The 3 decades from 1910 to 1940 were the formative years of cancer research in the experimental and clinical laboratories, medical clinics, surgical theaters, and radiology suites. Researchers in the basic sciences and clinical practice disabused fallacious hoary hypotheses that cancer was caused by, inter alia, demons, moral and religious deviations, and humoral imbalances. The initiative of Payton Rous (1879-1970) of using hens for cancer research,1 and the experimental demonstration by Theodor Boveri (1862-1915) that cancer can be triggered by chromosomal mutation,2 galvanized widespread use of animals in the research laboratories.
A few years after the first person, a radiology technician, died of cancer of the skin which was caused by years of exposure to incidental radiation by x-rays,1 Pierre Marie (1853-1940) of France succeeded in producing skin cancer in rats by using x-rays.3 Alexis Carrel (1873-1944) and Montrose T. Burrows (1884-1947) of the Rockefeller Institute for Medical Research in New York established a tissue culture laboratory and were the first to grow tumor tissue in vitro. They used extract from the Rous chicken sarcoma.4 Four years later, at the same institution, the first human cancer, an osteosarcoma, was grown in tissue culture5 (Fig. 1). After refinements of the tissue culture techniques, it was demonstrated that the accurate analysis of the microscopic differences between normal and malignant cells is feasible in tissue culture.6 Eventually, this observation lead to studies, in the 1930s and 1940s, of hundreds of human cancers in long-term tissue cultures.
Carrel, in collaboration with the American aviator Charles Lindbergh (1902-1974), advanced the in vitro techniques by designing a pump for perfusion of cancer-containing animal and human organs with oxygenated nutrient fluid. They demonstrated that the perfused organs and cancers maintained their preperfusion morphology.7 The prerequisite of oxygen for the maintenance of tissues was delineated for the first time by Otto H. Warburg (1883-1970), a German biochemist. He evinced by laboratory experiments that when oxygenation of tissue cells is irreversibly damaged and too little adenosine triphosphate is formed, the increase in fermentation may lead to the production of cancer.8 Subsequently, he discovered that cancer cells use glucose at a higher rate than normal tissues, a phenomenon remembered as the Warburg effect. The Warburg effect realized its full use 50 years later, as the principle behind positron emission tomography (ie, the PET scan). Warburg received the Nobel Prize in 1931 for fruition of his work in biochemistry.
The hypothesis that parasites were cancer-causing organisms was propagated by Johannes Fibiger (1867-1928), a Danish pathologist. He claimed that he produced gastric carcinoma in rats by feeding them cockroaches infected with parasitic nematodes, Spiroptera.9 Fibiger was awarded the Nobel Prize for his work in 1926. Years later, his reputation was tarnished because researchers failed to corroborate his results.
Katsusaburo Yamagiwa (1863-1930), a Tokyo pathologist, first performed a now time-honored experiment, by succeeding to cause tar cancer in animals. For 2 years, Yamagiwa and his associates painted daily the ears of rabbits with a solution of crude coal tar and produced invasive skin cancer in 7 of 137 rabbits. In 2 of these rabbits, the carcinoma metastasized to regional lymph nodes.10 After Yamagiwa's success, the tar-painting of animals became the favorite experimental method for inducing cancer. Researchers decried, for example, that injection of urethane into rabbits and rats was followed by decrease in the circulating lymphocytes11 (Fig. 2). This finding prefigured chemotherapeutic application of urethane in leukemia. More than a decade later, it was demonstrated in a series of experimental studies that by adding mustard gas to coal tar, the carcinogenic effect of tar was inhibited.12 After this germane discovery, nitrogen mustard was added to urethane as a new chemotherapeutic agent.
In 1930, Ernest L. Kennaway (1881-1958), of London, and his team of researchers isolated polycyclic hydrocarbons from coal tar and identified them as carcinogens in experimental animals.13 Two years later, 3,4-benzopyrene was also recovered from coal tar and was added to the list of active carcinogens.14 These nascent discoveries were followed by identification of several additional carcinogens in tars, industrial oils, and petroleum.15-17 The majority of the compounds produced cancer in the liver, kidney, lung, and breast of laboratory animals. After a decade of intensive research activity, hundreds of experimental carcinogens were identified.18, 19
The search for carcinogens extended intuitively to naturally occurring hormones, and in 1932, Antoine M. Lacassagne (1884-1971), a French physician, discovered that carcinoma of the breast can be induced by a female sex hormone (estrogen) injections in male mice.20 A few years later, Lacassagne's original experiment was confirmed by injection of estrogenic compounds into male and female mice.21 The theory was then introduced that the same normally occurring endogenous ovarian hormones, estrogen and progesterone, may play role in the development of breast carcinoma in humans.22 At this point, the notion was advanced whether breast cancer patients would benefit from hormonal antagonists23 (Fig. 3). Using endogenous hormones, Charles B. Huggins (1901-1997), a maverick American urologist, and his coterie of researchers demonstrated experimentally the dependency of prostatic hyperplasia and carcinoma on naturally occurring hormones.24 They proved that carcinoma of the prostate was stimulated by androgens and inhibited by female sex hormones. Not long after their discovery, Huggins began the treatment of carcinoma of the prostate with hormonal manipulation and castration.25 For his pioneering treatment of prostate carcinoma, Huggins received the Nobel Prize in 1966.
Viral research slowed dramatically in the 1920s and 1930s, and there were only 2 memorable original observations reported. Richard E. Shope (1901-1966), an American physician, working at the Rockefeller Institute in New York where Payton Rous made his discovery 2 decades earlier,1 identified a filterable virus which is capable of causing cancerous skin papillomas, a naturally occurring disease called infectious papillomatosis of rabbits. The virus is now known to be a pox virus. Shope was able to transmit the papillomas to other rabbits by rubbing the filtrate on the scarified skin.26 Another disease of infectious nature, Jaagsiekte disease (running sickness of sheep) was reported in South Africa and Australia.27 Because Jaagsiekte disease was transmitted from one animal to another by direct contact, a viral etiology was suspected. Three decades later, the virus was identified as a retrovirus. The striking macroscopic and microscopic similarity of pulmonary changes in Jaagsiekte disease in sheep to bronchioloalveolar carcinoma of the lung in humans has been demonstrated28 (Fig. 4), and is of particular interest at present concerning the epidemiology of lung cancers.29 An erudite reflection on tumor-causing viruses was published by Payton Rous in 1936. He prophetically predicted that some of the viruses may play pivotal role as initiators of carcinogenesis in animals and humans.30
Simultaneously with the aforementioned events in cancer research, multifarious inquires took place in the refinement of thoughts on the etiology and causation of cancers in humans. Twenty-two years after the initial report that Schistosoma hematobium may cause bladder tumor,1 the association between bilharziasis and carcinoma of the bladder was incontrovertibly established in a series of patients upon postmortem examination.31
It had been known for decades that miners in the European Erz Mountains were dying of lung cancer,1 but it was not discovered until 1932 that the miners' lung cancers were due to inhalation of dust containing radium and other radioactive substances.32 A report appeared, almost simultaneously with the European study, that osteosarcoma occurred in workers of a watch factory in New Jersey in the United States, from use of paint containing radium and mesothorium.33 After these reports, radium was added alongside x-ray as a potential carcinogen.
A gamut of veritable observations linked certain cancers to preexisting conditions, inter alia, gastric carcinoma to ulcer of the stomach,34 achlorohydria,35 and chronic gastritis36; linitis plastica to sclerosing degeneration of submucosal gastric glands37; squamous carcinoma of the tongue to leukoplakia38; carcinoid to hyperplasia of the ubiquitous enterochromaffin cells39; skin cancer to kangri basket burn40 and burn scar41; mucosal and cutaneous cancers to inflammatory, mechanical, and chemical irritations42-44; melanoma to traumatized nevi45; malignant tumors of the thyroid to goiters46; colon cancer to ulcerative colitis,47 and hereditary48 and nonhereditary polyposis49; liver carcinoma to cirrhosis and hemochromatosis of the liver35; osteosarcoma to Paget's disease of bone50; and lung carcinoma to squamous metaplasia of the bronchial mucosa.51 Six years after the discovery of asbestos bodies in pulmonary and pleural nodules of asbestos workers,52 it was demonstrated that some of the pulmonary carcinomas and pleural mesotheliomas are caused by asbestosis.53
Tobacco was recognized as a potentially harmful product shortly after it was imported to Europe from Central America in the 1500s. The saga of the danger of smoking is a long one,54 and in 1928, it was definitively established that excessive smoking causes cancer of the lip, jaw, cheek, and the tongue.55 Abstinence from smoking was advised to persons with sores of the oral mucosa, buccal leukoplakia, laryngeal lesions, and chronic bronchitis.56 Frederick L. Hoffman, a statistician of the Prudential Insurance Company of America, performed a survey in the 1920s to see whether there were any health problems associated with tobacco smoking.57 He analyzed his cases with consideration of the kind of tobacco used, the method of smoking, the quantity smoked, and the age at which the person had begun to smoke. He found that the increase in cancer of the lung was directly traceable to cigarette smoking, but older methods of smoking, such as pipe and cigar, were more injurious than the smoking of cigarettes. In Germany, it was demonstrated that of 86 men with lung cancer, the percent of heavy and moderate smokers and nonsmokers were 65%, 48%, and 16%, respectively.58
After reviewing potential etiologic agents from bacteria and chemicals to tobacco, it was concluded51 that external injury by inhalation and intrinsic predisposition of bronchial epithelial cells were the principal causes of lung cancer. In 1941, it was observed by 2 American thoracic surgeons that the increase in lung cancer was due to the increased consumption of tobacco and production of automobiles.59 They admitted the gravity of pulmonary cancer but they believed that due to early detection and advances in surgical therapy, the prognosis was becoming relatively favorable. It is perhaps apt to add that in the interim, Wendell M. Stanly (1905-1971), an American chemist, working in Princeton, New Jersey, isolated the tobacco mosaic virus from infected tobacco leaves.60 In recognition of his work, he received the Nobel Prize in 1946.
The heredity of cancer was debated for centuries,1 but the first credible report of the aggregation of cancer in one family was reported in 1913.61 More than a decade later, 13 members of a family of 30 individuals were reported to have polyposis of the colon.62 In 5 of the patients, the polyps progressed to carcinoma. Carcinoma of the ovary in twins was also published.63 Despite these and other sporadic reports of the occurrence of cancer of the breast, uterus, and prostate in certain families, the genetic nature of cancer remained belittled through the 1940s.
Pathologists in the early 1900s emerged from the autopsy rooms and became the helping hands and the microscopic eyes of surgeons and other physicians. The most noted surgical pathologists were James Ewing (1866-1943) of the United States, Pierre Masson (1880-1959) of France-Canada, and Albert C. Broders (1885-1964) of the United States.
James Ewing, a hematopathologist by background, became the first pathologist in 1913 at the Memorial Hospital for the Treatment of Cancer and Allied Diseases in New York City.1 Being the sole pathologist at the only cancer hospital in the United States afforded him the case material and daily contact with the radiologists, surgeons, and other physicians who cared for cancer patients. Thus, in addition to being a peerless tumor pathologist, he became an adroit clinical oncologist and diagnostic radiologist. Ewing was a polyglot and well-read. In 1919, his book, Neoplastic Diseases, a seminal text on tumors was published and fast became the standard text for the diagnosis and treatment of tumors64 (Fig. 5). It is a massive tome with 1027 pages, nearly 500 clinical and microscopic photographs, and more than 3000 references. After the introductory chapters, there are 39 chapters on specific oncologic entities and organs with tumors. Ewing's book went through 3 subsequent editions. Each updated and enlarged edition was viewed as the most authoritative work on the diagnosis, treatment, and natural history of benign and malignant tumors. The last edition was printed in 1940.65 Ewing summarized in his books his experience and all that was known about tumors. He had a profound interest in the genesis and the etiology of cancers, and believed that inflammation caused by an endless number of chemicals and other tissue-damaging agents was the main cause of cancers. The transformation of benign tumors to malignant ones is a recurring topic in all his writings. Ewing was an advocate of early diagnosis of cancer by radiologic and clinical examination of patients, and microscopic study of minute tissue fragments which were obtained by biopsy forceps, cutting needle, or needle aspiration.64, 65
In 1921, Ewing reported the clinical, radiologic, and pathologic features of a rare and deadly bone cancer in 7 youngsters.66 He named the tumor “diffuse endothelioma,” which has since become known as Ewing's sarcoma.
Shortly after Ewing was appointed as chief of pathology, he became director of the cancer hospital, a position he held until 1939. Ewing was a luminary in tumor pathology and was well versed in the clinical diagnosis and treatment of tumors. He opposed mutilating surgical procedures and was an advocate of radium and low-voltage x-ray therapy of cancers. Through his lectures, writings, and as a consultant, he influenced the way pathologists and clinicians diagnosed tumors and cared for cancer patients. Ewing advocated a multidisciplinary approach in cancer care, and directed in 1940 the first national seminar on the diagnosis and treatment of tumors of the breast. He demonstrated that large number of tumor cells in mitosis, cellular pleomophism, hypervascularity, and tumor necrosis are signs of increased malignancy.64, 65 Many of his redoubtable observations and thoughts are considered valid even today.
In 1931, Ewing's lectures on cancers were transcribed by his students and were printed as a monograph.67 Also, in 1931, the January 12 issue of Time magazine was dedicated to “Cancer Man Ewing,” and he was portrayed on the front cover as a formal homage in recognition of his many contributions to oncology. One can state without reservation that Ewing was the foremost tumor pathologist of the first half of the 20th century.
Pierre Masson (1880-1959), a French-Canadian neuropathologist turned tumor pathologist, in his book, Diagnostic de Laboratoire, which was published in 1923, introduced more new pathology terms than any other pathologists before his time.39 Masson was a prodigious writer. Among his many premier contributions to tumor pathology are: description of subcutaneous epithelioid sarcoma, intrahepatic bile duct carcinoma, adrenal paraganglioma, glomus tumor, myoepithelial tumor of the breast and rhabdomyosarcoma in peripheral nerve. He divided for the first time rhabdomyosarcomas into embryonal and pleomorphic, adult, forms. He explained in length his cogent theories on the genesis and pathomechanism of tumors.39 Masson's main tenet was that nevi and melanomas were of nerve origin.68 He identified the nerve sheath as the source of benign and malignant nerve tumors, or Schwannomas.39 He named carcinoid as an endocrine tumor69 and linked it to nerve hyperplasia.70 Two decades later, he advanced the theory that all intestinal carcinoids are potentially malignant neoplasms.
Albert C. Broders (1885-1964), a pioneer surgical pathologist at the Mayo Clinic in Rochester, Minnesota, was associate director of the Mayo laboratories from 1914. In 1920, Broders introduced an innovative numerical microscopic grading system for carcinomas of the lip,71 based on cellular differentiation on a scale of 1 to 4. A couple years later, he extended his grading method to cancers of other anatomic sites, and he reached the conclusion that tumors with the microscopic cellular morphology of carcinoma should be called carcinoma whether or not the cancer cells invaded beyond the basement membrane. He named noninvasive carcinomas as carcinoma in situ72 (Fig. 6). In the 1930s, Broders and his associates performed retrospective grading of soft tissue and bone sarcomas as well as breast carcinomas. By studying more than 4000 breast carcinomas, they were able to determine, by grading, the occurrence or nonoccurrence of axillary nodal metastasis.73 Broders's system of histologic grading was universally accepted and remains in use today. He was the first to demonstrate that the histologic grade of primary cancers is by far the most important, in addition to the size of the cancer and the depth of the invasion, in predicting outcome.
The roster of reported new malignant neoplastic entities is a long one. The most remarkable newly introduced terms that are still in use were: neurocytoma and neuroblastoma,74 hepatoma,75 chordoma,76 embryonal carcinoma,64 intraepidermal carcinoma,77 carcinosarcoma,64 medulloblastoma,78 dermatofibrosarcoma protuberans,79 oligodendroglioma,80 tubular carcinoma of the breast,81 oat cell carcinoma,82 arrhenoblastoma,83 reticuloendothelioma and histiocytoma,84 synovial sarcoma,85 comedocarcinoma,86 neurilemmoma,87 and mesonephroma ovarii.88
Memorable case reports and large series of cases were often published under the cooperation of pathologists, radiologists, and surgeons, which added much-needed credibility to the presented data. It is perhaps important to remember that many of the so-called first cases and series of cases were often reported by physicians who were not distinguished, and the authors are often forgotten. Some of the most remarkable first reports were: preinvasive carcinoma (carcinoma in situ) of the uterus,89 metastatic rhabdomyosarcoma,90 parosteal sarcoma,37 thymic tumors in association with myasthenia gravis,91 primitive neuroectodermal tumor,92 follicular lymphoma,93 oat cell carcinoma of the lung,94 malignant meningioma,95 microinvasive duct carcinoma of the breast,96 pleural mesothelioma,97 malignant melanoma of the eye,98 carcinoma of the bladder,99 primary lung carcinoma,100 biphasic and monophasic synovial sarcoma,101 chordoid tumor of the palm,102 extramammary Paget's disease,103 Ewing's sarcoma of soft tissues,104 and classification tumors of the testis.105
Many new and cogent classifications of cancers were introduced, but only a few achieved permanent acceptance. Ewing's classification of cancers lasted into the 1960s with little modification.64, 65 By studying the depth of invasion and the lymphatic spread of carcinoma of the rectum, Cuthbert Dukes (1890-1977), a London pathologist, classified the tumors into groups A, B, and C.106 According to this formidable design: A) The carcinoma was confined to the wall of the rectum, B) The carcinoma has progressed by direct spread to the perirectal tissues, and C) The carcinoma metastasized to perirectal lymph nodes (Fig. 7). Dukes extended his classification schema to carcinomas of the colon in the 1940s, and it remains in use to today to augur intestinal cancers. The prognosis of Hodgkin's disease was linked to histopathologic forms of the tumor. It was demonstrated that it made a significant difference whether the tumor was a paragranuloma, granuloma, or sarcoma.107
From the first time cancer cells were seen with the microscope in 1838 on smears from scrapings of tumors,108 the cytologic examination was gradually extended to body fluids and secretions.109 Introduction of laboratory stains, intraoperative microscopic examination,110 and the diagnosis of tumors on smears made from aspirates64 contributed to the burgeoning practice of cytology. In 1928, 2 physicians, Aurel Babès (1886-1961), a gynecologist in Romania, and George Papanicolaou (1883-1962), an anatomist in New York, presented their techniques of obtaining cells by scraping from the cervix and the vagina of gynecologic patients. The article by Babès with microscopic photographs illustrating precancerous cells and cancer cells of the uterine cervix was published in Paris in the April 1928 issue of the La Presse Médicale111 (Fig. 8). Papanicolaou, in January of the same year, presented his illustrated lecture at an international conference, the Third Race Betterment Conference, in Detroit, Michigan.112 Although Babès' and Papanicolaou's analogous techniques were well thought out and auspicious, their method was not appreciated by the medical community, and the smear technique was not accepted for the detection of uterine cancers until the 1940s.113 In the interim, the aspiration smear technique was perfected,67 and Fred W. Stewart (1894-1991), an associate pathologist of James Ewing at the Memorial Hospital for Cancer and Allied Diseases, extended needle aspiration to tumors at all body sites.114 During the same period, the diagnostic cytology techniques and microscopic examination of body fluids and secretions became routine procedures. It was reported, for example, that in 68% of the carcinomas of the lung and larynx, the diagnosis of cancer was established by examination of the sputum.115
From 1900 onward, surgery was developing special fields, and each subsequent decade added specialized knowledge to patient care to the extent that during the first half of the 20th century, the medical profession's zeitgeist was that radical surgical treatment was the best treatment for primary and metastatic cancers. Radical surgical procedures that were introduced in the late 1800s1 were perfected, and the tenacity of surgeons resulted in the decrease of operative mortality of cancer patients.116-119 Some of the most notable inventions and procedures that were put in routine use were: removal of bladder tumors by transurethral fulguration,120 diagnosis of cancer by laparoscopy and thoracoscopy,121 gastroscopy with an optical instrument equipped with a lamp at its tip,122 extended radical surgical procedure for tumors of the head and jaws,123 resection portion of the esophagus and reconstruction with a rubber tube,124 tracheobronchoscopy,125 extended retroperitoneal node dissection,126 hemipelvectomy,127 forequarter amputation,128 demonstration of the main lymphatics of the breast with collaterals to other sites129 (Fig. 9), trans-sternal thoracotomy,130 rectosigmoidoscopy with rigid scope using a lamp and mirror for illumination,131 technique of colostomy and the apparatus with rubber receptacle,132 uterine cervical biopsy with forceps,133 resection of the colon with excision of the lymph nodes,42 pulmonary resection for the treatment of metastatic tumors,134 technique of wide excision of cancers to prevent recurrence,135 interscapulo-thoracic resection,136 thoracotomy for metastatic carcinoma of the lung and mediastinum,137 transillumination to distinguish solid and cystic breast lesions,96 detection of uterine cervical carcinoma by painting the cervix with Lugol's iodine solution,138 pneumonectomy for primary carcinoma of the lung,139 peritoneoscopy,140 resection of carcinoma of the ampulla of Vater,141 modified pancreatoduodenectomy,142 segmental pneumonectomy,143 and surgical resection of metastasis to the liver.144
Although the surgeons' raison d'etre was to perfect their operative techniques with intent of improving the survival of patients, they also spent considerable time on publishing their cases with end results, and they occasionally described newly discovered entities. The most splendid reports were: The origin of most primary lung carcinomas were intraoperatively traced to the major bronchi.145 Primary malignant melanoma of the rectum, an invariably fatal disease, was reported for the first time to originate at the pectinate line and to grow upward into the rectal ampulla.146 Three decades after American surgeon William Halsted (1852-1922) introduced his radical operation for breast cancer,1 he reported permanent lymphedema of the upper extremity after surgery in a large percentage of his patients.147 In 1922, it was found in a large series of patients that life expectancy following radical mastectomy depended on the size of the carcinoma and the extent of axillary spread of the carcinoma.148
In a series of 878 patients treated by mastectomy at the Johns Hopkins Hospital, Baltimore, Maryland, during a period of 42 years, it was reported that the postoperative mortality was gradually reduced to 6%, and the 3-year survival of patients increased to an unprecedented 52%.149 The 5-year survival rate of patients, who had carcinoma of the colon and rectum and had surgical resection, by different surgeons who were using different methods, ranged from 13% to 29%.42 Twenty-eight cases of a new entity, inflammatory mammary carcinoma, with invariably grave prognosis, was reported.150 Forty years after the first abdominal desmoid tumors were reported,1 the natural history of desmoid tumors of the abdominal wall was presented with review of 59 published cases. It was concluded that because 80% of the tumors occurred in women who have borne children, trauma plays role in the etiology of the growths and the treatment should involve early and complete removal with wide tumor-free margins.151 The clinical presentation, radiology, treatment, and prognosis of bone sarcomas were presented by pointing out that, on average, fewer than 15% of the patients were alive for 5 years.152 A new deadly entity, superior pulmonary sulcus tumor, was described with presentation of the characteristic clinical signs and symptoms and radiologic appearance.153 A total of 54% of the patients who were treated for primary carcinoma of the ovary were alive 3 or more years after surgery.154 In 1934, Joe V. Meigs (1892-1963), an American surgeon, as a follow-up to his earlier observation,1 in his book Tumors of the Female Pelvic Organs155 described a series of new gynecologic observations including ovarian tumors with ascites and hydrothorax that became known as Meigs' syndrome. Alan O. Whipple (1881-1963), a New York surgeon, introduced a new and radical procedure, pancreaticoduodenectomy and resection of peripancreatic lymph nodes and the spleen. The operation became known as the Whipple procedure,141 and it was described after careful observation that carcinoma of the pancreas is associated with deep venous thrombosis in 25% of the patients.156 A large series of patients had surgical resection of their chordoma with limited success.157 Carcinoma of the kidney was deemed a highly malignant neoplasm, and only 7% of the 127 patients who had nephrectomy lived 10 years.158 On the other hand, the outlook for patients with thyroid carcinoma was excellent. A total of 58% of the 774 patients who had surgery were alive 10 years after surgery.159 It is perhaps important to add that the improved survival of patients in the 1930s did not come about solely because of improved surgical techniques. Undoubtedly, after the discovery of penicillin160 and sulfanilamide,161 patients were protected against some of the intraoperative, perioperative, and postoperative bacterial infections, whereas this added protection was not available in the prior decades.
Harvey W. Cushing (1869-1939), an American neurosurgeon, contributed more to improving the diagnosis and surgical treatment of tumors of the brain, meninges, and spinal cord than any other surgeon. He, along with his associates, discovered several new entities,78, 80 but above all, he was a master surgeon who advanced surgical techniques by adoption of new anesthetic methods, electrocoagulation, electric suction, and surgical decompression. Cushing was stringent about the preoperative preparation of patients. He insisted that the patients must have thorough physical and x-ray examination, electroencephalography, and ventriculography. His expertise and skills have transformed brain surgery, which was previously a highly fatal procedure, into a comparatively safe operation, and by the 1930s, he reduced the surgical mortality to 11% and the postoperative mortality to 16%.162 Cushing's classification of brain tumors with consideration of histopathologic appearance allowed him to delineate the prognosis80 (Fig. 10). There is no doubt that Cushing was a consummate brain surgeon, and his work is regarded as the most important surgical achievement in the first half of the 20th century. Even a synoptic review would not be complete without mentioning that in 1932, Cushing reported pituitary basophilic adenoma-associated centripetal obesity, moon face, hypertension, and gonadal dysfunction.163 The pituitary endocrine tumor-induced disease is eponymically known as Cushing's disease. As an addendum, Cushing as a medical historian authored the biography of William Osler (1849-1919), his much-admired mentor. The book is enticing and won for him a Pulitzer Prize for literature in 1926.
The penultimate portion of this review is on diagnostic radiology and radiation therapy. It is perhaps worth pointing out that amid all the advances in surgery, progress in radiologic diagnosis of tumors proceeded slowly, mainly due to the technical difficulties. Nevertheless, by 1908, fluoroscopy of the stomach, facilitated by the patient swallowing a suspension of bismuth, was adopted for radiologic diagnosis of gastric lesions,164 and 15 years later, barium enema was added for visualization of colonic tumors.132 Other groundbreaking techniques introduced were ventriculoscopy of the brain by using air,165 pneumocystography,166 transhepatic cholangiography,167 injection of radio-opaque oil (lipiodol),168 the use of thorium dioxide (Thorotrast) for visualizing the spleen,169 tomography,170 drinking of effervescent Vichy water for visualization of pancreatic tumors,171 and pyelography and cystography after injection of radio-opaque substance.172
It was recognized from the outset that accurate radiologic diagnosis depended on the technical know-how and expertise of the radiologists. The first radiologists were mostly surgeons who were eager to know what was hidden from them in the tissues and organs of the patients before they operated. It is interesting to note that bone tumors in animals were among the first tumors diagnosed by radiologic examination.173 The earliest remarkable diagnoses of malignant tumors in humans were: Ewing's sarcoma with the characteristic thickening of the periosteum,66 bone sarcomas with elevation of the periosteum at the edge of the tumor (Codman's triangle),174 primary carcinoma of the lung,175, 176 carcinoma of the colon,132 different types of bone sarcomas with clinical and pathologic correlation,152, 177 breast cancers with call for limited surgery and radium treatment,178 and carcinomas metastatic to bone with illustration of the skeletal distribution.179 In this latter article, the author listed breast carcinoma, carcinoma of the prostate, uterus, and thyroid as the most common primary neoplasms with metastases to bone. It was found disappointing that upon radiologic examination of the breast (mammography) of 142 asymptomatic patients, the differentiation between cystic tumors, solid benign tumors, and malignant neoplasms was not possible.180
Even though radiotherapy had its birth the year after Röntgen discovered x-rays,1 radiation therapy was still in the inchoate phase in the first decades of the 20th century. The majority of the problems were caused by the technical difficulties, setbacks in manufacturing, unsettled instrumentation, and the cost. Furthermore, it did not help that the progenitors of radiotherapy were physicians with diverse background and irresolute interest. At the beginning, it was a random decision in most cases whether x-rays or radium should be used.181, 182
However, after the 1920s, when radiology was recognized as a new medical specialty, for example by the American Medical Association, radiologists made concerted efforts to advance radiation treatment by selecting the best modality of therapy with attention to the size, location, and histological type and grade of the cancer. The majority of the earliest attempts in radiation therapy were made to treat the 2 most common and most dreaded cancers of women: breast cancer and uterine cervical cancer. For most of the breast cancers, treatment consisted of x-ray radiation67, 96, 149, 183, 184 (Fig. 11), whereas the majority of cervical cancers were treated by interstitial or endocavitary application of radium seeds (brachytherapy)133, 155, 185-189 (Fig. 12). In both cancers, the radiation was given either as palliative measure,188, 190 in inoperable cases, or it was delivered postoperatively to the primary site and regional lymph nodes.191-195 On rare occasions, the radiation was given prior to surgery to the tumor-bearing area.196 Some of the other first attempts at radiation therapy were treatment of carcinomas of the prostate,172, 197, 198 bladder,99, 172, 197 esophagus,199 thyroid,159, 200 pharynx and larynx,201, 202 rectum and anus,203 as well as metastases,179, 204 leukemia,205-207 Hodgkin's disease,107 non-Hodgkin's lymphoma,93 brain tumors,80 and sarcomas.152, 177, 208
Culling of the results of radiation therapy was bordering on the impossible due to dearth of accurate information and the variation of techniques and the way partial and complete response as well as disease-free survival were defined. The variations in reporting were extreme from country to country and from institution to institution. Some of the treatment results reported were: complete response of skin cancers in 65% of the patients,182 limited success in the treatment of inoperable cervical cancers and successful treatment in operable cases,209, 210 a 5-year cure rate of 18% in advanced cervical cancers,211 a 30% cure rate with postoperative radiation of breast cancers,192 prolongation of life in the majority of metastatic cancers,179 very limited success in treating anal and rectal cancers due to inability to treat the metastatic nodes,203 and temporary results in some of the bone sarcomas64, 67, 152 and lymphomas.107 Although the cellular damage caused by radiation was fairly well understood and was credited to disintegration of the cytoplasm, destruction of the centriole, segmentation of the chromosomes, and destruction of the nuclear chromatin,182, 212 the reason for radioresistance was not clear beyond suggesting that the decrease of oxygenation and the blood supply was somehow involved.213 Because of proven radioresistance of the majority of cancers, surgery continued to hold primacy in treatment of cancer patients. The quintessential examples of exceptions to this rule were Ewing's sarcoma and Hodgkin's disease.
At the end of the 19th century, Paul Ehrlich (1854-1915), a German biochemist, introduced the concept that chemicals might be useful in the treatment of cancers.1 By the turn of the century, an endless number of chemicals were used as internal therapeutic agents, including alcohol, arsenic, jodoform, selenium, potassium chloride, osmium, pyoctanin, thallium, and thyroid extract.64, 214, 215 In 1919, Edward B. Krumbhaar (1882-1966), a US Army pathologist, was the first to notice that soldiers who survived for several days the poisoning by mustard gas during World War I developed profound leukopenia.216 Krumbhaar's observation on leukopenia received no attention for years, but a decade later, it was demonstrated in experimental and clinical studies that certain malignant tumors temporarily decreased in size when nitrogen mustard was administered. However, nitrogen mustard treatment of patients was proscribed due to extreme toxicity.217 Again, surgery continued to hold its lead in the treatment of cancer patients, and the therapeutic use of nitrogen mustard did not resurface until the 1940s.
With the exception of the vaccination attempts by William B. Coley (1862-1936)1 and the first clinical use of autologous tumor cell suspension,218 the potentials of the discoveries in immunology and immunotherapy remained almost completely unexplored prior to the 1940s. Some of the noteworthy reported observations and therapeutic attempts were: patients were given autologous or allogeneic tumor vaccine without therapeutic benefit,219, 220 alterations in the chromosomes of cells were deemed prerequisite to cancer,2 the lymphocytes and eosinophiles were identified to play an important role in immunity against the growth and spread of cancer,221-224 antigen–antibody coupling was viewed as a precondition to immunity,225 DNA in the cell was recognized to play critical role in immunity,226 and finally, advanced age was regarded as “cancer age” due to immune deficit.227
Adding all up, although the advances made in detection of cancer by clinical and radiologic examinations coupled with innovative radiation therapy and improved radical surgical techniques resulted in longer recurrence-free survival of the majority of cancer patients by the end of the 1930s,65 the overall survival showed little improvement. Likewise, the worldwide incidence of the most common cancers64, 65, 228 remained very much the same as it was in the first decades of the 20th century64, 229-231 (Fig. 13). The exceptions were increase in gastric carcinomas65 and lung carcinomas.57-59, 228 At the end of the 1930s, mortality due to cancer, according to the American Society for Control of Cancer, ranked second as the cause of death in the United States.65, 232 In a very revealing comparative study of cancers in Jews and non-Jews in Europe, a significant difference was reported in the incidence of breast, ovarian, intestinal, and uterine carcinomas.233 It was noted that breast, ovarian, and intestinal carcinomas were more common, and uterine carcinomas were less common in Jews than in non-Jews.
Parenthetically, the events in cancer research, diagnosis, and treatment of cancers were intimately associated with the founding of cancer research institutions and cancer hospitals. Some of the new bastions dedicated to cancer research and specialized care of cancer patients were the Radiumhemmet, Sweden (1910); the Netherlands Cancer Institute (1913); the Russian Radiology and Oncology Institute (1920); the French Institut du Cancer (1921); the Cancer Research Centre of India (1922); the Institut du Cancer at Louvain, Belgium (1925); the Belgian Centre Anticanceraux (1925); the Leningrad Institute of Oncology (1926); the Research Hospital of the New York State Institute for the Study of Malignant Disease (1931); the National Cancer Institute of the United States (1937); and the Institute of Cancer Research of the Royal Cancer Hospital, London, England (1939).
In addition, the nexus between newly established cancer registries and organizations furthered the commitment to early detection, diagnosis, and treatment of cancers. The most notable associations that were formed are: the American Association for Cancer Research (1907); the American Commission on Cancer (1912); the American Society for Control of Cancer (1913); the American Registry of Bone Sarcomas (1920); the French Association for the Study of Cancer (1920); the German Cancer Registry (1927); the Polish Anti-Cancer Society (1929); the International Union Against Cancer, or UICC (1933); the Connecticut Tumor Registry, United States (1935); the Tumor Registry of the Armed Forces Institute of Pathology, United States (1937); and the Cancer Registry of New York (1940).
It would be a remiss not to recognize Jacob Wolff (1861-1938), a German physician, for his exhaustive 4 volumes on the history of cancer,234 which were published in 1907 through 1928, and Cushman D. Haagensen (1900-1990), an American surgeon, for publishing in 1933 an annotated bibliography of cancer.235
It is perhaps a fitting conclusion that during the 3 decades covered in this narrative, more discoveries were made in the etiology, early detection, diagnosis, and therapy of cancers than were made in all prior centuries combined.1, 108, 236, 237 Looking back, it is apparent that despite the many advances that were made in the care of cancer patients (Table 1), the optimism of ardent surgeons and radiotherapists about the prospects for conquering cancer was an early and unrealistic claim. By contrast, pathologists, as the result of interaction with surgeons and other physicians who cared for cancer patients, emerged as dependable custodians of the old and newly discovered neoplastic entities, histopathologic classifications, and histologic grading of cancers, all of which were recognized as prerequisite for planning of the most appropriate therapy.
|Year||Medical History||Year||World History|
|1910||Hepatoma, neuroblastoma and carcinoma in situ described. Transurethral fulguration of bladder tumors.||1910||Institut Océanographique de Monaco founded. Stravinsky's Firebird performed in Paris.|
|1911||Laparoscopy, thoracoscopy, and gastroscopy introduced. Wertheim's hysterectomy popularized.||1911||Marie Curie receives her second Nobel Prize. Mona Lisa stolen from the Louvre.|
|1912||Bowen's disease described. Extended radical neck dissection, and tumor vaccine introduced.||1912||Detection of protons and electrons. The Titanic sinks.|
|1913||Hereditary cancers reported. Esophagectomy with plastic reconstruction.||1913||Neils Bohr formulates his theory of atoms.|
|1914||Human cancer grown in tissue culture. Carcinoid indentified as neuroendocrine tumor. Parosteal sarcoma and the immunologic role of lymphocyte described. Tracheobronchoscopy introduced.||1914||The First World War begins. The Panama Canal opens.|
|1915||Tar-cancer produced in animals. Squamous carcinoma linked to leukoplakia.||1915||German troops introduce nitrogen mustard gas.|
|1916||Hemipelvectomy introduced.||1916||Ultrasound detects submarines.|
|1917||Radiation therapy of prostate and bladder carcinomas.||1917||Communist revolution in Russia. British occupy Baghdad.|
|1918||Carcinoma of stomach linked to gastric ulcer.||1918||Iceland becomes independent state.|
|1919||Mustard gas causes leukopenia.||1919||Versailles peace conference.|
|1920||Broder's histologic grading introduced||1920||Structure of Milky Way shown.|
|1921||Ewing's sarcoma and postmastectomy lymphedema reported. Transhepatic cholangiography.||1921||Isotopes successfully separated. British Broadcasting Company is formed.|
|1922||Nucleo-cytoplasmic ratio described. Forequarter amputation. Brachytherapy of uterine carcinomas.||1922||Self-winding wristwatch invented.|
|1923||Rectosigmoidoscopy and barium enema.||1923||Hitler fails to take power in Germany.|
|1924||Inflammatory breast carcinoma described. Abdominal desmoids linked to trauma. Leukemia treated with radiation.||1924||U.S. grants Cuba independence. The first winter Olympics are held.|
|1925||Urethane decreased lymphocytes in animals. Jaagsiekte disease, medulloblastoma, follicular lymphoma, and Codman triangle described. Lyphoma treated with radiation. Colon resection with node dissection.||1925||The concept of genes introduced by the Russian Vavilov. Afrikaans becomes the official language of South Africa.|
|1926||Tubular carcinoma and oligodendroglioma reported. Classification of brain tumors. Brain tumors irradiated.||1926||John Baird of Scotland invents television transmitter.|
|1927||Soft tissue and bone sarcomas treated with radiation.||1927||Charles Lindbergh flies from New York to Paris.|
|1928||Smear technique introduced for detection of cervical carcinoma. Colon carcinoma linked to polyposis. Smoking determined to cause cancer.||1928||The American Schick invents electric razor.|
|1929||The Warburg effect defined. Thyroid carcinoma linked to goiter. Mesothorium causes osteosarcoma. X-ray radiation of breast carcinoma.||1929||Russian-American chemist Phoebus Levene discovers RNA and DNA.|
|1930||Polycyclic hydrocarbons identified as carcinogens. Oat cell carcinoma described.||1930||France begins building the Maginot Line.|
|1931||Hepatoma linked to cirrhosis. Microinvasive breast carcinoma reported. Limited breast surgery and radium treatment.||1931||Lawrence, American physicist, invents cyclotron. New York's Empire State Building opens.|
|1932||Benzopyrene identified as carcinogen. Breast carcinoma induced by estrogen in animals. Miners' lung cancer caused by radioactive substances. Carcinoma in situ is named. Superior sulcus tumor described. Cancer is second leading cause of death in the United States.||1932||Antigen-antibody complex described. Positron and neutron discovered. Work begins on the Golden Gate Bridge in San Francisco.|
|1933||Aspiration biopsy promoted as a diagnostic procedure. Schiller's test and tomography introduced. Pneumonectomy for lung cancer.||1933||Hitler becomes Chancellor of Germany. The first Nazi concentration camp established at Dachau.|
|1934||Synovial sarcoma, comedocarcinoma, and the Meigs' syndrome described. Anorectal carcinoma irradiated.||1934||The S.S. Queen Mary is completed.|
|1935||Lung cancer and mesothelioma linked to asbestosis. Dukes' classification and Whipple procedure introduced.||1935||The radar is built.|
|1936||Biphasic and monophasic synovial sarcoma reported. Radioresistance is defined.||1936||DNA demonstrated in the cell nucleus.|
|1937||Benzanthracenes identified as carcinogens. Classification of Hodgkin's disease.||1937||The first jet engine is built.|
|1938||First mammography is performed.||1938||Xerography is developed.|
|1939||Prostate carcinoma inhibited by estrogen. Segmental pneumonectomy||1939||The Second World War begins.|
|1940||Pyelography and cystography introduced.||1940||Hemingway publishes For Whom the Bell Tolls.|