COLUMBIA LIBRARIES OFFSjTE HEALTH SCIENCES STANDARD HX64121682 RC261 .B162 The cancer problem/ RECAP (^Cz<.l "•"""""•"•""" -ntf : ^ Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/cancerproblemOObain THE CANCER PROBLEM THE MACMILLAN COMPANY NBW YORK • BOSTON • CHICAGO DAIXAS • ATLANTA • SAN FRANCISCO MACMILLAN & CO., Limited LONDON • BOMBAY • CALCUTTA MELBOURNE THE MACMILLAN CO. OF CANADA; Lnii TORONTO THE CANCER PROBLEM BY WILLIAM SEAMAN BAINBRIDGE A.M., Sc.D., M.D IBOFES80B OF SURGERY, NEW YORK POLYCLINIC MEDICAL SCHOOL AND HOSPITAL; BURGEON, ANI 8ECRETABT OP COMMITTEE OF SCIENTIFIC RESEARCH, NEW YORK SKIN AND CANCER HOSPITAL; CONSULTING SURGEON, MANHATTAN STATE HOSPITAL, WARd's ISLAND; HONORARY PRESIDENT, FIRST INTERNATIONAL CONGRESS FOR THE STUDY OF TUMOKS AND CANCERS, HEIDELBERG, I906 ^to |9orfe THE MACMILLAN COMPANY 1918 Copyright, 1914 B« THE MACMELLAN COMPANY Set up and electrotyped Published October, 1914. Reprinted September, 1915. The host of patient sufferers who are facing pain and death from cancer; to the men and women who are earnestly striving to discover the cause and cure of the disease; to the noble friends of humanity who are generously aiding in this struggle, this effort to gain light upon the cancer problem is dedicated. PREFACE The cancer problem, as it exists to-day, has a much greater significance than that with which the disease itself was invested by those who first fancied a similarity between its local manifestation, the tumor, with its "roots," and the crab, with its claws, and who applied to it the term "cancer," or "crab." These ancients who studied the disease had no conception of its prospective importance as a problem of far-reaching im- port to the human race. The deaths from cancer to-day are said to number at least half a million annually among civilized peoples alone. It is also asserted that the disease is increasing with alarming rapidity, and affecting ever younger and younger ages. If these things be true, then we have here a problem which, if not solved, bids fair to exterminate mankind as effec- tually as some earlier catastrophe wiped out the flying reptilian monsters whose fossil remains afford so much interesting food for speculation to-day. Even if, as is certain, this is too grave a prospect, cancer is nevertheless the one major problem of medicine still defying any real approach to solution, as regards prevention, reliable early diagnosis, or guaranty of permanent cure. The tumor was thought by early observers to be the manifest effect arising from the "roots" in the body because of some constitutional condition. To-day we know that the exact oppo- site is true. The tumor is the starting place, and its "roots" are the offshoots by which it sends out "runners" to the con- tiguous territory, extending further and further, by minute or by manifest passages, far beyond the original confines, until the whole body is invaded. So, to-day, interest in the "cancer problem" has carried it, by one kind of "runner" or another, into every phase of life. ISTot only is it a topic for discussion in the operating room and the medical convention, but in the home, in the business office, in the lecture room, and in the hall of legislation. "Is it con- tagious?" "May it be inherited?" "Is it caused by certain kinds of food ?" "Is it influenced by environment ?" "Can it be prevented?" "Can it be cured?" These, and many more vi PREFACE pointed questions, are being asked by laymen as well as by the profession. How best to answer them, in the light of our pres- ent knowledge concerning cancer, is a debatable matter. Much of the mystery which surrounds cancer, much of the ignorance concerning it, both within and without the medical profession, is due to the chaotic condition of the literature upon the subject. To acquire dependable information concerning any phase of the question entails tedious search through many books, pamphlets and periodicals. To give a clear, concise, comprehensive, and available resume of the world's work with reference to cancer, its history, distribution, etiology, diag- nosis, possibility of prevention, and treatment, together with various minor matters, is a most difficult task. With the development of the widespread interest in cancer there has arisen a definite need for a book of ready reference, of convenient size, giving in succinct and available form a svim- mary of knowledge concerning the subject. This is needed by the general practitioner, by the specialist, by the intelligent layman, by the lecturer on health matters; in fact, by all who are definitely interested in questions of health maintenance. In attempting to meet this need, at least in part, the magni- tude of the undertaking has been more and more fully realized as the work of collecting and formulating the data has pro- ceeded. It has been necessary to touch upon practically every phase of the cancer problem, to state theories^ to emphasize fadSj to review the work and opinions of those who are qual- ified to speak with authority, and to maintain throughout an attitude of "suspended judgment pending proof." In addition to this brief consideration of the essentials of cancer lore, a bibliography of some of the most important con- tributions of others has been compiled, in order that the reader who desires to continue the study of cancer in greater detail may do so with increased facility and lessened expenditure of time. Pictures which depict the horrors of cancer are pur- posely omitted. ISTo attempt is made to give a complete work on the surgical treatment of malignant neoplasms. It is manifestly impossi- ble, in a volume of the size and scope of this book, to cover the entire field. At a later date perhaps, a second volume, or a second edition of the present volume, may be put forth, giving a thorough digest of surgical technic as applied to cancer. The many difficulties of the task which this volume repre- sents will be most keenly appreciated by those who are familiar with cancer research, whether in the laboratory, in the operat- ing room, or at the bedside. To the host of coworkers in this PREFACE vii field who have generously given their encouragement and ad- vice I extend my sincere thanks. To members of my staff at the New York Skin and Cancer Hospital I am indebted for patient assistance. Particularly do I desire to express appre- ciation to Dr. J. Douglas Malcolm for the careful searching of records at the hospital for necessary clinical data ; to Dr. D. Stuart Dodge Jessup for painstaking pathological work, and to Dr. Worthington Seton Russell for assistance in the electro- therapeutic study of cases. To Dr. Loy McAfee I am indebted for valuable assistance in the arrangement of the subject mat- ter, especially for the bibliography and index. To the pub- lishers for their prompt and efficient execution of their part of the work I wish to express my sincere thanks. The mystery which to-day obscures the essential cause of cancer may be cleared away to-morrow ; the views held at pres- ent may of necessity be abandoned in the near future. Until such a fortunate contingent arises, it is sincerely hoped that this contribution to cancer literature may be of interest and profit to many who are, or who may desire to become, students of one of the most important questions of modern medicine — the Cancer Problem. CONTENTS SECTION I History PAGE Ancient History 1 History of Modern Cancer Eesearch 4 Influence of the Campaign Against Tuberculosis ... 4 New York the First to Establish a State Institution Devoted Exclusively to the Study of Malignant Disease ... .5 Cancer Commission of Harvard University ..... 6 Cancer Eesearch in Germany ....... 7 International Association for Cancer Eesearch .... 8 Cancer Eesearch in England . . . . . . .11 Cancer Eesearch Laboratories, Middlesex Hospital (London) . 13 Imperial Cancer Eesearch Fund 16 Other Cancer Eesearch Institutions ...... 25 Comparison of Methods of Investigation . . . . .28 Institutions which Combine Clinical and Experimental Work . 29 Eesearch Department, New York Skin and Cancer Hospital . 29 Possibilities of Clinical and Experimental Work and the Utility of Combining or Separating Them 32 Sunamary 36 SECTION II GENERAii Distribution Introduction 37 Chapter I. Botanical Distribution 40 Summary . . . . . . . . . . .45 Chapter II. Zoological Distribution 47 Influence of Environmental Changes, Including Diet . . .47 Influence of Chemical and Other Irritants . , . . .48 Influence of Heredity 48 Age Incidence .......... 49 Influence of Use on Organs — Site Incidence . . . .50 Cancer in: Dog 50 Cat 51 Horse . . > 51 Bovines ........... 52 Swine, Sheep, and Goats 52 Wild Animals in Their Native State and in Captivity . 52 Birds (Domesticated Fowl) 54 Wild Birds 54 Eeptiles and Amphibians 54 Fish 55 MoUusks 58 Summary .......... 59 ix X CONTENTS PAGE Chapter III. Geographical and Ethnological Distribution . . 60 Influence of Climate, Soil, Diet, and Habits of Life . . ,60 i-Jaeial Immunity • . . . .62 Influence of Environmental Changes in the Production of Cancer 63 illustrations of the Universality of Cancer . . . .66 India 66 Gilbert Islands 68 Iceland 68 Summary 69 SECTION III Statistical Considerations Significance and Value of Statistical Studies 70 Difficulties Encountered in the Collection of Statistics , . 71 Universality of Cancer, as Shown by Statistical Studies . . 72 Possible Errors in the Compilation of Statistics . . . .72 Fallacies of American Methods of Compiling Statistics . . 73 Importance of Autopsies in the Compilation of Cancer Statistics 76 Factors to Be Considered in Calculating Cancer Death-rate Occupational Mortality from Cancer Is Cancer Increasing? Cancer Mortality According to Locality . Relation of Statistics to Etiology . Summary 80 82 90 91 104 SECTION rv Etiology Chapter I. Theories 106 Early Theories 106 Theories Which Have Engaged Attention Since the Beginning of Modern Cancer Research 108 Biological Theories 108 Intuence of Humoral Theory Upon the Scientific Study of Cancer ". 108 Virehow's Theory Ill Thiersch's Theory Ill Waldeyer's Theory 112 Cohnheim's Theory 113 Ribbert's Theory 114 Hauser 's Theory 115 Other Theories 116 Parasitic Theories 117 Summary 121 Chapter II. Predisposing Causes 122 Bearing of Experimental Investigation upon Existent Theories 122 Atreptic Theory (Ehrlich) 124 Chronic Irritation ......... 126 Precancerous Conditions 127 CONTENTS xi PAGE Environment .......... 127 Diet 128 Summary ........... 128 SECTION V HiSTOPATHOLOGY Definition 130 Value of Histological Study . . . . . . . . 132 Histological Appearances 134 Classification 137 Origin and Spread 140 Basis of Surgical Treatment 141 Summary 142 SECTION VI Cancer Eesearch — A E^sume of the World's Work Practical Eesults 144 Failure of Modern Experimental Study of Cancer to Establish the Etiology of the Disease ....... 144 "Individuality" of Cancer Established by Experiment . . 147 Possibility of Transference no Proof of Infectivity of Cancer 148 ' ' Limitless ' ' Growth of Cancer ....... 149 Bearing of the Study of Propagation upon Other Phases of the Cancer Problem ......... 150 Microscopical Demonstration of the Facts of Transferring Cancer ........... 150 Propagation Experiments Justify the Surgical Treatment of Cancer ........... 151 Infectivity of Cancer in the Light of Propagation Experiments 151 Theoretical Eesults 154 Criticism of the Value of Propagation ...... 154 Criticism of the Value of Prolonged Propagation . . . 158 Bearing of Immunity Eeactions and op Propagation on the Na- ture OF Cancer 161 Constancy and Variability of Tumor Cells 162 Constancy and Variability of Histological Structure . . . 162 Constancy and Variability of More Subtle Properties . . . 163 Sarcoma Development ......... 164 Immunity Eeactions ......... 165 Eesistance to Heterologous Inoculation 166 Heterologous Immune Sera . . . . . . . . 167 Homologous Immunization and Eesistance ..... 167 Natural Eesistance 167 Active Eesistance Induced by Tumors 168 Active Eesistance Induced by Normal Tissue .... 169 Parallel in the Onset, Duration, and Distribution of the Eesist- ance Induced by Tumor and Normal Tissue . . . 170 Distinction between Living and Dead Tissues .... 171 Homologous Immune Sera ........ 171 Nature of the Change 171 xii CONTENTS PAGE Spontaneous Healing . . . . , . . , .172 Examination of the Site of Grafting ...... 172 Eeaction Throughout the Body 173 Eelative Weights of the Several Organs . . . . .173 Auto- or Concomitant Resistance . . . . . . .174 Autologous Inoculations ........ 175 Loss of Power to Induce Resistance and Acquisition of Powers of Continuous Growth 175 Hypersensitiveness . . . . . . . . .176 Possibility of Applying Results to Explain Nature of Cancer . 176 Summary 177 SECTION VII Clinical Course; Diagnosis; Possible Errors in Diagnosis Chapter I. Clinical Course 180 Summary 187 Chapter II. Diagnosis 188 Clinical 188 Microscopic 190 Serodiagnosis .......... 191 Summary ........... 194 Chapter III. Possible Errors in Diagnosis 195 Head 196 Tongue 199 Breast 201 Abdomen 204 Pelvic Organs 216 Summary 219 SECTION VIII Prophylaxis Introduction 220 Environment (Diet, Hygiene, Occupation, Etc.) .... 221 Precancerous Conditions 222 Local Manifestations op Other Diseases 224 Sources of Chronic Inflammation and Irritation .... 225 Case Reports 228 Summary 235 SECTION IX The Investigation op "Cancer Cures" Diversity of Agents Employed in the Treatment op Cancer . .237 What the Surgeon Has a Right to Know op a Proposed Method OF Treatment 239 What Constitutes a "Fair Test" 241 CONTENTS xiiL PAGE The Enzyme Treatment (Trypsin and Amylopsin, Plus R^&gime) 242 Serum from Birds of Prey 251 " Canckoidin, " " Antimeristem " (Otto Schmidt Serum oe Vac- cine) 252 Doyen's Serum 256 Chian Turpentine (Pistacia Terebinthus) 257 Sodium Oleate (Soap Solution) and Ox-gall . . . . . 258 Molasses 259 Violet Leaves 260 Investigation op "Quack Cures" 261 Mattei "Electricities" . . . . . . . . . 261 Cardigan (Wales) "Cancer Curers" 268 "^siAB Cancer Cure" 270 Davis Cancer "Cure" (Melbourne, Australia) . . . • , 271 Summary 276 SECTION X NON-SUBGICAL TREATMENT Chapter I. Caustics or Eschaeotics 277 Summary 286 Chapter II. Physiotherapy 287 Heat 287 Light 288; Sunlight 288 Electricity 289 Arc Light 289 Incandescent Light ........ 290 Fluorescent Stimulation 291 X-Rays 291 Eadio-activity 297 Eadium 297 Mesothorium 304 Radio-active Gelatin 305 Electrocautery (Byrne Method) 306 High-frequency Current . . . . . . . .308 Alto-frequent Cytolysis, Alto-frequent Scintillation, EflSeuvation, Etc. (Riviere) 309 "Destructive Fulguration" 310 Fulguration (de Keating-Hart) 310 Surgical Technic . . . . . . . , .314 Electrical Technic 314 Theoretical Basis of Fulguration 316 Thermopenetration (d'Arsonval) 316 Thermoradiotherapy (de Keating-Hart) 317 Diathermy, or Transthermy (Nagelsehmidt) .... 320 Electrocoagulation (Doyen) 321 Bipolar Voltaization (Doyen) 322 Oscillatory Desiccation (Clark) 322 Ionic Surgery (Cataphoresis) 323 Summary 324 CONTENTS PAGE Chapter ITT. Biotherapy 327 Classification of Agents ..... Definition of Terms ...... Antitoxin; Antitoxic Serum; Bacterial Toxins Residues; Extracts; Emulsions Sierous Exudates and Body Fluids (Sera) . Opotherapcutic Measures (organotherapy) . A. Based on Bacteriology ..... Sera (Bacterial Toxins) .... B. Based on Cytolysins or Cytotoxins Vaccines ........ Residues; Extracts; Emulsions Serous Exudates and Body Fluids (Sera) Opotherapcutic Measures .... Summary ........ . 327 . 328 . 329 . 330 . 330 . 331 . 332 . 332 . 338 . 338 . 338 . 341 . 343 . 343 SECTION" XI Surgical Treatment Chapter I. General Techntc of Surgery, as Applied to Cancer . 345 Purposes of Surgical Treatment of Cancer ..... 353 Summary ........... 355 Chapter II. Special Technic 356 A. Surgical Technic Based upon the "Permeation Theory" of Cancer Dissemination ....... 356 Modified Operation for Cancer of the Breast . . . 362 Permeation Theory Applicable to Other Localities . , 364 " Operability " of Cancer of Rectum Extended by Permea- tion Theory . .365 Permeation Theory Applicable to Melanotic Sarcoma . - 367 B. Plastic Procedures 368 C. Palliative Measures 369 Nervous System 369 Neurectomy ......... 369 Decompressive or Decompression Operations . . 369 Lymphatic System . . . . . . . . .370 Lymphangioplasty ........ 370 Paracentesis Abdominalis ...... 371 Thoracocentesis ........ 371 Vascular System 372 "Starvation Ligature" 372 History 372 Ligation and Exsection of External Carotid Artery (Dawbarn Method) in the Treatment of Ma- lignant Tumors of the Head and Face . . 374 Technic of Carotid Excision and Injection of the Two Terminal Branches ..... 376 Indications for the Operation 379 Table of Cases 381 ** Starvation Ligature," with Lymphatic Block, in the Treatment of Advanced Cancer of the Pelvic Organs ........ 383 History 383 Purposes of the Method 386 Objections Which May Be Raised Against the Pro- cedure ........ 389 Indications ........ 390 Technic 391 CONTENTS XV PAGE ^.Q"? Special Points of Technie to Be Observed Clinical Application 394 Table of Cases 396 E«spiratory System 412 Tracheostomy ........ 412 Alimentary System ........ 412 Esophagostomy ... .... 412 Gastrostomy 412 Gastroenterostomy . . .... 412 Colostomy 412 "Short-circuit" 413 Colectomy ......... 413 Urinary System ......... 413 Cystostomy 413 Nephrotomy ......... 413 Ureteral Transplantation 413 Biliary System 414 Cholecystostomy 414 Summary . . . .. . . . . « . 414 SECTION XII Irremovable Cancer Introductory Eemarks 415 Seemingly Irremovable . . . 418 Operable, but Irremovable, yet Curable 420 Operable, but Irremovable and Incurable 421 Treatment of Conditions Caused by or Complicating Cancer . 421 Treatment of the Cancer per se ...... . 422 Treatment of the Patient ........ 422 Inoperable, Irremovable, Incurable 422 Institutional Care 423 Mental Condition 423 Physical Condition 425 Diet 426 Pain 427 Care of Ulcerating Surfaces and Fungating Masses . . . 427 Summary . . . . 428 SECTION XIII Institutions for the Care of Cancer Patients Introductory Eemarks 429 In Europe 429 In America 431 Almshouse Hospital (New York City) 432 City Hospital (New York City) 432 General Memorial Hospital (New York City) .... 432 New York Skin and Cancer Hospital . . . ... . 432 Private Institutions • . 432 xvi CONTENTS PAGE Benevolent Institutions 432 Fordham Home for Incurables (New York City) . . . 432 House of Calvary (New York City) 433 St. Eose's Free Home for Incurable Cancer (New York City) . 433 "Quack" Cancer Institutions 433 The Lot op the Patient at Home 434 Need for Adequate Facilities 435 Summary 436 SECTION XIV The Campaign of Education Introductory Eemarks 438 The Education op the Medical Profession 440 The Education of the Public 445 Need the Layman Be Educated? 445 How Best to Conduct the Campaign? 447 Summary 451 THE OUTLOOK 452 BIBLIOGRAPHY 455 INDEX OF AUTHORS . 509 INDEX 513 PLATES Group of Natives of Kashmir with Kangri Baskets . Frontispiece PIATB FACING PAGE I. Kangri basket . .67 II. Group of natives of Kashmir with Kangri Baskets 67 III. Epithelial wart from wrist of a worker in paraffin distillation 126 IV. Early squamous-eelled carcinoma of tongue, natural size and magnified fifty times .... 134 V. Carcinoma (scirrhus) of breast .... 135 VI. Soft or medullary carcinoma of breast . . . 135 VII. Small carcinoma of breast, natural size and magnifi- cation 135 VIII. Squamous-eelled carcinoma growing in lymph gland 135 IX. Squamous-eelled carcinoma spreading by permeation of a lymphatic ....... 135 X. Ulcerating adenocarcinoma of breast .... 135 XI. Spread of adenocarcinoma of breast between muscle and inside muscle fibers ..... 135 XII. Adenocarcinoma of breast growing in a lymphatic gland 135 XIII. Invasion of a long bone by adenocarcinoma of the breast 135 XIV. Adenocarcinoma of rectum ..... 136 XV. Secondary deposit of adenocarcinoma of rectum growing in liver . . . . . . .136 XVI. Adenocarcinoma of rectum spreading by the blood- stream . o . ■ . . . . . . 136 XVII. Secondary deposit of adenocarcinoma of liver grow- ing in lung 136 XVIII. Malignant tumor of thyroid gland . . , 136 XIX. Papilloma of skin 136 XX. Margin of squamous-eelled carcinoma of tongue . 138 XXI. Squamous-eelled carcinoma of tongue spreading be- tween and destroying muscle fibers . . . 136 XXII. Deep aspect of a small malignant ulcer of tongue . 136 XXIII. Margin of rodent ulcer ...... 137 xvii PLATES PLATB XXIV. Paget's disease XXV. Small roiuul-cellod sarcoma XXVI. Large roiuul-cellcHl sarcoma showing marked tendency to necrotic des:oneration XXVII. • Spindle-eelled sarcoma .... XXVIII. Melanotic sarcoma of sole of foot following a punc- ture XXIX. Melanotic sarcoma XXX. Melanotic sarcoma. Secondai-y in liver, showing fatty degeneration of liver cells . XXXI. Fibroma XXXII. Fibroadenoma of breast .... XXXIII. Structure of subcutaneous capillary nevus XXXIV. Mixed tumor of parotid region XXXV. Choi-ion epithelioma of uterus . XXXVI. High-power view of failure to supply the specific scaffolding on the part of an immunized rat XXXVII. High-power view of the fonnation of new blood vessel and stroma scaffolding for a graft of ear einoma in a normal rat .... XXXVIII. Illustrating the permeation theory of Handley FACING PAQB 139 139 139 139 13fl 139 139 130 139 139 139 139 173 173 361 LIST OF ILLUSTEATIONS IN THE TEXT SECTION III FIG. PAGE 1. Map showing true state of American Vital Statistics in 1900 75 2. Map of McConnell 76 3. Chart giving analysis of cancer for women . ... .84 4. Chart giving analysis of the increase of cancer for men . 85 5. Chart indicating diagrammatically the increase in the age of the population of England and Wales . . .89 6. Chart giving percentage of deaths from mammary carcinoma 98 7. Chart giving death-rate from cancer in mice of cancerous ancestry 99 SECTION IV. CHAPTER I 1. Diagrammatic representation of differentiation of somatic and reproductive tissues in higher animals .... Ill 2. Diagram of hypothesis of Thiersch and Waldeyer . . 112 3. Diagram of Cohnheim's hypothesis ..... 114 4. Diagram of Ribbert's hypothesis 115 5. Diagram of hypothesis of "gametoid" nature of cancer . 117 6. Diagram of parasitic hypothesis 118 SECTION VI 1. Curves showing extent and duration of induced resistance in mice 170 THE CANCER PROBLEM THE CANCER PROBLEM SECTION I HISTORY ANCIENT HISTORY Abundant historical references lead to the belief that the disease which we now designate as cancer was known to the ancients at least two thousand years ago. They worked with- out lens or microscope, and hence could determine nothing con- cerning the minute structure of tumors and the various tissue manifestations with which they confused cancer. Undoubtedly many errors in diagnosis were made, and many diseases now accepted as of non-malignant nature were considered malignant by earlier observers, just as leprosy, which is so familiar to every child who has read the Bible, probably covered many forms of ulcerating sores as well as certain scaly skin diseases, and did not necessarily mean only the leprosy of which we speak to-day. It is not to be wondered at, therefore, that imagination was given full play in the evolution of the elaborate theories of etiology which have marked the development of the cancer problem, as in almost all problems of disease, from insanity to plague; nor is it surprising that the therapeutic history of the disease is one of the most fantastic of any in the annals of medicine and surgery. In looking back over the records of the past, we find such a diversity of opinions regarding the origin of cancer, that to give a brief catalogue of the various theories would be an unnecessary tax upon the reader's time and patience. This has been done in a very full and able manner by Wolff. ^ The causative factors involved range from the three "humors" of Hippocrates, Celsus, and Galen, through practically all the indi- ' Wolff, Jacob. — * ' Die Lehre von der Krebskrankheit von den altesten. Zeiten bis zur Gegerwart," Jena. Vol. I, 1907. Vol. II, 1911. 1 2 THE CANCER PROBLEM vidual tissues of the body;, and to a bewildering number and variety of extraneous agencies. Even the mysticism of the past has been invoked to account for this disease, for we are told by van Ilelmont (1578-1644) that cancer is due to a spiritual being, the Arcliwus, in the stomach and. spleen, which must be purified and thus prevented from sending its ferments into the wrong parts. The earlier theories which engaged scientific attention are briefly considered under the subject of Etiology (Section IV, Chapter I). Since the beginning of recorded medical history, and doubt- less long before, imagination was given full play in the treat- ment of cancer. The "witch doctor" combined the secrets of the "black art" with the brewing of the "witch's broth," and the unfortunate victim of cancer was given doses of the mix- ture. Throughout the centuries the sufferer from this disease has been the subject of almost every conceivable form of experi- mentation. The fields and forests, the apothecary shop and the temple, have been ransacked for some successful means of relief from this intractable malady. Hardly any animal has escaped making its contribution, in hair or hide, tooth or toe- nail, thymus or thyroid, liver or spleen, in the vain search by man for a means of relief. The hand on the dial has turned many times to the same point of effort during the progress of the centuries, and it is possible to find in remote districts to-day the same remedies being used that were employed by "cancer curers" of long ago. We are told, for example, that the idea that green frogs in some way influenced the course of cancer has prevailed for hundreds of years, and still prevails in certain quarters. Bonet, of Geneva, in 1682, gave a prescription for an ointment made of green frogs. In the "Kook-Koeck en Recepte Boek," by E. J. Dijkman, published in Cape Colony, eighth edition, 1905, occurs the following interesting item (Trans. J. Muir) : "An example of a woman who had cancer of the breast, which was already so severe that eight holes had been eaten into it, and who recovered through the following expedient : She took eight frogs applied to the breast in a muslin bag, which attached them- selves instantly thereto as firmly as leeches. When they had sucked to repletion, they dropped off in violent convulsions without the sucking causing pain. This was repeated until 20 frogs were used, which all from time to time, sucked until they died. And the breast was not only cured, but returned again to its normal size absolutely." Fabricius Hildanus, of Hilden near Cologne (1560-1634), HISTORY S is said to have asserted from certain experience ^ that the fol- lowing is admirable in curing ''ulcerous cankers." The receipt for the water is as follows : "Take suckling Puppies, put them in Wine, and distill it half off in Balneo ; then take the puppies out, and boil them in a sufficient quantity of Golden-Rod Water, or common Water with Golden-Rod in it ; when the Decoction is made, add the Water that was distilled off the young Dogs and boil them together till the flesh comes from the Bones. Then distill them all in Balneo. Keep the Water for use. Wet dry clothes or rags in this, and apply it to the ulcerous carcinoma. For from certain Experience it heals the sore by cleansing and drying." The liver of a tortoise "laid on the cancer and used con- tinuously" is a Cape Colony remedy in the "Kook-Koeck en Recepte Boek." Plunket, a famous "cancer curer" of the eighteenth century in England, used a paste of crow's feet, dog fennel, sulphur, and arsenic. The popularity of this paste is said to have suf- fered a severe setback when, according to report, it caused the death of Lord Bolingbroke (Henry St. John Vincent), in 1751. Arsenic, which was the base of this, as well as of many other pastes, continues to play an important role in the medical treatment of cancer. John Muir,^ M.D., District Surgeon, Sterkstroom, South Africa, gives an interesting account of the various "cures" and "curers" of South Africa. Of the herbal remedies the best known is the "cancer bush," or "kanker boschje," the Sutherlandia frutescens R. Br., order Leguminosae. An in- fusion is made of the bark and leaves, and a cupful of this is taken three times a day. As an external application, the oil which accumulates in the pipe of a dagga smoker is used by the inhabitants. In some instances cancer was claimed to have been cured in three days by this "wonderful remedy," which is still in use in South Africa. The list of non-surgical measures which have been employed in the treatment of cancer embraces hundreds of mineral, vege- table, physical, and animal products, which it would be profit- less to detail, or even to catalogue. Many of these are con- sidered in other sections. The history of the surgical treatment of cancer assumed rational proportions at a much earlier date than did the non- * " A Medico-Literary Causerie. Cancer Curers, ' ' Practitioner, April, 1899, p. 518. ^ Muir, John. — ' ' The Cancer Curer in South Africa, ' ' South Africa Medical Record, January, 1906, p. 5. 4 THE CANCER PROBLEM surgical. As far back as 2000 B.C., in the writings of ancient India, are to be found directions for the removal of cancerous growths. Kadical excision has been advocated for centuries, but it is only within comparatively recent years, or since sur- geons have come to understand the histopathology of cancer, that surgical technic has developed to such a degree of perfec- tion as to enable one to say with assurance that it is possible to effect a cure of the disease by means of surgical intervention. It has been said that more has been accomplished in the study of cancer during the past fifteen years, or since the initia- tion of modern cancer research, than during the preceding fif- teen hundred years. Such an enormous volume of literature has accumulated on the subject of the origin, development, nature, and treatment of cancer, that to give merely a chronological review of the history of the disease would fill more than one volume of this size. We must content ourselves, therefore, with a bibliography of the early history, devoting more detailed consideration to that later period which covers the era of scientific cancer research. HISTORY OF MODERN CANCER RESEARCH THE INFLUENCE UPON CANCER RESEARCH OF THE CAMPAIGN AGAINST TUBERCULOSIS The renewed activity in the investigation of cancer, which has characterized the past fifteen years, is directly traceable to the success attendant upon the organized campaign against tuberculosis. This campaign was initiated, at an international conference held in Berlin, in 1902, by the founding of the "International Anti-tuberculosis Association." Since that time eleven such conferences have been held. Inasmuch as the cause of tuberculosis was known, it was possible to proceed to the practical work, and to set in motion measures for the suppression or prevention of that disease. The movement speedily spread throughout the civilized world. Nursing homes, originally established in Belgium, were set up also in France and Germany. The rapid progress of the cam- paign is illustrated by the fact that the 18 modest hospitals for tuberculous out-patients founded in Germany in 1903, paved the way for the 819 nursing institutions existing in that coun- try in 1913. At the same time and in the same country there were 147 sanatoria, with 15,278 beds; 103 institutions with more than 9,000 beds for children threatened with tubercu- losis; 114 forest sanatoria, and 17 forest schools. In addition HISTORY 5 to all this, special tuberculosis wings — rather than sanatoria — were provided in 1913 in connection with 200 general hos- pitals. The great success of the movement against tuberculosis has nowhere been more strikingly evident than in New York City. It is not within the scope of this volume, however, to dwell upon the success of the tuberculosis movement, further than to show how it preceded the revival of interest in the cancer prob- lem, and how, in many instances, it actually determined the nature of the organization and the machinery with which a similar campaign against the latter disease was inaugurated almost simultaneously in America, England, and Germany. NEW YORK THE FIRST TO ESTABLISH A STATE INSTITUTION DEVOTED EXCLUSIVELY TO THE STUDY OF MALIGNANT DISEASE In America the inception of the movement for the study of cancer was largely due to the late Professor Roswell Park,^ who, in 1899, described its beginning as follows : "Lastly, let me invite special attention to work recently done and projected in ISTew York State. Last year, as the result of persistent efforts on the part of a number of men — ^both pro- fessional and laymen, both in and out of the legislature — the legislature of New York appropriated a small sum for the purpose of 'equipping and maintaining a laboratory' devoted to this kind of research. The money was placed at the disposal of the Medical Department of the University of Buffalo, which seems to be located in a region where cancer is more prevalent than in any other part of the United States. The laboratory was at once instituted and put into operation, the writer of this paper being made its director; and the pathological work was soon placed in charge of Dr. H. R. Gaylord. The equip- ment of the laboratory is of the very best, and the personnel of its working staff admirably adapted to the work in hand. The primary object of this institution is a determination, if possible, of the nature of the disease; secondary to that, of course, being whatever may be accomplished for its medication and cure. The heartiest cooperation of the profession has been publicly invited, and already, in many instances, obtained. The closest relation exists between the laboratory itself and the clinical opportunities which the University affords, so that by this means there may be the most careful study carried on at 1 Park, Eoswell. — ' ' A Further Inquiry into the Frequency and Nature of Cancer," The Practitioner, Vol. 62, April, 1899, p. 385. 6 THE CANCER PROBLEM the same time of the patient himself and of the specimen re- moved. The work, so far as projected, inchidcs everything that may he done in the way of clinical study of cases, espe- cially those which are under the personal observation of mem- bers of the laboratory staff, a most careful study of the patho- logical and histological elements found in every fresh specimen removed, a carefully conducted bacteriological examination, with systematic endeavor to cultivate in every known culture medium whatever living parasites may be obtained. As soon as means and space are afforded it is intended to conduct also most minute inA'estigations into physiological chemistry, in- cluding chemical and spectroscopic examinations of all the fluids, chemical analysis of secretions, etc. ... So soon, also, as the State places sufficient means at command it is intended to institute a series of examinations of whatever specimens may be sent us, just as at present in various city laboratories sus- pected sputum or exudate are examined for the determination of diphtheria, tuberculosis, etc." This laboratory at Buffalo was the first to be devoted ex- clusively to the investigation of cancer. It was definitely taken over by the State in 1901, and has since been known as the Cancer Laboratory of the l^ew York State Board of Health. Subsequently it has been housed at the Gratwick Research Lab- oratory, of the University of Buffalo. On November 1, 1913, the Research Hospital of the State Institute for the Study of Malignant Disease, was formally opened. Ewing,^ who made the address on this occasion, thus pointed out its significance — ''When a State legislature com- mits itself to clinical cancer research and devotes public funds to this purpose, it establishes important precedents." CANCER COMMISSION OF THE HARVARD UNIVERSITY The surgical department of the Harvard Medical School organized the above body of investigators in 1899. The Com- mission owes its existence to the generosity of the late Caroline Brewer Croft, and the work has been continued in the Medical School, especially in the department of surgery, by means of this gift and other sums contributed more recently to the cause of cancer research. For twelve years the work was largely restricted to the laboratory study of cancer, the investigations being conducted in the laboratories of the Harvard Medical School and at the Massachusetts General Hospital. The lab- lEwing, James. — "The Cancer Kesearch Hospital," N. Y. Med. Jour., December 27, 1913, p. 1241. HISTORY 7 oratories of the Medical School and of the different science departments of Harvard University are still utilized for the laboratory studies. Since April, 1912, however, the clinical researches have been made in the Collis P. Huntington Memor- ial Hospital, endowed by Mrs. Huntington. The aim of the hospital '4s the study of special problems with the view of adding to the knowledge of the natural history and the rational treatment of tumors, and also to be of public service in affording means for early diagnosis and in carrying out treatment or giving advice regarding therapeutic meas- ures." ''Another aspect of the work of the Huntington Hospital, of less value to the world at large, but of incalculable benefit to the individual, is the opportunity offered of supplying modern hospital care to the inoperable or recurrent cases of cancer for which other hospitals in the community have no place." The hospital provides accommodations for twenty-five in- patients. Out-patients are received at stated hours. An important part of the work of the institution involves the keeping of complete and accurate clinical and pathological records of all cases. Dr. E. E. Tyzzer, Assistant Professor of Pathology, is Di- rector of the Cancer Commission, and Dr. Thomas Ordway, Instructor in Medicine, is Physician in Charge of the Hunting- ton Hospital. CANCER RESEARCH IN GERMANY In Germany, as in the United States, the movement was inaugurated on the basis of cancer being infective. Professor von Leyden and Professor George Meyer, the interest and influ- ence of Professor Kirchner having been obtained, called a meeting, which was held at the Kultusministerium, Berlin, on February 18, 1900. It was attended by ten representative persons who constituted themselves into "Die Comite flir Krebsforschung" (The Committee for Cancer Research). Preparations already made enabled the Committee, with Gov- ernment assistance, to immediately advance, on October 15, 1900, to the taking of a census of all cases of cancer in Ger- many. This proceeding, and many other steps taken or advo- cated by this Committee, w^ere determined, as in the case of Roswell Park in America, by the belief that cancer is an infec- tive disease closely analogous to tuberculosis. At the inaugural meeting mentioned, Professor Kirchner was able to announce with the authority of the Kultus Minister — the famous Althoff — that the Government would assist, because "Since a parasitic S THE CANCER PROBLEM etiology is supposed, which view the speaker also inclined to, there is the possibility of seriously considering the prevention of this disease. Because it is the duty of the State to take its share in the suppression of avoidable diseases, there can be no doubt that the State officials will participate. The Kultus Min- ister, and the Directors of the Departments for Education and Medicine, express their lively interest in the matter. The Director Althotf is prevented from being present by official business. Geheimrat Forster, who is unfortunately prevented from being present, is willingly ready to collaborate." Tlius was inaugurated a scheme which has given rise to wide discussion and controversy, not only in Germany but prac- tically throughout the world, because the enthusiasm of this band of public-spirited men speedily attracted followers in Europe and America. The Committee issued the Zeitschrift fiir Krehsforscliung , and in other ways stimuli were ever emanating from Berlin to encourage those in other countries to imitate their example by founding committees and taking cancer censuses. The addition, in 1900-1, of a department for cancer to the Royal Institute of Experimental Therapeutics, Frankfort-on-Main, arose out of the influence which this Com- mittee exerted on the Government authorities, as did also the provision, under von Leyden, for special wards and labo- ratories for cancer in the famous Berlin hospital. The Charite. Throughout Germany there have been formed local com- mittees in the large tovms and in almost all of the federated states. There has been an organized effort to educate the pub- lic in the early s}anptoms of cancer, and a list has been issued recently of institutions which will undertake the microscopical examination of growths, as well as of dispensaries where advice may be sought. INTERNATIONAL ASSOCIATION FOR CANCER RESEARCH Out of the efforts of those who had participated in different countries, in founding societies and in their affiliation with the Berlin Committee, there grew up the International Association for Cancer Research, which has had a checkered career. It was inaugTirated with enthusiasm at Heidelberg at the opening ceremony of Czerny's Institute, in 1906, when a first Inter- national Conference was held. A second Conference was held in Paris, in 1910. This assumed the dimensions of an Inter- national Congress, attended by government plenipotentiaries from twenty-three countries; but internal dissensions, arising out of questions of organization, policy, office bearers, and the HISTORY 9 seat of the permanent secretarial bureau, were apparent. Eng- land and Norway persisted in refusing to join the Interna- tional Association, and France subsequently withdrew from membership. A third Conference, held in Brussels, in 1913, attained to nothing like the same proportions, and attracted little attention. A fourth Conference is foreshadowed in Den- mark, in 1916. From the outset the proceedings of the Cancer Committee met with criticism on the part of the many famous pathologists in Germany who did not care to associate themselves with a policy and proceedings based upon the foregone conclusion that cancer is a parasitic disease. All of them, with the exception of von Hansemann, held aloof, and there were at least two or three notable disclaimers of any share in the responsibility for the views expressed on behalf of the Committee. The taking of a cancer census (in 1902-3) also speedily met with Bash- ford's criticism. He maintained that it would fulfil no useful purpose in England, and that it should not be imitated in that country, claiming that it was unsound statistically and a need- less expenditure of money. The domestic difficulties of the German Committee natu- rally extended to the international relationships it attempted to establish. The policy originally laid down was persisted in, unfortunately, with great obstinacy. Had the views of the Committee and its proceedings been made more consonant with what is actually established, it is possible that minor difficulties of organization would have been overcome through the associa- tion of other and more numerous representative men, and that a truly representative international association would have been formed. Bashford,^ who throughout had been the chief spokesman of those opposed to the policy originally pursued by the German Cancer Committee, and to the taking of cancer censuses, plainly restated this position at Paris in 1910. The British Medical Journal," commenting editorially upon the proceedings of the second conference, said : "In Great Britain they had not a society or committee mod- eled upon the lines of those affiliated with the International Association, and Dr. Bashford explained that as he was there as the representative of the British Government at the invita- tion of the French Foreign Office, therefore he was not present as an actual member of the International Association, but ^ Bashford, E. F. — Verhandlung des Komitees fur Krehsforschung, Heft III, 1903-4, reprinted from Deut. med. Woch., 1904; First Annual Eeport Imperial Cancer Research Fund, 1903 ; Second Scientific Eeport Imperial Cancer Research Fund, Part I, 1905; etc. 'October 22, 1910, p. 1266. 10 THE CANCER PROBLEM rather as a guest of the French Association. As was well known to his fellow delegates, Great Britain had hitherto held aloof from membership of the International Association. That abstention implied no unwilling-ness to collaborate, practically, with other nations; on the contrary, it was common knowledge how materially British investigators had assisted their foreign colleagues. The abstention of Great Britain from affiliation with the International Association had no political significance whatsoever, no matter what might have been inferred to the contrary; it was based upon purely scientific grounds only. The presence of an official representative of the British Gov- ernment was due to the importance attached in all quarters, from the highest to the lowest, to the study of cancer in Eng- land, and was, on the one hand, an official recognition of the success with which it had been organized in Great Britain by a number of institutions in addition to the Imperial Cancer Besearch Fund, of which he (Dr. Bashford) had the privilege to be the Director. On the other hand, the presence of an offi- cial representative of the British Government was evidence of the interest of all in England in the proceedings of the Inter- national Association, and, in particular, in the proceedings of this Second International Conference. Although not at pres- ent a member of the International Association — a fact which he felt bound to emphasize — Dr. Bashford stated that he es- teemed it a high honour, a privilege, and a pleasure to be the guest of the French Association; in previous years he had entertained the same sentiments when he had been the guest of the German Association in Berlin and in Heidelberg. "Although in England they inclined to the belief that the present was rather a time for work — much work — in the hope of advancing knowledge of the disease of which they knew practically nothing, and could do little or nothing to prevent, rather than a time for the holding of congresses, which they thought were premature, since they had nothing revolutionary to discuss or to agree upon, still such a conference as the present might fulfil — indeed, his presence proved that he hoped it would fulfil — a useful purpose." An interesting exchange of views occurred at the closing ceremony. The President, von Czerny, made a direct appeal to Dr. Bashford to use his influence to obtain the adhesion of Great Britain to the International Association. In replying to this appeal, Dr. Bashford ^ "assured his hearers that his presence attested to the fact that in England they had no objection, in principle, to such conferences, pro- ' Editorial, Brit. Med. Jour., loc. cit., p. 1268. HISTORY 11 vided they fulfilled a useful purpose, nor had they the least objection to an international association for the study of can- cer, provided its international character was assured, and it was the outward expression of a workable, practicable scheme of collaboration. Speaking as the Director of the Imperial Cancer Research Fund, Dr. Bashford said that he need hardly remind them how substantially that institution had endeavoured to support foreign workers, great and small, and in many coun- tries, by distribution of material and other means, as well as by receiving them as guests in its laboratories. This had seemed to them international collaboration of a practical and useful kind. Addressing the more prominent German dele- gates by name, and speaking in German, Dr. Bashford assured them how highly he valued the foreign membership of the Ger- man Committee and his intercourse with its members. Having expressed the honour and the pleasure it had been to him to be again associated in Paris with his German colleagues, he con- gratulated von Czerny on the fruitful result of ideas first mooted at the opening of his Cancer Institute in Heidelberg in 1906, from which had sprung this second, larger, and suc- cessful international conference." When, if ever, the inner history of the various moves in this controversy comes to be made public, it will be found how steadfastly one man withstood the influences brought to bear, in favor of what he held — and as the course of events has shown, rightly held — was a mere scheme on paper. Even ques- tions addressed to the Prime Minister in the British House of Commons, and even a petition presented to King Edward VII. during his visit to Berlin, did not alter the conclusion come to, that the cause of the investigation of cancer would be better advanced by other methods than those advocated by the Berlin Committee. Unfortunately, the hopes which Czerny held out, that the objections would be removed, have not been realized. England and Norway still stand aloof, France has withdrawn, and the adhesion of many other countries, like Greece, Persia, Argentina, Peru, Bolivia, Turkey, and China, has little scien- tific or practical value. CANCER RESEARCH IN ENGLAND In England, during a series of years, many eminent sur- geons had repeatedly drawn attention to what they held was an alarming increase of cancer, calling for urgent investigation; but the new era in endeavors to probe the mysteries of cancer may be dated from April, 1899, when Malcolm Morris — now 12 THE CANCER PROBLEM Sir Malcobn Morris — issued a special number of The Prac- titioner,^ of which journal he was then editor. "The Editor wishes it to be clearly understood," he said in the editorial preface to this number, "that he has no idea of starting a movement for the suppression of cancer such as has been initiated with good prospect of success in regard to tuber- culosis. In the present state of our knowledge the efforts of an association for the prevention of cancer would be as purpose- less and as futile as the wanderings of Don Quixote in search of chivalrous adventure. And we should be as poorly equipped for such a campaign as the knight of La Mancha with his pasteboard helmet and his bareboned charger. The movement for the prevention of tuberculosis finds its justification in the reasonable hope there is of success, and this hope lies in the fact that the cause of the disease is positively known, and the means of counteracting its operations are in our hands. The case is altogether different as regards cancer. Its cause is still hidden, or at least too uncertain to be treated, in the practical sphere, otherwise than as an unknown quantity. Some of the best investigators have for years past been striving to wrest this secret from Nature. But life is short and the labour needed for the solution of the problem is long and arduous. If a col- lective investigation of the aetiology of cancer could be organ- ized on a sufficiently large scale, the prospect of ultimate suc- cess would be greatly increased. By 'collective investigation' is not meant the sending out broadcast of schedules of ques- tions, the answers to which are dealt with by a committee which endeavours to extract a kind of essence from the mass. Information collected in this manner may be of some value from the purely statistical point of view, but it is worthless for the elucidation of a pathological problem. What appears to be required is the formation of a band of scientific experts scattered through a number of laboratories in different parts of the world, all in touch with each other. The work should be organized as astronomical research is, each group being at once informed of any observation made elsewhere, so that it may be tested, and of any new line of research being opened, so that it may be followed up. There is too much individualism in scientific work, and the result is not only waste of power, but actual loss of knowledge, which is allowed to die with its dis- coverer because he could not get a hearing for it, or because it failed to find favour in the eyes of some superior person. With a proper organization of research on definite lines by a number of investigators working together to a definite end, there would ' The Practitioner, April, 1899, Vol. LXII, p. 362. HISTORY 18 be little or no leakage, and success would be merely a matter of time." Conspicuous examples of cancer research organizations in England are found in the Cancer Department of the Middle- sex Hospital, which combines the clinical with the laboratory investigation, and the Imperial Cancer Research Fund, which confines its work to the laboratory and statistical study of the disease. Because these institutions represent distinct types they are discussed somewhat more at length than are other research organizations. CANCER RESEARCH LABORATORIES, MIDDLESEX HOSPITAL Independently of the movement thus initiated by Sir Mal- colm Morris, steps were being taken to have the Cancer Wards of the Middlesex Hospital associated with a special investiga- tion department. From 1792 up to the present day, the Cancer Department of the Middlesex Hospital, London, has remained a distinctive feature of the establishment, affording not only a refuge for a vast number of those suffering from cancer, but also oppor- tunity for investigation and for the testing of alleged remedies. The objects of the donor, Mr. Whitbread, were therefore two- fold — the relief of suffering and the investigation of the dis- ease. Mr. Howard, who acted as intermediary for the bene- factor, expressed himself as regards the second object as follows.^ "With regard to the second object, namely, the investigation of the disease, Lord Bacon has observed that medical men should make themselves proficients in physic by studying one disease at a time. It is an opinion worthy of so great a man; it was particularly adopted by the late Mr. Pott, and by him recommended to all students in surgery. "By confining one or more wards to cancer only, the attention of pupils and others will be directed very strictly to the study of this disease. They will see facts as they arise in the aggre- gate from a large number of patients ; new lights will appear, and new discoveries will probably be made. " 'I have often thought,' says Dr. Sydenham, 'that if I knew accurately the natural history of any disease, I should never be at a loss for a proper method of treating it' ; and the wonderful 'Coupland, Sidney. — "The Cancer Charity of the Middlesex Hospital, 1792-1902." Eeports from the Cancer Eesearch Laboratories of the Mid- dlesex Hospital, Vol. I, London, 1902, p. 1. 14 THE CANCER PROBLEM improvements he made in science bj his great attention to the natural history of diseases, and the effects of medicine upon them, have been justly admired by practitioners of every coun- try. {Vide the Preface to Dr. Sydenham's "Observations on the History and Cure of Acute Diseases.") "The. natural history of caucers, although a common disease in the enlarged comprehensive sense in which this great man understood the natural history of diseases, is but little known, I would therefore, in order to improve a subject on which a successful practice greatly depends, propose that a faithful account of the history and circumstances of every case be kept : its antecedents and consequences should be marked, the effects of medicine and of operations, when necessary, noted, together with all the collateral helps to be gained by an inquiry into constitutional habits and diseases not strictly cancerous, but probably connected with it. This examination may be made by a medical gentleman of the hospital with the patient before him, his notes to be corrected by himself, and kept as a record of the history and circumstances of each case, to be recurred to, as an authority, by any intelligent or scientific person. A copy of these notes may be kept, fairly written, for general inspec- tion ; and if anything extraordinary or worthy of more particu- lar notice arise from these sources, let the circumstances be pub- lished to the world at large. "By an institution comprehending the two objects now pointed out, I have a hope not only that the diseased, but that practitioners in general may be benefited, that much useful knowledge may be disseminated, and that we may, in no gi'eat length of time, be furnished with documents on the disease and cure much more authentic than any we are at this time in pos- session of. It is a very important subject of inquiry, equally interesting to the rich and independent part of mankind as to the poor ; and if such an institution be fairly set on foot, it can- not fail of producing beneficial consequences to all descriptions of persons labouring under this dreadful malady." Since the foundation of the Cancer Ward, in 1792, various extensions and improvements have been undertaken, and in 1896 a more ambitious nature was given to the establishment when plans for a new cancer wing were approved. The new cancer wing was approaching completion in February, 1899, and, not unmindful of the wishes of the original founder, at a meeting of the Weekly Board, on February 7, 1899, "the Chairman having made a statement, as a preliminar}^, in view of the opening of the New Wing for Female Cancer Patients, and more particularly in regard to its medical supervision for HISTORY 15 carrying out the wishes of the original founders of the Cancer Wards, it was, after some discussion, moved by Sir Arthur Watson, seconded by the Hon. Spencer Lyttleton, and resolved unanimously : "That the Weekly Board of Governors are of opinion that, in the arrangements to be made for the medical supervision of the new Female Cancer Wards, endeavours should be made to give effect to the wishes of the original founders, which are expressed in the conditions submitted by the late Samuel Whit- bread, Esq., in 1791, in the following terms, viz.: 'The relief of persons affected with Cancer, and the investigation of a com- plaint which, though extremely common, is, both with regard to its natural history and cure, but imperfectly known' ; and likewise laid down in the will of the late Mrs. Alithea Maria Stafford, as follows, viz. : 'Curing persons affected with Can- cer, and of investigating and promoting our general knowledge of treating that dreadful disorder.' And the Board would be glad if the Medical Committee would consider how this could best be done. The enhanced facilities for pathological and bac- teriological study in the Hospital is, they consider, an addi- tional reason why some practical steps should be taken in this direction. "In establishing the Cancer Research Laboratories the Gov- ernors of The Middlesex Hospital have not only been faithful to the trust confided to them, but they have set an example to others similarly engaged in the warfare against disease. They have perceived that the only sure foundation upon which suc- cessful treatment can be based is that of knowledge of the na- ture and causes of diseases. In such investigations as can alone be carried on into the difficult and complex problems of cancerous affections, it may be long before any decided practi- cal result can be attained. But the labour will not be thrown away. Every additional fact, however small, will contribute to the better understanding of the conditions under which such diseases arise and the manner in which they spread. That in due time such knowledge will be the means of directing us where to look for the means of checking and preventing cancer there can be little doubt. Such a consummation will, however, only be attained by the exercise of unwearied patience and assiduity by those engaged in the task." ^ At a later date Dr. Lazarus-Barlow became Director of The Middlesex Hospital Cancer Investigation Department, which, in 1909, underwent an important extension and reorganization in consequence of the Barnato Bequest. The investigations ' Coupland, loc. cit., p. 34. 16 THE CANCER PROBLEM imder Dr. Lazarus-Barlow's leadership have become closely identified with the stiid_y of radium as a possible constituent of tumors as well as a therapeutic agent. IMPERIAL CANCER RESEARCH FUND In the First Report from the Cancer Research Laboratories of The Middlesex Hospital, Dr. Sidney Coupland gives an in- teresting and valuable summary of what had been done up to 1902, with a succinct statement of the object of the work. This summary ends as follows:^ "Finally, the present year (1902) has seen the formation in this country [England], under the auspices of the Royal College of Physicians of Lon- .d^}* Ct _/ ^ %-•• ">»--• y^ -^^^o^ ^ ^ / ^^■-« Lii^e ^a// Bk >ddi ^r .^ y — -— ^ // lies tine ^.- ,..-v ^ • ^ r ""r. 'ectL //77 USiA-. __Pl ^3r^ , — "-- 'Ski n '"■ ^ ^M.« Fig. 3. — Analysis of cancer for women. Shows absence of increase for skin, uterus, ovary, liver, and gall-bladder, and increase for breast, stomach, intestines, rectum. (After Registrar-General for England.) cancer for each single site separately for a period of ten years. In this way the enigma of the increase in the number of deaths recorded from cancer in general has been once and for all re- solved into simpler problems for each part of the body. The STATISTICAL CONSIDERATIONS 85 table given on page 73 shows how baffling was the increase of cancer in general as contrasted with the simplicity of the problem presented by the two accompanying curves (Figs. 3 and 4) for separate parts of the body. The results have been summarized as follows : ^ 195 00 o _ r^ o o O 0) 0) 0) ^ «0 • ^ ^ X y / Sto nac h ^ .^ Z/i ^er t iGa, 1 Bk idde r ^♦" • •• * •« .»••*' • • ,4^ ^•^ ^ ••"/ led um _ , - .^ — .— ''' -'^•- 1^ $un' s-s ^ T< ^ngrc re « Sk/r Fig. 4. — ^Analysis of the increase of cancer for men. Shows absence of increase for skin, Uver and gall-bladder and increase for tongue, stomach, rectum, intestines. (After Registrar-General for England.) "^For several reasons it has long been desired^ that the reports of the Registrar-General should contain detailed in- formation on the incidence of cancer in different parts of the 1 Introduction, Fourth Scientific Eeport of the Imperial Cancer Research Fund, 1911. ' The first serious attempt to attain this end was made by the late Sir Henry T. Butlin : ' ' Proposed letter to the Registrar-General for Eng- land of Births, Deaths and Marriages on the subject of the increase of Cancer, drawn up by Mr. Butlin, of which the following is a copy, ' ' Pro- ceedings of Council, Brit. Med. Jour., November 12, 1887, p. 1070; King, George, and Newsholme, Arthur, "On the Alleged Increase of Cancer," \oc. cit. 86 THE CANCER PROBLEM body, and Dr. Tatham was able to make arrangements for ob- taining this information at the outset of these investigations. The application of the law of age-incidence of cancer to short- lived as well as to long-lived animals, reinforced the other rea- sons for obtaining it, and suggested that knowledge would be advanced by more detailed information about the age-incidence of cancer in the several organs of man as distinct from its de- pendence on the age-distribution of persons.^ It was antici- pated that the data would be of both biological and statistical value, and the facts published by Dr. Stevenson in the last report of the Registrar-General show that this hope has been fulfilled in several directions. ''The new tabulation of the data for the years 1901-09, for England and Wales has permitted an analysis being made of the figures recording the increase of deaths attributed to cancer, which brings out the fact that the increase during this period is i-eferable to certain anatomical regions and not to others. Thus, for males the main increase falls on the alimentary tract, especially the stomach. The liver and gall-bladder and the skin show no, or only a slight, increase. For females the increase, although it falls mainly on the alimentary tract (stomach and intestines), affects also the mamma, while the uterus, ovary, liver and gall-bladder, rectum and skin show little or no increase. It is also of importance that the recorded mortality from cancer of the generative organs has not in- creased at the same rate as that for other organs, and that most of the increases affect the higher age-periods predominantly. "For the first time it is fully demonstrated that it is errone- ous to make statements of a disquieting nature about the in- crease of cancer in general. In conjunction with investiga- tions^ into the errors of diagnosis among hospital patients, means are afforded of determining, for parts of the body where the disease appears to be increasing, whether the increase is real or only apparent, and of ascertaining the causal factors peculiar to such parts. While it is evident that several of the differences brought out by the figures can be explained by more accurate diagnosis and by allocation of the seat of the disease from the secondary to the primary situations, as illustrated, 1 Bashford, E. F., and Murray, J. A.: "The Statistical Investigation of Cancer, ' ' Second Scientific Report of the Imperial Cancer Eeseareh Fund, Part I, pp. 3, 24, and 51. ' Comparison of the clinical diagnosis with the results of pathological and microscopical examination. See Second Scientific Report of the Imperial Cancer Research Fund, Part I, pp. 18-24; Bashford, E. F. : Address on Cancer in Man and Animals. General Meeting of the XVIth International Medical Congress, Budapest, 1909, and in The Lancet, September 4, 1909, p. 694; Berl. Jslin. Woch., 1909, Nos. 36 and 37. STATISTICAL CONSIDERATIONS 87 e. g., by the relation revealed between cancer of the liver and gall-bladder and the alimentary tract, this may not account fully for certain other features. In particular, the increased incidence of cancer recorded for the mamma in women, and the tongue in men, requires further study and elucidation. "The analysis also shows that the incidence is very unequally distributed among the several situations, indeed, that the whole curve of incidence may be different for different organs. A progressive increase up to the highest age-periods is character- istic of the face, lip, mouth, bladder, urethra, and breast only. The other organs show a distinct diminution in the highest age-periods ; but it is not yet possible to determine whether this curve indicates a liability rising to a maximum and followed by a fall, or is merely the result of ascribing deaths to other causes in the case of cancer of internal organs in aged people. The proportion of total deaths ascribed to the ill-defined cause of old age is 65.6 per 1,000 deaths from all causes as com- pared with 65.7 for cancer, and it must be borne in mind that the increases recorded for cancer affect principally the higher age-periods, and that the average age of the population is in- creasing [see below]. Sufficient has been said to indicate how important are the problems which are solved or revealed by the improvement in the details given in the national statistics. "The study of the occurrence of cancer in mankind, and in domesticated animals in widely separated parts of the globe, has shown that the practice of peculiar customs (involving the ap- plication of chronic irritants to particular parts of the body) provokes the disease in situations and organs from which it is absent when these customs do not obtain. It is reasonable to suppose that the frequency of cancer would be diminished if such practices as the use of the Kangri in Kashmir, chewing betel-nut in India, and eating very hot rice in China, were dis- continued. It is also reasonable to assume that the introduc- tion into England of these exotic customs would greatly in- crease the frequency of cancer in this country." If the numbers living in 1881 at each quinquennial age- period be reckoned as percentages of those living at the same age-periods in 1911, see pages 88 and 89, obtained from the Census of England and Wales in 1911,^ show that the proportion of the population in the cancer-ages was much smaller thirty years ago at all age periods except one. This phenomenon of itself will account for an increase in the abso- 1 Census of England and Wales, 1911, Vol. VII. Ages and Condition as to Marriage. London, 1913. 88 THE CANCER PROBLEM lute number of deaths, although not for the apparent relative increase. {Fig' 5.) Ratio of the Proportional Number Enumerated at Each Age-period in 1881 to the Corresponding Number in 1911 Taken as 100. Agea 1881 1911 Ages 1881 1911 Under 5 years 127 118 111 106 102 92 84 82 87 100 100 100 100 100 100 100 100 100 45 and under 50 years . . . 50 and under 55 years . . . 55 and under 60 years . . . 60 and under 65 years . . . 65 and under 70 years . . . 70 and under 75 years . . . 75 and under 80 years . . . 80 and under 85 years . . . 85 and upwards 83 89 88 99 86 88 91 92 83 100 5 and under 10 years . . . 10 and under 15 years . . . 15 and under 20 years . . . 20 and under 25 years . . . 25 and under 30 years . . . 30 and under 35 years . . . 35 and under 40 years . . . 40 and under 45 years . . . 100 100 100 100 100 100 100 100 In the most recent Report of the Registrar-General for Eng- land and Wales, that for 1911, published in 1913, the stand- point taken is siunmarized as follows : "While the figures for a single year would be far too small a basis for forming a definite conclusion on this matter, and there is evidence pointing to a real increase of cancer of certain parts of the body (Report for 1909, p. XCIII), the figures for 1911 seem to harmonize sufficiently well with the hypothesis that recorded differences in mortality depend upon varying degrees of accuracy in diagnosis to make it worth while to watch those of subsequent years from the same point of view. If these latter point in the same direction, then we must ask ourselves whether England and Wales in 1911 do not compare with England and Wales in 1881 more or less as London in 1911 does with the rural districts in 1911. The peculiar history of the increase of cancer mortality in regard to age and sex would then be explained. The records show continuous in- crease at all ages for males, whereas in females the increase at ages 35-45 ceased about 20 years ago, and more recently that at 45-55. At the latter age-periods the increase still con- tinues at rates which increase in rapidity with increase of age. The male increase at all ages would be explained by the fact that, taking the country as a whole, there is still considerable room for improvement in diagnosis at every age in males. The cessation of increase in middle-aged women is explained if we assume that cancer, being better diagnosed in the female sex and at the earlier ages, is now seldom over- looked in middle-aged females, although it formerly was so, the frequency of occurrence being assumed constant. Probably there is little doubt that cancer is more easily diagnosed, because STATISTICAL CONSIDERATIONS 89 more accessible, in females, but the assumption that it is more frequently overlooked in old than in middle age is more open to qviestion. ... It seems natural, however, that in the case of persons M^hose age alone suffices to explain failure of their vital 35 4-0 45 50 55 eo e5> TO 75 SO 85 lUU ■ / S70 / y" \ .0 +^ 85 \ / \ / / \ / \ Fig. 5. — This chart indicates diagrammatically the increase in the age of the population of England and Wales. The year 1911 is here taken as standard for each age-period and is reckoned as 100 living for each age- period. The fluctuating line indicates how many were Uving in pro- portion thirty years earlier. povrers the search into the cause of obscure illness should at times be less rigorous than is felt to be demanded vrhen a per- son of middle age is concerned, whose span of life is clearly cut short by definite illness of some kind." It would thus seem that the long debate as to the meaning 90 THE CANCER PROBLEM of the increase in the number of deaths recorded from cancer was to end by admitting the possibility of increase for some parts of the body, and in pointing very definitely to the lines ■along which statistical research may be pursued with profit. This result has been attained, not by compiling special sta- tistics of cancer by means of a "cancer-census," but by improv- ing national mortality statistics as a whole, and especially by considering those of cancer as an important part of all, as ad- vocated and successfully carried through in England largely at the instigation of Bashford, and as the result of his argu- ments, based upon the comparative study of cancer in mankind and animals, and upon experimental investigations. CANCER MORTALITY ACCORDING TO LOCALITY The relative frequency of cancer in town and country calls for brief reference. Everywhere the diagnosis and treatment of disease and certification of causes of death, are backward in the country as compared with the towns. It is therefore not surprising that cancer is more frequently recorded in towns than in the country. That this may be largely the explanation is supported by the fact that it cannot be shown that over- crowding in the towns has any influence upon the death-rate from cancer. In all such questions of relative frequency in one area, as contrasted with another, the question of the relative proportions of each sex and the numbers of each living at the several age-groups is important. This fact was brought out some years ago by King and Newsholme ^ in a striking com- parison between England and Ireland. The importance of the correction of cancer mortality for varying age-distribution of populations is particularly great when comparisons are made between different countries, or even between the different coun- ties of England. Comparison of Corrected and Uncorrected Death-rates Period Not Corrected Corrected England Ireland England Ireland 1860-66 498 597 719 902 1,091 553 627 680 807 894 825 747 911 1,152 1,393 614 1867-73 661 1874-80 699 1881-87 824 1888-90 912 ^ King and Newsholme. — ' ' On the Alleged Increase of Cancer, ' ' loc. cit. STATISTICAL CONSIDERATIONS 91 It will be observed that, by the uncorrected figures, Ireland stands a little above England for the first two periods, and a little below it for the other three, but that no very great dif- ference appears between the rates for the two countries. The corrected figiires, however, show that Ireland stands below Eng- land throughout, so that in the first two periods the position of the countries is reversed by the correction, and in the last three periods the difference in favor of Ireland is very great indeed. It is evident that the ordinary method of presenting statistics exaggerates the rate of cancer in Ireland as compared with England, a result which might have been expected, owing to the age-distribution of the populations of the two coun- tries. The fallacy here revealed when age alone is concerned — sex being left out of account — probably also invalidates all the statements that have been made as to the relative frequency of cancer in different states in America, and in different races, whether Indian, black or white, or of Teutonic, English, or Latin descent, more especially because persons are considered and no allowance is made for the relative proportions of the two sexes at the several age-groups. This criticism applies especially to the map (Fig. 2, page 76) which McConnell has constructed for America. This map is quite valueless be- cause it is based upon a stateraent of the deaths in different state groups per 1,000 deaths from all knov\m causes, which is well known to be a fallacious method. An epidemic of measles among children, for example, would upset the whole calculation by lowering the death-rate from cancer. Hoffman ^ has recently published figures which he claims show the liability of the negro and white populations in the South, and a change in the liability of the negro population. These figures are not considered here in detail because the Census Bureau points out in the "Physicians' Pocket Refer- ence" that the South has hitherto been entirely unrepresented by reliable state registration. RELATION OF STATISTICS TO ETIOLOGY It is well recognized that statistics should not be expected to prove the cause of any disease. They have often given im- portant indications of the line of advance ; they have likewise exploded fallacious views of etiology. * Hoffman, Frederick L. — ' * The Menace of Cancer, ' ' Am. Jour, of Ob- stetrics and Bis. of Women and Children, 1913, 68, p. 88; Trans. Am. Gyn. Soc, 1913. 92 THE CANCER PROBLEM The late Doctor Roswell Park,^ iu an address before the In- ternational Surgical Congress, Brussels, 1908, summarized as follows his position with reference to the infectivity and treat- ment of the disease : * 'Holding to these views, cancer must be treated much as we would treat a filth disease, especially when it has advanced to the ulcerative stage, namely by the most efficient cleanliness. Cremation should supersede earth burial, and all soiled dress- ings and discharges should be destroyed by fire, while rooms and even houses inhabited by cancer patients should be most thoroughly disinfected, both during illness and after death." These statements did not meet with any response from the Congress, but their echo has reached the American public, and such views have been widely spread among the ignorant, leading them to demand that all furniture, bedding, etc., be burned. A moment's reflection on what statistics have proved for the infective diseases, or, to use the exact term, ''filth diseases" — if typhus fever be taken as the filth disease par excellence — shows that sanitation has effected their marked reduction, and in the case of the typical filth disease, typhus fever, its ex- tinction, except where filth still obtains. This diminution in the infective or filth diseases has not been shared by cancer. It follows, therefore, that cancer conforms to other laws than those governing the occurrence and spread of filth diseases in the community. It should not be inferred, of course, that disinfection should not be practised for the sake of cleanliness, and for the pur- pose of allaying the fears of the timid; but only that those forms of disinfection which are efficacious for dangerous in- fective diseases, such as smallpox, should suffice to overcome any reasonable or unreasonable anxiety. Statistics dispose in yet another way of alarming statements such as the one quoted from Park. The enormously over- crowded and filthy conditions obtaining in parts of New York and London might be expected, in accordance with this view, to be hotbeds for breeding cancer, but there is no evidence of this being the case. Unfortunately there are no actual statistics which can be quoted for New York, but extremely valuable sta- tistics are available for the different parts of London. The highest cancer death-rate occurs, not in the slums of White- chapel, but in Hampstead, the highest lying suburb in London and the wealthiest residential section of the city, consisting of *Park, Roswell. — "The Nature of the Cancerous Process," 11 Congres de la Societe Internationale de Chirurgie, Brussels, Sept. 21-25, 1908, Vol. II, pp. 321 and 338. STATISTICAL CONSIDERATIONS 93 large villa residences in private grounds. There is no support found here for the view that the overcrowded tenement is more cancer-ridden than the mansion. The statistics directly refute any relation between overcrowding-filth and a higher incidence of cancer. Again, New York must be passed over, for there are no available figures. In Vienna,^ Stuttgart,^ and London ^ the relation between cancer and overcrowding has been care- fully investigated, and for all three it could not be shown that overcrowding had any effect — indeed, in London there was more cancer in the least densely populated areas. In view of such facts as the above the public has a right to demand that they shall not be made unduly anxious by wild and exaggerated statements, and in this demand they are sup- ported by the effects resulting from alarming prophecies like the following, also made by Roswell Park, in 1899 : ^ "If for the next ten years the relative death-rates are main- tained we shall find that ten years from now, viz., 1909, there will be more deaths in New York State from cancer than from consumption, smallpox, and typhoid fever combined." Apart from the fact that this way of putting the data is not permissible in connection with accurate statistics, the subse- quent course of events has not confirmed this prediction for New York State,^ and it is hoped that in future prophecy will be abandoned as a weapon in scientific controversy, and that the public will consider the impartial tribunal of statistics to be more reliable than exaggerated assertions. Another aspect of this same subject is raised by statements concerning "cancer houses," the occurrence of cancer in hus- band and wife — so called cancer-d-deux — and the risk of in- 1 Rosenf eld, Siegfried. — ' ' Kritik bisheriger Krebsstatistiken Mit vor- schlagen fiir ein zukiinftige Oesterreichische Krebsstatistik, " Wien and Lpz., Vienna, 1911. 2 Weinberg and Gastpar. — ' ' Die bosartigen Neubildungen in Stuttgart 1873-1902," Zeitsch. f. Krebsforschung, Bd. IV, 1906, p. 18. 3 Annual Report of the Public Health Committee of the London County Council, 1908. 4 Park, Roswell. — ' ' A Further Inquiry into the Frequency and Nature of Cancer," The Practitioner, 1899, Vol. LXII, N. S. IX, p. 385. 5 The total deaths in New York State from pulmonary tuberculosis (consumption), smallpox, typhoid fever, and cancer, for 1899 and 1909 (as given in the 13th Annual Report of the State Dept. of Health, 1909, Vol. I, pp. 177-178) are as follows: 1899. 1909. Pulmonary tuberculosis 13,412 13,996 Smallpox 21 4 Typhoid fever 1,604 1,315 Total 15,037 15,315 Cancer 4,533 7,060 Difference 10,504 8,255 yt THE CANCER PROBLEM fectiug the unborn babe because the grandmother is dying of cancer. The writer has failed to find any reliable statistician who supports the risk of infection in these ways. This is not surprising, in view of the fact that the large figures available for populations are now forsaken for the small figures of indi- vidual experience. The fallacies of small figures are notorious, and the risk of their creeping in is enhanced, in the case of cancer, bv the fact that ultimately it kills 1 in 7 women and 1 in 11 men above the age of 35. With so high an average fre- quency in the general population, in accordance with the law of probabilities, accidental exaggerations of cancer statistics are to be expected. This chance will be enhanced whenever the circumstances are such that many persons in a given locality attain the cancer-age or to old age, as in the case of occupants of old family mansions, of agricultural districts, or districts selected for habitation by those retiring from business. To have any significance they would have to occur with great frequency instead of the great rarity with which they are actually recorded. As regards contact — even less remote than that of a grand- mother with her unborn gTandchild — the figures for density of population deprive it of all significance, as indeed also do the negative results of experiments directly conducted with this possibility in view. That real accumulations of cancer do occur is not denied; it is only stated that reliable evidence — reliable from a statistical point of view — of contact being responsible does not exist. Even the actual handling of cancer, as prac- tised daily by the surgeon and the hospital nurse, has been found to have no risks for either. Nevertheless, should a sur- geon accidentally receive an injury at an operation, the obser- vation is not infrequently at once offered, "1 hope it was not a case of cancer," as happened to the author on his being at- tacked by blood-poisoning through a prick received while operating for appendicitis. All these evidences of alarm on the part of the public are directly traceable to rash or careless statements, apparently with a statistical foundation, that cancer is a pestilential dis- ease, or that it has been proved to be infective. This idea is carried much further by la^onen, with some of whom the notion is deeply rooted that cancer is allied to syphilis. The belief even obtains that cancer never develops without being preceded by syphilis. Anyone may call to mind noble individuals on whom no such suspicion could rest, and the occurrence of cancer in animals, among whom syphilis is unknowm, demonstrates its absurdity. Nevertheless, an in- STATISTICAL CONSIDERATIONS 95 stance may be cited in which a happy family, in one of whose members cancer appeared, was inflicted with the unnecessary additional misery caused by the assertion of a college-trained girl to the effect that in all cases of cancer, syphilis must have preceded its appearance. The effect of such indirect imputa- tions of immorality is disastrous. They are directly traceable to persons handling figures whose statistical significance or worth- lessness they are unable to appreciate. Especially is this effect seen in the desire to falsify death certificates of promi- nent or rich people, in order to conceal the fact that cancer was the cause of death. Under pressure from the relatives many deaths from cancer are doubtless returned as from some other cause. Even among the poor, especially in America, cancer is considered as loathsome a disease as leprosy, and the dread of having the truth disclosed often leads to the refusal, by rich and poor alike, of autopsy. Thus the alarm of the public, arising from statements claiming to have a statistical basis, but in fact having no such foundation, contributes largely, in its turn, to the invalidation of statistics. A final illustration of another popular fallacy, kept alive by figures quoted by dietetic enthusiasts, may be referred to in this connection, namely, that Jews, particularly orthodox Jews, never suffer from cancer. The statement is supposed to have a statistical basis, but in reality has none at all, such statistics as are available proving exactly the opposite. The idea origi- nated, no doubt, in the biblical classification of the pig as an unclean animal; indeed, those who declare the exemption of Jews from cancer generally direct attention to the consumption of pork by Christians. There are more Jews in ISTew York than there are in all Germany, but there are no statistics avail- able which would show their relative liability. For Berlin the deaths are classified according to religious confession, but un- fortunately no statement is made as to the relative frequency of causes of death in the separate confessions. The author, how- ever, has had the opportunity of operating for cancer upon many Jews. In one instance the patient, who had sarcoma, was the young daughter of a Rabbi, regarding whose orthodoxy there could be no question. This case attracted considerable attention, showing how widely spread is the belief that Jews are exempt. Theilhaber ^ has published figures from his clinic in Munich 1 Theilhaber, F. — ' ' Zur Lehre von dem Zusammenhang der Sozialen Stellung und der Rasse mit der Entstehung der Uteruscarcinome, ' ' Zeitsch. f. Krebsforschung, Bd. VIII, 1909, p. 466. Q6 THE CANCER PROBLEM recording some cases in Jews. Sir Frederic Eve * has pro- vided figures of the operations for cancer on Jews in the T^on- don Hospital, where provisions are made for orthodox and unorthodox Jews, there being actually a "Kosher" kitchen in that institution. Finally the attempt has been made to show that cancer is less frequent in Jews than in Christians in Amsterdam; but the figures, while demonstrating that cancer is by no means uncommon among the Jews of that city, are too small to permit of a comparison, nor has any attempt been made to separate the orthodox from the unorthodox, by which means alone the effect of diet and alcohol could be determined by the comparison of these cases with those of Christians. The following tables, compiled by the author from the records of the London Hospital in the summer of 1913, is interesting in this connection. Unfortunately the ages of the patients had not been obtained, and it is impossible to say to what ex- tent this factor modifies the relative frequency of cancer in Jews and Gentiles in this hospital. Hereditary influence is another problem that statistics have been called upon to solve. Every surgeon knows of cases in which, after operating on the mother, a lapse of years has found him performing the same service for the daughter, or for some other near relative. Many would be satisfied with these facts as evidence of the influence of heredity. This conclusion by no means necessarily follows. Percentages of Carcinoma Cases Admitted to London Hospital in the Year 1911. Males: Total admission 5,658 Gentiles 5,444 Jews 214 Among the 5,444 Gentiles there were 278 carcinoma cases, or 5.1 per cent. Among the 214 Jews there were 7 cases of carcinoma, or 3.3 per cent. Females: Total admission 3,681 Gentiles 3,408 Jews 173 Among the 3,408 Gentiles there were 212 carcinoma cases, or 6.2 per cent. Among the 173 Jews there were 11 cases of carcinoma, or 6.4 per cent. Females Admitted under Gynecological Department: Total admission 803 Gentiles 699 Jews 104 Among the 699 Gentiles there were 60 cases of carcinoma, or 8.6 per cent. Among the 104 Jews there were 3 cases of carcinoma, or 2.9 per cent. * Eve, Sir Frederic. — Personal communication. STATISTICAL CONSIDERATIONS 97 Detail Report of Total Number of Carcinoma Cases, Together with Columns Showing Number of Jews in Each Group. Gentiles Jewb Site Malea Females Males Femalea A = Abdominal. Appendix 30 4 5 39 31 5 1 28 6 8 19 21 3 Colon 1 Pancreas , 1 1 Peritoneum Rectum and Anus 2 Stomach 4 Various 1 Total 114 86 6 4 Total males, Jews and Gentiles . Total Females, Jews and G 'tiles 120 90 fi = Geni to-urinary System. Bladder and Kidney Penis, Prostate, Scrotum, and Testicle 16 21 9 1 Ovary, Uterus, and Vagina . . 8 Total 37 17 1 C = Upper Alimentary Tract. Lip 19 18 28 34 10 1 1 2 4 1 Mouth and Cheek Tongue (Esophagus 1 Various Total 109 8 1 1 Z) = Breast. Breast 1 90 5 £= Various. Various 17 11 Totals. A 114 37 109 1 17 86 17 8 90 11 6 1 4 B 1 C 1 D 5 E 278 212 7 11 All the difficulties raised by the great average frequency, when using associated cases as evidence of infection, arise here again even in an enhanced degree. Pedigrees constructed 98 THE CANCER PROBLEM for many generations awake mistrust, owing to the greater uncertainty of the canse of death as given one hundred, or even fifty, years ago, and because it is not granted to us personally to observe completely more than one generation of the human race. Hence directly contradictory views have been held in the l)ast by equally competent authorities. Sir James Paget ^ believed that heredity was responsible in as many as 26 out of 160 cases, or one-sixth, and was ''disposed to hold that it is not possible to conceive the origin of cancer, or of any disease of 31 months over 2"4 Fig. 6. — Percentage of deaths from mammary carcinoma to deaths from all causes at successive 3-monthly age-periods in female mice of recently cancerous ancestry (mother, grandmothers) , compared with the same ratio in female mice having more remote cancerous ancestry (mother and grandmothers non-cancerous) . the kind, except by inheritance." ^ Roger Williams ^ and Sir Henry Butlin ^ have more recently claimed importance for it, but equally recently Bashford ^ and Weinberg ^ have given 1 Paget, Sir James. — ' ' Lectures on Clinical Pathology, ' ' Vol. II, London, loOO. 2 Quoted by Harrison Cripps. — ' ' Cancer of the Eectum, ' ' London, 1880. ^Williams, Roger.— "The Natural History of Cancer," N. Y., 1908. * Butlin, Sir Henry T. — ' ' Discussion on the Influence of Heredity on Disease," Proc. Roy. Soe. of Med., London, November, 1908, Vol. 2, R.S.M., p. 75. = Bashford, E. F.— "Heredity and Cancer," Proc. Roy. Soc. of Med., London, November, 1908, Vol. 2, R.S.M., p. 63. 'Weinberg, W. and Gastpar. — Bosartige Neubildungen in Stuttgart," Zeitsch. f. Krebsforschung, Bd. II, 1904, p. 195. STATISTICAL CONSIDERATIONS 99 elaborate figuros from which they were unable to deduce proof of its influence for the human subject. These statistical difficulties led to a resort to experiment, and finally experiments, interpreted by the aid of statistics, have demonstrated, in the case of mice, that an hereditary in- fluence does obtain. Hence the lengthy disputations on this subject may be passed over. Mice of Recent Cancerous /incestry. . - « Remote - » » . .(Mother and both grandmothers non -cancerous^ 24 Months. J8-I-09 to /7/0-/2 (inc/uslye). Lilies at risk at ages more than six months, c/uring /5 censUs-u/eeks chosen at interya/s of t/iree months, in the period under reviei^. Fig. 7.— Curves showing the death-rate from cancer. Stated in this way the figures correspond to human mortality statistics. There is still a higher incidence in mice of cancerous ancestry. (After Murray, Proc. of International Medical Congress, London, 1913.) For some years experiments on inbreeding cancerous mice led to negative results, but ultimately Murray ^ was able to ob- tain positive findings, and to confirm these by prolonging the experiments over many years. Murray's findings are briefly set forth in the following tables, for which also the accompany- ing curves (Figs. 6 and 7) have been constructed, one of them giving the latest results. ^ Murray, J. H. — ' ' Cancerous Ancestry and the Incidence of Cancer in Mice, ' ' Fourth Scientific Report of the Imperial Cancer Research Fimd, London, 1911, p. 114. 100 THE CANCER PROBLEM Table I. (24th October, 1910). Female Mice of recent cancerous Ancestry. (Mother,, one or both grandmothers, or all three cancerous.) 0-3 -0 -9 -12 -15 -18 -21 -24 Over 24 To- tal No tumour. Living 9 49 7 48 1 7 6 39 2 15 8 28 2 18 7 22 1 10 4 20 "5 6 18 1 3 47 Dead 224 Tumour Mice» Organs other than manuna 7 Mamma 4 6^ Total 62 63 62 56 40 29 28 340 Per cent 6.5 11.1 24.2 32.1 25.0 17.2 10.7 18 ? Table II. (24th October, 1910). Female Mice of remote (No cancer in mother or grandmothers.] cancerous Ancestry^ 0-3 -6 -9 -12 -15 -18 -21 -24 Over 24 To- tal No tumour. Living 7 30 '37' 1 24 2 28 9 19 1 5 17 1 3 15 6 2 2 3<» Dead 161 Tumour Mice. Organs other than mamma 4 Mamma 1 4 1 8 19 Total 38 41 26 38 29 26 25 223 Per cent 2.6 9.8 3.8 21.6 0.0 11.5 8.0 8 6 ■" These breeding experiments show distinctly that in the case of mice the occurrence of cancer of the mamma in the mother or grandmothers increases the frequency of cancer of that organ by ahnost 10 to 15 per cent, at certain age-periods, espe- cially the earlier age-periods. Equally accurate knowledge is not obtainable for the human subject owing to the greater length of life and the impracticability of always obtaining an autopsy and a histological examination. In the light of the results of these experiments the question arises as to the im- portance attaching to those rare family histories with an ex- ceptionally high incidence of cancer. Family histories like the following are certainly very remarkable : ^'A man, one of a family of nine, died of cancer of the liver, the others being all alive and well. The patient's mother was one of a family of thirteen, seven of whom (four males and three females) STATISTICAL CONSIDERATIONS 101 died of cancer. Two died of cancer of the bladder, two of can- cer of the liver, and one each of cancer of the throat, uterus, and breast. The patient's father died of diabetes, but his sister (the patient's paternal aunt) died of cancer of the bowel. Again, five members (four males and one female) of a family of nine children died of cancer. The four males died of ab- dominal growths and the female of cancer of the uterus. The mother and mother's brother also died of cancer; the father died of phthisis. The son of the eighth son died at the age of 28 of cancer of the boweh" To these histories Bashford ^ added the following comment at a time when the breeding experiments in his laboratory were still yielding negative results: "Family histories of this kind are, however, rare, in proportion to the number of indi- viduals attacked, and they are mainly of interest as showing that if cancer be transmissible by heredity, then transmission takes place both through the male and the female, without any- thing corresponding to what is known for haemophilia and col- our-blindness. These histories are so infrequent that they cause no surprise when the table of the relative frequency of cancer in the general population given above is considered ; for, did these forms of family history imply hereditary transmission, then w^e should be able with ease to obtain tables of a hundred fam- ilies in which the figures for no deaths, one, two, three, or more were the inverse of what they are in the population ; but this is not the case. The isolated instances recorded in the lit- erature serve only to show how rare this phenomenon really is. When recorded, it is more than probably to be looked upon as what would be expected to happen in the case of so frequent a cause of death as cancer, from a consideration of the distribu- tion theoretically calculated according to the law of probabili- ties." Raymond Johnson and Lawrence^ give the following recent experience : "Among 500 consecutive cases of carcinoma of the breast treated in University College Hospital, there was a family history of malignant disease in 81, and in 37 of the 81 cases the disease was stated to have been in the breast. In one of this series of cases the patient's mother and her sister died from cancer of the breast, and the father's sister from cancer of the mouth ; of the patient's sisters, 2 died from cancer, 1 of the stomach and 1 of the breast. If heredity plays any impor- tant part in the causation of the disease, it might be expected 1 Bashford, E. F. — ' ' Heredity and Cancer, ' ' loc. cit. ^ Johnson, Eaymond, and Lawrence, F. W. P. — Article on Tumors, in "A System of Surgery," edited by C, C. Choyce, Vol. I, p. 470. 102 THE CANCER PROBLEM that it would lead to its incidence before the average age. In this connection it may be stated that among the 500 cases of cancer of the breast referred to above, the average age at which the disease was first noticed M'as 40. (J2 years, whereas among the 81 cases in which any evidence of heredity could be traced, the averaffc ac'e was 48.7-i vears. The difference in this series of cases is so small as to be negligible, but individual cases of carcinoma occurring at an unusually early age are sometimes met with, as in one of the families mentioned above, in which the probable effect of heredity cannot be disregarded." It seems, therefore, that the evidence both for the human subject and for breeding experiments on mice, points in the same direction. Heredity does have a slight influence, and occasionally may exercise a quite appreciable influence. Bash- ford and Murray,^ however, issue an emphatic warning against alarm, by writing: "To guard against pessimistic conclusions it is well to point out that the influence of heredity has only been demonstrated by studying stocks in which this factor has been concentrated by careful mating, and that the influence is mainly exerted in the immediate descendants. Such a concen- tration as can be attained in experimental animals can only occur in the human subject by hazard, as a coincidence of considerable rarity, and it is probable that the influence of heredity in the general population is manifested as an average predisposition of low general intensity." It is apparent that there are many difficulties in obtaining the facts upon which to base statistics of cancer, and that these difficulties are not all capable of being completely overcome even under the most favorable circumstances. The difficulties are greater in the country than in the towns, even in coun- tries with the best developed statistics; they are still greater in the United States in general, owing to the vast distances, the numerous breaches of the registration laws, and the difficulty of obtaining correct records in small, isolated places. The immigration of from 900,000 to 1,000,000 persons annually, the floating character of this annual additional popu- lation, and of much else besides, greatly augment the diffi- culties of properly accounting for age and sex distribution. Moreover, the great inequalities in the education of those prac- tising medicine in the United States militates against a general leveling up of the accuracy of the certification of causes of death. The falsification of the causes of death, in consequence of the physician's heeding the demand of the patient's family 1 Introduction to the Tourth Scientific Eeport of the Imperial Cancer Research Fund, London, 1911. STATISTICAL CONSIDERATIONS 108 that the return of the record of death shall not say cancer, is capable of being overcome to a large extent by making the record confidential and the intentional falsification of the death return a criminal oftence both on the part of the doctor and on that of the persons instigating it. If the statistics of mor- tality are not to defraud the public which pays for such reports on the state bill of health, it is as essential to guard against the wilful suppression of a cause of death as it is to prevent the suppression of a birth, or the misstatement of the cause of a death really due to an illegal operation. The difficulty of obtaining autopsies may be overcome by law, but is more likely to be overcome by educating the public concerning the value and harmlessness of the proceeding, and the fact that it is in their own interest. Autopsy is often re- fused, especially among some members of the Church of Rome, not from any doctrine of the Roman Catholic faith, but because many adherents of this church celebrate "wakes" over the dead body. For other reasons the poor hold to the sacredness of the dead body. For example, among certain foreigners in the lower parts of ISTew York it is customary for the funeral cortege to proceed around the block before going to the cemetery, and thus to pass the tenement in which the deceased person had lived. Whether this custom be followed "for luck," for the deceased to have one last look, as it were, at the former place of abode, or out of respect to the dwelling place, it defeats the ends of science in many instances in which, otherwise, autopsy would be permitted, and in so far militates against the statisti- cal study of the causes of death. All such practices and preju- dices can be overcome only by education, just as objections to anatomical study have been overcome. The greatest efforts are made to obtain accuracy of mor- tality statistics in England. For many years, whenever a death has been certified vaguely, the doctor has been written to, and exact information obtained. In this way, in 1911 alone, out of 12,563 such inquiries made, 10,718 replies were received. The data of the population, the numbers of the two sexes, the numbers living at each quinquennial age-group, and in town and country, are therefore ascertained with a fair approach to accuracy, although little account can be taken of the effect of emigration. Moreover, the deaths occurring in institutions are known and are transferred to the place of abode. As regards cancer, the individual sites are tabulated and a vague statement of death from cancer is inquired into and the site or organ ascertained. In this way, although the ideal has by no means been attained in that country, the statistics of 104 THE CANCER PROBLEM death can have a larger numher of "corrections" applied to them than anj-where else. SUMMARY The statistical study of cancer is valuable in many direc- tions, both negative and positive — in other words, by what it proves cancer is not, as well as by what it proves cancer is. It has brought out marked differences between cancer and the epidemic or filth diseases ; it has shown that all races and creeds are liable to the disease, irrespective of diet, soil, or climate, although the question of relative liability of different parts of the world and of different races has not been settled. It has revealed the importance of chronic irritation by dem- onstrating how the distribution of cancer in the body may be altered by peculiar practices pertaining to native customs or occupations. Statistics have revealed the relation between cancer and age — that it is rare under 35, but frequent after middle life — and that the relation of age ("age-incidence") differs for different organs, but is the same for the same organ in the two sexes. Women suffer more from cancer solely because of the lia- bility of the mamma and uterus to the disease. If these organs are deducted, the stomach and intestines are most liable in both sexes, although the male is more prone to attack, the indica- tions being that alcohol and other irritants may determine his greater liability. There has been a great increase in the total number of deaths recorded from cancer, partly due to improved certification of causes of death and improved diagnosis, and also because more people nowadays attain to ripe years. This must not be con- founded with the question of a relative increase. When the figures are analyzed it is shown that there has been no relative increase for some parts of the body, for example, skin, uterus, ovary, liver, but that for other sites, notably stomach and in- testines, breast and tongue, there has been a relative increase. The question whether this relative increase is real or only ap- parent has not yet been decided. There is some probability that a good deal of the increase for the stomach and intestines may be explained by improved diagnosis and certification of causes of death, owing to the improved methods of surgical diagnosis, but for the tongue and breast this would hardly hold. In the case of the breast, the increase in the inability of women to suckle their children calls for investigation. STATISTICAL CONSIDERATIONS 105 Heredity has been shown to play a role, but not one to cause anxiety. Finally, statistics have disposed of some popular fallacies regarding "cancer houses" and the risks of infection so widely feared. SECTION IV ETIOLOGY CHAPTER I THEORIES EARLY THEORIES Despite the seeming absurdity of such theories, Hippocrates, Celsus, and Galen conceived that there were four cardinal fluids in the body — blood, mucus, yellow bile, and black bile. An excessive accumulation of black bile was thought to be the cause of cancer, which term, for them, covered not only such of the true carcinomata and sarcomata as they had recognized, but much else besides. Their classification went little further than distinguishing malignant ulcers from malignant tumors, cancer apertus from cancer occlusus. Early anatomists, like Vesalius, Fallopius, and Leonardo da Vinci, did much to break away from the domination of the humoral theories, which had held for centuries. Paracelsus made a further advance; and the treatment adopted by the famous surgeon, Ambroise Pare, shows that, like his predeces- sor, Leonidas, he had emancipated himself from the doctrine of Hippocrates, never to operate on an "open" cancer. But, even at the end of the eighteenth century, famous an- atomists, like John Hunter and Alexander Munro, still re- mained under the influence of the old humoral theories as modi- fied by Descartes. The discharge of ulcerating cancer came to be widely designated as the "cancerous virus," and was regarded as its chief characteristic; so much so indeed, that, in 1773, a prize was awarded to the author of a famous book (Peyrilhe), describing how sloughing had been produced in a dog by sub- cutaneous injection of a discharge obtained from a man. Walshe,^ writing in 1846, said with reference to the various 1 Walshe, Walter Hayle. — ' ' The Nature and Treatment of Cancer, ' ' London, 1846, p. 35. 106 ETIOLOGY— THEORIES 107 theories of the origin of "cancerous substance" : "The majority of these are either so prima facie absurd, so insignificant, or so repugnant to the results of sound observation, that they are only fitted to figure among the curiosities of medical literature. The reader may well be spared an inquiry into speculations ascrib- ing cancer to atrabilis or a melancholic humor — to lymph con- verted into an acrid and destructive fluid — to the presence of a gas possessing properties analogous to those of hydro-sulphuric acid — to fluids spontaneously effused and rendered corrosive by putrefaction — to the depravation of the nervous fluid — or to the presence and action of a virus composed of an ammoniacal fluid containing oxide of nitrogen in excess." "With these vain hypotheses," quoting further from Walshe, "may assuredly be classed that which, under different forms, seeks to connect the appearance of cancer with the presence and agency of parasitic animals. I should indeed," he con- tinues, "scarcely have conceived it necessary to advert more particularly to this theory than to the others, just mentioned, had it not been very recently revived with considerable pre- tension. It appears to have first attracted attention through the writings of Justamond,^ an author of the last century, who ascribed the formation of cancer to 'insects, or the germina of these, taken up from the air by the lymphatic vessels.' He quotes a thesis by Martin Schumacher, and the work of Qua- drio,^ to show that he was by no means singular in entertaining this opinion. The latter writer had seen the insect, and de- scribed its length, breadth, and colour." I have reverted to the opinion of Walshe, who was a dis- tinguished member of the medical profession of his day, a careful observer, and a fluent writer, to show how, so far as the etiology of cancer is concerned, the past is linked with the present. The last influence of the old humoral conception of cancer did not disappear until the time of Virchow, or about the middle of the last century. The influence of the theories of the parasitic origin of the disease may be said to continue to be felt down to the present moment. Those who have fol- lowed the history of the modern study of cancer have been carried through a succession of hypotheses as to the causative influence of protozoa, entozoa, and various vegetable and animal parasites, some of which still figure in cancer literature. 1 Justamond, J. O. — ' ' An Account of the Methods Pursued in the Treat- ment of Cancerous and Scirrhous Disorders and Other Indurations," 1870, p. 65. ^ Quadrio, Giuseppe Maria. — ' ' Nuvo metodo por curare ogni eanehero eoperto e specialmente le ghiande scirrhose delle mamelle, e di altre porti del corpo, " Venezia, 1750. 108 THE CANCER PROBLEM THEORIES WHICH HAVE ENGAGED ATTENTION SINCE THE BEGINNING OF MODERN CANCER RESEARCH BIOLOGICAL THEORIES Influence of Humoral Theory upon the Scientific Study of Can- cer. — Virchow, while forever liberating pathology as we know it to-daj from the incubus of the humoral conceptions of dis- ease, had not entirely rid himself of their influence when he considered tumors and cancer as crystallizing out of a universal connective tissue matrix. He showed his common sense, how- ever, by not continuing his Onkologie ^ after the publication of the investigations of Thiersch ^ and Waldeyer,^ whose dem- onstrations as to the histogenesis of cancer from corresponding tissues, entirely upset his ideas. Yet how tenaciously the old humoral ideas of disease con- tinued their hold upon the medical mind, and how widely they separate the standpoint of forty years ago from that of to-day, may be illustrated by the writings of the distinguished English surgeon and pathologist. Sir James Paget.* That he was fa- miliar with the work of Virchow is evident from frequent references in his "Lectures on Surgical Pathology," published in 1853. Yet in 1874, in a debate at the Pathological Society of London, he still defended the views he had set forth in 1853 as to the humoral origin of cancer. As it is most important in the interest of medical education, alike of the profession itself, and of the laity, that there should be no misunderstanding as to what was known or debatable forty or fifty years ago, and what is no longer even debatable to-day, it seems advisable to give the following quotation from Paget's famous book. Writ- ing of cancerous growths, he held that "They are local mani- festations of certain specific morbid states of the blood; and that in them are incorporated peculiar morbid materials which accumulate in the blood, and which their growth may tend to increase." "In the terms which are more usual in discussions respecting the nature of cancers, I would say that a cancer is, from the first, both a constitutional and a specific disease. I believe it 1 Virchow, Rudolph.— " Die Krankhafte Geschwiilste, " 1863-65. ' Thiersch, Carl. — * * Der Epithelialkreba, namentlich der Haut, ' ' Leipzig, 1865. 'Waldeyer, W. — "Die Entwicklung der Carcinome, " Virchow 's Archiv, Vol. 41, 1867, p. 470. Ihid., Vol. 55, 1872, p. 67. 3 Paget, Sir James. — ' ' Lectures on Surgical I'athology, ' ' London, 1853. ETIOLOGY— THEORIES 10<> to be constitutional, in the sense of having its origin and chief support in the blood, by which the constitution of the whole body is maintained; and I believe it to be specific, first, in the sense of its being dependent on some specific material, which is different from all the natural constituents of the body, and difi^erent from all the materials formed in other processes of disease; and, secondly, in the sense of its presenting, in a large majority of cases, structures which are specific or peculiar both in their form and in their mode of life. ''The evidences of this hypothesis appear in the conformity of cancer to the other specific diseases, for which a similar hypothesis is nearly proved, and in the fitness of the terms which it supplies for the general pathology of cancer." "The general history of cancers," he continues, ''and their analogy with other diseases that are, in the same senses, specific and constitutional, imply that, before the formation of a can- cerous growth, two things at least must co-exist; namely, a certain morbid material in the blood, and some part appropriate to be the seat of a grovrth incorporating that material, some place in which the morbid material may assume, or enter into, organic structure. "The existence of the morbid material in the blood, whether in the rudimental or in the effective state, constitutes the gen- eral predisposition to cancer ; it is that which is, by some, called the predisposing cause of cancer. The morbid material is the essential constituent of the 'cancerous diathesis, or constitu- tion' : and when its existence produces some manifest impair- ment of the general health, independently of the cancerous growth, it makes the 'primary cancerous cachexia.' "That which evidently makes some part of the body appro- priate for the growth of a cancerous tumour is a so-called excit- ing cause of cancer; but it is a cause of cancer only in so far as it fits some part of the local manifestation of a disease which already, in its essential material, exists in the blood. "It seems very important to keep constantly in view that these two conditions must coincide before the appearance of a cancerous growth ; important not only to recognize their existence, but, if we can, to measure the several degrees in which, in each case, they are present ; because, upon our recog- nition of the shares in which they respectively contribute to the production of the cancerous tumour, must depend the chief principles of practice in relation to the removal of such tumours. The larger the share taken by the constitutional ele- ment of the disease, — that is, by the cancerous condition of the blood, — in the production of a cancerous growth, the less is the 110 THE CANCER PROBLEM probability of advantage to be derived from the removal of that growth ; while, on the other hand, the more largely the local state enters into the conditions upon which the cancerous growth is founded, the more benefit may we anticipate from the re- moval of the cancer and of the locality with it." It is not surprising that Paget, holding such views, despaired of the treatment of cancer by surgical removal, as did S^ine, Benjamin Brodie, and other distinguished surgeons of that time. As shown in the chapter on Histopathology (Section V, jD. 142), such theories were then opposed only by IMoore and De Morgan, who were ahead of their times in advocating views in accordance with modern conceptions of the circumscribed origin of cancer. To-day the old pathology of Paget is paraphrased and set forth as something new by certain self-styled "cancer- specialists" w'ho do not scruple to use the name of Paget, Syme, Brodie, and others, to give the appearance of authority to their writings. By 1887 the morbid condition in the blood had become a micro-organism for Paget. He then wrote : ^ "I think that we may justly hope to find a remedy in the constant and care- ful study of the likeness of these diseases to others of which we already have means of useful treatment. We may be the more hopeful because of the nearest likenesses of cancer and cancerous diseases are to two other groups of diseases, concern- ing w^hich there have been in most recent times, very useful ad- ditions to our knowledge. In one direction we have their like- ness to the simple or innocent tumours, in the surgical removal of which the risk of life has been diminished, even while the range of operating has been increased ; and in the other direc- tion we have their likeness, which I believe to be much more intimate, to some of the specific and micro-parasitic diseases, a group in which there has been progress toward both preventive and remedial treatment." Paget developed his views along the lines that the dissemina- tion of cancer was like that of pyemia rather than what would be expected if transported cells gave rise to emboli. In 1887 he still deplored the many failures of surgery, but nothing now justifies quoting him as an opponent of surgery even in those days of still unperfected technic and vague knowledge. As has been described under structure, it is now known that cancer arises in a circumscribed area, and is derived from cells preexisting in the part in which it arises, whether these cells be in their normal situation or displaced because of some ab- 1 Paget, Sir James. — The Morton Lecture on Cancer and Cancerous Dis- eases. Lancet, November 19, 1887, p. 999. ETIOLOGY— THEORIES 111 normality of development. The problem of causation resolves itself into explaining the progressive growth of cells derived from corresponding cells of the organism itself, and behaving, anatomically and physiologically, quite independently of it. Virchow's Theory. — Virchow ^ put forward the first rational theory of causation. As we have already seen, his idea that the cancer cells crystallized out of a connective tissue matrix was shown to be wrong, but his attribution of cancer to the ef- fects of chronic irritation is still widely held to be correct. Virchow thought chronic irritation produced a granulation tis- sue which, like early embryonic tissue, was undifferentiated in appearance, and thereupon differentiation took place in the form of the tumour. FERTILISED ' rri'ri'i'riM'ri'riTn'iTi'i ri iTi'i'i'iTri aECaODUCTIvE DlFFERtNTlf>TEO'SOMATI{rTlSSUt Of ADULT TISSUE Fig. 1. — Diagrammatic representation of the differentiation of somatic and reproductive tissues in the higher animals, indicating the Umitation of the amount of growth which determines the size of the body, and also the duration of life. Thiersch's Theory. — Thiersch,^ benefiting by the advance of embryological and histological study, was able to derive carci- noma of the skin from the skin itself, and sharply to differen- tiate the epithelium from the connective tissue. He sought the explanation in a disturbance of the equilibrium established be- tween epithelium and connective tissue. According to him, with advancing age the connective tissue ceased to be able to hold the epithelium in check, and it therefore grew into the former. The modern conceptions of development and of the relations between cancer cells and the connective tissue are quite the opposite, viz., that the epithelium determines the character of the connective tissues during the development of the several organs, and that the cancer cells mold the con- 1 Virchow, op. cit. ■" Thiersch, op. cit. 112 THE CANCER PROBLEM nective tissue to their special requirements. Thiersch did not deny that chronic irritation, inflammation, or injury might be indirect causative factors. Waldeyer's Theory. — Waldeyer,* following up Thiersch's work, came to the conclusion that all carcinomata were epi- thelial growths derived from the corresponding epithelium, and that the secondary growths were the offspring of transplanted cells, and, not a transformation of the tissue in which they occurred. He drew a sharp distinction between carcinoma and sarcoma, and held that the latter was likewise a connective FtRTIUSED Pig. 2. — Diagram of the hypothesis of Thiersch and Waldeyer. The earlier senihty of the connective tissues was assumed to allow of renewed, unUm- ited growth of epithehum. The cells were further assumed to revert to an embryonic type as represented in the last row. tissue tumor. Waldeyer was impressed with the great vascu- larity of early malignant new growths, and with the accumula- tion of white blood corpuscles, so that the appearances were almost those of inflamed tissues. He asks, therefore : ''Is it not possible that the excessive nourishment and loosening {'Locke- rung') of the connective tissues thereby involved, assist in the advance of the epithelial cells ? Is it not possible that in this way local chronic inflammatory processes — especially those arising from repeated irritations which cause circumscribed inflammation — may eventually pass over into cancerous de- generation ?" These questions, he held, deserved the most 1 Waldeyer, op. cit. ETIOLOGY— THEORIES 113 earnest examination, as perhaps from them might be obtained some valuable indications for the prophylaxis of cancer, par- ticularly as already a number of other experiences, especially those of a clinical nature, pointed to some connection between chronic inflammatory stimulation and cancerous degeneration. Thus Waldeyer, while finally disposing of the actual descrip- tive basis of Virchow's views, and of those of all his predeces- sors, was also able to give a renewed lease of life to the impor- tance which Virchow attached to chronic irritation. It will be noted that Waldeyer conceived repeated irritation to be the essential factor. He also entertained the probability that an entire organ was liable to cancer, and for this reason advised extensive operation. Waldeyer differed from Thiersch in holding, that not the connective tissue, but the epithelium, became weakened with advancing years, and that the greater or increased activity of the connective tissue led to the epithelium being isolated and surrounded with sclerotic tissue, in consequence of which it might undergo cancerous transformation. Cohnheim's Theory. — Cohnheim ^ elaborated a view originally expressed by Remak.^ According to this theory, which was dominant for many years, cancer arose in persistent embryonic rests which, owing to their displacement from their normal environment, had not been incorporated during the normal development of the organism, and had not degenerated. Thus cancer was simply a renewal of embryonic growth, the po- tentiality for which, in consequence of the displacement, had been retained. The theory did not explain why these cells remained latent for years, nor why only an occasional "cell rest" developed into cancer. Subsidiary hypotheses were called in. Irritation was again called upon to explain why latent germs began to grow actively. The greater frequency of cancer at the openings of the body than throughout the length of the tubes ; its greater frequency in parts where congenital displace- ments were more common or the processes of development more complicated, were alleged as evidence. It would take too much space to put forward all the argu- ments for and against Cohnlieim's theory. It may be stated, however, that tumors and malignant new growths do arise at times from what are the results of anomalies of development, for example, teratomata and mixed tumors, l^evertheless, the * Cohnheim, Julius. — Vorlesungen iiber allgemeine Pathologie. Vols. 1 and 2, 2nd ed., Berlin, 1882. 2Kemak, Robert.— " Ueber die Entwicklung der Gesehwiilste, " Deutsche Klinik, 1854, No. 19. 114 THE CANCER PROBLEM superposition of malignant new growths upon the growth of embryonic tissue is to-day regarded as being just as much a problem for solution as is its acquirement by tissue still growing in normal continuity with its surroundings. Ribbert's Theory. — Ribbert ^ further developed the idea of displacement of cells. According to his view, it was not so much development as post-natal displacement which was an- swerable for cancer. This theory has undergone so many modi- fications in order to meet criticism that it is not easily de- scribed. He held that displaced cells were without the f CRTIUStt A B Fig. 3. — Diagram of Cohnheim's hypothesis. The different behavior of the progeny of "rest" A and "rest" B indicates the important assumption which the hypothesis entails. The necessity for this assumption was recognized by Cohnhelm and deUberately made by him. restraining influences of the body, and therefore simply gave expression to their natural powers of growth. Weigart had argued that there was no such thing as a stimulus to growth, and Ribbert accepted the view, maintaining that, in respect of their powers of growth, cancer cells had not departed from the normal. It cannot be denied that, following injury and repair, as well as inflammatory conditions of all kinds, cells are often dis- placed and cut off from their normal connections. At the same time, the development of cancer is the exception and not the rule under these circumstances. Ribbert sought to show that very early growths were always sharply circumscribed and de- fined from the adjacent tissue, even from the corresponding lEibbert, Hugo.— " Geschwiilste, " Bonn, 1904. ETIOLOGY— THEORIES 115 epithelium. Against his studies, however, must be placed reliable observations which show that an early carcinoma may maintain continuity with the normal epithelium. Ribbert at- tached great significance to the occurrence of cellular infiltra- tion in the connective tissue adjacent to early carcinomata, as being evidence that changes are taking place in the connective tissue, and that the epithelium never grows into unaltered connective tissue. The alteration in the connective tissue is affected by chemical substances proceeding from the epithelium. There are other subsidiary hypotheses, one of which is that the TtRTlLlStO jFig. 4.— Diagram of Ribbert's hypothesis, showing the manner in which the differences in the degree of differentiation of different tumors was ex- plained by him. new connective-tissue environment effects secondary alterations, such as loss of differentiation, in the carcinoma cell. The great value of Ribbert's theory lies in the stimulus given by it to the study of the earliest stages of cancer development, and in its revelation of the minute size of the area within which cancerous changes may be fully demonstrated, as opposed to the theory that an entire organ or tissue undergoes transformation. Thus, in great part, was built up the theory that cancer, once formed, grows from its own resources only, and not by accretion around the margins. Hauser's Theory.- — Hauser ^ put forward views almost cate- gorically different. He postulated a fundamental biological 1 Hauser, Gustav. — * ' Das Cylinderepithel. des Dickdarms, " Jena, 1890. Carcinom des Magens und 116 THE CANCER PROBLEM difference between normal cells and cancer cells, the latter, in his opinion, being a ''new race of cells," added to by the further production all round the margins of cells of the same kind. lie reasoned by analogy with the variations in individuals and the production of species. He saw proofs of a biological change in the changed microscopical structure, in the alterations in the size of the cells, their nuclei and the chromatin, as well as in the increased power of multiplication. Other Theories. — Adami, Benecke, Marchand, von Hanse- mann, and others, are responsible for a large group of theories which have something in common in that they seek to explain the power of grow^th in terms of loss of some other cell function ; for example, differentiation and secretion, or injury to one part of the complex cell mechanism, permitting undue manifesta- tion of what Adami calls the "habit of growth." According to Adami,^ a cell which has lost its differentiation, or which has never acquired it, continues to take up nourish- ment, passes into an active vegetative stage, and "gains the habit of growth." Benecke " holds that the lowering of functional activity is accompanied by increase of growth energy. Marchand ^ distinguished sharply between the undifferenti- ated embryonic cell and the undifferentiated tumor cell. The former, after continued growth, undergoes differentiation; in the latter the power of differentiation has not only become latent, but is permanently lost. There is some degeneration in the cell, leading to faulty metabolism, and the exercise of toxic action on neighboring cells weakens them and leads to their progressive growth. Von Hansemann,* extending the work of Cornil,'^ Klebs,*' and Podwyssozki '^ on cell division in cancer, described in detail the irregularities of cell division. He argued that these must result in changed biological characters, among others loss of function and differentiation, with acquirement of increased powers of growth. This alteration he names anaplasia, and as- serts that it is not a theory of the origin of cancer, but only a description of actual findings. Even more closely identified with changes in the nucleus are * Adami, J. George. — ' ' The Principles of Pathology, ' ' London, 1909. 2 Benecke. — Ziegler 's Beitrage zur path. Anat., 1892-1893. ' Marchand. — See General Bibliography. ■•Von Hansemann, David. — "Studien iiber die Spezificitat, den Altruis- mus und die Anaplasie der Zellen, " Berlin, 1893. ° Comil. — See General Bibliography. ' Klebs, E. — ' ' Handbuch der pathologischen Anatomic, ' ' Berl., 1869. I, 307. 'Podwyssozki. — Ziegler 's Beitrage zur path. Anat., 1886. ETIOLOGY— THEORIES 117 the views put forward by Farmer, Moore, and Walker,^ that the cell divisions resemble those occurring in the ripening of the sexual cells. These views lack all independent confirma- tion, and Bashford and Murray^ have shown the sources of fallacy underlying this interpretation of the chromatin figures in dividing cells. Oertel ^ has suggested that the nuclear chro- matin is of two orders, one governing function, the other pro- liferation. By the loss of the former only the vegetative prop- erties are transmitted to future cell generations. Gametes Fig. 5. — Hypothesis of "gametoid" nature of cancer (Farmer, Moore, and Walker). Cancer is assumed to arise from adult tissues in a manner analogous to that by which the normal reproductive tissues are separated from the soma in development. The properties and power of growth of cancer are regarded as analogous to those of reproductive tissue. PAEASITIC THEORIES There remains for consideration the theory that cancer is caused by an external parasite. This view has long been held * Farmer, Moore, and Walker. — ' ' Resemblances Exhibited Between the Cells of Malignant Growths in Man and Those of Normal Reproductive Tissue," Proc. Roy. Soc, Vol. 72, 1903. ' Bashford and Murray. — ' ' On the Occurrence of Heterotypical Mitoses in Cancer," Proc. Roy. Soc, B, Vol. 77, 1906. ' Oertel, Horst. — ' ' On the Heterogenesis of Tumors, Particularly Can- cer," JV. r. Med. Jour., July 6, 1907. 118 THE CANCER PROBLEM in various forms, and a legion of parasites has been discov- ered. Not one of these has found anv reasonable amount of support, and if cancer be communicated bv such means, it may safely be said that the parasite still remains unknown. The grounds on which cancer is held to-day to be infective are mainly statistical — the increase in the number of deaths from it recorded throughout the world, its alleged or apparent higher incidence in some districts than in others, and the al- leged occurrence of ''cancer houses.'' Alleged epidemics have FERTlLlStO Zr^ FCCTION ASx Fig. 6. — Parasitic hypothesis. (The numerous aasumptions entailed are discussed in the text.) also been described in cows, rats, and fish. These have been dealt with in the section on Statistics. It is also held that cancer is infectious because of a supposed resemblance to tuberculosis, but this view is based on a false analogy. In tuberculosis the tubercle bacillus is the cause of the disease, the bacillus itself being transported and spreading throughout the body, transforming its fresh nidus into the tuberculous process. In cancer, as is discussed under Histo- pathology, actual portions of the body grow in places where they should not be, having themselves been transported. Al- though the use of the term is hardly permissible, one part of the body has become parasitic on another part. All the preceding theories may be placed in one or the other of two categories. It is assumed that an external stimulus of some kind causes gTowth, or it is assumed that some change ETIOLOGY— THEORIES 119 taking place internally in the cell itself, permits of growth. The parasitic hypothesis is stated in both ways by its sup- porters. ^ The alternatives have been succinctly expressed by Powell White, ^ who is not a supporter of the parasitic hy- pothesis : "If the continued cell proliferation in tumours be the result of direct stimulation by an extrinsic irritant, such irritant must of necessity be a living organism, since the proliferation, being continuous and progressive, demands a continually increasing irritant. This applies equally to the histiomata and cytomata, and since, as we have seen, there is no sharp boundary between the two classes of tumours, we must infer that the essential causal factor is of the same nature in both cases. The supposed parasite must be either intra- or extracellular. If it is extra- cellular it is impossible to explain the absence of infection of the surrounding tissues; for, as we have seen, the growth of a tumour is the result of proliferation of its own cells, and the surrounding tissues take no part in it, except, in certain cases, in connection with the area of origin. ... If, on the other hand, the parasite is supposed to be intracellular it would seem necessary to suppose that the division of the cell and of the parasite was so timed as to be simultaneous, each daughter cell receiving a daughter parasite. In all cases in which parasites are found within cells the effect is the destruction either of the parasite or of the cell. ''Since cell proliferation in tumours is similar to cell pro- liferation under normal conditions, the assumption of a parasite to explain it is quite unnecessary, and makes an explanation of tumour growth more difficult. "Direct stimulation- of cell growth by a parasite is an un- known occurrence in biology and is opposed to the facts of parasitism, and the difficulty is not avoided by applying, as some do, the term symbiosis as explaining the association be- tween the supposed cancer parasite and the organism. In symbiosis the partners receive mutual benefit from the associa- tion, but symbiosis does not lead to proliferation. "Numerous micro-organisms have been described by differ- ent observers as occurring in cancers, and for many years there has been a great controversy between those who uphold and those who deny that cancer owes its origin to one or more specific parasites. Investigation has been carried out both hy histological and by cultural methods and, at different times, bacilli, cocci, torulae, protozoa, myxomycetes, spirochsetes, nem- 1 White, Charles Powell. — ' ' The Pathology of Growth. Tumourg. ' ' Lon- don, 1913. 120 THE CANCER PROBLEM atode worms, and acari have been suspected as specific organ- isms for cancer, but no organism yet described has stood the test of criticism. No one has yet isolated from cancers any organ- ism which will give rise to cancer when inoculated into other animals, except the cancer cell itself, which, as we have seen, will, under suitable conditions, continue to live and produce cancer when grafted into an animal of the same species as that from which the cancer was derived. Recent observations ap- pear to show that it is possible to some extent for cells, both of normal tissues and of cancers, to proliferate in vitro as do bac- teria. Undoubtedly bacteria and other organisms may be ob- tained from cancers, but their occurrence is apparently acciden- tal, or at most incidental, as they do not stand in direct causal relationship with the cell proliferation." . . . "We have seen," he continues, "that we cannot ascribe the increased proliferative capacity of the cells to specific parasites, and it does not seem possible in any other way to explain tumour growth by the as- sumption of a specific causal parasite. It is impossible to account for the histiomata on this basis, and it is equally im- possible to explain the complicated tumours such as blastocyto- mata, teratomata, and compound sarcomata. There only re- main the sarcomata and carcinomata, and even in these cases the assumption of a specific parasitic origin leads to numerous difficulties. There are three possibilities to be considered. "(a) There may be a single parasite for sarcoma and car- cinoma. In this case it is impossible to explain the regularity with which metastatic tumours repeat the structure of the pri- mary. We never find a primary carcinoma giving rise to secondary sarcomatous tumours as we should expect if both were due to the same causal parasite. "(b) There may be one parasite for sarcoma and another for carcinoma. Here again the similarity of the metastatic tumours to the primary provides an insuperable difficulty. If all forms of carcinoma were due to a single parasite we should expect the metastases in the liver, in some cases at least, would show the type of hepatic carcinoma ; this does not occur. "(c) Each form of sarcoma and carcinoma may have its own specific parasite. Here we are at once met with the difficulty that the different forms of these tumours are almost innumer- able, corresponding to the innumerable kinds of cells in the body. While they may be reduced to a limited number of type forms, yet there is no sharp boundary between the different groups, and there is considerable variation within the limits of each group. We should have to suppose a different set of cancer parasites for each organ, and not only this, but we ETIOLOGY— THEORIES 121 should have to assume a different series of parasites for each species of animal ! The fact that tumours are found in all genera of the higher animals, and have the same characters throughout, and yet it is impossible to graft a tumour from an animal of one species into another animal of a different species, while it is possible to do so within the same species, tells strongly against the theory of a parasitic origin. "Other difficulties in the way of the parasitic theory are found in the close relationship of the cytomata to the histiomata and the relationship of tumours generally to malformations and to such conditions as progressive hypertrophy. "We thus see that the assumption of a specific parasitic origin for cancer leads to insuperable difficulties in explaining the observed phenomena. These difficulties entirely disappear if we consider the cancer cell itself as a parasite and cancer as a process of infection by cancer cells." SUMMARY ISTaturally all older theories have been criticized in the light of the extensive experiments that have been performed since the beginning of the present century. For the most part the net result has been to show that all theories that yet have been advanced, constitutional, parasitic, or strictly cellular, are in- sufficient. The true, or even a satisfactory working explana- tion of the nature of cancer, has not yet been discovered. CHAPTER II PREDISPOSING CAUSES With the inauguration, within the past fifteen years, of the ^T^ of experimental cancer research, efforts to solve the prob- lem of the cause of cancer have assumed a character different from that of all previous investigation. ISTone of the theories of the past concerning the essential cause having proved dem- onstrable, attention has nov7 come to be more or less confined to the determination of the predisposing factors — with the hope that, in thus working out from indirect causes, the direct or essential cause may be discovered. With this end in view, an enormous amount of experimental work has been done, and is now being carried on in the various research laboratories of the world, with reference to the in- fluence of heredity, irritation, environment, diet, etc., upon the production of this disease. Of necessity the major pro- portion of these investigations has been made with short-lived animals, such as are available for laboratory use. Observations with respect to the various predisposing causes of cancer hav- ing a direct bearing upon the prevention and cure of the dis- ease have been made, however, upon human subjects. The Bearing of Experimental Investigation upon Existent The- ories.- — As explained in the section on Statistical Considera- tions, breeding experiments with mice have shown that a lia- bility to cancer of the mamma may be inherited, but it is not settled whether this is a general constitutional liability or only a predisposition on the part of a single tissue. The balance of evidence favors the latter view. It has been made sufficiently evident that the effect of heredity is slight, and not of itself sufficient to explain the development of cancer. The parasitic theory has received no support from experi- ment. Shortly after the transplantation of cancer in mice was demonstrated, von Leyden ^ expressed the view that this ivon Leyden, E. — " Ueber die parasitare Theorie in der Aetiologie der Krebse," Berl. Min. Woch., 1905. 122 ETIOLOGY— PREDISPOSING CAUSES 123 achievement demonstrated that cancer is infectious. The opin- ion, however, was based upon a misconception of the process, and upon confounding infection with transplantation. By in- fection is understood the conversion of healthy tissue into can- cerous tissue; transplantation, on the other hand, is the embed- ding of ready-made cancer cells into a healthy animal whose tissues no more become cancerous than does the soil change into geraniums when the latter are planted in it. Borrel,^ a firm upholder of the parasitic nature of cancer, has not used either his own or the transplantation experiments of others to support his view. He relies on apparent cage epi- demics such as have been referred to elsewhere (see Section VI, p. 152). Some authors have thought that the phenomena of immunity supported the parasitic theory, but the weight of authority goes to show that these phenomena have no analogy with what is established for infective diseases. Recently Fibiger ^ has recorded that he was able to produce tumors of the stomach by feeding rats with cockroaches in- fected with nematodes. Out of several thousand rats experi- mented upon, true carcinomata developed in three. Some have thought the nematodes acted as the carriers of a virus in the way that Borrel first incriminated them for mouse tumors, because of the frequency with which he found nematodes in the lungs of that animal. Against this view it has been urged that the nematodes were not certainly shown to have caused the tumors, of which they may have been mere accompaniments, or alternatively, their causal relationship was merely that of any other chronic irritant. The congenital or embryonic theory of the origin of cancer has received no support whatever from the experimental and comparative investigations of recent times. The production of cancer by irritants is determined solely by the point to which the irritant is applied, as by the Kangri in Kashmir, the chew- ing of betel nut in other parts of India, and the harnessing of a wagon to the right horn in cattle. To assume that congenital germs just happen to be present at the point where the irritant is applied is a needless assumption. It must be remembered, of course, that cancer sometimes de- velops in a congenital anomaly, for example, in a teratoma ; but ^Borrel, A.— "Le Probleme du Cancer," Bull, de I'Inst. Pasteur, 1907, Vol. V, p. 497. ^ Fibiger, J. — ' ' Ueber eine durch Nematoden hervorgeruf eiie papillo- matose u. carcinomatose Geschwiilstbildung im Magen der Eatte, ' ' Berl. Jclin. Woch., 1913. 124 THE CANCER PROBLEM the explanation of the origin of cancer there is jnst as difficult as in the case of apparently normal adult tissues. Experiment has shown that, after transplantation, tumors having no differentiation at all do not progress to differentia- tion as embryonic tissue does. Moreover, even when not dif- ferentiated the connective tissue or stroma usually has dis- tinctive characters for different tumors. If cancer were merely undifferentiated tissue, one would expect the stroma always to show a uniform character. On the constructive side, experiment, while revealing a very large number of new facts, has produced very little in the way of new theories. Atreptic Theory (Ehrlich). — To explain his experimental results, Ehrlich has put forward the atreptic theory, which is a sort of mixture of a constitutional and a cellular theory. In it he seeks to explain the increasing frequency of cancer with age as the result of a lessening of the appetite for food on the part of the body as a whole, while certain cells retain their normal hunger, or at least lose less of it than does the rest of the body, Albrecht," without performing any experiments, had previously put forward the view that the tumor cells acquired an increased avidity. It must be remembered that Ehrlich's theory was advanced early in the development of recent experimental research, and therefore it is not surprising that the observations on which it is founded are not regarded as reliable by some other investi- gators. It is based on the following facts and conclusions : It is difficult to transfer a primary growth to new animals. The conclusion was therefore drawn that this was because the avid- ity of the bodies of normal animals was too high for the tumor cells. Ehrlich's transplanted tumors did not form any metas- tases, and he concluded that this was because the primary, transplanted tumor withdrew to itself all the food, thus starv- ing the cells which were transported to the lungs. The same 1 Ehrlich, P., and Apolant, H. — ' ' Beobachtungen liber maligne Maiisen- tumoren, ' ' Berl. klin. Woch., July, 1905. Ehrlich, P. — ' ' Experimentelle Karzinomstudien an Maiisen, ' ' Zeitschr. f. drtstliche Fortbildung, iii. Jahrgang, No. 7, April, 1906. Also: ' ' Experimentelle Karzinomstudien an Maiisen, ' ' Arbeiten aus dem Kgl. Instiiut f. exiJ. Therapie, Heft I, 1906, pp. 77-102. ' ' Experimentelle Karzinomstudien an Maiisentumoren, ' ' Zeitschr. f. Krebsforschung, 1907, Bd. V, Hefte 1 and 2, pp. 59-80. Abhandlung der Internationalen Konferens fiir Krebsforschung, Heidelberg, Sept. 25-27, 1906. Ehrlich, P., and Apolant, H. — " Ueber die Genese des Carcinoms, " Ferhandl. deutschen Path. Gesellsch., Zwolfte Tagung, Kiel, 1908. 2 Albrecht, E. Rand. — "Bemerkung zur Geschwiilstlehre, " Frankfurter Zeitschr. f. Pathologic, Vol. I, 1907. ETIOLOGY— PREDISPOSING CAUSES 125 explanation was given as to why he could not reinoculate a mouse already bearing a tumor. Ehrlich also found that mouse tumors would grow for only a short time in rats, and he concluded that this was because the tumor cells were starved as soon as the foodstuffs introduced with them were used up. All investigators are agreed on the difficulty of transferring a primary tumor from the animal in which it was produced to a normal animal, although the difficulty appears to vary with different investigators and with different methods employed. Bashford,^ for example, found that young mice gave very much better results than did old mice, a fact now generally admitted by all workers, and which does not at all accord with Ehrlich's assumptions as to the part played by bodily avidity, because the contrary result, should then be obtained. Bashford and his colleagues have recorded a large number of other discoveries quite the opposite of those observed by Ehrlich. One of these is the fact that metastasis is frequent in their experience. They also explain Ehrlich's failure to reinoculate a mouse already bearing a transplanted tumor, as due to active immunity, which they claim to have fully demon- strated. The phenomenon of the transitory growth of mouse tumors in rats they explain as due to this active immunity, re- sulting from the formation of a true cytotoxin, such as is pro- duced by the injection of the blood of one species into that of another. Moreover, the demonstration by I. B. Murphy,^ of the Rockefeller Institute, that mouse tumors may be kept growing through a long series of hen's eggs, nullifies entirely Ehrlich's opinion that, because of inability to assimilate foodstuffs spe- cific to mice, mouse tumors grow only transitorily in rats. The London school, consisting of Bashford, Murray, Haaland, Russell, and their colleagues, are apparently unwill- ing as yet to identify themselves with any particular theory or hypothesis, but full reference to their work is reserved for the section on Modern Cancer Research. At one time Bashford and Murray ^ confirmed certain findings by Farmer, Moore, and Walker,* to the effect that cancer cells had forms of cell- division similar to those characteristic of the ripening of sexual cells. They differed, however, from the conclusions drawn by 1 Bashford, Murray, and Bowen. — ' ' The Experimental Analysis of the Growth of Cancer," Proc. Roy. Soc, B, Vol. 78, 1906. ^ Murphy, I. B. — ' ' Transplantability of Tissues to the Embryo of For- eign Species," Jour, of Exp. Med., 1913, p. 482. ^Bashford and Murray, op. cit. (p. 117). ^Farmer, Moore, and Walker, op. cit. (p. 117). 126 THE CANCER PROBLEM Farmer and his colleagues, and subsequently withdrew their confirmation of the findings of these investigators. Chronic Irritation. — Although not openly expressed, the pur- pose which apparently lies at the basis of all the work of the Imperial Cancer Research Fund is an attempt to explain the association of many forms of cancer with chronic irritation. As the chronic irritants have nothing in common, it is held that there must be some properties in cells which are elicited by chronic irritation. Chronic irritation leads to prolonged or intermittent irritation, and for years, in propagating tumors, Bashford and his colleagues have demonstrated that many variations in structure and in powers of growth may take place. Just as what they describe as "new tumors" are pro- duced during propagation by cell variation, so, they leave it to be inferred, by some such process, or a similar one, cancer is developed. It is not possible to define their position with any greater precision at present. (See Section VI, — Modern Can- cer Research.) Among the views recently expressed, mention must be made of the remarkable statement of Lazarus-Barlow,^ who claims to have demonstrated that radium is present in larger quanti- ties in cancer than in normal tissues; also that many of the irritants associated with cancer, like the clay pipe, or gall- stones, are radioactive. These views are based on highly tech- nical experiments and require confirmation. Opinions differ as to how chronic irritation is related to cancer, some holding that it merely serves to make an entrance for a ubiquitous cancer parasite, others that the prolonged cell proliferation leads to cell variation. Notwithstanding such divergent points of view as regards etiology, one of the most clearly established facts about cancer is its production in tis- sues which have suffered chronic irritation, often of long dura- tion. This association is naturally most often observed on the surfaces of the body; for example, on the skii and mucous membranes. The irritants are manifold — chemical, mechan- ical, actinic, bacterial, etc. One of the most striking instances is that of the development of cancer in a tongue attacked by leukoplakia. The well-known prevalence of cancer of the scro- tum in chimney-sweeps is due in some way to soot ; as paraffin, tar (Plate III), and arsenic are causative factors in other cases. 1 Lazarus-Barlow, W. S. — ' ' On the Presence of Radium in Some Car- cinomatous Tumours and Other Tissues, ' ' Arch, of the Middlesex Hosp., Vol. XXVII, 1912. "On the Presence of Radium in Some Gall-stones and on a Correlation of This with the Frequency of Gall-stone Occurrence in Carcinoma, ' ' Ibid. ETIOLOGY— PREDISPOSING CAUSES 127 In all these cases there has been long-standing dermatitis on which warty growths appear. In the bladder, cancer becomes superadded to the papillomata which develop in anilin workers or in bilharziosis. Chronic ulcers, sinuses, and even old scars from burns may undergo cancerous changes. On the surface of the body it may not be difficult to deter- mine that there has been chronic irritation, but with the inter- nal organs, of course, such a cause is far more difficult to estab- lish. For the stomach, opin'^n is divided as to the etiological significance of chronic ulcer ^ for the biliary and urinary pas- sages, the same is true with reference to gall-stones and urinary calculi. In the case of the uterus, previous chronic metritis, or fissures of the cervix, have long been present. In the breast, however, chronic mastitis may never have been detected, and cancer of the breast may develop when it has never occurred. Certain pigmented moles may take on a malignant character either in consequence, or without the intervention, of irrita- tion. In certain instances, as when cancer develops in a tera- toma or sarcoma in the retina, it is very difficult to determine the part played by chronic irritation. Simple injury, such as a blow on the breast, or a fracture, may be followed by a new growth ; but in these casfes it is not always easy to de- termine whether the trauma simply draws attention to an al- ready existing growth, or whether it exercises a causative in- fluence. I have repeatedly called attention to the importance of re- moving elevated nevi, papillomata, adenomata, and other be- nign growths which are subject to chronic irritation. Precancerous Conditions.- — It has long been customary to use the term "precancerous" with reference to certain conditions, notably glossitis and dermatitis, on which cancer supervenes. In Section V (Histopathology), p. 133, Butlin's experience with such supposed precancerous conditions of the tongue is re- lated. It will be seen that five out of seven cases were proved to be early carcinomata. Therefore it has seemed to the author that the use of this term involves the danger that patients or their professional advisers may be encouraged to wait until can- cer has developed before seeking surgical assistance, and that conditions which are of the nature of chronic inflammatory processes predisposing to cancer should be carefully watched, and any minute area which shows the changes which Butlin in his earlier experience would have called "precancerous" should be treated as if it were already cancerous. Environment. — It is difficult to come to any conclusion re- garding the etiological influence of environment. The effect 128 THE CANCER PROBLEM of overcrowding has been considered in the sections on General Distribution and Statistics (Chapters II and III). The different liability of races living in widely separate parts of the globe ciinnot be determined. Soil, especially chalk, is held by some authors, whose statistics are called in question by others, to be important in increasing the frequency of cancer. It is said that cancer is more common in river beds than on ele- vated areas; more common where trees grow than where they are absent. It is held to be more frequent in the central pla- teau of Europe than elsewhere. But all these statements are of the nature of hearsay, and no reliance may be placed upon them. The one form of environment, however, which does seem of importance in connection with cancer incidence is occupation. The liability of different parts of the body to develop either precancerous or cancerous conditions, in consequence of ex- posure to chronic irritation in connection with certain occupa- tions, is fairly well established. Workers in tar, soot, petro- leum, and anilin furnish illustrations of this contention. This is so well recognized that, in England, those trades in connec- tion with which warty growths or cancer develop are scheduled as coming under the Workmen's Compensation Act. In some instances it is not the occupation so much as the liability to alcoholism that is held to be responsible for the development of cancer. Diet. — The question of diet has given rise to a great deal of discussion, mostly taken part in by extremists. Hardly an article of food has escaped condemnation. Salt, tomatoes, coffee, meat — especially frozen or chilled meat — pork, and al- cohol, all come under the ban. But the possible influence of diet is shown not to be very great by the liability to cancer of vegetarian castes in India, and of the rice, or rice and fish-eat- ing Japanese. Cows never eat meat, and although both tame and wild mice are occasionally cannibalistic in their habits, they do not come in contact with pork, tomatoes, or alcohol. N^either do cows or other herbivorous animals liable to cancer eat their vegetable food cooked. Therefore, it seems that such sweeping views on diet as are published from time to time in lay papers are calculated to do a lot of harm. SUMMARY While the modern experimental investigation of cancer has thrown considerable light upon certain predisposing factors in the production of cancer, the essential cause is yet to be dis- ETIOLOGY— PREDISPOSING CAUSES 129 covered. Perhaps the most practical outcome of such study is the emphasis to be placed upon the removal of all possible sources of chronic irritation, and of benign neoplasms which are subjected to irritation. SECTION V HISTOPATHOLOGY 1 DEFINITION The difficulty of considering cancer apart from tumors in general is as great with regard to questions of classification and structure as it is when considering the disease from the clinical point of view. It is apparent, of course, that all tumors or swellings are not malignant new growths ; it is equally evident that malignant new growths — cancer— may be present when no swelling, but rather an actual loss of tissue, exists. Examples of the latter are seen in the shrinkage which occurs in scirrhus of the breast; in ulcer formation, as in squamous-cell carcinoma of the tongue ; and in rodent ulcer of the skin. These circumstances explain the difficulty of defining can- cer, as they do that of defining tumors in general, particularly because the causation of both is unknown, and because all at- tempts at a sharp separation of benign from malignant new growths, or of either from tumors in general, meet with insur- mountable difficulties. Mere hypertrophy, or overgrowth, and inflammatory swell- ings, offer greater difficulties, as a rule, than do abscesses or cysts, although the latter, in certain instances, are not so easy of differentiation as abscesses, and may be malignant in nature. The difficulties are further enhanced by the fact that hyper- trophy or chronic inflammation may precede or exist alongside of cancer, which may be superimposed upon such conditions. In genera], hypertrophy is diffuse, and the normal arrange- ment is maintained ; whereas a tumor, especially a malignant 1 The literature of histological investigation cannot be cited in a book of this scope without serious injustices and without calling forth serious criticism. A very full literature is given in the works of Borst ("Die Lehre von dem Geschwiilsten mix einem mikroskopischen Atlas. ' ' Two volumes, Wiesbaden, 1902), and of Ribbert ("Gesehwiilstlehre fiir Aerzte und Studirende, ' ' Bonn, 1904. ' ' Das Karzinom des Menschen, sein Bau, sein Wachstum, sein Entstehung, " Bonn, 1911), to which the reader is referred. 130 HISTOPATHOLOGY 131 new growth, is localized in one part of an organ whose normal form is disturbed thereby. Acute inflammation, when accom- panied by a swelling, also exhibits other clinical features, such as rise of temperature, pain, etc., different from those present in the case of a true, uncomplicated tumor or a cancer. Chronic inflammation, however, owing to the formation of granuloma, such as one sees in syphilis, tuberculosis, or actino- mycosis, may be associated with a localized increase in size. Such tumors often present great difficulty of diagnosis, more especially because the process of chronic inflammation leading to the formation of granuloma may pass on to true malignant growth, although, as a rule, with the removal of the cause such granuloma formations cease to increase in size and become absorbed. As a general rule tumors grow progressively, although this is not universally the case. Some cartilaginous tumors, for example, found at the ends of the long bones, grow only during the period of development of the bones. It will thus be seen that it is difficult to define a true tumor and quite impossible at present to give an exact definition of cancer. Adami ^ selects Powell White's ^ definition : "A tumour proper is a mass of cells, tissues, or organs resembling those normally present, but arranged atypically. It grows at the expense of the organism without at the same time subserv- ing any useful function." Malignant tumors, in addition, usually exhibit active proliferation; they are not surrounded by a capsule, but fade off diffusely into surrounding tissues by virtue of their property of infiltrative growth ; and they form fresh centers of growth at a distance, owing to the dissemina- tion of cells by the lymph or blood stream. When the normal structure is perfectly reproduced, or if it is sharply separated from surrounding tissues by a capsule, the i tumor is said to be benign or innocent. When the structure is entirely lost and only a mass of imdifferentiated cells is to be seen, it is said to be histologically malignant. It must be dis- tinctly understood that these are merely terms of convenience, and that the biological properties of the tumor determine whether it is clinically malignant or benign. Some tumors, for example, the thyroid, are highly malignant and yet reproduce the normal structure perfectly. There are all grades between total loss and complete retention of structure. ^ Adami, J. George. — * ' The Principles of Pathology. ' ' Two volumes. London, 1909. 2 White, C. Powell. — "The Pathology of Growth — Tumours." London, 1913. 132 THE CANCER PROBLEM Practically all the cells and tissues of the body, with the probable exception of nerve cells/ are liable to tumor forma- tion and to the development of malignant new growths. The term carcinoma is applied if the malignant growth be of epithe- lial origin, sarcoma if it be of connective-tissue origin. The essential feature of cancer, whether it develops in a solid organ like the mamma, or on the covering surface of the skin of a hollow organ, is the continuous proliferation of cells. Since the process is practically the same for all. it is unneces- sary to describe it in detail for each tissue. VALUE OF HISTOLOGICAL STUDY Many volumes have been written upon the minute anatomy or histology of cancer, often with the idea of setting up theories as to causation. The monumental work of Borst,^ extending to 998 pages of print and 293 colored illustrations, and that of Ribbert,^ amounting to G62 pages and 590 figures, may serve to show the mag-nitude of a subject which may be only briefly sur- veyed here. It is intended to convey merely the essential anatomical and microscopical features of the disease ; to demon- strate its relation to normal tissues, in many cases its origin from them ; its mode of growth, and the manner of its dissem- ination throughout the body. The microscopical study of tumors, of their relations to sur- rounding textures, and of the spread of such of them as are malignant in character, has had a profound influence on con- ceptions of the nature of cancer, its origin, and its treatment. It should be more fully recognized that this microscopic 1 The thyroid gland illustrates this difficulty for epithelial tissues, but the development of secondary growths assists in arriving at a definite conclusion, which is not possible in the case of another class of tumors — - in those developing in the central nervous system. These tumors, known as glioma or as gliosarcoma, are still of uncertain origin. Some, by growing progressively, produce a tumor whose effects may be described as those of mechanical pressure. Others grow in a diffuse and infiltra- tive way and rot only involve the membranes of the brain, but may even penetrate the skull. Under the microscope these gliomata or glio- sarcomata have the appearance of what is held to be the connective tissue of true nerve cells, but there is still discussion as to whether the normal gland is an epithelial or a connective tissue. In the retina so-called glio- sarcomata also develop, but in that case it appears not to be doubtful that they are really careinomata. ^ Borst, Max. — ' ' Die Lehre von dem Geschwiilsten mit einem mikro- skopischen Atlas." Two volumes. Wiesbaden, 1902. ^Eibbert, Hugo. — " Geschwiilstlehre fiir Aerzte und Studirende, " Bonn, 1904. "Das Karzinom des Menschen, sein Bau, sein Wachstum, sein Entstehung," Bonn, 1911. HISTOPATHOLOGY 133 study is a modern method of investigation, which has proceeded in part along with, and in part subsequently to, the employ- ment of anesthetics and antiseptics in surgery ; and that, to- gether with them, histology has placed a wide gulf between the surgery of cancer of thirty years ago and surgery as it is prac- ticed to-day. That the influence of the study of the minute anatomy of new growths is still spreading is shown by the fol- lowing quotation from the late Sir Henry Butlin,^ who did so much to place the surgery of cancer of the tongue upon a scien- tific basis : "I have frequently been greatly distressed at the long time during which actual cancer of the tongue has been under ob- servation before either the medical man or the patient has become aware of the gravity of the disease. But I never knew until two years ago that I was myself guilty of failure to recog- nize cancer of the tongue in its earlier, if not its earliest, stages. And I might have remained in the same condition of ignorance had it not been for the work of the Imperial Cancer Research and the assistance of Dr. Bashford and his colleague, Dr. Murray, who have been associated with me throughout the investigation on which this paper is based, and to whom I am more indebted than I can tell. "About two years ago Dr. Bashford asked me whether I could furnish him with very early conditions of cancer of the tongue for the Imperial Cancer Research. I replied that I would certainly do so, and that if I could I would do more than this, for I would furnish him with specimens of precan- cerous conditions of the tongue, so that he might study the transition into actual cancer. . . . "Two years ago, before my eyes were opened by the work of the Imperial Cancer Rese'arch, I should have regarded five out of the seven as precancerous conditions, and I am now won- dering whether there are really any conditions perceptible to human sight and feel which are precancerous in the sense in which I have been accustomed to employ the term. "Many persons will wonder why I have been so slow to dis- cover the true nature of these conditions. I can only answer that I am humiliated at my ignorance, and can only plead, in excuse for it, that I could scarcely ever, a few years ago, per- suade patients to submit to operation for these conditions. And, if I had removed them, it is quite possible that their real nature might have been overlooked unless they had been exam- 1 Butlin, Sir Henry. — ' ' Illustrations of Very Early Conditions of Can- cer of the Ton^e, " Brit. Med. Jour., May 26, 1906. (With colored plate of clinical appearances and histological illustrations.) 134 THE CANCER PROBLEM ined in continuous sections after the manner which is now commonly practised in the investigations of cancerous and douhtful growths." These conchisions of Sir Henry Butlin were accepted by another distinguished surgeon to whom he showed the micro- scopical preparations. In view of their far-reaching impor- tance I thought it necessary to inform myself of the exact nature of the lesions upon which they were based. Owing to the lamented death of Butlin, application was made to Bash- ford, who had prepared a series of sections from which the drawings of an early cancerous ulcer of the tongue (Plate IV) were made. HISTOLOGICAL APPEARANCES The microscopical appearances of a tumor differ according to the degree with which the normal structure is reproduced or is departed from. When the tendency is to reproduction of the normal structure, as in the mamma, the cancer cells are arranged in groups somewhat after the manner of a bunch of grapes, but this characteristic of the normal mammary epithe- lium is not perfectly reproduced. The structure is easily recognized as not being typical of the gland, and varies from one area to another, so that the irregularity of the arrangement dominates the picture. In transverse sections the natural gland spaces or lumina are imperfectly reproduced and are often of irregular shapes. Instead of being of uniform size they may show wide differ- ences in this respect. The lumen of the normal gland may not be developed at all, and in its place only a solid mass of cells may exist. The walls of the liunina are formed, not by a single layer of cells, but by two, three, or more layers. When cut lengthwise the glandular tubules present similar irregularities in arrangement and size. Their branchings and their connec- tions one with another depart widely from the normal, and often appear as if determined by spaces in the connective tissue in which they are embedded. The masses of cancer cells may be very minute or they may form relatively large masses con- nected by all imaginable branchings. The cells may be closely pressed together in solid masses, or they may be arranged in a single layer closely approximating to that of the normal gland, and all intermediate arrangements may be observed. The cells themselves, instead of being uniform in size, may vary greatly in their dimensions, generally tending to be larger than normal. When the tendency is toward an entire loss of structure, the iDtfij^ ^ *«t^* - , i^ l<^ ^ ^' ^ V -to Vi_ r .'^7f ^' :5: ! rt <» 2 ->^ c '"o-c .2 > as S ^ "3 cs MS o to V CO §5 £ =3 §■« a; -in ^— S o 'S.S ^ . f ^ x/. "--='. Z / '^^/^ ^^.O"^''^' \ *^ "-^z //^.^■■^ '?( c 5- "3 u r 3 o o ^§ O t-. ^ *- c o -a o ^ ej3 2H o 1^ ^^M^^?"^ I Plate IX. — Squamous-celled carcinoma (epithelioma) spreading by permea- tion of a lymphatic vessel, of which the hning endothelium is still partly retained. "^^ -^°.A;t5>"C "'l^^sA?' ■^•^5;'!C>S», '.I '•* 'SI •. 4," •*•■ ^ 3 5d S ^ Plate XIII. — Invasion of along bone by adeno-carcinoma of the breast. 0) 4) 1 l^'£-^^>:.S-#^-v>, ^t3 o 3 M P <^ ¥ a; &.J, C -S III ill o ^ OJ3 ^ o °feb S o .5 c II ■©■ ■ j^--- 'O CO bo HISTOFATHOLOGY 135 cells are closely packed together in solid rods or narrow bands embedded in dense connective tissue, as in the well-known scirrhus of the breast, or they occur in large masses much less closely packed together, with a fine connective tissue, as in the typical soft or medullary cancers. In each there may be very little or absolutely no indication of the normal mammary struc- ture. The connective tissue varies in amount, being much more or much less than normal. It carries the blood vessels as in the normal gland. The vascularity is also disturbed, a great increase in the number of vessels being not uncommon. The general arrangement of the connective tissue and of the cancer cells gives the appearance of the cells being contained in spaces in the connective tissue. These spaces, which have been termed alveoli — corresponding with the branchings of the masses of cancer cells — naturally communicate one with an- other, so that the whole structure resembles that of a sponge of which the branching tubules would represent the spaces filled with cancer cells in the case of a malignant tumor. The relative amount of connective tissue or stroma and of cancer- ous epithelium has led, to a great extent, to the classification of tumors into hard and soft, or scirrhous and medullary. In scirrhous cancer of the breast the connective tissue dominates the picture; in medullary cancer the epithelial cells are much the more abundant element. All sorts of intermediate stages may be noted with regard to the arrangement of the epithelium, its approach to or departure from that of the normal gland, and the amount of connective tissue. An abundance of solid rods of cancer cells sparsely embedded in an abundant connective tissue gives the "typical" picture of scirrhus of the breast — the commonest and one of the most dangerous of malignant new growths (Plate V). With the tendency to retention of structure, there may be a diminu- tion in the amount of the connective-tissue element (Plate VI), but, as the accompanying figures show, even where the pre- dominating histological picture tends to reproduce the struc- ture of the normal mammary gland, the growth is still malig- nant, invading and destroying adjacent tissues, and disseminat- ing to distant parts (Plates VII, VIII, IX). A pure adenoma would be regarded as benign, but the term adeno-carcinoma con- veys the difficulty of being sure, notwithstanding the micro- scopical structure, that the growth is really one endowed with malignant properties, as the figures of dissemination by way of the muscle fibers and lymph glands clearly show (Plates X, XI, XII, XIII). The only other glandular epithelia for which illustrations 136 THE CANCER PROBLEM of the cancerous transformation have been chosen are those of the liver and rectum (Plates XIV, XV, XVI, XVII). The accompanying figures illustrate for them also the essential features described for malignant new growths of the breast. There are, however, growths of which the structure is indistin- guishable from the normal, and which nevertheless are highly maligTiant. The most noteworthy is one occurring in the thy- roid gland (Plate XVIII). Notwithstanding its complete re- semblance to the normal histology, it is highly malignant, dis- seminating widely, especially in the bones. (Plate XVIII.) When a tumor or malignant new growth occurs on a surface, as, for example, of the skin or intestine, the continuous prolif- eration of cells leads to an increase in surface area, which may have one of two consequences. This increase in surface area may cause a bulging outward, with foldings of the growing area, or the growing portion may extend below the surface. In the first case there is formed a wart-like growth or papilloma (Plate XIX). Such growths are often benign, but are by no means necessarily so, since the warty outgrowth may be com- bined with a malignant down-growth, for example, in paraffin or arsenic cancer of the skin, in cancer of the lip, in papilloma of the bladder, or in the polypoid growths of the intestines, rectum, and uterus. When growth proceeds downward at an early stage, the continuity with the normal covering epithelium becomes lost and the growth is sharply defined. The definition becomes more clearly marked by the undermining of the adjacent healthy covering, leading to its exfoliation and the formation of an ulcer over the tumor cells. The simplest case is that of the squamous epithelium covering the tongue where the hairs and glands are absent, their presence complicating the picture for the skin itself (Plates XX, XXI, XXII). The squamous epithelium growing downward produces large masses of an ir- regular branching nature, sometimes like enlarged and ab- normal papilla of the skin, but often rounded or so divided up as to have no connective tissue. In the center of these masses the differentiation to a resemblance to horny material, or kera- tinization, gives a characteristic picture. This condition is due to the cells not being now on a free surface, owing to the atypical growth. The cells become arranged concentrically, the keratin being in the middle. The appearance is characteristic, and is known as pearl formation. An exceptional position is occupied by one of the most fre- quent forms of cancer of the skin, especially of the face, namely, rodent ulcer (Plate XXIII). For a long time it was considered to ® >i» . -• •. •?/, .V <:»' •'•- Is- '^i-^^'v..,4 •■»-. - *>» "^ ^ ^ OJ a> > > ;:a "o 'o c3 -rt ;:; r. c j^ rt ■ -*— ^ o- 43. S- ts o o fl3 d «3 OJ ■Si -six ^|x " « c «-- o.- '^ i5 S egg ft ^ -*^ c3 te OJ Ph -i^"" I 4) CO I- .b; _ > H OJ C H ^ C Afa/cgnant ulcer Msrg'Ln of Plate XX. — Margin of squamous-celled carcinoma (epithelioma) of tongue. Note the down growth of the mahgnant epithelium, its continuity with healthy epi- thelium, its liabihty to ulceration. O 5 & ~ c3 -« a 1Z 4) . ■3.C 5P -^ ?3 0/ O 7i £ ^ 2 ^2 0/ -5 ill ii it- ^ S tJ C C ?3 - ^ 53 K >-, ai t_ a, O o-c -^ -- srb 0^ C 3 S =^ O C' yj _ a; S n C O . I. tc 2 '"' a; ;S ^ c « « a a^ « w ., r, ^'^ -*:; 7i c5 j. r^ 5^ r .^ e r s-.ot; vo ^^B.-^ P-^^ .S -^ ~ 7- .^ ::. it 0^^ ^ ^ -S ^ ^ t(f 0/ c-^ £'T^ c: r^j ■^•^ ^^ . ,^ r ^ *-' "E '^^ > s -2 'o ;i ^ aj 'fl rt »i -CtI OP 0) "^ G — ; r- nv rt ?, CO ^ a- "3 c? X ^ -•5 — < -r; - 9% n =^ 3 (1-) "0 '/J cian • -^ ^ ci p ^ Q a; a b£ ^ -C c: -3 1 ^ -c > a; S H ^ 1— 1 ■^ r^ '"^ rj X "no H -C X 01 CU .3 a J2 « -!j :^ OJ ^ bfi OJ 0) o Y o F^ OJ B/ooaf y'e.sse/ 'Jf' 4 ^/^'■f^' ^ #/ ""^^-^^ Plate XXVII. — Spindle-ceUed sarcoma. ?^'m # •.,€«! .^'^ f^^^ © "i %■*■■ «?. * ^ ^ S Off ^ \^ ^A. '• r "J^ A bJj-3 o . a> 3 h2 3 -? I- 13 ^ -^ ,;i^ o3 o grN OS OJ aj o _t» ci o t» '" S O'o >"^ S-S-c o P ^-^ to C3 C rH CQ CO OJ '^ 53 2 £ ^ c ^1 s i OJ CO © ^ ® ® "»' M.ti Ph -Cl^4. Plate XXX. — Melanotic sarcoma. Secondary in liver, showing fatty degenera- tion of liver cells and pressure effects on the liver. Also natm-al size showing number of secondary nodules in a small piece of liver. iS o O s o u X < V Vy/.//^' k-^^^^yy- • S to Sis' p o -/] CD -c a, 2 oo «^~ V Plate XXXIII. — Structure of subcutaneous capillary nevus, or birthmark. In the capillary spaces are seen blood corpuscles. Such a nevus may, under chronic irritation or from an unknown cause, become a malignant growth. Plate XXXV. — Chorion epithelioma of uterus. This is a somewhat rare and highly interesting gi-owth arising during pregnancy. It gives rise to numerous secon- dary growths which often exhibit the remarkable phenomenon of spontaneous heahng. The tumor is invading the muscles of the uterus. It shows the char- acteristic structure of the two epithelial layers of the chorionic villus, viz., the outer darkly staining syncytial layer without definite cell boundaries, giving rise to plasmodial masses, and the deeper layer of Langhans, consisting of large clear cells. The spaces are usually filled with blood. HISTOPATHOLOGY 189 terms applied to the tissues comprising them. The most com- plex tumor, in all probability, is the teratoma, which is the result of the inclusion of portions of an imperfectly developed twin in the fully developed organism. When the tumor of any tissue departs largely from the normal structure, it is known as a carcinoma of the epithelial tissue or organ of origin, and as a sarcoma, if it arise in connective tissue. Tumors which ap- parently arise from the endothelium covering serous surfaces, or lining lymph, and blood vessels, are known as endothelioma. The following tumors are named in accordance with their tissue of origin : ^ Fibrous tissue Fibroma Cartilage Chondroma Bone Osteoma Eed marrow Myeloma Muscle Myoma Fat Lipoma Mucous tissue Myxoma Dental tissue Odontoma ISTerve ]^euroma Glia of nervous system Glioma Lymphatic gland or tissue Lymphoma Blood vessel Angioma Lymph vessel Lymphangioma Resembling any gland Adenoma of the particular gland Resembling wart or out- Papilloma or polypus of the growth. particular site. In the case of the connective-tissue tumors which are malig- nant, i. e., sarcomata, the adjective malignant may be prefixed. Usually, however, the idea of malignancy is conveyed by com- bining the terms given above with sarcoma, thus, osteosar- coma, fibrosarcoma. Similarly, when it is intended to convey the idea of malignancy of a tumor of a gland, carcinoma is combined; thus, adenocarcinoma of the breast, stomach, rec- tum, or other organ of origin. The connective tissue of a tumor, as explained below, is partly inherent in the tumor itself, it is partly derived from the preexistent connective tissue of the surroundings, and it is partly a new formation. All connective tissues, with the excep- ^ Illustrations of many of these appear in the foregoing Plates, as well r,s in Plates XXIV to XXXV. 140 THE CANCER PROBLEiM tion of bone and cartilage, may serve as a scaffolding, and their nature and amount may lead to tumors being classified, for exiimple when fibrous tissue forms an important part of the growth, as fibrosarcoma, fibrolipoma, or fibro-adenoma. When both the epithelial and connective-tissue components of a tumor exhibit malignant properties, it is customary to speak of a mixed tumor or a carcinoma-sarcomatodes. ORIGIN AND SPREAD Histological study, confirmed by the experimental inocula- tion of cancer cells, has now definitely established that cancer arises in a minute circumscribed area where a progressive proliferation of cells takes place. There is usually only one center of growth, but there may be several, which ultimately coalesce within a minute area. It is rare, and indeed it has been denied, that cancerous transformation of an entire organ occurs. It must be remembered that histological study tells us little or nothing as to the biological change which starts the cancerous proliferation. The consequences of the progressive proliferation are local and remote. A lump may form locally, or an ulcer may de- velop. The lump is found, on microscopical examination, not to be encapsulated, and the ulcer is not sharply defined at its base and sides ; both fade off into the surrounding tissues be- cause they have been infiltrated by the growing cells. Actual destruction of tissue may have occurred, especially of a cover- ing skin or mucous membrane, of a bone or of a cartilage. These, although not affording a scaffolding for cancer cells, as does connective tissue, do not become incorporated in the malig- nant growth. The cancer cells penetrate between and destroy muscle fibers by pressure, thus causing disorganization of muscles. The columns of cancer cells may actually spread along inside the sheath of the muscle fibers. They get into the blood vessels, especially the veins, the stronger elastic coat of the arteries being more resistant. They spread along the lymphatic channels either with or against the lymph stream. Both in the veins and lymphatics particles may be carried away and lodged in distant parts, or growth may take place by conti- nuity, as described by TIandley in his "lymphatic permeation" theory. (See Section XI, Chapter 2.) These growing points, as it were, thus proceed ever farther and farther from the parent tumor. Eemote consequences may occur, therefore, anywhere ; but HISTOPATHOLOGY 141 their relative frequency in any particular site is determined by the lymphatic or vascular connections of the site or organ primarily attacked. Thus, owing to the fact that the cancer cells are carried to the liver by the portal system after they have entered the large veins in the submucous tissue of the bowel, the liver is the common site of secondary growths from the rectum or the intestines. The lung is another fre- quent site for secondary growths, extension in this case taking place through the lymphatics or blood vessels, or through the blood stream by way of the thoracic duct When extension takes place through the lymphatic channels, the lymphatic glands are attacked in consequence. Some growths manifest a tendency to the formation of sec- ondary deposits in the bones. Thus colonies arise from trans- planted cells and then reproduce in their new surroundings all the features of the primary growth, so that, as it has been briefly expressed, a piece of rectum is found growing in the liver, liver in the lungs, mamma in lymph glands or bones, and skin in lymph glands or lungs. These exhibit also all the de- structive and infiltrative properties of the primary growth, invading in their turn and destroying the tissues of the im- portant organs in which they have established themselves, caus- ing the destruction of blood vessels and giving rise to hemor- rhages, leading to ulcerated surfaces and to abscesses, destroy- ing bone and leading to spontaneous fractures, settling in the brain and producing unconsciousness and other disturbances. BASIS OF SURGICAL TREATMENT Thiersch and Waldeyer demonstrated that carcinomata are derived from preexisting epithelium, and not, as held by Vir- chow, from connective tissue. They thus dealt the last and final blow to the old views concerning the constitutional nature of the disease — views which had caused surgeons to despair of successfully treating a ''blood disease" by surgery. The first consequence of this change of view was the establishment of the fact that the secondary growths which appear in other parts of the body are the result of the transplantation there of cells from the original focus, thus setting up a fresh colony, and that they are not the result of some influence, proceeding from the primary tumor or pervading the constitution, w^hereby a transformation is effected in the normal tissues of the parts so attacked. Thus the surgical treatment of cancer came to have a rational 142 THE CANCER PROBLEM basis, namely, the removal of the primary focus before any spread had taken place, or, at any rate, before it had extended beyond the immediate neighborhood. Waldeyer ^ recommended the removal of the entire mammary gland, because he thought if one part of an organ had shown itself liable to cancerous change, then the rest, if left behind, would likewise ultimately undergo a similar change. Since that time the doctrine of the circumscribed area within which cancer arises has been estab- lished as the general rule, and to-day the surgical practice of wide removal is based not so much, and often not at all, upon the fear of the liability of the organ as a whole to the disease, as upon the recognition of the necessity for removing the primary focus, together with all the tissues to which there is any possibility of its having already sent offshoots. As long ago as 1867, Charles Moore - was of the opinion that recur- rence after an operation was not due to constitutional taint or to cancer being a "blood disease," but to incomplete removal of the primary tumor and its secondary offshoots. It will be remembered that this view was put forward before Lister had triumphed over sepsis. It is therefore not surprising that the view, and the extensive operation which Moore based upon it, met with strong opposition for years. In a great debate in 1874, before the Pathological Society of London, the above innovations were hotly contested.^ The late Sir James Paget, among others, championed the constitutional or "blood disease" theory as against the circumscribed origin upheld by Moore and de Morgan. Since that time correlated histological study and surgical achievement have established the fact that cancer arises in a minute area which can be excised, and that by thus removing this area the patient may be cured. The experiments of the Imperial Cancer Research Fund have proved that all the features of the disease can be reproduced by implanting the minutest fragment, thus giving additional foundation for mod- ern surgical practice as applied to cancer. SUMMARY The development of knowledge concerning the histopathology of cancer, and the experiments which have proved the trans- * Waldeyer, W. — "Ueber den Krebs, " Vollkmann's Sammlung Minischer Yortroge, No. 33, 1872. 2 Moore, Charles. — ' ' On the Influence of Inadequate Operations on the Theory of Cancer," Trans. Royal Med. Cliir. Soc, London, 1867. 3 Trans. Path. Soc. of London, Vol. XXV, 1871. HISTOPATHOLOGY 143 plantability of cancer tissue, have had a most important bear- ing upon the treatment of the disease, establishing, beyond question, the view that the complete surgical removal of the primary focus results in the eradication of the malignant process and in the cure of the patient. It is therefore greatly to be regretted that the public is encouraged to give ear to old discarded views which to-day are still put forward as if they were new, and which appeal with especial force to the ignorant and to the timid who fear ''the knife." SECTION VI CANCER RESEARCH— A RESUME OF THE WORLD'S WORK PRACTICAL RESULTS The Failure of Modern Experimental Study of Cancer to Estab- lish the Etiology of the Disease. — Before considering the net results of the modern experimental investigation of cancer, it is well to recall the fact that in the essential matter of etiology no entirely new or revolutionary conceptions have been evolved. Cancer continues to offer an exception to the general rule of the gradual change in the prevailing views concerning the causation and treatment of diseases. It likewise fails to come within the category of the revolutionary change in the concep- tion of etiology and treatment which has marked the discovery of the infective nature of many diseases. Dominated for centuries by primitive humoral ideas of dis- ease, it was only in the middle of the nineteenth century, and largely owing to the work of Virchow, that, by observation, facts were established on a basis sufficient to permit students of morbid anatomy, and, later, students of morbid histology, to pursue paths of their own. Leaving medieval dogma and humoral conceptions of cancer out of all account, and considering only those hypotheses which are of modern importance, there has been, in the whole medical history of cancer, no more dramatic clash of theory with fact than that which caused Virchow ^ to cease the publication of his ''Onkologie" (see Section IV, Chapter 1, p. 108), in conse- quence of the appearance of the papers of Thiersch,- whose views were confirmed and extended by those of Waldeyer.^ That ^Virchow, Eudolph.— " Die Krankhaften Geschwiilste, " Berl., 1863, Vol. II, Onkologie, Part I. ^ Thiersch, Carl. — ' ' Der Epithelialkrebs, namentlieh der Haut. Eine anatomisch klinische Untersuchung. Mit einem Atlas mikroseopischer Abildimgen, " Leipz., 1865. ' Waldeyer, W. — ' ' Die Entwicklung der Carcinome ' ' : Virchow 's Archiv, XLI, 1867, No. XXIV, p. 470; ihid., LV, 1872, pp. 67-159; "Ueber den Krebs": Sammlung klin. Vortriige, No. 33, 1872, pp. 163-196. 144 CANCER RESEARCH 145 event marked one of the final breaks from the old belief in the humoral nature of cancer. Another event of importance was the gradual emancipation of investigators from the idea that cancer must of necessity be due to an inherited dyscrasia or ''condition of the blood." The freedom thus obtained has led to the study of cancer by innumerable w^orkers in the autopsy room and in the histopathological laboratory. The final result of the clash between dogma and fact may be said to have resolved itself into an agreement that cancer is local in its beginning. There remained, however, a difference of opinion as to whether or not the increase in the size of the original small area affected is the consequence of the communi- cation of the disease to adjacent tissues. Thus two sharply op- posed schools have arisen, holding, respectively (1) that there is a progressive transformation in the adjacent tissues (apposi- tional transformation), and (2) that the increase in the size of the affected area is due to the progressive growth of the cells primarily attacked and to the displacement by them of adjacent tissues. This discussion was pursued, without final result, up to the time of the establishment of experimental study upon animals. In the past twelve years conflicting views on the nature of cancer have been subjected to the impersonal arbitrament of experiment. By this means a judgment has been obtained en- tirely favorable to the endogenous origin of cancer from the tissues with which it grows in continuity, and in which it has its primary site. In this respect experiment may be said to have but confirmed conclusions arrived at in 1867 by Waldeyer, who, while generously acknowledging the work of others along the same lines, concluded that all primary carcinoma arose by growth in continuity from the covering epithelium, and metas- tases, by the growth of fragments transported by the blood or lymph streams. Waldeyer extended these results to the sar- comata. The results of experiment go further, however, than merely excluding all conclusions other than that a malignant new growth is part and parcel of the body of its host; they permit a choice to be made among many alternative views con- cerning the manner in which cancer is derived from normal tissue. These have been considered in the section of Histopath- ology. Experiments on mice demonstrated very early that it was necessary to separate the problem of the genesis of malignant ne vv growths from that of the conditions suitable for growth ; that is, from the causes which determine mere increase in size 146 THE CANCER PROBLEM and extension in the animal primarily affected.^ Transplanta- tion was shown to be essentially similar to the process of metas- tasis as it occurs in the individual providing the spontaneous tumor. The experimental transmission of carcinoma showed that, while conditions leading to the initiation of malignant tumors were relatively infrequent, once begun, this cancerous proliferation, under favorable conditions, could persist for a long time unaltered; and could give rise to masses of tissue of great size in a large proportion of healthy animals, quite unham- pered by the restrictions which determine the growth and limit the size attained by adult organisms." The value of studying, for its own sake, the problem of growth as presented under experimental conditions has been an incentive to much investigation, especially by the workers of the Imperial Cancer Research Fund, London, and of the Royal Prussian Institute of Experimental Therapeutics, Frankfort-on-Main.^ They have recognized the value of the opportunities afforded by such study for obtaining indirect knowledge of the nature of cancer, and each school has made guarded inferences as to etiology. By a study of hoiu cancer grows, each has hoped to obtain knowledge of why it grows. According to their conceptions the processes of growth present a rational starting point for the study of some of the problems . of cancer, but Ehrlich and his associates on the one hand, and Bashford and his coworkers on the other, have arrived at di- vergent conclusions. In the human subject only the stage at which a tumor has arrived can be subjected to clinical and pathological or micro- scopical examination ; the stages through which it has passed and those through which it may pass in future are necessarily left to the imagination. The discussion of any influence which surroimding tissues, or the body and its fluids as a whole, may exert on the process, is equally hypothetical. So far as the fully developed cancer-cell permits, these gaps may be and already have been partially filled by experiment. Only by experiment, supported by knowledge previously acquired through morbid anatomy and histology, has it been possible to come to certain unequivocal conclusions, such as the following: 1 Bashford and Murray. — ' ' The Significance of the Geographical Distri- bution of Cancer," First Annual Report, Imperial Cancer Research Fund, London, July, 1903. - Bashford and Murray. — ' ' The Significance of the Zoological Distribu- tion, the Nature of the Mitoses, and the Transmissibilty of Cancer." Proc. Roy. Soc, Vol. 73, Jan. 12, 1904. ^ Ehrlich, P. — ' ' Experimentelle Karzinomstudien an Mausen, ' ' Zeit. f. Aertzl. Forthildung, 1906, III, 205; ibid., Arbeit, aus dem Kgl. Inst, fiir experimentelle Therap., Hft. 1, 1906, p. 75. CANCER RESEARCH 147 The "Individuality" of Cancer Established by Experiment — rrom the study of tumors in animals spontaneously affected, as compared with those in normal animals which are the hosts of transplanted tumors, it has been considered proved that the tumor is peculiar to the individual in which it arises, contain- ing nothing demonstrably extraneous. From the study of the life-history of tumors, as made possible by prolonged propaga- tion, the morphological and biological metamorphoses of which tumor-cells are capable have been clearly demonstrated. For all that was known to the contrary, the undifferentiated, "em- bryonic" tissue of a cancer might have exhibited typical differ- entiation promptly after transplantation in the way that trans- planted embryonic tissues do ; that this did not occur in the case of cancer shows that mere arrested growth of embryonic tissue is not a sufficient explanation of the origin and nature of cancer. The individuality of cancer has long been maintained, under various guises, on the basis of deductions drawn from the his- tological examination of the tissues at the site of the primary lesion and on those of the nature of the secondary or metastatic formations. It has also been as vehemently denied. When every consideration is paid to the evidence and arguments which have been adduced for or against the idea of the individuality of cancer, it must be admitted that the purely microscopical findings in themselves were insufficient for decision in all the points in question. Although the advocates of an extrinsic (parasitic) genesis were never able to convince their opponents, the pathological anatomists, the latter were also obliged, on their part, to confess that they did not absolutely refuse to ad- mit the possibility of an extrinsic parasitic etiology. By the simple process of inoculating a bit of cancer tissue, and by observing the local growth and dissemination of the same, long and patient experiment has ultimately supported the view that all the characteristics of cancer may be explained by consequences emanating from a small circumscribed area. For reasons quite different from, and independent of, those ad- vanced by pathological anatomists, investigation of propagated cancer has advanced to two conclusions exceeding all others in theoretical and practical importance: A malignant new growth arises (1) in a circumscribed area, and (2) for reasons par- ticular to the host as an individual. A portion of malignant tumor, transferred to another part of the body, is usually extremely dangerous to the individual. Transferred to the body of another subject, it is very rarely dangerous to the new host, and then only under conditions which obtain in experiments upon lower animals. 148 THE CANCER PROBLEM Experiment appears to have limited the genesis of cancer, more strictly than before, to a combination of causes peculiar to each individual and perhaps to the reaction of his tissues to extraneous irritative agencies, a susceptibility to which may be inherited, as shown in the section on Statistical Consid- erations. Experiment likewise indicates, with equal empha- sis, that no one case of cancer has any direct relation to an- other, as is also pointed out in the section on Statistical Con- siderations. If this be true, then the question may be asked — Why propa- gate cancer? To grow cancer indefinitely is simply to retire farther and farther from the genesis of the disease. For many experimenters, propagation is sufficiently justified as being an indirect way of attacking a problem which hitherto has defied all frontal attacks, while at the same time, it is an objective method of studying the biology of tumor cells. Leaving out of consideration those experimental exigencies which may be met only by having constant sources of tumor material, and leaving for reference later the indirect bearing of the study of propagation, some of its other advantages may be noted. The Possibility of Transference no Proof of Infectivity of Can- cer. — The circumstances under which cancer may be transferred artificially from one animal to another are now accurately known. The strict limitations under which this is possible, even when the experimental conditions are most favorable, are such that, for practical purposes, the danger of natural trans- ference does not require consideration, and is not even of suffi- cient importance to merit debate as an academic question. It is worth while, however, to endeavor to dispel a certain amount of confusion which prevails among many who, having no practical experience with reference to the experimental transmission of cancer, are unable to interpret its significance. As a rule the transference of a primary cancer is very difficult, and must not be confounded with the transference of a propagated cancer. In the former case a growth is removed from its natural environment and placed in strange surround- ings. The cancer-cell rarely survives this procedure. In the latter case the difficulties of the first procedure have been arti- ficially surmoimted, the cancer-cell is no longer a natural one, but one adapted to transference, which, in some cases, but even then by no means always, may be easily performed. There are two important points to be borne in mind with reference to the inoculation of cancer. First, should trans- ference be held to indicate a cause of the great frequency of CANCER RESEARCH 149 cancdr, the reasoning must start from tlie difficulty of trans- ferring primary tumors, and not from the ease with which some artificially propagated tumors may be transferred. Second, transference is effected by the implantation and continued growth of living cancer-cells only. To assume that such an engrafting of cells peculiar to each species, yet parasitic for each, occurs in nature, not only from one individual to another, but from one generation to another throughout the vertebrates, postulates that it has occurred throughout unknown geological ages, and presupposes also the existence of an animate world of which biology knows nothing. A little reflection at once shows the absurdity of such an assumption. Nevertheless, it is entertained by some who do not sharply differentiate be- tween infection and the implantation or grafting of living cells.^ According to their view the implantation of cancer from one generation of mice to another is an experimental reproduction of relations existing in nature. This involves a grave fallacy. It is now universally agreed that experimental cancer is neither more nor less than the grafting of the tumor of an animal (part and parcel of whose body it was) into the same animal or into others to which it is alien. Apolant " writes that the cultivation of a true tumor of the dog has been performed successfully by Bashford ; that this ob- servation has importance because it proves that the transplan- tation through series of animals is not peculiar to the growths of the rat and mouse, but is shared by the higher animals. Therefore the objections raised that the tumors of the mouse and rat are fundamentally different from those of other ani- mals, for example, the dog and man, have no basis in fact. The "Limitless" Growth of Cancer. — Before the experimental era the growth of cancer was loosely spoken of as "limitless," although it terminated with the death of the individual organ- ism attacked. ISTo single fact of itself reveals the fundamental problem so clearly as does the continuous growth of tumors when transferred from one animal to another over a period of time exceeding the duration of the lives of many successive generations of animals. It has been pointed out that the enor- mous amount of growth obtained by artificial propagation is a problem new to the biology of vertebrates, and that the suc- cessive cell generations are comparable to growth as seen in 1 Infection signifies the transformation of normal into diseased tissues through the intervention of micro-organisms. The implantation of cancer cells does not effect any such transformation. ' Apolant, Hugo. — ' ' Die experimentelle Erf orschung der Geschwiilste, ' ' Handbuch der pathogenen Micro-organismen. Herausgeben von Kolle und Wassermann. Bd. Ill, 1913, p. 176. 150 THE CANCER PROBLEM the continuity of species, rather than to that of individual ani- mals ; as, for example, a mouse, a rat, a guinea-pig, a rabbit or a dog; these being the animals in which unquestionable tumors have been or are at present being propagated in different parts of the world. Bashford and j\iurray likened the bulk of mouse tumor which they had produced by 1905 to a mass greater than tliat of an elephant, and in 1906 Ehrlich calculated that his ex- perience signitied the speedy production of a mass exceeding that of the sun. The study of propagation, however, is also of interest in it- self. Are any limits of time or amount set to it, such as are set to the other activities of vertebrate organisms — for example to the length of life itself, or to the length of the gestation' period ? Does it give indications of how it originated or how it is maintained 't Do tumor-strains of different origin, and otherwise distinguishable at the outset of propagation, advance during their continuation to a common type, either in morpho- logical characters or in biological behavior, under the influence of a constant environment ? Is growth purely vegetative, or is it renewed from time to time ? Some of these questions were raised many years ago as the result of the microscopical study of cancer in man. Experiment has only recently replied to some of them ; others have been answered only in ambiguous terms. The Bearing of the Study of Propagation upon Other Phases of the Cancer Problem. — The propagation of cancer has thrown light upon the spontaneous healing of natural cancer in human beings. The study of this important phenomenon, either as it occurs during propagation or in primary tumors in animals, points to the primordial moment of phases in the life of the tumor-cells. Propagation has revealed phases in the suscepti- bility of the tumor-cells to the extracellular factors accompany- ing spontaneous healing. The Microscopical Demonstration of the Facts of Transfer- ring Cancer. — The successful inoculation of cancer — carcinoma and sarcoma — had already been made in rats and mice ; but was neglected and misconstrued. It was therefore reserved for Jensen, in 1902, in the case of carcinoma of the mamma of the mouse, to obtain full recognition for work which clearly demonstrated true transplantation or grafting. In the case of carcinoma previous work by Hanau -^ and Morau ^ had not been 1 Hanau, A. — ' ' Erf olgreiehe experimentelle Uebertragung von Car- cinom," Fortschr. d. Med., Berl., 1889, VII, 321-329. 2 Morau, H. — "Eeeherches experimentales sur la transmissibilit6 de cer- taines neoplasmes (epitheliomas cylindriques) , " Arch, de Med. exper., 1894, 677. CANCER RESEARCH 151 carried out with such great attention to detail ; and in the case of sarcoma the results had been imperfectly or ambiguously de- scribed, largely owing to the difficulty of dealing with sarco- mata as material for experimental observation. The experi- mental reproduction of all the features of natural cancer was completed by the observations of Borrel and Haaland, but mainly it was the result of some years of study on the part of the workers of the Imperial Cancer Research Fund. These in- vestigators demonstrated in 1905 that out of the minute particle of tissue inoculated there were developed, with one and the same tunior strain, not only a local tumor, but also expansive or benign and infiltrative or malignant growths, as well as sec- ondary growths in internal organs and the lymphatic glands, terminal cachexia and death. In succeeding years the workers in this laboratory, notably Haaland and Murray, have added all the details necessary to complete the analogy with the malig- nant new growths in man. Propagation Experiments Justify the Surgical Treatment of Cancer. — This experimental reproduction of all the features of the natural disease has proved conclusively that growth takes place, not by converting healthy cells into cancer cells, but in consequence of the proliferation of the cancer cells introduced. Furthermore, it has established the fact that if the cancer cells are surgically removed early enough after inoculation, all evil effects are obviated. Thus experiment has absolved the surgical treatment of cancer from the last vestiges of the charge that it is unjustifiable, and that, at best, it is a mere empirical pro- ceeding. This is perhaps the most valuable practical result yielded by modern cancer research. Surgical removal is as yet the only sure way in which an animal can be protected against the ultimate consequences of inoculation with cancer-cells. The Infectivity of Cancer in the Light of Propagation Experi- ments. — Modern cancer research has yielded no evidence of the communicability of the disease by infection, and much fresh evidence that this is improbable; while there is quite definite proof that the cause of the great frequency of cancer is not the transplantation of cancer-cells from one person to another. Bearing upon the last point, among many others, three very important facts may be mentioned : ( 1 ) The housing of cancer animals in large numbers with others has not led to any epi- demic. (2) It has been found possible to protect all animals against the inoculation of a tumor from other animals of their own species, but it is quite impossible to protect the animal in which the tumor developed naturally against reinoculation with its own tumor. (3) While it is possible completely to protect 152 THE CANCER PROBLEM animals against an inoculation, and to hold them continuously in that state, nevertheless they may develop tumors of their own. In other words, the animal is resistant to outside agen- cies, namely, the extraneous cancer-cell, but not to processes taking place inside its own body. Although all the foregoing facts are not disputed in the par- ticular cases for which they have been described, the idea that cancer is -infective still finds staunch supporters, even among experimenters themselves ; notably Borrel, of the Pasteur Insti- tute ; Gaylord, of the New York State Laboratory ; and, more recently, Klempcrer ^ and C. Lewin, of the Berlin Charite Can- cer Department. It must be admitted, however, that where they have sought to maintain their position, on the basis that the resistance which may be experimentally produced against the inoculation of cancer is like the immunity which may be in- duced against infective diseases, and due to antibodies, their contention has completely broken down, since they have not been able to adduce satisfactory positive results in support of their claims; Borrel, who originally inclined to the idea that the immunity reactions would clear up the nature of cancer — presumably the infective nature — later assumed the position that these reactions are all against the cancer-cell, and not against a cancer virus, and that they have little or no etiological value. Apparent endemics of cancer in mice have been observed and explained as due to cage infection. Apolant,^ in reviewing the evidence, writes : ''In the first place the statistical data regard- ing cancer epidemics and cage infection are by no means gen- erally recognized as of value. The occasional observation of accumulations of spontaneous tumors in mice and rats is not denied ; I refer only to the communications of Borrel, Asher, Thorel, Gaylord, Kock, Loeb, Haaland. Since, however, simi- lar occurrences have never been observed in the gigantic under- takings of Bashford and Ehrlich, it appears necessary to avoid drawing any far-reaching conclusions from the peculiar isolated observations which in part are also difficult to comprehend." Apolant goes on to review some of the most important instances of "endemics," including that of Thorel, which was proved at a later date to be possibly the consequence of a slow develop- ment of inoculated cancer cells ! Borrel, like Gaylord, has claimed alleged epidemics in labor- ^ Klemperer, G. — "Der jetzigen Stand der Krebsf orschung, " Berl., 1912. 'Apolant, Hugo. — "Die experimentelle Erf orschung der Geschwiilste, " Handbuch der pathogenen Micro-organismen. Herausgeben von KoUe uud Wassermann. 1913. Bd. Ill, p. 220. CANCER RESEARCH 153 atory and other animals as evidence of infection. Other inves- tigators, like Bashford and his colleagues, who have recorded the ages and ancestry of their own animals among whom cancer frequently appeared, declare that such concurrences are not epi- demics at all, but the natural result of a high proportion of aged animals, possibly of the inbreeding of cancerous stock ^ and of exposure to certain specific parasites acting as irritants, for example, nematodes and cestodes in mice, or liver flukes in cows. Borrel ^ first drew attention to the frequency of nematode infection in mice, and has relied upon the frequent presence of these organisms as evidence that they act as intermediate hosts for a cancer virus. Haaland ^ has described them in the connective tissue of the mamma of mice, where cancer so often arises, and has explained the frequency of chronic inflammation as caused by their secretions and excretions. Fibiger * also has employed nematodes in feeding experiments with rats, and in two or three cases carcinomata actually developed. Fibiger, however, did not incline to the above view, but rather to the opinion that the nematode had acted as an irritant. In this view he has been supported by Bashford ^ and others. It is remarkable that so very few true carcinomata developed in Fibiger's 2,000 rats. Thus, while experiment has yielded no fresh evidence in favor of an infective etiology, it has not yet enabled those who hold to the purely cellular view to rout effectually their op- ponents. The latter, however, have been forced to abandon the idea of direct infection,^ and to seek an explanation in a virus conveyed by an intermediate host, of whose existence, however, no direct evidence is forthcoming. On the other hand, even where upholders of the cellular views have admitted that parasites play a part, they have found no difficulty in fitting this role into the conception that chronic irritation is the essential factor. With the exception of these investigators, and those, like Lazarus-Barlow, who seek to prove that all the irritants associated with cancer are radioactive, ^ See remarks on heredity in Sec. Ill, p. 96 et seq. 2 Borrell, A. — ' ' Epithelioses inf ectieuses et epithelomas, ' ' Ann. de 1 'Inst. Pasteur, 1903, XVII, 81. 3 Haaland.— Fourth Scientific Eeport, Imperial Cancer Eesearch Fund, 1911. * Fibiger, J. — "Ueber eine durch Nematoden (Spiroptera sp. n.) hero- orgen ufere papillomatose u. karzinomatose Geschwiilstbildung im magen der Ratte," Berl. Min. Woch., 1913, p. 289; Zeit. f. Krehsf., 1913, 13, 217. => Bashford, E. F.— Nature, 1913. * See remarks on goiter and ' ' cancer ' ' in trout in hatcheries, Sec. II, Chap. 2, p, 55 et seq. 154 THE CANCER PROBLEM the view is generally held that the irritants have no property in common beyond their association with cancer. Their interven- tion is not direct, but mediate. The common factor lies in the prolonged proliferation occurring under chronic irritation. Under this circumstance of prolonged proliferation, oppor- tunity is given for cell variations, some of which are inimical to the rest of the cellular community of which the organism is composed. When we leave the field of generalization for that of special- ized work with the transplanted cancer-cell we enter a region where there is even greater disagreement. Some investigators hold that the study of the cancer-cell can teach nothing, that a virus has started cancerous growth, and is not, therefore, neces- sary for its continuation. Others assert that only by observing the transition from the normal to the cancerous cell is any evi- dence to be expected. Others again claim that the study of the transplanted cancer-cell has not taught anything which morbid anatomy and histology have not already clearly proved. Still others have steadfastly held that in studying the transplanted cancer-cell they are but imitating Darwin's study of the tame pigeon, with the application of his deductions to animals in a state of nature. The last school finds its chief exponents in the adherents of the Imperial Cancer Research Fund of Lon- don, who reason that the study of the transplanted or "tame" cancer-cell is bound to reveal some of its fundamental prop- erties, arguing that its behavior during years of propagation must offer indications of what its possibilities were in its "wild" state, for example, in the animal in which it originally devel- oped. THEORETICAL RESULTS Criticism of the Value of Propagation. — With regard to the value of the continuous propagation of the cancer-cell there has raged some acrimonious controversy, and it is only fair that a review of the criticisms of some eminent pathologists should be placed before the reader. The earlier work appeared to offer many contradictions to human pathology. Notably, Ehrlich's tumors did not produce metastases, and growth was commonly found to be expansive rather than infiltrative. Von Hansemann vigorously attacked all experimental work as being based upon endothelioma, and not on carcinoma. All these objections have been overcome. CANCER RESEARCH 155 and von Hansemann's argiiments have been refuted by Apo- lant,^ Bashford and Murray,^ and Haaland.^ It is still too early to appraise properly the share played by experiment in the abandonment of certain views on cancer, and in the elevation of others to positions of prime importance as profitable working hypotheses. Opinions of representative pathologists are divided as to what has been accomplished in the past, and as to what may be accomplished by this means in the future toward advancing knowledge of the nature and etiology of cancer. Adami,* an unbiased spectator so far as the interpretation of experiments is concerned, frankly ranks the evidence de- rived from experiments with that obtained from other sources. The enlightened outlook sometimes taken is illustrated by the following remarks by Ewing:^ "No experimental evi- dence is needed to show that a naalignant tumor may often be grafted from one part of the animal's own body to another, since the several recognized modes of metastasis daily demon- strate this process. Hahn, Cornil, and others have needlessly performed inoculations in human beings without contributing any important scientific information, while to-day such experi- ments are being successfully performed on animals for legiti- mate objects in many laboratories." Although, as Ewing says, no experimental evidence is needed to show merely that a malignant new growth may often be grafted from one part of an animal's body to another, the fact that it can almost always be done experimentally illustrates the value of that method when applied to elicit exact information as to the relations obtaining between an animal and its own tumor. In short, such experiments have valuable bearings on every aspect of the highly important question as to whether a tumor contains anything foreign to the individual attacked ; as well as on the part played in the inception of cancer by the relation between an organism and its tumor. This procedure is also valuable in testing immunity to inoculation, and in ^ Apolant, Hugo. — ' ' Die epithelialen Geschwiilste der Mause. ' ' Arbeit, aus dem Kgl. Inst. f. experiment. Therap. zu Frankfurt a. M., 1906-8 (Parts 1-4), Pt. I, p. 1. 2 Bashford and Murray. — ' ' On the Genesis of Mouse Tumours. ' ' Second Scientific Eeport, Imperial Cancer Eesearch Fund, 1905, No. 2, Part II, p. 15; "Carcinoma Mammae in the Mouse," Lancet, 1907, Vol. I, p. 798. 3 Haaland, M. — * ' Contribution to the Study of the Development of Sar- coma under Experimental Conditions. ' ' Third Scientific Eeport, Imperial Cancer Eesearch Fund, 1908, p. 175; "Spontaneous Tumours in Mice." Fourth Scientific Eeport, Imperial Cancer Eesearch Fund, 1911, p. 1. *Adami. — "The Principles of Pathology," Chap. XV — The Neoplasms, London, 1909. * Ewing, J. — "Cancer," Harvey Lectures, New York, 1908. 156 THE CANCER PROBLEM studying dissemination. From the standpoint of practical therapeutics it is the sine qua non for testing' the value of al- leged "cures.'' In many other ways the implantation of a tumor in the animal in which it arose has contributed and promises to contribute valuable knowledge. The eminent German pathologist, Ribbert/ who has done so much toward demonstratinc: that tumors grow onlv from their own resoul'ces, and not by apposition through progressive trans- formation of surrounding tissue, is a hostile critic of the ex- perimental method. He says : ''Incidentally I might remark that in general the results which have been gained by extended experimentation on animals have been considerably overvalued, that is, if it was hoped to utilize them in explaining tumor genesis. Of the origin of tumors we have learned nothing that we did not know before. So far as the transplantability of tumors is concerned it should not surprise us in the least, only it could not be demonstrated so long as one tried to transfer human tumors to animals, for altero-transplantation is in gen- eral unsuccessful. Here, however, it is nothing else than a modified metastasis-formation." Those who are familiar with the progTCss of knowledge on the difference in reactions obtaining when heterologous or ho- mologous tissues are inoculated into animals will be struck by such a gloss of the reasons as to why efforts were ultimately con- centrated upon the transference of cancer from one individual to another of the same species. The notion that cancer owes its inception to some common outside cause, led to all these at- tempts to transfer cancer from man to animals, or from an ani- mal of one species to an animal of another species. It was the demonstration of blood relationship, as developed by the study of hemolysins and precipitins (as used to-day, for example, to discover if the blood stain found on a criminal's clothes is of animal or human origin), which led to the concentration of at- tempts to inoculate cancer by restricting such experiments to efforts on animals of the same species. Therefore it was not left for Ribbert to designate the artificial transference of cancer as a modified metastasis. With the exception of a few authors, who have sought to use successful inoculation as proof of infection, or as being respon- sible for the spread of the disease, the implantation of cancers has always been recognized as artificial metastasis. However, Ribbert elsewhere confesses that with the microscope alone it is not easy to combat the assumption that a continually extending metamorphosis of neighboring cells, with consequent apposi- 1 Ribbert, Hugo.— "Das Wesen der Krankheit," Bonn, 1909, pp. 48-49. CANCER RESEARCH 157 tional growth, occurs around malignant tumors. He says : ^ "I cannot disperse my opponents with histological evidence, be it ever so exact. We are not in a position to follow growth itself, but are reduced to the determination of isolated findings in dead material. Their significance is often not easily ap- preciable. What one thinks he has substantiated is reversed by another. It is just for this reason that I have brought for- ward theoretical considerations again . . ." Acknowledging that solely by the exposition of his microscopical findings he cannot succeed, Kibbert is obliged to fall back upon the results of recent experiment. This, by demonstrating that all the con- sequences of the local growth and dissemination of cancer may follow on multiplication, from their own resources, of a little group of cells implanted into a new host, has vindicated the justice of much that Ribbert has so ably sought to establish. Ribbert ^ refers to the results of experiment as follows : ''I may perhaps emphasize that investigation of the growth of animal tumors, particularly during transplantation, has led to the same result. This is of great significance, since such im- portance is ascribed nowadays to these experiments." ''The mention of experimental investigation impels me," he continues, "to discuss briefly a point which is able to support the conception that tumor-cells are not materially different from body-cells. In immunizing experiments one would nat- urally start from the assumption that the origin of immunity is a specific one, in a similar sense as with bacteria. However^ Schone, Michaelis, Borrel, and others have lately stated that one can also immunize with normal embryonal tissue.^ From this fact it emerges that one need not use the cells of the tumor against which he wishes to produce immunity; that thus the normal elements already contain all that characterizes the tumor-cells, and that conversely these latter possess nothing which is not present in the normal cells. I have always thought so, and pointed out, upon a previous occasion,* that one might succeed in immunizing against carcinoma with normal epithe- lium, or perhaps with that of an atheroma." Whether extension of a new growth ever occurs by apposi- tion, and whether Ribbert is right in denying that a biological alteration takes place, transforming the normal cell into a cancer cell, are questions which cannot be settled by mere ^Eibbert — Op. cit. ^ Ribbert — Loc. cit. ^ The First to immunize with normal tissues were Bashford and Murray in 1906. * Eibbert.— DewtecTi. med. Wocli., 1906, No. 42. 158 THE CANCER PROBLEM microscopical examination. It may be recalled in this connec- tion, that the view upheld by others before Ribbert embodies one of the most important facts as to the nature of cancer. Charles II. Moore/ as long ago as 1865, on the basis of his investigations at the Middlesex Hospital, London, and, later, his colleagTie, Campbell de Morgan,- held that cancer arises in a circumscribed area, and that growth or recurrence after operation results only from the cancer cells confined within this area. How much less satisfactorily this point is established by the theoretical method of Ribbert than by the application of experiment, must be evident to all who have read Ribbert's work. Especially is it unconvincing to those who have com- pared its results, as embodied in the foregoing quotations, with the simple fact of the experimental reproduction of the local and disseminated lesions of the disease after the implantation of a minute fragment of tumor. Criticism of the Value of Prolonged Propagation. — So much for criticism as to the value of studying the manner and conse- quences of transference. When, however, the possible profit to be derived from studying cancer during prolonged propaga- tion has come under criticism its usefulness is not admitted even grudgingly. Not only is it asserted that it has taught nothing, but it is declared that it cannot possibly teach any- thing. Even Orth, who is a supporter of the experimental investigation of cancer, and who has acknowledged its value, fails to see utility in studying the life-history of a tumor as prolonged by artificial propagation. ^'ISTot the study of trans- planted cancer, but only the production of the causal genesis of cancer," is Orth's verdict in his latest available contribu- tions.^ Even where it appears probable that cancer has been produced experimentally, for example, by exposure to X-rays, or by feeding rats with cockroaches infected with nematodes, direct attacks have failed to elucidate the processes involved. It has never been denied by experimenters that the study of propagated cancer is only an indirect way of attacking the prob- lems upon which Orth would make a direct attack ; namely, through the relation obtaining between the reactive prolifera- tion induced by chronic irritation and the development of can- ^ Moore, Charles H. — ' * The Antecedents of Cancer, ' ' Brit. Med. Jour., August 12 and 26, 1865, pp. 164 and 201, also p. 473. " De Morgan, Campbell. — Discussion on Cancer, Trans. Path. Soc. of Lon- don, Vol. XXV, 1874, pp. 287 and 387. ^ Orth, J. — * ' Ueber die Krebsgeschwiilst des Menschen, ' ' Sitzungs- berichte der Kgl. pr. Akademie der Wissenschaften, Jan. 28, 1909, p. 107; "Ueber einige Krebsf ragen, " ibid., Dec, 1909, p. 1225; "Pracarcino- matose Krankheiten und kiinstliche Krebse, " Zeitschr. fiir Krebsf or schung, Bd. X, 1910, p. 42. CANCER RESEARCH 159 cer. Thus the study of propagated cancer is regarded by some investigators as devoid of all etiological bearings, while others regard it as futile until more is known of the growth of spon- taneous primary cancer. With regard to the first objection it may be stated that the results of the study of propagated cancer are already recognizable in many directions. For example, it affords no proof of a parasitic or infective etiology; it gives new reasons for delimiting the problem of origin as one peculiar to the individual from causes which are not constitutional, but local ; ^ and it has defined the "age-incidence" of cancer as in- fluencing inception, but not continued growth. With regard to the second objection, it must be remembered that a study of the abnormal is often more practical than a study of the normal, and that, in the history of biological in- vestigation, the study of the abnormal has frequently given the key to the solution of problems presented by normal proc- esses. More than this, after exhaustive and inconclusive in- vestigation of the normal, resort has been had to the deliberate production and investigation of the abnormal, as in the cases of the fertilization of the ovum ; the elucidation of problems of embryology, regeneration, differentiation ; and of the investiga- tion of the parts played in heredity by the cytoplasm and nucleus of the cell. The maintenance of the idea that only the production of primary cancer at will can carry us further in the investigation of the causal genesis of cancer, is one presentation of an atti- tude adopted from time to time during many years by eminent morbid-anatomists. They have not succeeded, however, in pro- ducing cancer and in describing the process, and it is there- fore strange that they should not appreciate the value of eman- cipation — even if only for a time — from the restrictions im- posed by the study of cancer at its site of origin, and by the material provided by the operating theater and autopsies. They appear equally inappreciative of the value of freedom from the limitations imposed by a study of what a cancer is at the time it is found, without clear evidence of what stages had preceded it, or through which it had already passed, and without evi- dence of any kind as to what all the future potentialities of can- cerous growth might be. The experimenters themselves, however, have pointed out and had acknowledged from the first that they claimed to do no more than study the ready-made cancer-cell for prolonged pe- 1 See Introduction, Fourth Scientific Keport, Imperial Cancer Research Fund, 1911. 160 THE CANCER PROBLEM riods of time, under altered environment. They have persis- tently correlated their study of propagated cancer with the study of the disease as it develops naturally in man and animals. They have been studying "the pathology of the living," as Moynihan expresses it, for man, and some of them claim that they have seen the development of new tumors from the mate- rial they have propagated. The comparative knowledge acquired has made it evident that the negative results of attempts to produce cancer in ani- mals are to be explained by the fact that this was attempted, perhaps quite irrationally, by subjecting the animals to various agencies reasonably held to be associated with the development of cancer in man. It early became evident, for example, that chronic irritants having a relation to cancer did not act by virtue of a common factor. Indeed, although to-day it is known how manifold and different are the irritants having relation to cancer in man (apart from certain physical injuries and the less definite evidence of the mediate intervention of some para- sites), little is known of the extent to which irritants may be responsible for cancer in animals. However, the frequency of cancer on the surface of the body of vertebrates living in a state of nature is suggestive in this connection. At the same time, the remarkable divergencies in the liability of a single organ to cancer, for example, the mamma and the liver in mammalia, have acquired enhanced significance, since they show that fac- tors other than the mere intervention of irritation, with its pro- longed sequelae, are operative. Such divergencies in the inci- dence of cancer in organs common to the mammalia ^ point to the possible importance of peculiar idiosyncrasies of species, and, in so far as irritants or parasites play an intermediate role, it follows that those effective for one species may not be effective for any other. Claims have been made that cancer has been produced experimentally in rats ; for example, sarcoma at the root of the tail after exposure to X-rays (Clunet, of Paris), and carcinoma of the stomach (Fibiger, of Copen- hagen). Sarcoma is at present a risky field, owing to the many grada- tions to granulomata of unknown or uncertain etiology, and in the Fibiger experiments the remarkable fact that so few cases of carcinoma developed must be brought into relation with the circumstance that we do not have control of the frequency of carcinoma of the stomach for rats under other conditions, for example, such as the hereditary influence which has been proved to act in mice. 1 See Zoological Distribution, Section II, Chapter 2. CANCER RESEARCH l6l THE BEARING OF IMMUNITY REACTIONS AND OF PROPAGATION ON THE NATURE OF CANCER When the general results of recent research are left, in order to consider the highly specialized investigations of the phenomena of growth and immunity, it is difficult to present a short review of the enormous mass of literature which has rap- idly accumulated in the past twelve years. An excellent review of practically all that has been done has been made by Woglom,^ of the Crocker Cancer Fund of Columbia University, New York City. This author, however, unfortunately refrains from weighing up the evidence in favor of this or that conclusion, except in an all too short final chapter. He gives, however, a very valuable bibliography and a most excellent index to all details. During many annual visits to Europe I have had oppor- tunities of becoming familiar with the details of the investiga- tions of the Imperial Cancer Research Fund in London, and of studying the painstaking scientific work which has been car- ried on by the staff of that institution. It is perhaps unfortunate that the adequate investigation of cancer on an experimental basis requires such enormous re- sources in money, in men, and in animal material. These re- sources have been available, in practically only two centers in the world — to Ehrlich, of Frankfort-on-Main, and to Bashford, in London. In the scope and magnitude of his investigations Bashford has been enabled to outstrip his teacher, Ehrlich. In all essential records of fact, teacher and pupil are in agreement, but as would naturally be expected from men who by nature are determined to cut out paths of their own in any wilderness, even that of cancer, there are divergencies of interpretation ta which reference will be made. In view, therefore, of the unique and extensive experience of Bashford, who, as the Director of the Imperial Cancer Re- search Fund, has had at his disposal a material greater than that commanded by any other investigator, it has seemed expe- dient, for the details of the particular subject now under dis- cussion, to rely mainly upon the summaries which he formu- lated for the International Medical Congress held in London in 1913, more especially since they met with no criticism in- validating any single statement of fact. In other paragraphs the divergencies of these views from those of Ehrlich will be ^Woglom, W. H. — "The Study of Experimental Cancer," Columbia University Press, 1913. 162 THE CANCER PROBLEM summarized ou the basis of the hitest publication from his In- stitute. The text has been paraphrased in order to avoid techni- calities which are not commensurate with the scope of the pres- ent volume. The reader who is interested will find them de- scribed in detail, and well indexed, in Woglom's excellent mono- graph and in Apolant's article in the well-known encyclopedia of Kolle and Wassermann. The Constancy and Variability of Tumor Cells. — In no labora- tory has the propagation of cancer been undertaken upon the scale adopted at the Imperial Cancer Research Fund, where as many as 8G mouse-tumors of different primary origin were kept in propagation for a long time for the purpose of studying their relative constancy and variability. In many cases these tumors were growing also in several parallel sub-strains. This enor- mous material has given unrivaled opportunities for the com- parative study of the biology of the tumor-cells of the mouse. In addition, tumors of the rat, rabbit, guinea-pig and dog (for three generations only) have been successfully cultivated for the sake of the general application of the facts to mammalia in general. Ehrlich's is the only other institution which has kept going a large number of strains restricted to the mouse and rat. At one time Ehrlich had as many as 10 strains of mouse tumors of different origin. These, however, were only a frac- tion of the number grown in London, and they had not the greatly varied character found in Bashford's laboratory. Therefore, while permitting of some conclusions of great im- portance, Ehrlich's views have met with contradiction from other laboratories. On the basis of the experience of the Im- perial Cancer Research workers they have been found to be sub- ject to limitations, and some of the essential facts observed by Ehrlich have been shown to be capable of other and more valid interpretations. Constancy and Variability of Histological Structures. — Evi- dence of the tenacity with which the same structure may be retained is furnished by a tumor which, after eight years and 71 sub-transplantations, retained in two separate strains the structure of the original primary growth, namely, a papillifer- ous adenoma. Two other tumors of similar structure, after growing for seven and five years respectively, still retained the original structure. On the other hand, a fourth tumor, which in earlier transplantations was very gland-like, presented later a solid structure. Other tumors exhibiting a solid structure at the beginning of propagation, continued to do so. One particular tumor, which caused the development of sar- coma (see below), because of the extreme variability which it CANCER RESEARCH 163 showed was propagated for about three years in as many as 17 separate parallel series. Later seven of these parallel series were maintained in growth for another two years. The struc- ture of the several carcinomatous and sarcomatous strains, al- though differing markedly one from another, yet remained quite constant in each strain: (a) alveolar carcinoma; (b) three strains of adenocarcinoma; (c) one strain of carcinoma with spindle-shaped cells; (d) polymorphous-celled sarcoma; and (e) spindle-celled sarcoma. Six tumors were propagated which showed keratinization as the typical differentiation of the primary growth. Two of them continued to produce typical squamous epithelium after two and three years' growth, and 31 and 33 transplantations, respectively. A third, in which keratinization was combined with the formation of sebaceous material, continued to do so after three years and 27 sub-transplantations. The other three completely lost the power of keratinization after varying lengths of propagation. Of tumors showing sebaceous differentiation, two maintained this character in full, one for four years, during 29 sub-trans- plantations. The third showed sebaceous differentiation regu- larly for the first 30 transplantations. In the succeeding six transplantations this change was usually absent, and when present was only small in amount, the tendency to sebaceous differentiation apparently disappearing completely. The fourth showed sebaceous material and keratin in the original primary tumor. The keratin continued in one strain for seven trans- plantations, then disappeared, to reappear again slightly from the nineteenth to the twenty-fifth transplantation. In the fortieth transplantation it was found that the vacuoles con- tained, not sebaceous material, but glycogen. This must have been going on for some time, the glycogen being mistaken for j fat. Another strain showed keratin and a small amount of sebaceous material continuously for 20 transplantations, when both were lost and had not reappeared throughout another 20 transplantations. Relatively enormous quantities of glycogen continued to be formed by a tumor which was propagated for five and one-half years. On the other hand, a tumor which showed considerable amounts of glycogen in the earlier transplantations did not fully retain this character. The glycogen became gradually less in amount during six transplantations, and almost disappeared. Constancy and Variability of More Subtle Properties.^ — While keratin, glycogen, and fat formation are biochemical activities of the cancer-cell capable of microscopical study, there are 164 THE CANCER PROBLEM others which cannot yet be made evident to the eye, except in their consequences. Such are, particuhirly (1) the power pos- sessed by some rare carcinomata of producing- sarcoma in the connective tissue of healthy mice, and (2 ) the conditions known as imnnmity reactions, referred to below. Sarcoma Development.- — The remarkable phenomenon was first described by Ehrlich and Apolant.^ The process has since been observed in other laboratories. It consists essentially in a transformation of the stroma into sarcoma because of some hitherto undefined influence proceeding from the carcinoma cells. Ehrlich and Apolant assumed that the end of all carci- nomatous tumors during propagation would be their replace- ment by sarcoma. Therefore the loss of power to induce sar- coma is of great theoretical interest. The loss of the power to eff'ect a sarcomatous transformation of the connective tissues occurred in five carcinomatous sub- strains derived from a strain which called forth sarcoma devel- opment irregularly, and its appearance was promoted rather than hindered by rapid repetition of the transplantations. An- other tumor caused the development of sarcoma in practically every animal, from the twelfth to the twenty-fifth transplanta- tion, in all the sub-strains propagated, if the tumor was per- mitted to grow for about two months ; but remained pure carci- noma if transplanted at intervals of a month or less. Four car- cinomatous sub-strains which were kept growing presented variations from this behavior. In the first sub-strain the variation was in the direction of an earlier appearance of the sarcoma. This occurred after the twenty-fifth, and continued during the next twenty transplanta- tions, until, finally, the early onset of sarcoma development, combined with slow growth of the carcinoma proper, rendered it impossible to retain the carcinoma in propagation, and the strain became pure sarcoma. In the second sub-strain the change began to appear at a later period, occurring only after one hundred days or more, instead of after sixty days. Subse- quently, even after two hundred days, the tumors remained pure carcinoma. This condition continued during fourteen transplantations, or fifteen months, and the power of producing sarcoma was ultimately lost. Sub-strains 3 and 4 began by causing sarcoma about the sixtieth or seventieth day, continu- ing to do so up to the fifty-third transplantation, but thereafter the appearance of sarcoma was delayed, so that the complete loss of this power seemed probable. ^ Ehrlich and Apolant. — ' ' Beobachtungen iiber maligne mausetumoren, ' ' Berl. Jclin. Woch., 1905, 28, 871. CANCER RESEARCH 165 The power to induce sarcoma development is characteristic of only a small minority of transplantable tumors. When it occurs it is almost certain that it is a characteristic of the pri- mary tumor. The same phenomena have been observed in transplantations of spontaneous tumors into the mice from which the primary tumors were obtained. This condition has also been demonstrated in man. At the Eockefeller Institute growths in the fowl have been discovered which, imder the microscope, it is impossible to dis- tinguish from sarcoma, and which are transmissible by means of a virus contained in a cell-free filtrate obtained through a porcelain filter and by a dried powder. Cell-free filtrates pre- pared from carcinomatous tumor, and tumor of mixed carci- nomatous and sarcomatous structure, as well as pure sarcoma of the mouse, did not lead to tumor formation after inoculation. It has been impossible, therefore, to separate the property of producing sarcoma from the vital activity of mouse tumor cells. The same negative results followed the inoculation of these tumors when dried in vacuo. The differences between the "sar- coma" of the fowl and the mouse in these respects are not fully cleared up, and the sarcomatous nature of the fowl tumor is received with skepticism by some authorities. The nature of this activity of some mouse carcinomata is still as obscure as that of the origin of malignant new growths in general. The attempt to explain sarcoma development by the transference of a virus from the carcinoma cell to the connective tissue is unsat- isfactory, since it will not explain the subsequent loss of this property and at the same time the continued growth of the carcinoma cells. The Immunity Reactions.- — The employment of the term "im- munity" with reference to cancer signifies nothing more than the exemption of the individual — under clearly defined circum- stances — from the consequences of transplanting a tumor from another individual of the same species. Resistance to the transplantation of cancer includes a large number of phenomena which are of the nature of hindrances to the continued growth of the already fully developed cancer- cell. The analysis of these phenomena has permitted the dis- covery of some subtle properties of the cancer-cell, as well as of some of the relations existing between it and the animal in which it grows, both in the case of the natural and in that of the transplanted cancer-cell. Artificially induced resistance to the continued growth of grafts does not create any exemption from the liability to the development of cancer. It is certain, too, that cancer is rarely, 166 THE CANCER PROBLEM if ever, communicated naturally or spontaneously from one individual to another by transplantation, and that its great frequency cannot be explained in this way. Therefore the mechanism of its natural development differs fundamentally from transplantation, and the use of the term "immunity" may be justified only by convenience. The study of such artificial resistance, however, has thro^vn light upon the nature of the tumor-cells and their relation to the individual serving as food purveyor. But sharp distinctions must be drawn between heterologous, homologous, and autol- ogous ^ inoculations, whether employed for the purpose of inducing or of testing resistance. Resistance to Heterologous Inoculation.. — Heterologous inocu- lation may be practiced in two ways. One species of animal, say a rat, may be inoculated with the tumor of another animal, say a mouse, and the rat may then be tested as to resistance to an inoculation of its own kind of tumor, or for resistance to mouse tumor. In the first instance no resistance is induced ; in the second there is. There is general agreement that the normal tissue of tumors of one species of animal is incapable of progressive growth, or even of continued existence, in another species. Very ex- tensive investigations have been made into this subject, and the few positive results cannot be set up against the enormous pre- ponderance of negative results obtained. By far the greater mass of accumulated data shows that tumors of one species are incapable both of progressive growth in another species and of power to induce resistance to tumors of the species inoculated. These two lines of inquiry, therefore, agree in bringing out general exemptions which can be explained only on the basis that tumors have a specificity analogous to that distinguishing the organisms from one another as zoological species. Of them- selves these two groups of phenomena have no bearing upon the resistance which may be induced against the inoculation of tumors into other individuals of the same species. In conjunc- tion with other studies they do have a bearing upon the ques- tion of whether an immunity is induced analogous to that against infective diseases, by showing that, when induced, it does not depend on a virus common to cancer in whatever species of animal it occurs. Induced resistance to a repetition of the heterologous inocu- 1 Heterologous inoculation ^ from one species to another. Homologous " = from one animal into another of the same species. Autologous " ^ reinoculation into the same individual. CANCER RESEARCH 167 lation has been demonstrated to occur and to give reactions identical in nature^ both in vivo and in vitro, to the well known hemolytic and cytotoxic reactions induced by immunizing with antigens from strange species. It is possible that the tumors and tissues of nearly related species — for example, the blood of the rat and of the mouse — do have a slight reciprocal influ- ence ; but, if so, its existence only serves to emphasize the im- portance of blood-relationship rather than the intervention of a cancer parasite common to the different zoological species. The tissues need not be alive m order to induce the hemolytic, cytolytic, and heterologous cancer immune reactions, but retain this power, for example, after mechanical disintegration. Heterologous Immune Sera. — One of the hopes awakened by the knowledge of the cytotoxins was that of a further develop- ment of a rational organotherapy. In the promotion of more accurate diagnosis, and in forensic medicine, the methods relied on have yielded advances of prime importance ; but the hope of fresh therapeutic triumphs has not been fulfilled. The sharp specific distinctions which at times may be drawn in vitro be- tween normal and cancer-immune sera do not necessarily obtain also in vivo. In the test-tube they present, in varying degree, hemolytic precipitin and cytolytic reactions which as yet have not been shown to have any distinctive characters. '^Cancer- immune" sera must to-day be regarded as devoid of all action in the living body. As vehicles for the communication of pas- sive immunity, such heterologous sera have proved valueless, and likewise they have not been demonstrated to possess quali- ties which may be relied upon for purposes of diagnosis. Under this category it is convenient to refer to the results which have been interpreted as toxic or anaphylactic phenom- ena following a repetition of an inoculation. On the basis of careful and numerous repetitions of the method on which such observations have been advanced, the conclusion has been reached that they are due, not to anything specific to cancer tis- sue, but rather to accidental bacterial contamination. Homologous Immunization and Resistance.- — Homologous re- sistance may be considered from the standpoint of whether it is preexistent and natural or induced by active changes follow- ing various procedures. Natural Resistance. — Natural resistance played a much more prominent part at the beginning of the investigation of im- munity to cancer than it does to-day. During the period when an appropriate technic was being developed, many observations could not be otherwise than tentative. For example, with one form of technic the primary transplantation of certain hemor- 168 THE CANCER PROBLEM rhagic mammarv growths of mice succeeded not more than once in 500 attempts. With a different technic these growths were as easy to trausphmt as other manmiary tumors. Naturally the appearance of 499 resistant mice out of 500 was calculated to give great importance to natural resistance. The real explana- tion, however, was found in the employment of such large doses for inoculation that auto-immunization was induced and growth stopped. , Perhaps also the greater suitability for growth of young than of old mice was not fully recognized at that time. The existence of a certain amount of natural variability in power of reaction in different animals cannot be denied, and account must also be taken of age, site, dose, and time interval. Although some tumor-strains are relatively indifferent to age, no strain has been found which grows better in old than in young animals. Young animals, as a rule, are more susceptible than old ones, w^hether they come of normal or of cancerous stock, the latter not offering a more favorable soil. Since young animals are more suitable for inoculation and continued growi:h than old animals, the rarity of cancer in the young is not due to constitutional resistance to growth, and its frequency in the old is not due to a constitutional change, occurring with senescence, favorable to the growth of cancer in general. This conclusion suggested experiments to determine whether animals naturally suffering from the disease offered a more suitable soil than others for the growth of cancer in gen- eral. It was found that they did not do so. Whereas the re- inoculation of an animal with its own tumor is almost always successful, the success of the primary transplantation on in- oculating other cancer-animals is on a level with that for normal animals. The strict individuality of spontaneous tumors has been demonstrated by the resistance which the majority of strange hosts offer to the introduced cancer-cell, and by the fact that it is impossible to immunize a mouse against an in- oculation of its own tumor. Active Resistance Induced by Tumors. — Active resistance may be induced in a variety of ways — by inoculating with spontane- ous or propagated tumor without obvious growth following; by inoculation with propagated tumors w^hich, after a considerable amount of transitory growth, become absorbed; or by inoculat- ing with normal tissues. If the dose of spontaneous tumor inoculated without giving rise to daughter-tumors in normal mice has been sufficiently large, they will exhibit resistance to a second inoculation of a propagated tumor which takes in maximum percentage and pos- sesses extreme power of grow^th. The extent of the resistance is CANCER RESEARCH 169 not uniform for all such negative inoculations with spontaneous or propagated tumors. If the dose be too small resistance may be practically absent, and the animals may react almost nor- mally by giving a number of tumors approximating to the con- trol. Conversely, the dose used to test the existence of resist- ance, if present, may be so large as to overcome it. Spontaneous tumors also vary among themselves in the extent to v^rhich they induce resistance against the same test tumor-strain. Propagated tumors exhibiting the phenomenon of transitory growth followed by spontaneous healing, induce resistance to re- inoculation whenever this results. This resistance is usually absolute for a secondary inoculation of the same tumor-strain, but may be only partial or altogether absent in the case of dif- ferent tumor-strains. There is, thus, a degree of resistance common to all tumors. Active Resistance Induced by Normal Tissue. — ISTormal tis- sues — defibrinated blood, erythrocytes, liver, spleen, testis, mammary gland, kidney, placenta (freed from blood), entire embryos, embryonic skin, etc. — induce a high degree of resis- tance. The most convenient tissues with which to work are blood and embryonic skin. The latter is especially suitable, be- cause of the great uniformity that may be obtained, both tech- nically and in the results, and because it is also the most potent. Spleen, while giving a high degree of resistance, is apt to be infected. Liver is also liable to be infected, and is not so good an immunizing agent. Serum and plasma do not induce any resistance. The dosage of normal tissues can be more accurately adjusted because of the uniformity of the material and of the amount of growth exhibited on transplantation — a variable factor which may be excluded in the case of blood. The power to induce resistance varies from one tissue to an- other, and the same tissue does not induce the same degree of resistance against all tumor-strains. The blood produces a high degree of resistance against one strain, but not against others. Embryonic skin was found to produce the highest de- gree of resistance against a squamous-celled carcinoma. This gave rise to the surmise that histological relationship might have some specific influence, although the possible influence of a high and pure dose of epithelium could not be excluded. Further experience has not yet tended to confirm this view as to histological relationship, and the results may be explicable rather by the varying qualities of the tumor-strains, rendering some more susceptible to resistance, as described below. The high degree of resistance induced by spleen is remark- able, and has attracted particular attention, owing to the ap- 170 THE CANCER PROBLEM parent rarity of metastases in this organ. Testis was stated not to produce resistance, but lias also been found to do so. The Parallel in the Onset, Duration, and Distribution of the Resistance Induced by Tumor and Normal Tissue. — After an immunizing inoculation the parallel in the rise, duration, and disappearance of immunity induced by normal and tumor tis- sue, as sho^vn in the accompanying curve (Fig. 1), is of great JS" 3>aY# t,TnJiTyp mkin—^. I oTTi on._.. Lonlro Ift FxG. 1. — *Curves showing the extent and duration of the resistance induced in mice with embryo mouse skin and spontaneous adenocarcinomata of the mammary gland of the mouse, respectively. The percentage of immune animals is depicted on the vertical, the duration of immunity on the horizontal. importance. Of normal tissues skin always induces a higher, and kidney a lower level of resistance than does spontaneous tumor. There is throughout, however, a parallel course for all three curves, the maximum being attained at about ten days, with a return to the nomial level after about eighty days. This parallel of itself would serve as evidence that resistance is identical in nature, whether induced by normal or cancer tissue. An extraneous agent or virus cannot be made responsible for the resistance induced by embryonic skin, and there seems no * From Woglom, in Journal of Experimental Medicine, Vol. XVI, No. 5, 1912. CANCER RESEARCH 171 reason to suppose that the resistance induced by cancer tissue is due to any property other than that of cancer qua mouse tissue. The resistance conferred by an immunizing inoculation is distributed all over the subcutaneous tissues of the body, the peritoneum, and the internal organs (kidney), extending even to the blood. If a tumor-strain naturally giving rise to metas- tases be injected as fine emulsion into the tail vein, metastases in the lungs can be stimulated, but in immunized animals the number falls far behind that of the control. The wide dis- tribution of resistance throughout the body almost makes the assumption of the presence of some substance in the body-fluida a necessary postulate, and the indications of quantitative rela- tions point in the same direction. Distinction Between Living and Dead Tissues. — Both tumor and normal tissue must be alive in order to call forth resistance. If killed, or disintegrated so that no intact cells remain, no resistance is induced. This applies whether the means em- ployed be chemical, mechanical (as effective crushing at or below 0° C), or actinic (as heat or exposure to radium). The absence of immunizing effect cannot be overcome by enormously increasing the dose. Even red blood corpuscles, if completely ground at the temperature of ice and salt, lose all power to induce resistance. It would appear that growth following in- oculation must contribute to the production of resistance by actually increasing the dose of the effective substances; yet mere growth of itself seems to be non-essential, since growth of the inoculated red blood corpuscles may certainly be excluded. Some subtle product of metabolism of the living cell, in conse- quence of whose action a change is effected in the body-fluids of the resistant animal, appears to be essential. Homologous Immune Serum.^ — The serum of immunized ani- mals has not yet been shown in in vitro experiments to differ from that of normal mice, nothing of an antitoxic or cytolytic reaction having been discovered. Neither has it been shown to possess curative powers, nor has passive resistance been con- ferred by its means. The milk of highly immune mothers con- veys no resistance to their offspring. Nature of the Change.- — The nature of the change effected by immunizing has been elucidated in part by studying the proc- esses of the spontaneous healing of tumors; by examining the site of grafting in normal and in immune animals ; by searching for histological evidences of reaction throughout the body; by analyzing the results of double inoculations of different tumor- strains; by observing the effects of the progressive and trail- 172 THE CANCER PROBLEM sitory growth of tumors on the rohitive weights of the sovpral organs of the body ; and, histlj, by observing any changes which may occur in the metabolism. Spontaneous Healing.^ — The phenomenon of spontaneous heal- ing may bo obtained with any desired freipiency from a suffi- ciently representative series of different propagated tumor- strains. It is extremely rare, however, in spontaneous growths, not occurring as often as once in every hundred of the spon- taneous tumors observed. Very characteristic histological pictures of tumors under- going absorption, after growing for a time, and perhaps attain- ing huge dimensions, have been described by Bashford and ^Furray, Cramer, and Gaylord. There are hemorrhages; the tumor-cells vary in their staining capacity, exhibiting light and dark areas, or they are more obviously degenerating; aggrega- tions of plasma-cells are more frequent than in growing tumors ; later the tumor-cells are cut up into groups surrounded by a large zone of phagocytes, and ultimately scar-tissue forms. The conditions obtaining between the connective tissue and the cancer-cells are obviously quite the opposite of those exist- ing in a growing tumor. From the histological investigation the primary change appears to arise in the tumor-cells them- selves. While this cannot be determined by direct microscopical observation, it is shown to be the case by the fact that, while one tumor goes on growing, another, in the same host, is being absorbed. That the primary change is in the tumor-cells has been determined by studying the site of inoculation in normal and in immune animals, and by investigating the resistance which tumors induce against themselves, as described below under auto-immunization. The histological appearances are exactly analogous in the rare phenomenon of the healing of spontaneous tumors, and in their case also changes in the tumor- cells themselves play the determining role. As in transplanted tumors, one spontaneous tumor may be absorbed while another continues to grow. Whether or not constitutional hindrances to gi-o^vth also develop, as in transplanted tumors, has not yet been determined. Examination of the Site of Grafting. — When a minute graft is made into a new host the carcinoma-cells persist and grow progressively. The supporting scaffolding of blood vessels and connective tissue degenerates and is supplied afresh by the new host reacting to the chemotactic powers of the cancer-cells in such a specific manner that the structure of the mother-tissue is exactly reproduced, perhaps after years of continued propaga- 1 See General Bibliography. i:i I to «« ' /r'r h ■•! i»i