The rejection of Galen's 1000‐year‐old humoral theory by 3 French physicians and surgeons, Lanfranc (1252‐1315), Henri de Mondeville (1260‐1320), and Guy de Chauliac (1300‐1368), coincided with the first public postmortem dissection of 2 human bodies in 1315 in Bologna, Italy and came after the introduction of movable‐type printing in 1450 in Germany by Johannes Guttenberg (1395‐1468). These events signaled the end of the Dark Ages and the beginning of the Renaissance of the arts and sciences, including medicine. The first medical book was printed in 1478. It contained the medical writings of Celsus (25 BCE – ACE 50), a renowned Roman physician. The publication of Celsus' text1 (Fig. 1) was followed shortly by the printing of several ancient medical classics, most of which were reviewed in a recent article.2

The first printed case report of a cancer was published in 1507 in a 54‐page booklet, De Abditis, together with the autopsy protocols of 19 noncancerous cases3 (Fig. 2). The cases were compiled by Antonio Benivieni (1443‐1502), a practicing physician and surgeon in Florence, Italy, and were published posthumously by his brother. The patient was a relative of Benivieni. He treated the patient, without any benefit, for vomiting and wasting. At limited autopsy by abdominal incision, Benivieni found thickened and nodular gastric folds and firm induration of the stomach, which had caused complete obstruction of the pylorus. The description is clearly a portrayal of gastric carcinoma with pyloric obstruction. Although Benivieni did not recognize it as carcinoma and did not explore the abdomen, his narration clearly refers to gastric carcinoma.3

Although sporadic application of chemical agents was introduced by the Egyptians and Greeks before the common era (BCE), the earliest systematic therapeutic use of chemicals was initiated in the 16th century by Paracelsus (1493‐1541). Paracelsus was a physician‐chemist and native of Switzerland. He traveled all over Europe and promoted his chemical remedies and dispensed samples to ailing patients to the annoyance of university professors. His opponents caught up with him in Salzburg, Austria, and beat him to death. Paracelsus was a pioneer in chemistry and chemotherapy. He introduced mercury, lead, sulfur, iron, zinc, copper, arsenic, iodine, and potassium as internal remedies. But he gave due warning in his writings that all chemicals are potentially poisons, and concentration and dose are what make them poisonous or nonpoisonous. His collected papers on chemotherapy of various ailments, including cancers, were published by his followers in 1567 in a book,4 De Grandibus. In it, there is the first description of industrial cancer, cancer of the lung in miners of metal ores and in the workers who smelted the ore. Arsenic was the most common ingredient in chemical formulas.5 Repeated application of arsenic paste of various concentrations was highly recommended for cervical and other superficial cancers by Gabriele Fallopius (1523‐1562), Italian priest‐physician. However, he is best remembered for naming the vagina, clitoris, placenta, and the uterine tubes.6

Army surgeons who cared for wounded soldiers on battlefields were fully aware of the importance of knowing regional anatomy. Between wars, they used their connections in the inner circles of society and advocated anatomic dissection of the bodies of executed criminals. Conversely, physicians, who looked down on surgeons, urged postmortem examination of patients who died of disease. French army surgeon Ambroise Pare (1510‐1590) had limited interest in things other than trauma‐induced wounds but was an ardent proponent of excision of superficial cancers of the lip and other sites by wide excision. He treated breast cancer by placing a sheet of lead covered with quicksilver (mercury) on the tumor, but he was against using compression of the breast, which was a highly recommended treatment by physicians in his day. Pare felt that cancers were far more common and more dangerous in women than in men. He considered cancer of the uterus and other deeply situated organs incurable and used only palliative treatment, purgatives, and diets rich in fruits and broths. His collected works, La Method, were published in Paris7 in a single volume in 1575 (Fig. 3).

A contemporary of Pare, Parisian physician Jean Fernel (1497‐1558) is recognized for introducing the terms physiology and pathology. In his 1555 book, Morbis Universalibus, he devoted a section to cancers8 (Fig. 4). He felt that he was able to differentiate carcinomas and sarcomas with his naked eye because carcinomas were firm and irregular and sarcomas were soft and fleshy. But he cautioned that consistency and form of tumors may vary from organ to organ.

As postmortem examination of deceased patients became accepted as routine procedure, the search for hidden causes of diseases often produced surprises and rendered explanations for clinical signs and symptoms. An example is the autopsy case by Felix Platter (1526‐1614), a Basel physician. By examining the brain of an adult male, who gradually lost his mind, an apple‐sized round fleshy tumor was discovered in the top middle part of the brain. The tumor was encapsulated, and it compressed the substance of the brain. Clearly, the description is a portrayal of a meningioma.9 Platter is also recognized for describing the first case of death in infancy due to an enlarged thymus.

It is perhaps of historical interest to note that medicinal and recreational use of tobacco went on for more than 100 years in Europe before Thomas Venner of London gave warning about smoking in his Via Recta, published in London10 in 1620. He wrote that immoderate use of tobacco hurts the brain and the eye and induces trembling of the limbs and the heart. He concluded that the use of tobacco is tolerable as medicine for toothache, aches in the throat, and indigestion, but not as a substance for pleasure.11

By the early 1600s, anatomic dissections and illustrations had been perfected to the point that very few anatomic details remained undemonstrated. As more and more operative procedures and pathologic autopsies were carried out, time arrived for correlating surgical and pathologic findings in living patients. The first surgeon who made it routine to compare surgical and pathologic findings was Marco Aurelio Severino (1580‐1656) of Naples, Italy. He was a reformer in surgery and introduced many novel surgical procedures. In his 1632 book, De Recondita, he described and illustrated benign and malignant tumors of different organs.12 Severino described tumors of the testis, ovary, breast, and the extremities. He wrote that when breast tumors were fixed to the chest wall, they were malignant, and those that were freely movable were benign glandula (fibroadenoma). He advocated surgical excision of benign tumors because of the possibility that they may become cancerous. By including 17 plates in his book, illustrating some of the largest carcinomas and sarcomas he operated on, he pioneered medical illustration of tumors (Fig. 5). Severino was aware of the potential value of microscopic examination, and in the latest edition of his book, he recommended the use of the microscope for examination of surgical specimens. Another astute surgeon, Peter Lowe (1552‐1612), a Scotsman, observed by operating on tumors that cancers extended far beyond the anatomical edge of the tumor, and he became a fervent proponent of wide excision of all tumors.13

Two physicians in Holland, Zacutus Lusitani (1575‐1642) and Nicholas Tulp (1593‐1674) concluded almost simultaneously that cancers were contagious. They arrived at their shared conclusion by seeing breast cancer in members of the same household. Lusitani and Tulp publicized the contagion theory in their monographs, which were published independently14, 15 in 1649 and 1652, respectively. As to prevention of cancer, they proposed that cancer patients should be isolated in separate quarters, preferably outside of cities and towns. Abdominal distention (ascites) was observed in cancer patients by Jean Riolan (1577‐1657), a French physician. He recommended paracentesis for the relief of abdominal distention as often as needed. However, he had no suggestions for treatment beyond his newly invented procedure.16

German surgeon Johannes Scultetus (1595‐1645) in his Armamentarium Chirurgicum, published in 1655, described and illustrated surgical treatment of cancers by excision and amputation.17 He treated breast cancer by mastectomy followed by cauterization to control bleeding and to eliminate potential foci of remaining cancer (Fig. 6). Published articles, notes, and texts of ancient and contemporary physicians and surgeons on tumors and cancers were collected, catalogued, and published in 1678 in a comprehensive volume,18 entitled Compleat Treatise of Preternatural Tumors, by English surgeon John Brown. Brown's text was an addition to a less elaborate collection of published works on tumors by Giovanni Ingrassia (1510‐1580) of Naples, Italy, published19 in 1553.

Mastectomy with excision of axillary lymph nodes (modified radical mastectomy) was described by German surgeon Guilielmus Hildanus (1560‐1634) in his book, Opera Observationum, published posthumously in 1682. He was an advocate of treating cancer at all body sites by radical surgery.20

Practicing physician and London surgeon William Salmon wrote in his 1686 text, Systema Medicinale, that cancers were surgical diseases and could be diagnosed at an early stage of growth provided that attention was paid to warning signs21 (Fig. 7). He indicated that bloody urine and obstruction of urine flow were caused either by inflammation, caruncle, or cancer. Likewise, he wrote that blood in sputum, cough, and shortness of breath may be due to obstruction of a bronchus by mucus or tumor in the lung. Salmon knew that pulmonary tumors could be primary or secondary, arising from cancers in other parts of the body (metastasis). He held that if the cause of a disease, including cancer, is not known, then its cure will be doubtful.

In 1687, French physician De Saint Andre published in his monograph, Reflexions, that cancers were due to accumulation of body secretions such as saliva, bile, pancreatic juice, and menstrual blood. Despite his misconception concerning the role of secretions in carcinogenesis, he observed with perspicacity that acidity in the stomach favors an ulcer and alkalinity favors cancer.22 A series of unusual anatomic lesions and tumors were described and illustrated by Dutch surgeon Fredericus Ruysch (1638‐1731) in his book,23 Observationum, published in 1691. In it, there is the earliest illustration of papillary tumors of the urinary bladder (Fig. 8). It is of interest that in an era when cutting into the urinary bladder for stones was common practice, he did not offer operative excision of papillary tumors of the bladder. Treating benign and malignant tumors by compression gained ground because of the efforts of Charles Le Clerc (1644‐1727), an eminent surgeon in Paris. However, he admitted in his La Chirurgie Complete, published in 1695, that when compression failed, surgical excision was mandatory.24

In the year of 1700, 3 influential books were published. Italian physician Bernardino Ramazzini (1633‐1714) wrote in his De Morbis Artificum about the harmful effects of metals used in various professions.25 He described the damage caused by mercury to surgeons, chemists, and pharmacists. Ramazzini called attention to an occupational disease, pneumoconiosis, in masons (stone cutters) and miners and pointed out the virtual absence of cervical cancer and the relatively high incidence of breast cancer in nuns.25

Although up to this time many theories of the origin of cancer were advanced, it was French surgeon Deshaies Gendron (1663‐1750) who offered the most realistic view of the genesis of cancer in his book,26 Recherches sur la Nature et la Guerison des Cancers. His understanding was that cancers derived from the transformation and continuous growth of glandular, lymphatic, vascular, and solid structures in the body. He was convinced that cancers are untreatable with drugs and that wide surgical excision was the only curative treatment. Gendron was familiar with cancerous degeneration (metastasis) that often followed initial localized growth of cancer. He deemed such cancers incurable, and he offered no treatment.26

The third publication of note in 1700 was the text, Sepulchretum sive Anatomia Practica, by Swiss physician Theophilus Boneti (1620‐1689). He collected more than 2000 autopsy reports and corresponding clinical records from the notes of his contemporaries and earlier physicians and surgeons and added his own cases and those of his associates to this collection. The amassed material of 2806 cases was published in 3 volumes containing 2260 pages27 (Fig. 9) 11 years after Boneti's death. On cursory review and translation into English from the original Latin, one can find 43 case reports that contain information that can be viewed as descriptions of cancer.28 Among these cancer cases, there are cancers of the brain, head and neck, lung, breast, esophagus, stomach, colon, liver, pancreas, kidney, uterus, cervix, bladder, and prostate. Cases consistent with abdominal carcinomatosis from an unknown primary and a probably malignant lymphoma are also described.28 By tradition, most autopsies were limited to the clinically suspected diseased organs. Therefore, it is not a surprise that metastases were often missed or remained unrecognized. In addition to the 43 cancer cases, Boneti's volumes contain a storehouse of original observations on many benign tumors and medical and surgical conditions. Boneti introduced many new terms, including papillomatosis, carcinomatosis (local metastasis), miliary spread (distant metastasis), carcinomatous dropsy (malignant ascites), strumatosis (lymphoma), and carcinoids (small carcinomas). Despite all the shortcomings of Boneti and his contemporaries, by correlating the results of their clinical and postmortem examinations of cancer patients, they established the foundation for tumor pathology and clinical oncology.27, 28

The routine use of the microscope for diagnosis of tumors and other diseases was first suggested by English physician Michael Etmullerus (1644‐1683). In the expanded edition of his Complete System published posthumously29 in 1712, he warned that chronic cough may be caused by cancer in the lungs or bronchi and that swellings at the joints may due to cancer (sarcoma). Etmullerus knew that cancer occurs in internal organs. For curative purposes, he used several remedies of unusual nature. His favored concoction consisted of fermented powder of crab's eye, red coral, salt of tartar, oil of clove, and opium.5, 29 If medications failed to stop the growth, then he resorted to surgical removal of the tumor.

Francisco Suarez, a Spanish surgeon, recommended the opposite.30 He advised treatment of deep cancers and cancers of internal organs surgically because surgeons were familiar with anatomic structures such as nerves and vessels. However, for superficial cancers, for example cancer of the buccal mucosa, uterine cervix, and the penis, he used powder of jalapa or balsamic and mercurial solutions to induce cicatrization.

Lorenz Heister (1683‐1758), who is regarded as the founder of German surgery, routinely performed postmortem examination of his deceased cancer patients. Autopsy findings gave him the idea that breast cancer should be treated by removal of the breast, axillary lymph nodes, and the pectoralis major muscle31 (radical mastectomy). Heister in his Chirurgie, published in 1719, also described and demonstrated how to perform excision limited to the cancer (lumpectomy). French surgeon Jean‐Lewis Petit (1674‐1750), despite his specialization in treating diseases of bones, was the primary advocate in France of radical mastectomy. In his 1723 book, Traite des Maladies de Os, he described osteomalacia, chondromatosis—including the familiar one—chlorosis, and intramedullary sarcoma with bone formation (osteosarcoma). Petit felt that medical remedies were of no use and all bone tumors should be treated by amputation.32 Another French surgeon, Nicholas Andry (1658‐1742) also specialized in bone diseases and described several forms of skeletal malformations, bone tumors, and chloroma. Above all, by publishing his 1741 monograph entitled, L'Orthopedie, he introduced the term orthopedy.33 (Fig. 10).

Stagnation and coagulation of body secretions, particularly of lymph, and bad substances in water and in the soil were regarded as causes of cancer by Hermann Boerhaave (1668‐1738), a Dutch physician,34 and Jean Astruc (1684‐1766), a French physician.35 Both of them felt that chronic inflammation played a crucial role in the induction of cancer because inflammation blocked the excretory ducts of glands. They named breast cancer as a typical example. Astruc pointed out the need for new techniques for distinguishing inflammatory (reactive and infectious) ulcers and cancerous ulcers. He is also remembered for carrying out a self‐experiment by comparing the taste of cooked breast cancer and beef. He found no difference in taste.35 To the satisfaction of many physicians and surgeons, the role of local irritation and inflammation in causation of cancer was confirmed by London surgeon John Hill (1716‐1775). In his 1761 book,36 Cautions Against the Immoderate Use of Snuff, he wrote that tobacco snuff is able to produce swellings and polyps in the nose. He had personal experience with 6 such cases, 2 of which changed to ulcerated cancer, after their many years of using a large quantity of snuff (Fig. 11). In his text, Hill also confirmed the validity of the concern of Thomas Venner, who had described the danger of immoderate use of tobacco 150 years earlier.10, 11

In the 1700s in the official publication of the Royal Society of London, The Philosophical Transactions, clinicopathology case reports of unusual tumors were introduced. Among the tumors reported were breast cancer, bilateral ovarian mucinous cancer, cancer of the testis, and sarcomas of the femur and the tibia. Printing of such cases signaled the beginning of publication of case reports in medical periodicals37 (Fig. 12).

Reflecting on this narrative of landmarks in the history of cancer during a period of 250 years, it should be recognized that the achievements and failures of physicians and surgeons did not take place in isolation. They were tied to discoveries and omissions of numerous pioneer scientists, including Andreas Vesalius (1514‐1564), William Harvey (1578‐1657), Athanasius Kircher (1602‐1680), Thomas Bartholin (1616‐1680), Marcello Malpighi (1628‐1694), Robert Hooke (1635‐1703), and Antony van Leeuwenhoek (1632‐1723).

In conclusion, the emergence of tumor pathology, surgical oncology, and medical oncology can be traced to medical events that took place between 1500 and 1750 (Table 1).

CONFLICT OF INTEREST DISCLOSURES

The author made no disclosures.