red when, in some way, the regular reciprocation between argued that the occurrences of certain tumors, such as tissues elements became disturbed—when the normal neuromas at amputation sites, appeared to fall beyond the physiologic demarcation between tissue components ceased scope of the theory. Other gaps in the hypothesis also to be preserved. The embryonically inherent potential became apparent; e.g., isolated tissue-rests or superfluous for normal or pathologic growth was a critical factor ; ex embryonal masses did not invariably give way to neoplastic ternal stimuli merely aroused a quiescent tendency within growths, nor was there any apparent reason why they the cell toward proliferation. Weigert speculated on the should. Cohnheim's theory laid heavy emphasis upon the causes for a breakdown of normal growth control, among ready tendency for proliferation in embryonal elements. which Cohnheim's and Thiersch's views were given special Nevertheless, the influence channeling this tendency into due. (Endocrine regulation was unknown.) either the normal or neoplastic route stifi remained un Implementing Weigert's ideas at the anatomic level, explained. Ribbert focused his attention upon the pathogenic staging Cohnheim himself did not specify exact circumstances of neoplastic growth, particularly carcinoma (343, pp. 13— leading to disordered growth in embryonic rests; the role 74). The process was defined by: (a) the existence of an of certain indirect influences such as vascular complications inherent capacity for multiplication in cellular complexes and inflammatory hyperemia seemed to be implicated. in whatever situation. (Release of growth restraints, The idea of gross mechanical insult as a prime cause of imparted by the tissue environment, induced the resump tumors at the body orifices was rejected by Cohnheim who tion of reproductive activities in cellular complexes (i.e. claimed that tumors appeared rarely on the hands and tissue rests)). (b) The resumption of proliferation, cvi feet, sites particularly susceptible to trauma. The oc denced through subinfiltration at the margins, coincided with hypertropic changes in the subjacent tissue (through 13 At the present time, Durante's priority claim, according to all of the commentators consulted, is cited from his 1894 article means suggested by Cohuheim, although Ribbert also in the Policlinico (119). A rare copy of his 1874paper (118) re specified the indirect influence of trauma) which further cently has been located and will be reviewed at a later time (406). lessened the natural resistance to renewed multiplication

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 96 Cancer Research Vol.25,February1965

of the cellular complexes. (c) The concomitant occurrence 16],Schleich, 1891 [378], Ribbert, 1891 [333], Noeggerath, of cellular dedifferentiation enhanced the capacity of the 1892 [292].) Hansemann (1890 [170]) emphasized that cellular complexes to more vigorously penetrate neighbor each asymmetric karyokinesis, resulting in the formation ing tissues. Embryonal tissues were most disposed to of disproportionate daughter cells, signified an altered state renewed multiplication by virtue of a lack rather than a of cellular differentiation which conferred upon their prog loss of differentiation. eny growth potentials differing from cells following a regu Ribbert's emphasis upon the joint role of the connective lar mitotic course. Subsequently (1891 [171]), this investi tissue in the tumor process was ostensibly a retrograde step gator correlated his conclusion with other cytologic data in the view of Gustav Hauser, (1890 [178]) and also in the such as his separation among cancer cells having an ab opinion of Borst, although the latter (58, p. 686) praised normally poor chromatin complement (hypochromatism) Ribbert's analysis of the transformation from normal to and other atypical cell formations having an excessive abnormal epithelium as well as his generally balanced per chromatin complement (hyperchromatism). spective on the behavior of the epithelium in cancer forma These results which comprised the factual essentials of tion ; however, he could not entirely subscribe to Ribbert's Hansemann's theory of anaplasia (1893 [172]) provided, view of a concurrent hyperplastic modification of the con according to the author's own specification, only a partial nective tissue even though inflammation of the subepithel answer to the etiology of cancer. First, anaplasia merely iai regions in cancer might in fact indirectly stimulate the represented a relatively abnormal situation; cells tended to pathologic production of epithelium. Hauser was more become more anaplastic with respect to their degree of emphatic in his insistence that the initiative in the neo functional isolation from parent tissues. Secondly, in plastic process lay exclusively with the cell. contrast to embryonal rests, the loss of cellular differenti In a series of articles (179—182)Hauser contended that ation in anaplasia might hypothetically arouse within them connective tissue alterations were entirely incidental to the a capacity to express biologic tendencies culminating in performances of the epithelium in the development of car growth deviations. Thirdly, the anaplastic cell would cinoma. These performances—here Hauser cited the re theoretically require an incitatory influence acting upon it in suits of his own investigations—were evidenced through an order to alter into a neoplastic cell. ever-widening zone of glandular degeneration proceeding Hansemann's claims were met with countercharges such into the underlying tissues. (This claim stood in contrast as that posed by Ribbert (1897 [343, pp. 32—36])that the to Ribbert's conclusion that the progress of cancer must be theory of anaplasia overlooked the hereditary growth defined essentially in terms of constitutive rather than controls built into cells at the inception of the organism. degenerative events.) According to Hauser, cancerous This rendered unlikely the radical alterations of cells or degeneration was associable with a biologic disordering of their descendents specified among the conditions of the the epitheium, in which the cells appeared to undergo a theory. Hansemann's hypothesis was also weakened by a loss of normal physiologic function by virtue of derange variety of exceptions. For example, Stroebe (1892—1893 ments in the cellular and nuclear dimensions, chromatin [394, 395]), Vitalis Muller (1892 [282]), Karg (1892 [214]), content, mitotic behavior, and protoplasmic character. and others argued that asymmetric mitoses could not be These changes also appeared to be correlative to the tre correlated with a specific pathologic circumstance since mendous proliferative tendencies in disordered epithelium they were to be found not only in cancer tissues but also in and pointed to the conclusion that neoplastic cells repre sarcomatous and benign growths, as well as in regenerating sented a new biologic species. and other normal tissues in which prolific mitotic activity Anaplasia.—A chronicle of late nineteenth century occurred. By 1900 more critical opposition to the theory developments in cellular biology is beyond the scope of this was spearheaded by investigators such as Rudolph Beneke report; however, it should be mentioned that by 1895 much (1900—1901[37,38]) who began to stress the possibility of fundamental knowledge on the vital processes of the cell less apparent, but more fundamental functional reversions under normal and pathologic circumstances had been laid (kataplasia) which prompted disordered cellular growth. down (473). Hauser's attitudes are consonant with the new research perspective on the functional character of the CONCLUSIONS cancer cell. This outlook has already been previewed in A recapitulation of the principal topics discussed in this reference to Bard's suggestion (1885) that the neoplastic review is as follows. cell existed as an atavistic type demonstrating reproductive deviations. Bard, in support of his premise, also pointed TUMOR MORPHOLOGY to the bizarre cytologic appearances of the neoplastic A settlement of problems relating to the pathologic varieties. anatomy of neoplastic diseases emerged as the crucial The cytology of cancer was given special consideration research issue in cancer at the turn of the nineteenth by the peripatetic pathologist Edwin Klebs (1889 [211, p. century. Solutions were attempted through various con 524]; 1890 [212]) whose theory of cancer formation as a temporary aspects of medicine; i.e., through a well-estab conjugation of epitheial cells and leukocytes largely grew lished surgical tradition in the British Isles, and through out of the assumption that the neoplastic cell demonstrated newly organized clinical centers in France and later in a characteristically atypical (asymmetric) mitotic behavior Germany, Switzerland, and Austria. An early approach @ in which fragments of leukocytes participated. (The to the structural pathology of tumors proceeded from the question of pathologic mitosis already had become a lively infant science of histology; investigators began to think of research issue (Arnold, 1879—1884[14—17]),Alberts, 1890 cancer and related diseases as de novo tissue productions.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0Lo—Foundations of Cancer Research 97

A newly ascendant constitutional theory of cancer, with its influential workers who expressed the common medical pronounced emphasis upon empirical criteria, now came consensus that this disease was to be ranked in the cate into vogue. Nevertheless, a concomitant advance in the gory of an occupational hazard. Many investigators competing localistic doctrine bore more promising conse (cited by Lortet, 1861 [242, p. 47]) also took into account quences (a) as an experiential background for tumor trans the influences of climate and geographic location, among plantation research, (b) as the modern beginnings of the other factors, in their evaluations of the neoplastic theory of metastases, specifically in the quarter century processes. By virtue of these observations the critical from Récamier(1829) to von Helmsbach-Meckel who role of external functional stimuli became the mainspring recognized (1856 [267, pp. 62, 103]) the backward trans of many theoretical approaches to tumorinduction. These port of cancer through the lymphatics, and (c) by virtue aspects lent weight to the rapidly ascendant research of improved clinical conceptions of tumor induction conviction that cancer and related diseases presented mcd through environmental stimuli. ical science with a many-faceted problem.

CELL BIOLOGY RESEARCH ON HUMAN CANCER AND EXPERIMENTAL TUMOR The study of cancer was carried to the cellular level PATHOLOGY through the availability of achromatic lenses for micro The principal research advances discussed in this report scopes, particularly after 1830. This technical innovation, are the results of gross and microscopic diagnoses of human despite its incipient deficiencies, ultimately secured a per cancers, which made possible a sound edifice of knowledge manent taxonomic edifice for oncology on two fronts: (a) for the prosecution of experimental pathology. Thus, the microscopic diagnoses of tumors at various sites provided experimental trials by Peyrilhe and his contemporaries the clinician with exact histologic data incorporating a predated by more than a century the opening of the first variety of biologic details (e.g., the nature of secretory fruitful moves in the area of tumor transplantation re changes) ; by 1880 the diagnostician was working success search. “Atatime when the test of direct experiment is fully with precise categories of neoplasms; (b) through being applied for the elucidation of many of the complex microscopic and other newly devised laboratory technics, problems of animal life and its modification by disease,― the pathologist simultaneously settled many pathogenic according to one prominent pathologist of the era (1883 questions in oncology. This research assessed both the [128, p. 241]), “itwould be surprising if the mystery of structural and functional sources of tumor materials tumour formation had not been attacked from the same through a succession of growth concepts which eventually direction.― focused investigative thought upon the behavioral peculi As an incipient discipline before 1900, experimental antics of the neoplastic cell itself. By 1900 it became pos oncology added suggestive rather than conclusive details sible to think of cancer and other autonomous new growths to the research picture. For example, the early record of as submicroscopically defective cellular species. implantation research in the nineteenth century led to a rapid awareness of the need for studying growth under INHERENT SUSCEPTIBILITY standardized conditions. Epidemiologic oncology was Hereditary aberrations and physical and chemical dis stimulated by the recurrent questions of infective and turbances within the tissue environment as internal seats of environmental influences in cancer. It is interesting to disordered growth, became pivotal issues in oncology after note in this connection that not only a ‘virus' theory 1850; the static dyscrasic viewpoint, in consequence, took emerged from this background, but also a ‘tobacco'hy on the more meaningful aspects of a search for physiologic pothesis of carcinogenesis. Although each of these aspects irregularities in cancer (Broca, 1852 163]). In later years began its experimental history in the new century (e.g., this evidence combined with other features of the constitu Bans, 1910; Yamagiwa and Itchikawa, 1915), each had tional character was summoned as direct proof for the significant precursors in the old century (e.g., see Wilhelm existence of intrinsic, predisposing causes of neoplastic Muller, 1871 1283]; Power, 1893 [315]). diseases. Cohnheim's hypothesis, supported by a broad Cancer research thus represents a slowly unfolding spectrum of anatomic knowledge, emerged as the highpoint episode in which the past and present are but sequential of this approach though it failed as an all-encompassing scenes. etiologic argument. However, this and other theories in ADDENDUM the same genre allowed for the coincidence of extrinsic This article is offered (a) as a vehicle to the older literature in influences in tumor genesis; they thereby constituted oncology, and (b) as a general survey of earlier trends in cancer sufficiently enlarged platforms for subsequent experimental research. Such limited dimensions do not permit the incorpora efforts. tion of critical evaluations and expanded discussions. This is a task for historically oriented professionals in clinical and experi ENVIRONMENTAL C@itcn.@oo@EsIs mental medicine. It has not been possible to go beyond the rudiments of pat,ho Interest in the carcinogenic potential of environmental physiologic concepts of metastases. This topic has been developed constituents grew into a strong current of activity in mid in several articles by Dr. Wilson I. B. Oniugbo (An Historical nineteenth century cancer research programs. Perceptive Criticism of Tumor Metastases, J. list. Med., 13: 529—31,1958; clinical judgments underlay the early advance of this Lung Cancer in the Nineteenth Century, Med. list., 3: 69-77, 1959; Patterns of Metastases in Lung Cancer, A Review, Can. field; for example, Sir Astley Cooper (1830 [86, p. 226]), a Res., 21: 1077—85,1961; Historical Trends in Cancer Surgery, significant contributor to the diagnosis and surgical treat Med. Hist., 6: 154—61,1962;and The Paradox of Virchow's Views ment of chimney-sweeps cancer, was among the more on Cane@@@Metastases,Bull. Hist. Med., 36: 444-49, 1962). More

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 98 Cancer Research Vol. 25, February 1965

over, space limitations have made it necessary to deemphasize al'hôpitalSaint-Louis,etexpositiondesmeilleunesméthodes technics of biopsy and the numerous auxiliary procedures involved suivies pour leur traitement, p. 118. Paris : Crapant, Caille in histologic research. It should be remembered that these were et Ravier, 1806. as essential as the achromatic microscope to the advance of cancer 8. AMANN, J. A., Jn. Ueber Ovanialsarcome. Arch. Gynakol., research. Simultaneous progress in veterinary pathology (see 46:484—96,1894. Stricker's review of animal cancers in Arch. klin. Chir., 65: 616- 9. ANDRAL, G. Précisd'anatomie pathologique (2 vols.), 1:492- 96, 1023—87,1902)is an important collateral area of development. 503. Paris: Gabon, 1829. Occupational and other facets of environmental carcinogenesis 10. ANGER,T. Des tumeurs lymphatiques (adénolymphocUes). are superficially treated. A comprehensive monograph on this Paris : Asselin, 1867. subject would be a valuable addition to the historical literature 11. ARAN, F. A. Note sun un fonme particulièreet encore peu on cancer. The complexities of environment, occupation, and connue de cancer de la dune mere et des os du crane (cancer cancer require special considerations in historical development. vent, chloroma). Arch. gen. med., 4(5s.):385—412, 1854. Pending the availability of such a history, the reader is referred 12. ARNDT,R. Em Cancroid der Pia mater. Arch. pathol. Anat. to historical data included in reviews of recent research in car u. Physiol. Virchow's, 51:495—505,1870. cinogenesis and epidemiologic oncology; e.g., P. R. Peacock 13. AaNou, J. Em Myxosarcoma teleangiectodescysticum den (Cancer, R. W. Raven, editor, Butterworth: London, 1957—59, Pia mater den linken GrosshirnhemisphAne. Ibid., 51:441—57, Vol. 1: 32-75) and W. C. Hueper (Ibid., pp. 404-496). 1870. Various readers may note the omission of American contribu 14. . Ueber feinere Structur den Zellen unten nonmalen tions in this review. There was little justification for an ‘Amen und pathologischen Bedingungen. Ibid., 77:181-206, 1879. can School' since nineteenth century American investigators 15. . Beobachtungen Uber Kerntheilungen in den Zellen were, for the most part, apprentices in the laboratories of the den Geschwulste. Ibid., 78:279-301, 1879. European masters. Carmalt, Hoeber, and Wadsworth, mentioned 16. . Beobachtungen überKernund Kerntheilungen in den in the discussion, are examples. John Collins Warren (Boston), Zellen des Knochenmarkes. Ibid., 93:1—38,1883. a pupil of Sir Astley Cooper and Dupuytren, was the first Amen 17. . Weitene Beobachtungen überdie Theilungsvorgange can to write a treatise on tumors (Surgical Observations on an den Knochenmarkzellen und weissen Blutkorpern. Ibid., Tumours with Cases and Operations, London : Churchill, 1839); 97:107—31,1884. its influence on European authors such as Walter Hayle Walshe is 18. AaNo@rr, H. Cancer; Its Varieties, Their Histology and discussed by Pollay (313). The universality of scientific interests Diagnosis, pp. 1-14. London: Churchill, 1872. which characterizes Johannes Muller and Virchow also distin 19. ARNSTEIN,C. Zur Casuistik der Makroglossie. Arch. pathol. guishes the career of the anatomist Joseph Leidy (Philadelphia). Anat. u. Physiol. Virchow's, 54:319-24, 1872. Leidy (Proc. Acad. Nat. Sci., Philadelphia, 5: 201, 212, 1851— 20. Asmuc, J. Traite des tumeurs et des ulcéresou 1' on a tâché 1852), implanted fragments of human (mammary) cancer beneath de joindre a une théoniesolide,la pratique la plus sure & la the dorsal integument of a frog. After 5 months Leidy noted that mieux éprouvée(2vols.), 2:1—70.Paris: Cavelier, 1759. the fragments had formed vascular attachments to the integument 21. BALFOUR,J. H. Case of a Peculiar Disease of the Skull and and to each other. The experiment was repeated with similar Dura Mater. Edinburgh Med. Sung. J., 43:319-25, 1835. results, from which Leidy concluded that cancer was inoculable, 22. BALFOUR, F. M. On the Structure and Homologies of the “for,as in the experiments, the cancerous fragments continued Germinal Layers of the Embryo. Quart. J. Microscop. Sci., to live when introduced into cold-blooded animals, they would 20(n.s.):247—73, 1880. probably not only continue to live when introduced into warm 23. BAMBEKE, C. VAN. Recherches sun le developpement du blooded animals, but would grow or increase in size―(p. 212). pélobatebrun (PélobatesFuscus, Wagl.). Mém.cour.acad. Leidy perhaps may be considered the Peynilhe of America. roy. Belg., 34:1—66,1867—70. 24. BARD, L. Anatomie pathologique généraledestumeurs, leur ACKNOWLEDGMENT nature et leur classification physiologique. Arch. physiol. The continuing advisory assistance of Dr. Elizabeth C. Miller norm. pathol., 5:247—65,1885. and Dr. use L. Riegel is gratefully acknowledged. The author is 25. . Anatomic pathologique généraledestumeurs, leun deeply indebted to Dr. Michael B. Shimkin for many valuable nature et leur classification physiologique. Ibid., 6:493-525, suggestions. Special acknowledgment is owed Dr. Harold P. 1885. Rusch for the support he has given to all aspects of this project. 26. . Des tumeurs du type épithélial,épithéliomeset adénomes.Ibid., 6:564—76,1885. REFERENCES'@ 27. . La spécificitécellulaire et l'histogénese chez l'em bryon. Ibid., 7:406—20,1886. 1. ABERNETHY,J.SurgicalObservationsContaininga Classi 28. . Dc l'induction vitale ou influence specifique a distance fication of Tumours, with Cases to Illustrate the History of des élémentscellulairesles uns sur lee autres. Arch. med. Each Species, pp. 1-107. London : Longmann and Rees, 1804. exp., 2:337—410,1890. 2. ACKERKNECHT,E. H. Rudolph Virchow. Madison: University 29. . La spécificitécellulaire et ses principles consequences. of Wisconsin Press, 1953. Semaine med., 14:113—20,1894. 3. . Historical Notes on Cancer. Med. Hist., 2:114—19, 30. . Précisd'anatomie pathologique, Ed. 2, pp. 1—25. 1958. Paris: Masson, 1899. 4. ACKERMANN,T. Die Histogenese und Histologie den Sarkome. 31. BARENSPRUNG, F. G. F. VON. Beitrage sun Anatomie und Sammi. Klin. Vortr. (R. Volkmann, ed.), Nos. 233—U4(Chin. Pathologie den menschlichen Haut, pp. 109—116.Leipzig: No. 74) : 1971—2040.Leipzig: Breitkopf u. Hartel, 1883. Breitkopf u. Härtel, 1848. 5. ALBERTS, J. E. Das Carcinom in historischen und expeni 32. BAUMGARTEN,P.Ueber Transformation und Proliferation mentall-pathologischer Beziehung. Jena : Fischer, 1887. des Lymphgefass-Endothels (Lymphangioitis hyperplastica) 6. . Den heutige Stand den Knebsfrage. Deut. med. den Darmwand. Centn. med. Wiss., 20:33-36, 1882. Zeitung, 11:1043—50, 1890. 33. BAYLE, B.-L., AND CAYOL, J.-B. Cancer. Diet. Sd. Med., 7. ALIBERT,J. L. Descriptions des maladies de la peau observées 3:537—679,1812. 34. B@cr@.&iu,P.-A.Additions a l'Anatomie généraledeXav. 14 In order to enlarge the scope of this bibliography, rare first Bichat. pp. 119—32.Paris:Bnosson& Chaudé,1821. editions as well as principal translations of key works have been 35. BEELA, R. Die Carcinomlittenatur. Eine Zusammenstellung consulted and are usually cited. The author is indebted to the den in- und auslãndischenKrebsschniften bis 1900. Berlin: National Library of Medicine (Bethesda), the Library of the New Schoetz, 1901. York Academy of Medicine (New York City), the Welicome 36. BENEKE, R. Neuene Anbeiten zun Lehre vom Cancinom Historical Medical Library (London), and the University of (1886—1891).Jahrbüch.Ges. Med., 234:13—100,185,212, 261— Wisconsin Medical Library (Madison) for making these treatises 87, 1892. available. 37. . Em Fall von Osteoid-Chondnosancom den Hannblase,

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRIOLO—FOUndationc of Cancer Research 99

mit Bemerkungen uben Metaplasia. Arch. pathol. Anat. u. i'examen de la doctrine médicalegénénalement,adoptée, Physiol. Virchow's, 161:70—114,1900. etc. , precede de propositions renfenmant la substance de la 38. . Noch einmal die Anaplasie. Ibid., 163:174—78,1901. medicine physiologique (2 vole.), 1:xlvii—viii;2:588—91,696— 39. BENNETT, J. H. On Cancerous and Cancroid Growths, pp. 97. Paris: Mequiqnon-Marvis, 1821. 175-97. Edinburgh: Sutherland and Knox, 1849. 67. BROWN,R. Observations on the organs and mode of fecunda 40. BERTHOLD,H. Ueber die pathologisch-anatomischen VerAn tion in onchideae and asclepiadeae, pp. 511—14. London, derungen den Augen-Medien und -Haute bei intnaocularen 1833 in The Miscellaneous Botanical Works of Robert Brown Tumoren. Arch. Ophthalmol. Gnaefe's, 15:159—83,1869. (3 vole.), 1:487—543.London: The Ray Society, 1866. 41. BICHAT, F.-X.-M. Anatomie génénale,appliquéea la physio 68. BRUCH, C. Die Diagnose der bosartigen Geschwulste. Nach logie et a medicine (4 vols.), 1:99—103,Paris: Brosson, Gabon eigenen Untensuchungen, pp. 213-24, 233-49, 318-48. Mainz: et C@, 1801. Zabern, 1847. 42. BIDDER, F. Ijeber einen aus cylindnischen Zellen zusammen 69. . Ueben den Erweichungsprozess bosartiger Geech gesetzten Epithelialknebs. Arch. Anat. u. Physiol. Wise. wulete. Zt. Rat. Med., 7:35-57, 1849. Med., pp. 178-98, 1852. 70. . Ueber Carcinoma alveolane und den alveolAren Ge 43. BIEsI@tnzcxI, A. VON. Beitrage zun physiologischen und webstypus. Ibid., 7:357—403,1849. pathologischen Anatomie den Haut. Sitzber. Akad. Wise. 71. . Ueben Magenknebs und Hypentrophie den Magen Wien, (Math.-naturw. Kl.), 56:225-50, 1867. hAute in Anatomischer und klinischer Hinsicht. Ibid., 8:249— 44. Biu@no@rn, T. Untersuchungen überdie Entwicklung den 416, 1849. Blutgefaese, nebst Beobachtungen aus den Koniglichen 72. BRUN5, P. Das Ranken-Neurom. Eine Beitrag zur Geech chinungischen Univensitats-Klinik zu Berlin, pp. 55-69. wulstlehre. Arch. pathol. Anat. u. Physiol. Virchow's, 50:80— Berlin: Reimen, 1856. 112, 1870. 45. . Beobachtungen überGeschwulste den Speicheldrusen. 73. BURNs, J. Dissertations on Inflammation (2 vole.), 2:302— Arch. pathol. Anat. u. Physiol. Vinchow's, 17:357—75,1859. 330. Glasgow: Murdoch, 1800. 46. . Untersuchungen überden feineren Bau mid die 74. BUTLIN, H. T. Report on Inquiry No. XIII, Cancer (of the Entwicklung den Brustdrusengeschwulste. Ibid., 18:51—81, breast only). Bnit. Med. J., 1:436-41, 1887. 1860. 75. CARMALT,W. Bemerkungen zur Lehre von den Entwickelung 47. . Ueben die feinere Struktur den medullanen Gesch der Carcinoma nebst Beobachtung überdie spontane Be wUlste. Ibid., 18:82—99,1860. wegungsfahigkeit von Geschwulstzellen. Arch. pathol. Anat. 48. . Ueber Cancroide mit Schleimcysten. Ibid., 1&99-105, u. Physiol. Virchow's, 55:481—87,1872. 1860. 76. CARMICHAEL,R. An Essay on the Effects of Carbonate, and 49. . Ueber eine eigenthumliche gelatinose Degeneration Other Preparations of Iron, upon Cancer: With an Inquiry den Kleinhirnde nebst einigen Bemenkungen Uber die Bezie into the Nature of That and Other Diseases to Which It hungen den Gefasserkrankungen zun chronischen Encepha Beans a Relation, pp. 467—84.Dublin: Gilbert and Hodges, litis. Arch. den Heilk., 3:47—62,1862. 1809. 50. . Kritische and erlAutennde Bemerkungen zu dem 77. CARSWELL, R. Carcinoma. Illustrations of the Elementary Werke von Professor Dr. C. Thiensch in Enlangen. Arch. Forms of Diseases. London: Longman, Orme, Brown, Green, kim. Chir. Langenbecks, 7:848-59, 1866. and Longman, 1838. 51. . AphonisemüberAdenomund Epithelialknebs. Ibid., 78. - . Scirrhus. The Cyclopaedia of Practical Medicine 7:860—75,1866. (4 vole.), 4:82—104.Philadelphia: Blanchard and Lea, 1849— 52. , AND CZERNY,V. Beitrag zur Geschwulstlehre.Ibid., 54. 11:230—52,1869. 79. CHAMBARD,E. Note sur un cas de cancer pnimitif de la peau 53. BIRCH-HIRSCHFELD,F. V. Zur Cylindromfrage. Ueber eine (carcinoma néticulé). École practique des hautes etudes. eigenthUmliche Gefassgeschwulst den Bnauchhöhle. Arch. Laboratoine d'hietologie du college de France : Travaux des den Heilk., 12:167—86,1871. annees 1879—80,5:99-122,Paris : Masson, 1880. 54. BOETTCHER, A. Ueben Stnuctun und Entwickelung den als 80. CLASSEN,A. Ueben em Cancroid den Comes und Sclera, em “Schlauchknorpelgeschwulst, Cylindroma' ‘etc bekannten Beitrag zur Entwickelungsgeschichte den Carcinoma. Arch. Neubildung. Arch. pathol. Anat. u. Physiol. Vinchow's, pathol. Anat. u Physiol. Virchow's, 50:56-79, 1870. 38:400—28,1867. 81. CLELAND,J. On the Epithelium of the Cornea of the Ox. J. 55. BOLL, F. Das Pnincip des Wachsthums. Eine Anatomische Anat. Physiol., 1(2s.):361—65,1868. Untersuchungen, pp. 67-82. Berlin: Hinschwald, 1876. 82. COHNHEIM, J. Congenitales quengestreiftes Muskelsarkom 56. BORREL, A. Note sun la division multiple du noyau pan den Nieren. Arch. pathol. Anat. u. Physiol. Virchow's, kanyokinèse. Compt. rend. soc. biol., 2(9s.)22—24, 1890. 65:64—69,1875. 57. . Dc la division du noyau et de la division cellulaire 83. . Geschwulste. Vonlesungen überallgemeine Patho dans les tumeuns épithéliales.J. anat. et physiol., 28:129— logic. Em Handbuch fun Aerzte und Studirende (2 vole.), 42, 1892. 1:622—91.Berlin: Hirschwald, 1877—80. 58. Bons@, M. Die Lehre von den Geschwulsten, mit einem 84. , ANDMAAS, H. Zur Theonie den Geschwulstmetasta mikroskopischen Atlas (2 vols.), 2:512—784.Wiesbaden: sen. Arch. pathol. Anat. Physiol. Vinchow's, 70:161—71,1877. Bengmann, 1902. 85. COOPER, A. P. Illustrations of the Diseases of the Breast 59. BOSTOCK,J.Analysis of a steanoidtumour. Edinburgh Med. (2 Pts.), 1:51—68,76—84.London: Longman, Rees, Onme, Sung. J., 2:14—16,1806. Brown, & Green, 1829. 60. BOSTROEM, E. Das Endothelcarcinom. Em beitrag zun 86. . Observations on the Structure and Diseases of the histogenese des Cancinome. Erlangen : Jacob, 1876. Testis, pp. 116-155. London: Longman, Rees, Orme, Brown, 61. BRE5CuET,G., AND FERRUS,G.-M.-A. Cancer. Diet. Med., & Green, 1830. 4:131—220,1822. 87. CORNIL, V. Sun la production de tumeuns epitheliales dane 62. BRI5T0wE, J. S. Muscular (So-called Fibrous) Tumours of lee nenfs. J. anat. et physiol., 1:183—98, 1864. the Uterus. Phil. Trans. Path. Soc. London, 4:218-23, 1853. 88. . Recherches sun la structure de la muqueuse du col 63. BROCA,P.-P. Anatomie pathologique du cancer. Mém.acad. uténina l'etat normal. Ibid., 1:386—403,1864. nat. med. Paris, 16:453—820,1852. 89. . Mémoiresunlee tumeursepithelialesdu col de 1' 64. . Traite des tumeurs (2 vols.), 1:116—141.Paris: Asselin, uterus. Ibid., 1:472—507,1864. 1866-69. 90. . Contributions a l'hietoire du developpement histo 65. BRODOWSKI, W. Em ungeheures Myosarcom des Magens logique des tumeurs épithéliaies(equirrhe, encephaloide, nebst secundãren Myosarcomen den Leben. Arch. pathol. etc.). mid., 2:266—76, 476—96, 1865. Anat. u Physiol. Virchow's, 67.227—31,1876. 91. . Mode de multiplication des noyaux et des cellules 66. BRoussAls, F. J. V. Examen des doctrines médicaleeet des dans l'épithélioma.Ibid.,27:97—116,1891. systèmesde nosologie ; ouvrage dans lequel se trouVe fondu 92. , ANDRANVIER, L. Manuel d'histologie pathologique,

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 100 Cancer Research Vol. 25, February 1965

Ed. 2, (2 vole.), 1:139—143,Paris: Germer Baillière et C', logischen Anatomic der Froechhaut. Leipzig: Engelmann, 1884. 1869. 93. COURTY,A. De Ia malignitérelativedeediversestumeuns. 121. . Myoma earcomatodes renum. Arch. pathol. Anat. u. Compt. rend. din. Montpellier, pp. 125, 135. Montpellien, Physiol. Virchow's, 55518—20,1872. 1851. Cited in reference 409, pp. 486—87. 122. ECKER,A. Ueber den Bau den unter dem Namen ,,Lippen 94. CRAwFORD,A. Experiments and Observations on the Matter knebs― zusammengefassten Geechwulste den Lippe. Arch. of Cancer, and on the Aerial Fuids Extricated from Animal Physiol. Heilk., 3:380—84,1844. Substances by Distillation and Putrefaction ; Together with 123. . Ueber eine eigenthumliche Form von Geechwulsten Some Remarks on Sulfurous Hepatic Air. Phil. Trans. Roy. den Haut. Z. Rat. Med., 3:118-25, 1845. Soc. London, 80(2):391-426, 1790. 124. ENGEL, J. Ueber knebsige Destructionen. Ostern. med. 95. CREIGHTON,C. Anatomical Research towards the Aetiology Wochschr., No. 34: 793—796,1841. of Cancer. Reports of the Medical Officer of the Privy Council 125. - . Die krankhaften Geschwulste ubenhaupt und die and Local Government Board, 3(n.s.):95-112. London: Eyre fibröeenGeschwülste in besondere. Z. Gee. Aerzte zu Wien, and Spottiswoode, 1874. 2:10;87;159;225,1844. 96. . Report of a Further Anatomical Research towards 126. Die Krebsdyscrasie. Ibid., 2:267—92,1844. the Aetiology of Cancer. Ibid., 6(n.s.):125—208. London: 127. . Die fibnöeenGeschwülste. Ibid., 3:1—33,93—113,1846. Eyre and Spottiswoode, 1875. 128. EVE, F. S. Lectures on Cystic Tumouns of the Jaws, and on 97. . Report on the Infectiveness of CancerousTumours, the Etiology, General Characters and Relations of Tumouns. with Special Reference to Infected Lymphatic Glands. Ibid., Bnit. Med. J., 1:241-43, 1883. 8(n.s.):102—116. London : Eyne and Spottiewoode, 1876. 129. EWETSKY,T. VON. Zun Cylindenomfrage. Arch. pathol. 98. . On the Infection of the Connective Tissue in Scinnhous Anat. u. Physiol. Virchow's, 6936-55, 1877. Cancers of the Breast. J. Anat. Physiol., 14:29-49, 1879. 130. EWING,J. Neoplastic Diseases, Ed. 1, p. 22. Philadelphia 99. CRISTIANI, H. Recherches sun lee tumeuns malignes des and London : Saunders, 1919. muscles stries. Arch. physiol. norm. pathol., 19:107—125, 1887. 131. FABRE-DOMERGTJE,P. Sun la désonientation de la cytodiérese 100. CRUVEILHIER,J. Eseai eur l'anatomie pathologique en ge dane lee cancers epitheliaux. Compt. rend. soc. biol., 4(9s.): néraleet sun les transformations et productions organiques 158—161,1892. en particulier (2 vole.), 1:81—89.Paris : Cnochand, 1816. 132. . Lee cancers epitheliaux. Histologic -Histogenese 101. . Traite d'anatomie pathologique generale (5 vole.), -Etiologie -Applications thenapeutiques, pp. 40—SO.Paris: 5:1—4etpassim. Paris: Baillière, 1849-64. Came & Naud, 1898. 102. CZERNY, V. Beitrag zur Geschwuletlehre. I. Entwicklung 133. FEARON,H. B. A Treatise on Cancers, with an Account of a eines Epithelialcarcinomas aus einen angebonenen Sacral New and Successful Method of Operating, Particularly in geschwulst. Arch. klin. Chin. Langenbecke, 10894—908, 1869. Cancers of the Breast on Testis by Which the Sufferings of 103. . Eine Elephantiasis Arabum congenita mit plexiformen the Patient Are Considerably Diminished, the Cure Greatly Neuromen. Ibid., 17:357—84,1874. Accelerated, and Deformity Prevented, Ed. 2, pp. 5, 25-26. 104. 1)Ei.nET, P. Neoplasmes. Traite de chinungie clinique et London: Johnson, 1786. operatoine publie sons la direction de MM. A. Le Dentu et 134. FETZER, B. K. Beitnag zun Histologic des Leberkrebe. Tü P. Delbet (3 vole.), 1:393. Paris: Bailliène, 1896. bingen: Laupp, 1868. 105. DEMONCHY,A.Definition et classification de l'epitheliome 135. FOERSTER, A. Beitrage zur Entwicklungsgeschichte und pavimenteux (cancroide). pp. 1—9.Paris: Parent, 1867. Histologic den Geschwulste. Illus. med. Zeitung, 2332—50, 106. DENMAN,T. Observations on the Cure of Cancer. London: 1852. Johnson, 1810. 136. . Beitrage zur Entwicklungsgeschichte und Histologie 107. DEsrossEs, L. Sun Ia theonie epitheliale du cancer. J. anat. den GeschwUlste. Ibid., 3:37; 113; 152, 1855. et physiol., 17364—401,1881. 137. . BeitrAgezunpathologischenAnatomic und Histologic. 108. Discussion. Du diagnostic et de Ia cunabilitédu cancer. Bull. Das Cylinderepithelial-Cancroid den Magen- und Darm acad.mt@d.(Paris),19:1113—1117,1853—54. schleimhaut und scm Venhaltniss zum Plattenepithelial 109. Discussion. Du diagnostic et de la cunabilitéde cancer. Ibid., Cancroid den Haut. Arch. pathol. Anat. u. Physiol. Vinchow's, 20:7;21;55;69;75;120;156;194;221;242;279;349;376;411, 14:91—109,1858. 1854-55. 138. . Lehnebuch den pathologischen Anatomic Ed. 8, pp. 110. Discussion on Cancer. Phil. Trans. Path. Soc. London, 97-98. Jena: Mauke, 1868. 25:287—402,1874. 139. FOLLIN, E. Suite de la discussion sun la classification des 111. DONOHUE, M. D. Evaluative Checklist of the Literature of tumeune malignes. Bull. soc. chin. Paris, 3.327-45, 1852—53. Neoplastic Diseases. Med. Lib. Aseoc. Bull., 48:308-30, 1960. 140. . Du cancer, du cancroide epithelial, et du tissu fibro 112. DOUTRELEPONT,J. Ueben Gallertkrebs den Brustdrüse. Arch. plastique au point de vue de la clinique et de la micnographie klin. Chin. Langenbecks, 12:551—72,1871. pathologique. Arch. gen. m&i., 4(5s.):729—39,1854. 113. LE DRAN, H. F. Memomre avec un precie de plusiers obeerva 141. FRERICHS,F. T. Ueben den Begriff und die Diagnose den tione sun le cancer. Mem. acad. roy. chin. Paris, 3:1—54,1757. bosartigen Neubildungen. Hannovenieche Ann., 6:684—703, 114. DRESSLER, W. Em Fall von sogennanten Chlorom (mit 1846. Zusatz vom Rud. Virchow). Arch. pathol. Anat. u. Physiol. 142. . Ueber den Begriff und die Diagnose den bosantigen Vinchow's, 35:605—7,1866. Neubildungen. Ibid., 7:1—16,1847. 115. DUJARDIN, F., AND PEYRILHE, B. Histoine de la chirurgie 143. . Ueber Gallent-oder Colloidgeschwulste (abgedruckt (2 vole.), 1:391, 533. Paris: Impr. Royale, 1774—80. aus den Gottinger Studien), pp. 22—23,56—81.Gottingen: 116. Dupur, J.-N. Du cancroide ou cancer epitheliale, sourtout Vandenhoeck u. Ruprecht, 1847. au point de vue de sa generalization. Paris: Rignoux, 1855. 144. . Ueben die destruinenden Epithelialgeschwulste. 117. DURAND-FARDEL,M. Tumeur des meningee. Bull. soc. anat. (Epithelialkrebe, Pseudocancer cutaneous.). Jena. Ann. Paris,2(3s.):195—99,1836. Phyeiol. Med., 1:3—15,322, 1849. 118. DURANTE, F. Nesso Fisio-patologico tna la Struttura dci 145. FRIEDLANDER,C. Ueben Epithelialwuchenung und Knebs. Nd Materni e la Genesi di alcuni Tumoni Maligni. Archivio Pathologisch-Anatomische Unteneuchungen, pp. 17—39. di Memonie ed Oseervazione di Chinungia Practica (pen F. Strassburg: Tnübnen,1877. Palasciano), Gennaro a Decembre, 1874, pp. 217—226.Napoli, 146. FRIEDREICH,N. Zur Casuistik der Neubildungen. Arch. 1874. pathol. Anat. U. Physiol. Virchow's, 27.375-388, 1863. 147. . Zur Casuistik den Neubildungen. Ibid., 30:474—476, 119. . Intorno alla nieposta critica fatta dal prof. Fob. al 1864. lavoro eui parassiti del cancro, del dott. Enrico D'Anna. 148. . Beitrage zur Pathologic dee Knebeee. I. Krebsme Policlinico, 2(Sezione chirurgica):33—37, 1894. tastase auf den Fötus. Ibid., 36:465-477, 1866. 120. EBEETH, C. J. Untersuchungen zur normalen und patho 149. FÜHRER,F. Umnisse und Bemenkungen zun pathologiechen

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRIOLo—Foundations of Cancer Research 101

Anatomic der Geschwulste. Deut. kiln. Berlin, 4:157 ; 166; 179. . Zun Histogenese des Knebees. Arch. pathol. Anat. u. 187;199;222;233;260;265,1852. Phyeiol. Vinchow'e, 138:482—99,1894. 150. GERLACH,J. Ueber Oeteoid-GeschwUlete. Z. Rat. Med., 180. . Nochmale überRibbert's Theonie von den Hietogeneee 6:377—386,1847. des Knebsee. Ibid., 141:485—504,1895. 151. . Der Zottenkrebs. Eine pathologische-anatomische 181. . Beitrag zur Histogenese dee Plattenepithelkrebsee Untersuchungen. Mainz : Janitsch, 1851. Cited in reference und zur Lehre vom regionanen Recidiv Thiersch'e. Beitr. 475,1:143,182,261—62. pathol. Anat. U. allgem. Pathol., 22:587—607,1897. 152. . Das Oeteoid. Ibid., Mainz: Janitech, 1851. Cited in 182. . Neurere Arbeiten Uber Carcinom, 1891—1898.Zusam reference 475, 1:143, 184. menfassendes Referat. Centr. ailgem. pathol. u. Pathol. 153. GLOCKNER, A. Ueber den sogenannten Endothelkrebs den Anat., 9.221—68, 1898. SerösenHaute (Wagner-Schultz). Z. Heilk., 18:209—319,1897. 183. HELLER, A. Untersuchungen überdie feineren Vorgange bei 154. GLUGE,G. Recherchee microecopiques sun le fluide contenu den Entzundung nach fremden und eigenen Expenimenten. dane lee cancers encéphaloides. Compt. rend., 4:20—21,1837. Erlangen : Jacob, 1869. 155. GOErFE, A. Zun Entwickelungegeschichte den Wirbelthiere. 184. HENLE, J. Rohrengeschwulst, -Siphonoma, eine neue Art Vonlaufige Mittheilung. Centr. med. Wissen., 7:404-6, 1869. pathologieche GeschwUlste. Z. Rat. Med., 3:130—36,1845. 156. G0LGI, C. Sulla struttura e sullo eviluppo degli Psammomi. 185. . Ueber Siphonoma. Ibid., 3:319-20, 1845. Opera Omnia (4 vole.), 8:808. Milano: Hoepli, 1903. 186. HENOCQUE,A. Dc l'inoculation de cancer a propos d'une 157. . Ueber Bau und Entwicklung des Psammomes. Arch. assertion de M. Chauffard. Gaz. hebd. med. chin. Paris, pathol. Anat. u. Physiol. Vinchow's, 51:311—12,1870. 4(2s.):705—707,1867. 158. GOTTSCHALK,S. Das Sarcom den Chonionzotten. Arch. 187. HERRMANN,G., ANDLESUR, R.-A. Contributions a l'anatomie Gynakol., 46:1—100,1894. des epitheliomas de la mamelle. J. anat. et physiol., 21:100— 159. GouJoN, E. Expose de quelquee faite nouveau tendant a 180, 1885. demontrer que lee productions dites canceneuses de l'homme 188. HERTWIG, 0., ANDHERTWIG, R. Die Cölomtheonie. Vensuch sont susceptibles de se greffer chez lee animaux , et de produire einer Erkiarung des mittleren Keimblattee. Jena. Z. Naturw., I'infection chez ces derniens. J. anat. et physiol., 4319-22, 15:1—150,1882. 1867. 189. HERZ, M. Zun Kenntnis des Endothelioms im Anschlussan 160. . Inoculation de matière melanique. Compt. rend. em Endothelioma Lymphaticui ovanii. Monateschr. Ge soc. biol., 4(4s.)93—98, 1867. burtshülfe u. Gynakol., 9:458-69, 1899. 161. GRAZFE, A. VON.Zur Casuistik der Tumoren. Arch. Ophthal 190. HEURTAUX, A. Du cancrolde en general, pp. 21-43, 42-61. mol. Graefe's, 10:176—221,1864. Paris: Coccoz, 1860. 162. GREENSTEIN, J. P. Biochemistry of Cancer Ed. 2, p. 1. 191. HEY, W. Practical Observations in Surgery Illustrated with Academic Press: New York, 1954. Cases, pp. 233-85. London : Cadell and Davies, 1803. 163. GUENBBURG,F.Die pathologieche Geweblehre. Studien zur 192. HIRSCHBERG,J. Em Fall von Melanocarcinoma polyposum speciellen Pathologic (2 vole.), 2:361. Leipzig: Brockhaus, praecorneale. Arch. pathol. Anat. u. Physiol. Vinchow'e, 1845-48. 51:515—519,1870. 164. GUSSENBAUER,C. Em Beitrag von Verebneitung des Epi 193. HIS, W. Beobachtungen überden Bau des Saugethier thelialkrebses dunch Lymphdrusen. Arch. klin. Chin. Langen Eieretockee. Arch. mikroekop. Anat. Schmidt's 1:151—202, becks, 14-.561—621,1872. 1865. 165. GYORGJEVI@,V.Ueben Lymphorrhoe und Lymphangiome. 194. . Die Haute und Höhlen dee Korpere. (Akademieches Ibid., 12.641—706,1871. Programm), pp. 5-34. Basel: Schweighaueen, 1865. 166. HANES,F. M., ANDLAMBERT,R.R. AmöboideBewegungvon 195. . Die Lehne von Bindesubetanzkeim (Parablast). Arch. Knebzellen ale em Fakton des invasiven mid metaetatischen Anat. U. Entwicklungeges. (Anat. Abt.), pp. 63-108, 1882. Wachstums malignen Tumoren. Arch. pathol. Anat. u. 196. HODGKIN,T. On the Anatomical Characters of Some Ad Physiol. Virchow's, 209:12—21,1912. ventitious Structures. Medico-Chirurgical Trans., 15:265— 167. HANNOVER,A. Den pathologiske Anatomies Svar pan Spørge 338, 1829. maalet: Hvad en Cancer?, pp. 1—8,76-104. Kjøbenhavn: 197. HOEBER, E. W. Ueber die crete Entwicklung den Knebs Schultz, 1843. Elemente. Sitzsber. deut. Akad. Wise. Berlin, (Math. naturw. 168. . Benichte übendieLeietungen in den Skandinavischen Kl.) 72(Dnitte Abt.):9, 1875. Litterature im Gebeite der Anatomic mid Physiologic ui den 198. HOFFMAN, C. E. E. Zur pathologisch-anatomischen Verän @ Jahnen 1841-43.Arch. Anat. Physiol. Wise. Med., p. 18, 1844. derung des Hannstrange. Arch. Heilk., 11:373—90,1870. 169. —.Das Epithelioma. Eine eigenthumliche Geschwulet, 199. HOFFMANN,F.A. Ueben Contractilitatsvorgänge im vonderen die man in aligemeinen biehen ale Knebs angesehen hat, pp. Epithelium den Froschhornhaut. Berlin : Lindow, 1868. 12—39.Leipzig: Voss, 1852. 200. . Epithelneubildung auf den Cornea. Arch. pathol. 170. HANSEMANN,D. VON. Ueben asymmetnisehe Zelltheilung in Anat. u. Physiol. Virchow's, 51373—390, 1870. Epithelknebsen mid denen biologische Bedeutung. Arch. 201. H000AN, G. Cancer in Its Relations to the Lymphatic Sys pathol. Anat. u. Physiol. Vinchow's, 119299—326,1890. tem. Phil. Trans. Path. Soc. London, 29:384-388, 1878. 171. . Ueben pathologieche Mitosen. Ibid., 123:356-370, 202. HOME, E. Observations on Cancer, Connected with Histories 1891. of the Disease. London: Nicol and Johnson, 1805. 172. . Studien überdie Spezificitat, den Altruismus und die 203. . A Short Tract on the Formation of Tumours, and the Anaplasie der Zellen mit besonderen Benucksichtigung den Peculiarities That Are Met with in the Structure of Those Geechwulste, pp. 62—96.Berlin : Hirechwald, 1893. That Have Become Cancerous, with Their Mode of Treat 173. . Ueber Endotheliome. Deut. med. Wochechr., 22:52- ment, pp. 21—23.London : Longman, Rees, Orme, Brown, and 53, 1896. Green, 1830. 174. . Ueber die Benennung den boeantigen Geechwulste. 204. D'HÔTEL,V. J. Du cancroide. Paris: Rignoux, 1855. Aligem. med. Central-Ztg., 65:973—75,1896. 205. HUBER,K. Studien überdas sogenannte Chlonom. (Metas 175. . Die rnikroekopiecheDiagnose den bosartigen Gesch tasirendee penioetales Sancom.) Arch. den Heilk., 19:129—159, wülste,p. 165. Berlin: Hirschwald, 1897. 1878. 176. HARRISONR. G. The Outgrowth of the Nerve Fiber as a 206. HUNTER, J. A Treatise on the Blood, Inflammation, and Mode of Protoplasmic Movement. J. Exptl. Zool., 9:787—848, Gun-shot Wounds. pp. 311-312. London: Nicol, 1794. 1910. 207. HYVERT, J. Dc l'inoculation canceneuse. (Experiences 177. HAUSER,G. Zun Histogenese des Cylindenepithelcarcinome. nouvelles), pp. 34—54.Montpellien: Boehm et Fij@, 1872. Enlangen: Jacob, 1883. 208. KLAATSCH,H. Ueber den jetzigen Stand der Keimblattf rage 178. . Das Cylinderepithel-Carcinom des Magen und dee mit Rucksicht auf die Pathologic. Munch. med. Wochschr., Dickdanms, pp. 53-74, 89-108. Jena: Fischer, 1890. 46:169-172, 1899.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 102 Cancer Research Vol. 25, February 1965

209. KLEBS, E. Bemerkungen überLanynx-Geschwulete. Arch. 241. LORAIN, P., AND ROBIN, C. Memoire sun deux nouvelles pathol. Anat. u. Physiol. Virchow'e, 38:202—20,1867. observations de tumeure heteradeniques et sun la nature de 210. . Beiträgezur GeschwUletlehre (1. Hft.), pp. 17—96. tissu qui lee compose. Compt. rend. soc. biol., 1(2e.).209—21, Leipzig: Hirschfeld, 1877. 1854. 211. . Die ailgemeine Pathologic oder die Lehre von den 242. LORTET, L. Eesai monographique sun le pretendu cancroide Ursachen und dem Wesen den Krankheitsprocesse. Eine labiale, pp. 14—23.Paris: Rignoux, 1861. Handbuch fürStudirende und Aerzte (2 vole.), 2:553. Jena: 243. Lorr, G. Ueber den feineren Bau und die Regeneration den Fischer, 1887—89. Epithelien inebesondere des Conneaepithels. VonlAufige 212. . Ueber das Wesen und die Erkennung den Carcinom Mittheilung. Centr. med. Wise., 9:577—79,1871. bildung. Deut. med. Wochschn., 16:517—20,1890. 244. LOTZBECK,K. Em Fall von Schweieedrusengeschwulet an den 213. KNOLL, P. Beitrag zur Geschwuletlehre. Arch. pathol. Anat. Wange. Arch. den Heilk., 9:537-55, 1868. u. Physiol. Virchow's, 54:378—95,1872. 245. Louis, A. Memoire sun plusiers maladie de globe de l'oeil, 214. KARG, C. Ueber das Carcinom. Deut. Z. Chin., 34:133-86, ou l'on examine particulienement lee cas qui exigent l'extirpa 1892. tion de cet organe, & la methode d'y proceder. Mem. acad. 215. KOCHER,T., AND LANGHANS,T. Eine Nephrotomie wegen roy. chin. Paris, 5:193—95,1774. Nienen Sarkom (zugleich em Beitrag zur Histologic des 246. LUBARSCH,0. Ueben pnimaren Knebe des Ileum nebet Be Nieren Krebses). Ibid., 9312-28, 1878. merkungen überdas gleichzeitige Vorkommen von Knebs 216. KOESTER, K. Cancnoid mit hyaliner Degeneration (Cylin und Tuberculose. Arch. pathol. Anat. u. Physiol. Vinchow's, droma Billroth'e). Arch. pathol. Anat. u. Physiol. Virchow's, 111:280—317,1888. 40:463-504,1867. 247. . Die Metaplasiefrage und ihne Bedeutung fürdie 217. —@ -. Die Entwicklung denCancinomeund Sankome(Erete Geechwulstlehre. Arbeiten aus den Pathologisch-Anatomi Abt : Krebe den Haut (Epithelialkrebs), alveolarer Gallert echen Abteilung dee Konigi. Hygienischen Institute zu Posen knebs des Magens), pp. 29, 36—37,70—94.Wurzburg: Stuben, (Virchow Feetschnift), pp. 205—31.Wiesbaden : Bergmann, 1869. 1901. 218. . Ueber Myxom. Sitzungeb. Niederrhein. Gee. Natur. u. 248. LUCAE, A. Beitrage zur Kenntnis den Penlgeechwulet den Heilk. in Bonn, pp. 51-53, 1881. Felsenbeines. Arch. Orenheilk. , 7:255—79,1873. 219. KOLACZEK,J. Ueber das Angio-Sarkom. Deut. Z. Chin., 249. LUcxz, A. Beitrage zur Geschwulstlehre. III. Lympho 9:1—48,1878. sarkom den Acheeldnüeen ; embolische GeschwUlete der 220. . Ueber das Angio-Sankom. Ibid., 9:165-227, 1878. Lungen; allgemeine Leukämie; Tod. Arch. pathol. Anat. u. 221. KOLLIKER, A. Die Entwickelung den ZahnsAckchen den Physiol. Virchow'e, 35:524—30,1866. Wiederk.äuer. Z. wise. Zool., 12:455-460, 1863. 250. . Beitnage zur Geschwulstlehre. IV. Ueben Gesch 222. KUss, E. Tumeur epidermique et cancereuse de la main. wülste mit hyalinen Degeneration. Ibid., 35:530—38,1866. Gaz. med. Strasboung, 5:109—10,1845. 251. LUDWIG, E. Ueben einige Bestandtheile dee Tabakrauches. 223. LABB@,L., AND COYNE, P. Traite des tumeuns benignes du Arch. klin. Chin. Langenbecks, [email protected],1877. scm, pp. 100—1.Paris: Masson, 1876. 252. MAIER, R. Beitnag zur Cylindnom-Fnage. Arch. pathol. 224. LABOULB@NE,A.Nouveaux elements d'antomie pathologique Anat. u. Physiol. Virchow's, 14:270-81, 1858. descriptive et histologique, pp. 43—45.Paris: Bailliène, 1879. 253. . Zun Casuistik den Geschwulstbildung, insbesondere 225. LAENNEC, R. H. T. Anatomic pathologique. Dict. eci. med., des Cylindnoms. Arch. Heilk., 7:145-55, 1866. 2:46—61,1812. 254. . Lehrebuch den allgemeinen pathologiechen Anatomic 226. . Degeneration. Ibid., 8:201—208,1814. fürStudirende mid Aenzte, pp. 179-239. Leipzig: Wigand, 227. . Encephaloides. Ibid., 12:165-178, 1815. 1871. 228. LANCEREAUX,E. Traite d'anatomie pathologique (3 vole.), 255. MALASSEZ, L. Examen hietologique d'un ens de cancer en 1:296—470.Paris: Delahaye et Lecroenier, 1875-85. cephalolde du poumon (epithelioma). Écolepratique des 229. LANGENBECK,B. Ueber die Entstehung dee Venenknebses hautes etudes. Laboratoine d'histologie du college de France: und die Moglichkeit, Carcinoma vom Menechen auf Thiere Travaux de l'annee 1876, 3.81—100.Paris: Masson, 1877. zu ubentragen. JahrbücherGee. Med., 25:99—104,1840. 256. MALHERBE,A. Quelques mote sun la classification dee tumeurs 230. LANGHANS,T. Ueben Krebs und Cancroid den Lunge nebet de genre epitheliome et sun quelques eepèces necemment einem Anhang Uber Corpora amylacea in den Lunge. Arch. decnitee (epitheliome calcifie et epitheliome polymorphe). pathol. Anat. u. Physiol. Vinchow's, 38:497—543,1867. Arch. gén.med., 16(7e.):513—27,656—69,1885. 231. . Das maligne Lymphosarkom (Pseudoleukamie). 257. MANDL, L. Dc la structure intime des tumeuns ou des pro Ibid., 54:509—37,1872. ductions pathologiques. Analyse dee travaux sun cc eujet. 232. LAURENCE, J. Z. The Diagnosis of Surgical Cancer Ed. 2, Ibid., 8(3e.):313—29,1840. pp. 1-42. London: Churchill, 1858. 258. M@itc@, L.-V., AND RoBIN, C. Note sun un nouveau cas do 233. LEBERT, H. Physiologic pathologique ou recherches clinique tumeur heteradenique. Compt. rend. soc. biol., 1(2s.):223— expenimentalee et microscopiques sun l'inflammation, la 229,1854. tubenculization, lee tumeurs, la formation du cal, etc. (2 259. MAECJIAND,F. Ueber einen Fall von Myoxarcoma striocellu vole.), 2:1—434. Paris: Baillière, 1845. lane den Niere. Arch. pathol. Anat. u. Physiol. Virchow's, 234. . Dc la nature locale ou generale des tumeure. Compt. 73289—301,1873. rend.soc.biol.,2(ls.):145—157,1850. 260. . Ueber die Beziehungen den pathologiechen Anatomic 235. . Ueben Krebe und die mit Krebs verwecheelten Ge zur Entwickelungsgeechichte, besonders den Keimblattlehre. schwulete im Gehirn und semen Hüllen.Arch. pathol. Anat. Verhandl. Deut. pathol. Gee., 2T:38—W7, 1899. u. Physiol. Virchow's, 3:463—569, 1851. 261. MABJOLIN, J.-N. Sun lee tumeurs fibroplastique—Diecussion. 236. . Traite pratique des maladies canceneusee et des Bull. soc. chin. Paris, 3:298—326,1852—53. affections curables confondues avec le cancer, p. 611. Paris: 262. MARSHALL,J. The Morton Lecture on Cancer and Cancerous Baillière, 1851. Diseases. Lancet, 2:1045—1049,1889. 237. - . Des productions fibroplastiques accidentellee et dee 263. . Observations on the Nature of Cancer. Ibid., 2:415— tumeune fibroplastiques. Bull. soc. chin. Paris, 3:248—56, 17,1891. 1852—53. 264. MAUNOIR, J.-P. Memoire sun lee fongus medullaine et hema 238. LEDOUX-LEBARD,A. Le cancer, maladie parasitaire. Arch. tode, pp. 130-31. Paris et Geneve: Paschoud, 1820. gen. med., 15(7e.):413—441,1885. 265. MAURER, F. Em Beitrag zur Kenntnies den Angio-Sankom. 239. LEONTOWrISCH,A. Zun Lehre übendie Entetehung dee Epi Arch. pathol. Anat. u. Physiol. Vinchow's, 77:346-63, 1879. thelialkrebeee (Cancroid). Vorlaufige Mittheilung. Centn. 266. MAYOR, F.-F.-I. Recherches sun lee tumeune epide@miques med. Wise., 7:193—96,1869. et leurs relations avec l'affection cancereuse, pp. 12—25,50— 240. LOBSTEIN, J. G. C. F. Traité d'anatomie pathologique (2 60. Paris: Rignoux, 1846. vole.), 1:399-456, 467—79.Paris: Levnault, 1829—33. 267. MECKEL, H. VON H. Ueber Knorpel-Wuchenung. mit einem

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. TRI0Lo—Foundations of Cancer Research 103

Anhang zu vonstehendem Aufsatz von T. Billroth. Ann. d. 294. OATFIELD,H. Literature of the Chemical Periphery. I. Can Chanitekrankenhauses, Berlin, 7:60—115,1856. cen. Med. Lib. Aesoc. Bull., 30(1):9—22,1950. 268. M@N@TRIER,P. Dee polyadénomes gastniques et de buns 295.OLLIER,L.Recherchesanatomo-pathobogiquessunla struc rapponts avec be cancer de l'eetomac. Arch. physiol. norm. tune intime des tumeurs cancéreusesaux divenses peniodes de pathol., 20:32—55,236—62,1888. bun deveboppement. Montpellier: Boehm, 1856.

. 269. MICHEL, M. Du microscope, de see applications a b'anatomie 296. ORvn, J. Ueber Heilungevorgange an Epitheliomen nebet pathobogique, au diagnostic et au traitement des maladies. ablgemeinen Bemerkungen über Epitheliome. Deut. med. Mém.acad.imper. med., 21:241—442,1857. Wochschr., 30(Ven. Beil., 34):1262—1263,1904. 270. MICHON, L.-M. Du cancer cutane, p. 13. Paris: Rignoux, 297. OTTo, A. W. Seltene Beobachtungen zur Anatomic, Phyeio 1848. logic und Pathologic gehonig, pp. 119—20.Breslau: Holaufer, 271. MONDOR, H. Depuytren, pp. 53-58. Paris: Gaillimard, 1945. 1816. 272. MONOD, C. Etude sun l'angiome simple eous-cutane circons 298. PAGENSTECHER, F. Beitrag zun Geschwuletlehre. Arch. cnit (Naevus vasculaire soue-cutane, Angiome lipomateux, pathol. Anat. u. Physiol. Virchow's, 45:490-500, 1869. Angiome lobule.) Suivi do quelques remanques sun lee Angio 299. PAGET, J. Lectures on Surgical Pathology Delivered at the mes circonscnits de l'onbite. Paris : Bailbière, 1873. Royal College of Surgeons of England (2 vole.), 2:413. Long 273. MONRO, A., III―. The morbid anatomy of the human gullet, man, Brown, Green, and Longman, 1853. stomach and intestines, pp. 160-79. Edinburgh: Constable, 300. . The Morton Lecture on Cancer and Cancerous Die Longman, Hurst, Rees, Orme, Brown, and Murray, 1811. eases. Bnit. Med. J., 2:1091—1094,1887. 274. MORGAGNI, B.-B. Dc sedibus, et Caueie Morborum pen 301. PEARSON, J. Practical Observations on Cancerous Com Anatomen Indagctie. Libeni Quinquae, 4(@50):267—284. plainte, with an Account of Some Diseases Which Have Venetiie : Remondini, 1761. Been Confounded with Cancer. Also, Critical Remarks on 275. DE MORGAN, C. The Origin of Cancer: Considered with Some of the Operations Performed in Cancerous Cases. Reference to the Treatment of the Disease. London: London: Johnson, 1793. Churchill, 1872. 302. P@R@WERSEFF,J. Entwicklung des Nierenknebses aus den 276. MOSLER, F. Zur Aetiobogie den LeukAmie. Arch. pathol. Epithelien den Harnkanälchen. Arch. pathol. Anat. u. Anat. u. Physiol. Virchow's, 56:14-27, 1872. Physiol. Vinchow's, 59:227—36,1874. 277. MULERT, D. Em Fall von multiple Endotheliomen den 303. . Sur l'onigine et ba propagation du carcinome epi Kopfhaut, zugbeich em Beitrag zun Endotheliomfrage. Arch. theliale de l'estomac. J. anat. et physiol., 10:337—52,1874. kim. Chin. Langenbecks, 54658-73, 1897. 304. PERLS, M. Beitnage zur Geschwulstlehne. III. Zun Histologic 278. Mt@LLER,H. Ueber die Entwickelung den Knocheneubstanz des Lebercarcinome. Arch. pathol. Anat. u. Phyeiol. nebst Bemerkungen überden Bau rachitiecher Knochen. Z. Virchow'e, 56:448-63, 1872. Wiss. Zool., 9:147—233,1858. 305. . Beschreibung einee wahren Neurome des Nervus 279. MtYLLER, J. Ueben den feineren Bau den Krankhaften Ge opticus. Arch. Ophthalmol. Gnaefe's, 19:287—302,1873. schwülste.Benichte Uben die Bekanntmachung geeigneten 306. PEYRILKE, B. Diseertatio academica de cancro, Quam duplici Verhandi. den Konigi. Preuse. Akad. den Wise. Berlin, 1:107— pnaemio donavit Illustnie Academia Scientiarum Human 113, 1836. iorum, Litterarum Et Articum, p. 34. Lugdunensis, in Con 280. . Ueber den feineren Bau und die Fonmen den Krank ventu publice habito die octava Decembnie, anno 1773. haften Geechwulete. Berlin: Reimer, 1838. Paris: Haney et Didot, 1774. 281. . Ueber oseificirende Schwämmeoder Osteoid-Ge 307. . Dissertation academique sun le cancer, qui a rem echwulste. Arch. Anat. Physiol. Wise. Med., pp. 396—442, porte be pnix double de l'Academie des Sciences, Arts & 1843. Belbee-Lettree de Lyon, be 8 Decembre 1773 (trans. Mathey), 282.Mt@LLzR,V.IJeber cellulãreVongangein Geschwübsten. pp. 10-13, 46-48. Paris: Ruault, 1776. Arch. pathol. Anat. u. Physiol. Virchow's, 130:512—528,1892. 308. PIANE5E, G. Beitrag zun Histobogie und Aetiobogie dee Car 283. Mt@nR, W. Zwei Fable von Epithelioma cylindro-cellubare cinoms. Hietobogische und expenimentebbe Untersuchungen. den Schilddnüsenebst Bemenkungen zur Theonie den Epi Beitr. pathob. Anat. u. aligem. Pathol., 1(Supplhft.):13—15, theliombildung. Jena. Z. Med. u. Naturw., 6:456—76,1871. 1896. 284. NAUNYN, B. Ueben die Entwicklung den Leberkrebse. Arch. 309. Picx, L. Ueber Sarcome des Uterus und den Vagina im Kinde Anat. Physiol. Wise. Med., pp. 717—734,1866. salter und das pnimare Schbeidensancom den Erwacheenen. 285. NEELSEN, F. Untersuchungen übenden Endothelialkrebe Arch. Gynakob., 46:191—255,1894. (lymphangitis cancinomatodes). Deut. Arch. kiln. Med., 310. . Zur Histogenese und Cbassification den Gebflnmutten 31:375—404,1882. sarcome. Ibid., 48:24-79, 1895. 286. N1@LATON,E. D'une nouvelle espèce de tumour benigne des 311. PIcK, L. Zur Lehnevom Myxoma sarcomatosumund übendie Os, ou tumeuns a myeloplaxee, p. 350. Paris: Delahaye, 1860. eogenannten Endothebiome den Gebärmutter. Ibid., 49:1—29, 287. NEUMANN, E. Beiträge zur Kenntnie den Entwicklung den 1895. Neoplasen. Arch. pathol. Anat. u. Physiol. Virchow's, 312. P0RL, 0. Zur Entwickbungsgeechichte des Epithebiabkrebses 20:152—165,1861. und den AdhAsionen. Arch. pathol. Anat. u. Physiol. 288. . Zur Casuietik den Myxome und Cylindrome. Arch. Vinchow's, 8:348—349,1855. den bilk., 9:480—486,1868. 313. POLLAY,M. The First American Book on Tumors. Unpub 289. . Ueber Sarcome mit endothebialen Zelben nebet Be lished Thesis submitted for the Degree, Doctor of Medicine merkungen überdie Stellung den Sarcome zu den Carcino at the University of Wisconsin, pp. 8—9.Madison, Wisc., men. Ibid., 12:305-24, 1872. 1955. 290. NIEDEN, P. Ueber einen Fall von Lymphangiectasie mit 314. POPPER, F. Beiträge zur naheren Kenntnies den Entwicklung Lymphornhagie. Arch. pathol. Anat. u. Physiol. Virchow's, des Knebees in den quengeetneiften Muskein. Z. Gee. Aerzte 90:350-88, 1882. in Wien (Medizinische Jahrbücher),21:37—80,1865. 291.NISBET,W.An Inquiry into the History, Nature, Causes, 315. POWER, D'A. Some effects of chronic irritation upon living and Different Modes of Treatment, Hitherto Pursued in the tissues, being first steps in a rational study of cancer. Brit. Cure of Scrofula, Pulmonary Consumption, and Cancer, Med. J.,2:830-834,1893. Ed. 2, pp. 182—86,266-69.London: Johnson, Kay, Scott, 316. Queries. Published by the Institution for Investigating the Watson, 1800. Nature and Cure of Cancer. Edinburgh Med. Sung. J., 2:382— 292. NOEGGERATH,E. BeitnAge zur Stnuktun und Entwickelung 389,1806. des Carcinoms, pp. 7-8. Wiesbaden : Bengmann, 1892. 317. QUINQUAUD,E. Inoculation du cancen a un cabiais. Bull. 293. NoRRIs, W. F., ANDSTRICKER,S. Versuche überHornhaut soc.anat.Paris,8(2s.):540—541,1868. EntzUndung. Studien aus dem Institute fürExpenimenteble 318. RAJEWSKI, A. Ueben secundAne Krebsentwickelung im Pathologie in Wien aus dem Jahre 1869 (S. Stnicker, ed.), Diaphnagma. Arch. pathol. Anat. u. Physiol. Virchow'e, 1:1—17.Wien: Braumülben,1870. 66:154—71,1876.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 104 Cancer Research Vol. 25, February 1965

319. RANVIER, L., AND CORNIL, V. Contributions a l'etude du 345. R:NDFLEISCH, E. Lehrebuch den pathobogischen Gewebe deveboppement histologique des tumeurs epithebialee (can behne zur Einfuhrung in das Studium den pathobogischen cnoIde). J. anat. et physiol., 3:271—286,1866. Anatomic, pp. 51—142.Leipzig: Engelmann, 1867-69. 320. RASPAIL, F.-V. Rechenches chimique et physiobogique 346. ROBIN, C. Mémoinepour senvir a l'histoire anatomique et deetinéesa expbiquer, non-seubement la structure et be de pathobogique do la membrane muqueuee uterine, de son veboppement de la feuille, du tronc, ainei quo des organes mucus, do la cauduque et des oeufs, ou mieux glandes do qui n'en sont qu'une transformation, mais encore ba stnuc naboth. Arch. gen. med., 17(4s.):257—86, 1848. tune et la déveboppement des tissue animaux. Mem. soc. 347. . Sun l'exietence de deux espèces nouvelles d'elements hist. nat. Paris, 3:17—88,208—313,1827. anatomiques qui so trouvent dans be canal medullaine des os. 321. RICAMIER, J. C. A. Rechenches sun be traitement du cancer, Compt. rend. soc. biol., 1(ls.):149—50, 1849. pan in compression methodique simple ou combinee, et sun 348. . Sun beetumeuns colloides et epitheliales. Ibid., 5:(ls.): l'histoire genenale de ba même maladie (2 vole.), 1:179—83, 61—65,1853. 185—93,198,1829. 349. . Mémoiresun ba production accidentelle d'un tissu 322. RECKLINOHAUSEN,F. D. VON.Anatomische Untereuchungen ayant ba structure glandulaine dans bee panties du corps den Geschwulst. Arch. Ophthabmol. Gnaefe's, 10:62—77,1864. depourvues de glandes. Ibid., 2(2s.):91—114, 1855. 323. . Ueber die mubtiplen Fibrome den Haut und ihre 350. . Memoinesunbetiesuhetenadenique.Gaz.hebd.med. Beziehung zu den multiplen Neunomen (Vinchow Feet chin. Paris, 3:35—37,1856. echnift), pp. 99—130.Berlin: Hinschwald, 1882. 351. . Memoire sun lee divers modes do la naissance do Ia 324. REINCKE, J. Mittheilungen von den inneren Station des all substance organisee en genenabe et des elements anatomiques gemeinen Krankenhauses in Hamburg von den Abtheilung en panticulier. J. anat. et physiol., 1:26—61,1864. dee Dr. Engel-Reimers. I. Zwei FäbbevonKrebsimpfung in 352. . Memoine sun lee divers modes do in naiesancede la Punctionskanäben bei cancinomatösen Peritonitis. Arch. substance organis@e en generale et des elements anatomiques pathol. Anat. u. Physiol. Vinchow's, 51:391—99,1870. en panticulier. Ibid., 1:153—83, 1864. 3?5. REINHARDT,B. Ueber die Hypentrophie den Drusenfoblikel 353. . Mémoinesun lee divers modes do Ia naissance do la den Inteetinalschleimhaut. Ann. Chanite-Knankenhausee, substance onganisee en genenale et dee elements anatomique Berlin, 2:1—18,1851. en particulier. Ibid., 1:337—71,1864. 326. REMAK, R. Ueber die Entwickebung des Hühnchens im Ei. 354. . Memoire sun los divers modes do la naissance do Ia Arch. Anat. Physiol. Wise. Med., pp. 478-84, 1843. substance onganisee en generale et des elements anatomique 327. . Ueben em seibstandigee Darmnervensyetems, pp. en panticulien. Ibid., 2:113—52,1865. 21—26.Berlin : Reimer, 1847. 355. , ANDLABOULB@NE,A. r@1emoiresun tnois productions 328. . Ueben extraceblulane Entetehung theirscher Zellen monbides non decnites. Compt. rend. soc. biol., 5(ls.):185— und überdie Vermehrung derselben dunch Theilung. Arch. 96, 1853. Anat. Physiol. Wise. Med., pp. 47—57,1852. 356. ROKITANSKY,K. Handbuch den albgemeinen pathobogischen 329. . Ueber die Entstehung des Bindegewebes und des Anatomic (3 vole.), 1:342—44.Wien: Bnaumüllenu. Seidel, Knonpebs. Ibid., pp. 63—72,1852. 1842-46. 330. . Em Beitnag zun Entwickelungsgeschichte den krebe 357. . Ueben die Entwickelung den KnebsgenUete mit Hin haften GeschwUbete. Deut. kim. , Berlin, 6:170—74, 1854. blick auf das wesen und di Entwickelung anderen Maschen 331. . Untersuchungen übendie Entwickelung den Wirbel werke. Sitzben. Akad. Wise. Wien, (Math.-natunw. Kb.), 8: thiere, pp. 164—179.Berlin : Reimer, 1855. 391-405, 1852. 332. RESSEL, J. Beitrag zur pathobogischen Anatom.ie dee Epi 358. . Ueben den Zottenknebs. Ibid., 8513—35,1852. thebialkrebses mit besondened Berucksichtigung semen Bil 359. . Ueber den Gallertkrebs, mit Hinblick auf die gutan dung im vengleich zur Bibdung und zum Wachethum normalen tigen Gabbertgeschwulste. Ibid., 9350-85, 1852. Horngebibde. Studien des Physiobogiechen Institute zu Bres 360. . Ueben die pathobogieche Neubildung von Brust lau (K. B. Reichert, ed.), No. 4:138-46. Leipzig: Engelmann, drusentextur mid ihne Beziehung zum Cytosancom. Ibid., 1858. 10:134—47,1853. 333. RIBBERT, H. Ueben EinschlOsse im Epithel den Carcinome. 361. Rou@TT, A. Ueben Elementantheibe und Gewebe und denen Deut. med. Wochechn., 17:1179—83,1891. Unterscheidung. Untensuchungen aus dem Institute für 334. . Beitnage zun Hietogenese des Carcinoms. Arch. Physiologic und Histologic in Gnaz (A. Rollett, ed.), Hft. pathol. Anat. u. Physiol. Virchow's, 135:433—69, 1894. 2:111—142.Leipzig: Engebmann, 1871. 335. . Weitene Beobachtungen Uben die Histogenese dee 362. ROZINSKY, B. Zun Lehre von den endothelialen Ovanial Carcinoms. Centn. albgem. Pathol. u. pathol. Anat., 5:697— geechwülsten. Z. Geburtshilfe. u. Gynakol., 35:215-267, 1896. 706, 1894. 363. RUMLER, A. Ueber Myxom und Schleimgewebe. Bonn: 336. . Ueber die expenimentelle Enzeugung einen Ecchon Geongi, 1881. drosie physalifora. Verhandl. XIII. Congresses Inn. Med. 364. RusT, J. N. Helkobogie odor übendie Natur, Erkentniss und (Deutsch Geselbech. Inn. Med.), pp. 455-464. Wiesbaden: Heilung den Geschwure (2 vole.), 139—55,also 286—90.Wien: Bengmann, 1895. Camesina, 1811. 337. . Ueben die Entstehung den Geschwulste. Deut. med. 365. RUZTIZKY, J. vOn. Epithebialcancinom den Duna mater mit Wochschn.,21:24;45;62,1895. hyaliner Degeneration. Arch. pathol. Anat. u. Physiol. 338. . Ueber die Hietogenese und das Wachethum dee Car Virchow's, 59:191—201,1874. @ cinoms. Arch. pathol. Anat. u. Physiol. Virchow's, 141:153— 366. SACHS,0. Die Entwickelung den Carcinome, pp. 35-36. 177,1895. Bneslau: Jungfen, 1869. 339. - . Bemerkungen zu einem Falle von pnimarem Lungen 367. SAMUEL,S. Handbuch den abbgemeinen Pathobogie ale patho cancinom. Deut. med. Wochschn., 22:165—167,1896. logischer Physiologic, pp. 583—588.Stuttgart : Enke, 1879. 340. . Zur Entstehung den GeschwUlste. Ibid., 22:471—474, 368. SATrLER, H. Ueben die soganannten Cylindrorn und denen 1896. Stellung im onkobogischen Systeme, pp. 65-98. Berlin : Rei 341. . Des pathobogieche Wachsthum den Gewebe bei den men, 1874. Hypentrophie, Regeneration, EntzUndung und Geschwulst 369. SAVORY,W. S. Bradehaw Lecture on the Pathology of Can bildung. Bonn : Cohen, 1896. con, delivered at the Royal College of Surgeons (1884). In 342. . Ueben das Endothel in den pathobogischen Histologic. Tracts, 172 Royal College of Surgeons of England. London: Vientebjahneschn. natunforsch. gee. Zurich, 1896. Churchill, 1884. 343. . Ueber Ruckbildung an Zelben und Geweben und üben 370. SCHLEIDEN, M. J. Beitrag zun Phytogenesis. Arch. Anat. die Entstehung den GeechwUbste. Bibliotheca medica, Abt. Phyeiol. Wise. Med., pp. 137—76, 1838. C. : Hft. 9: Stuttgart: Nagebe, 1897. 371. ScuornEMus, M. Em Fall von pnimaren Lungenkrebs, p. 30. 344. RICHTER, A. G. Anfangsgnuende den Wundanzneykunst, Wurzbung: Becker, 1874. Ed. 2, 5 vole., 1:260-298. Gottingen: Dietenich, 1787—1802. 372. SCHUCHARDT,K.BeiträgezunEntstehung denCarcinome aus

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. Thioi@o—Foundationsof Cancer Research 105

chronisch entzündlichenZuständendenSchleimhAutemid 403. ToMi&AsI, C. Ueber die Entetehungeweise des Fniedreich' Hautdecken. Samml. Klin. Vortr. (R. Volkmann, ed.), No. echen Schlauchsarkoms. Arch. pathob. Anat. u. Physiol. 257'.2195-2238.Leipzig:Bneitkopfu. Härteb,1885. Virchow's, 31:111—17,1864. 373. Scuun, F. Ueben die Erkenntniss den Pseudoplasmen, pp. 404. TRIOLO, V. A. Bichats Krebstheonie in Wolfe ,,Lehre von den 7—14,349—54.Wien: Seideb, 1851. Krebskrankheit.― Eine Benichtigung. Arch. Gee. Med., 374. SCHULTZ,F. E. Zun Kenntniss den alveolaren Galbentgesch 48:82-86, 1964. wulet. Arch. mikroskop. Anat., Schultz's 1:336-43, 1865. 405. . Nineteenth Century Foundations of Cancer Research. 375. SCHULTZ, R. Klinische-anatomische Betnactung überdas Origins of Experimental Research. Cancer Research, 24:4—27, “Deemoidcancinom.―Arch. den Heilk., 15:193—238,1874. 1964. 376. SCHUPPEL, 0. Zun Lehre von den Histogenese des Leber 406. , AND GIOVANELLA,B. Francesco Dunante and the krebees. Ibid., 9387-405, 1868. Cohnhoim Theory of Oncogenosis (in press). Physis. Rivista 377. SCRWANN, T. Mikroskopische Unteneuchungen über die Intennazionabe di Stonia della Scienza (in prose). Uebeninstimmung in den Struktur mid dem Wachetum den 407. URLE, J. P., AND WAGNER,E. Handbuch den allgemeinen Thiere und Pflanzen, pp. 41-190. Berlin: Reimer, 1839. Pathologic. Ed. 4, pp. 357-460, 483—524.Leipzig: Wigand, 378. Scnn@nicu, C. L. Infection mid Geschwulstbildung. Deut. 1868. med. Wochschr., 17:83—87,1891. 408. VAJDA, L. Ueber Entstehung doe Epithelialknebees und 379. SgDn.LoP, C. H. Rechenches sun be cancer, pp. 108-9. Stnas Regeneration dee Epithebs im Abbgemeinen. Vorlaufige Mit boung: Silbermann, 1846. theilung. Centr. Med. Wiss., 11385-89, 1873. 380. SENFTLEBEN, H. Zur Casuistik eeltenerer Geschwubste. 409. VELPEAU, A. A. L. Traite dee maladies du sein, pp. 481-504. Arch. pathol. Anat. u. Physiob. Virchow's, 15336—352,1858. Paris : Masson, 1854. 381. SIcK, P. Zur Entwickelungsgeschichte von Knobs, Eiter 410. VERNEUIL, A. Observation pour senvin a l'histoiro des ab mid Sarcom nebet einem Fall von Venenknebs. Arch. pathol. terations locales des nerfs. Arch. gen. med. , 18(5s.) :537—52, Anat. u. Physiol. Virchow'e, 31:265—343,1864. 1861. 382. SIMON,J. A course of lectures in general pathology (Lecture, 411. VIEL-HAUTMENSIL, A. V. A. Considerations genenales me VIII: Tumours). Lancet, 2:107, 1850. dico-chirungicabes sun be cancer, p. 23—24.Paris : Didot 383. . An address on some points of science and practice Jemio, 1807. concerning cancer. Bnit. Med. J., 1:219—24,1878. 412. ViRcHow, R. Zun Entwickelmigsgeschichte des Knobs, nebet 384. SNOW, H. Is cancer hereditary? Ibid., 2:690-92, 1885. Bemenkmigen übenFettbildmig im thierschen Korper und 385. . A treatise, practical and theoretic on cancers and the pathobogische Resorption. Arch. pathol. Anat. u. Physiol. cancer-process, pp. 28—72.London: Churchill, 1893. Virchow's, 1:94—204,1847. 386. SOEMMERRING,S. T. Do morbis vasorum absorbentium con 413. . Zur pathobogischen Physiologic des Bluts. Ibid., 1: ponis humani. Pans pathobogica, p. 109. Traiecti ad Moenum: 547—83,1847. Vennentrapp & Wenner, 1795. 414. . Gesellschaft für wiseenschaftliche Medicin. Die 387. Soxoi.ow, A. A. Ueben die Entwickelmig des Sankoms in Mod. Reform, 51:271—72,1849. den Muskein. Arch. pathol. Anat. u. Phyeiol. Vinchow'e, 415. . Ueber Kankroide mid Papillangeschwulste. Verhandl. 57:321—370,1873. Phyeik.-Med. Gee. Wuerzburg, 1:106—li, 1850. 388. SPENCER, W. G. Soot in Cells of Chimney-Sweep's Cancer. 416. . Combinations- und Uebergangefahigkeit Knankhafter Bnit. Med. J., 2:1122, 1890. Geschwülste.Ibid., 1:134—40,212—13,1850. 389. SPENCER-WELLS,T. The Morton Lecture on Cancer and Can 417. . Knochen-und Knorpelkorpenchen. Ibid., 1:193-97, cerous Diseases. Ibid., 2:1201—05,1265—69,1888. 1850. 390. STEUDENER,F. Beiträge zun Onkobogie. Arch. pathob. Anat. 418. . Pathologische Neubildmig von quengestneiften Mus U. Physiol. Virchow's, 4F.39-50, 1868. kolfasern. Ibid., 1:189—91,1850. 391. . Zur Kenntnis den SandgeschwU.lste. Ibid., 50:222-32, 419. . Die Identität von Knochen-, Knonpel- und Binde 1870. gewebekonperchen, sowie übenSchleimgewebe. Ibid., 2:150— 392. . Beitrage zun Onkologie. Ibid., 59:413—26,1874. 62, 1851. 393. SThICKER, S. Ueben die Zebbtheibung in entzündeten Geweben. 420. . Die endogene Zellonbildung beim Knobs. Arch. Studien aus dem Institute fürExpenimentelle Pathologic pathol. Anat. u. Physiob. Vinchow's, 3:197—227, 1851. in Wien aus dem Jahre 1869 (S. Stricken, ed.) , 1:18—30.Wien: 421. . Zun pathobogischen Physiologie des Bbute. Ibid., 5: Braumülber, 1870. 43-128,1853. 394. STROEBE, H. Zun Kenntniss verechiedenen cellulfirer Von 422. . Ueben em zusammengesetztes, gablertartiges Cystoid gänge und Enscheinungen in Geschwulsten. Beitr. pathob. mit ausgezeichneter RecidivfAhigkeit. Thid., 5216-50, 1853. Anat. u. ailgem. Pathob., 11:1—38,1892. 423. . Das normabe Knochenwachsthum mid die nachitische 395. . Ueber Vonkommen und Bedeutung den asymme Stoning derselbon. Ibid., 5:409-507, 1853. tniechen Karyokinese, nebet Bemerkungen uber die ,,Schbum 424. . Tnoie observations do tumeurs epitheliales generali merzeblen―in den verbetzten Cornea. Ibid., 14:154—173,1893. sees; communiquecs pan M. Vinchow a M. Vebpeau. Gaz. 396. SUDROFF, K. Ueber das Pnimanes multiple Carcinom des med., Paris, 10: 208—13,1855. Knochensystems, pp. 33-35. Enlangen: Jacob, 1875. 425. . Celbulan-Pathobogie. Arch. Pathol. Anat. u. Physiol. 397. TANCHOTJ,S. Rechenches sun be cancer. Compt. rend. 14:755, Virchow'e, 8: 3—39,1855. 877, 1842. 426. . Ueber Penlgeschwulste. (Chobesteatoma Joh. Mul 398. TgALLIER,P.4.-S. Du cancer de la matnice, do seecauses, ion's.) Ibid., 8:371—416,1855. do son diagnostic et do son traitement, pp. 39—44,75-93. 427. . Ueben die Theilung den Zellkerne. Thid, 11:89—92, Paris: Baiblibre, 1836. 1857. 399. TuxEiwca, C. Den Epithebialkrebs, namentbich den Haut. 428. . Die Cellulanpathobogie in ihre Begrundung auf phy Eine anatomischen-klinische Ilntensuchung. Leipzig: Engel siologieche mid pathobogieche Gewebobehre, pp. 380-433. mann, 1865. Berlin: Hinschwald, 1858. 400. TILLMANN8, H. Histobogieche Beitnäge zur Lehne von den 429. . Reizmig und Reizbankeit. Arch. pathol. Anat. u. Sarcomen mid metastatischen Tumonen. Arch. den Heibk., Physiol. Virchow's, 14:1—63,1858. 14(n.f.3).530—50,1873. 430. . Myxoma lipomatodes malignum. Ibid., 32:545-46, 1865. 401. . Ileber Theer-, Russ- und Tabakknebs. Deut. Z. Chin., 431. . Die krankhaften Geschwubete (3 vols.). Berlin: 13:519—34,1880. Hinechwald, 1863-67. 402. ThIN, G. On some of the histological changes found in cancer 432. . Ueben die Entstehmig des Echondroma mid seine of the skin or epithelioma, with special reference to the Beziehmig den Ecchondrosis und don Exostosis cantilaginea source of newly formed epithelial cells. Bnit. Med. J., 1:412— Monatab. Konigl. Preuss. Acad. Wise Berlin, pp. 760-73, 13, 1876. 1875.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 106 Cancer Research Vol. 25, February 1965

433. ——. Krankheitswesen und Krankheitunsachen. Arch. 459. WALTHER, P. Ueber die schwammigen Auswuchse auf den pathol. Anat. U. Physiol. Vinchow's, 79:1—19,186—228,1880. harten Hinnhaut, nach eigenen Beobachtungen. J. Chin. u. 434. . Ueber Metaplasie. Vontnag, gehalten am 15. August Augen.-Heilk.,1:55—105,1820. 1884 auf dem intennationalen medicinischen Congress in 460. WALTRER,J.C. G. ; JAEGER,M.; ANDRADIUS,J. Handwönten Kopenhagen. Ibid. , 97:410—30,1884. buch den gesammten Chirurgie und Augenheilkunde (6 435. . Zur Diagnose und Prognose des Carcinoms. Ibid., vols.), 2:145—204.Leipzig: Gebhand u. Reisland, 1836—40. 111:1—24,1888. 461. WARDROP,J. Observations on Fungus Haematodes on Soft 436. . Transfonmismus und Descendenz. Berliner klin. Cancer in Several of the Most Important Organs of the Hu Wochschn., 30:1—5,1893. man Body : Containing also a Comparative View of the Struc 437. . Bindegewebs-Haute und Lymphspalten. Em Brief tune of Fungus Haematodes and Cancer. Edinburgh: Con wechsel zwischen Rudolph Krausse und Rudolph Virchow. stable, 1809. Arch. pathol. Anat. u. Physiol. Vinchow's, 162:543-44, 1900. 462. WEBER, K. 0. Ueben die Entwickebung des Epitholialknebsee 438. VOGEL, J. Pathologische Anatomic des menschlichen koen in inneren Organen, nebst Bemerkungen überdie Struktur pens (Erste Abtheilung), in Sommenning, S. T. Vom Baue des den Leben und Lunge. Arch. pathol. Anat. u. Physiol. Vin menschlichen Koerpers (8 vols.), 8:256—288.Leipzig:Voss, chow's, 29:163—89,1864. 1845. 463. . Zur Geschichte des Enchondroms, namentlich in 439. VOLKMANN,R. Em neuen Fall von Cylinden-Geschwulst. Bezug auf dessen heneditänes Vonkommen und sekundAno Arch. pathol. Anat. u. Physiol. Vinchow's, 12:293—302,1857. Venbneitung in inner Onganen dunch Embolio. Ibid., 35:501— 440. . Zur Histologic des Muskelknebses. Ibid., 50:543—549, 24, 1866. 1870. 464. . Ueben die Betheilgung don Muskelkorperchen und 441. . Ueber Theen- und Russknebs. Verhandl. Deut. Gee. den quergestreiften Muskeln an den Noubildungen nebet Chin., 1(Abt.):3—5, 1874. Bemerkungen übendieLehre von den Specificatat den Geweb 442. . Peben Theen- und Russkrebs. Berliner kIm. Woch selement. Ibid., 39:254—69,1867. schn., 11:218, 1874. 465. WEGNER, G. Ueber Lymphangiome. Arch. klin. Chin., 20: 443. . Beitnage zun Chinungie, anschlieesend an omen Be 641—707,1877. nicht überdie Thatigkeit den chirungischen Universitäts 466. WEIGERT, C. Entzündung (Inflammatio, Phbogosie). Real klinik zu Habbe im Jahne 1873, pp. 370—81.Leipzig: Bneitkopf Encycbopadie den gesammten Heilkundo (ed. A. Eubenbung), U. Härtel, 1875. 4:644—76.Wien u. Leipzig: Urban & Schwarzenbeng, 1880. 444. . Ueben den pnimiinen Knobs den Extnemitäten. Samml. 467. WENDT, H. Deequamative Entzundung des Millebohs (,,Cho Klin. Vortr. (R. Volkmann, ed.), Nos. 334—335(Chin. No. lesteatom des Felsenbeins― den Autonen). Arch. den Heilk., 102): 3123—3192.Leipzig: Bneitkopf u. Hhntel, 1889. 14:428—46,1873. @ 445. Ueber endotheliale Geschwülste, zugleich em Beitrag 468. . Ueben em enthebiales Cholesteatom des Tnommel zu den Speicheldnusen- und Gaumentumonen. Deut. Z. Chin., felbes nebst Bemenkungen zun Histologic den Eigenschicht. 41:1—180,1895. Ibid., 14:551—61,1873. 446. WADSWORTH, (?), AND EBERTH, J. Die Regeneration des 469. WENZEL, C. Ueben die Induration und dae GeschwUr in in Hornhautepithels. Arch. pathol. Anat. u. Physiol. Vinchow's, dunirten Theilen, pp. 48—77.Mainz : Kupferberg, 1815. 51:361—372,1870. 470. WIEDEMANN,H. Ueben die Sandegeschwulst.Z. Rat. Med., 447. WAGNER, E. Weitene Beitnage zur Kenntnis dee ,,Knebses 24(3s.):127—42, 1865. mit negelmassigen Zellenlagerung― (Cylindenzellen-Knebs). 471. WILLIAMS, J. On some periodical changes which occur in Arch. Physiob. Heilk., 3(n.f.):246—82, 1859. fibroid tumours of the uterus and their significance. Lancet, 448. . Das Schleimmetamonphose dee Knebses und ihne 1:764—65,873—75,1880. Verhäbtniss zum 50g. Galbert- und Cystenkrebs. Arch. Heibk, 472. WILLIAMS, W. The family-history of cancer patients. Bnit. 1:157—75,1860. Med. J.,1:1039—40,1884. 449. . Die Combination von Krebs, Sarkom und Dnusen 473. WILSON, E. B. The Cell in Development and Inheritance. geschwulst (Zwei Fable von Nienengeschwulsten, ähnlich do, New York: Macmillan, 1896. sog. Siphonoma, Cylindroma etc.) Ibid., 1:313—21,1860. 474. WOGLOM, W. H. Studies in Cancer and Allied Subjects: The 450. . Die Nichtspecifitat des Gallentknebses. Ibid., 3:143— Study of Experimental Cancer. A Review (3 vole.), 1:50. 154, 1862. New York: Columbia University Press, 1913. 451. . Das tuberkelähnliche Lymphadenom. (Den cytogene 475. WOLFF, J. Die Lehne von den Knebsknankheit von den ältee odor reticulinte Tuberkel.) Ibid., 12:1—25,1871. ten Zeiten bis zur Gegenwant (4 vole.). Jena: Fischer, 1907— 452. WALDEYER,W. Grosses Lipo-Myxom des Mesenteniums mit 29. secundAnem sarcomatosen Heerden in den Leber und Lunge. 476. WOLFFBERG, S. Ueben die Entwickelung dee vennarbendon Arch. pathol. Anat. u. Physiol. Vinchow's, 32:543—44,1865. Bnustdrüsenknebses. Arch. pathol. Anat. u. Physiol. Vir 453. . Die Entwicklung den Carcinoma. Ibid., 41:470—523, chow's, 61:241—53,1874. 1867. 477. WOODHEAD,G. S. The etiology of tumours. Edinburgh Med. 454. . Die Entwickelung den Cancinome. Ibid., 55:67—159, J., 34:26-56, 1888. 1872. 478. Wyss, 0. Die heterobogen (bosartigen) Neubildungen den 455. . Ueber den Krebs. Samml. Klin. Vontn. (R. Volk Vonstendruse. Arch. pathol. Anat. u. Physiol. Vinchow's, mann, ed.), No. 33 (Chin. No. 10): 162—96.Leipzig: Bneitkopf 35:378-412, 1866. u. Häntel,1872. 479. ZIEGLER, E. Ueben Proliferation, Metaplasie und Resonp - 456. . Archiblast und Panablast. Arch. Mikroskop. Anat. tion des Knochengewebes. Ibid., 73:355—79,1878. u. Entwicklungsmech., 22:1—77,1883. 480. —------.Lehnebuch den ailgemeinen und specielbon Pathobo 457. WALSHE, W. H. The Anatomy, Physiology, Pathology, and gischen Anatomie und Pathogenese. Mit einom anhange Treatment of Cancer, pp. 7—38.Boston: Ticknon, 1844. überdie Technik den pathobogiech-anatomiechen Unter 458. . The Nature and Treatment of Cancer, pp. 12—29.Lon euchung. FürAnzte und Studirende (2 vole.). Jena: Fischer, don: Taylor and Walton, 1846. 1881-85.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. Nineteenth Century Foundations of Cancer Research Advances in Tumor Pathology, Nomenclature, and Theories of Oncogenesis

Victor A. Triolo

Cancer Res 1965;25:75-106.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/25/2_Part_1/75

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/25/2_Part_1/75. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research.