Volume 118, Issue 4 p. 1155-1168
Communication
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A note from history: Landmarks in history of cancer, part 3

Steven I. Hajdu MD

Corresponding Author

Steven I. Hajdu MD

Westlake, California

Fax: (805) 496-0620

1759 Drumcliff Court, Westlake Village, CA 91361Search for more papers by this author
First published: 12 July 2011
Citations: 31

Abstract

In the early 19th century, microscopy in pathology replaced gross descriptive pathology of the 18th century. Cells became known as the most important and distinct elements of benign and cancerous tissues. Thus, by the mid-1800s, a solid foundation had been laid for microscopy, and surgeons recognized that microscopic diagnosis by pathologists merited attention. In due course, preoperative microscopic diagnoses and classification of cancers in biopsy specimens were incorporated into choosing the most fitting surgical operation. Cancer 2012;. © 2011 American Cancer Society.

Advances made between 1500 and 1750 in pathology and surgery1 served as ground for further progress in the 18th and 19th centuries in understanding the nature and the macroscopic and microscopic composition of benign and malignant tumors. In general, physicians like Giovanni Batista Morgagni (1682-1771) of Italy were clinical practitioners who made routine practice postmortem examination of the bodies of their deceased patients. Morgagni, in his book De Sedibus, et Causis Morborum (De Sedibus), published in 1761, correlated clinical and postmortem findings in 700 autopsied cases2 (Fig. 1). He knew about malignant ascites and advocated paracentesis with a syringe. In addition, he introduced colposcopic examination of the uterine cervix by inserting a funnel into the vagina.

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This is the title page of Morgagni's De Sedibus published in Louvain in 1767.

Morgagni reported 17 cases of cancer in his De Sedibus. To a certain extent, his postmortem examination was incomplete in most cases, because he used limited incision and examined only the apparently diseased organs. He examined 5 cases of cancer of the stomach. He noted that, shortly before death, some of the patients vomited soot-like material and voided per rectum similar black material (occult blood). Although, in 1 of his cases, at autopsy, he observed grape-sized, white nodules in the liver (metastases) and enlarged supraclavicular lymph nodes (Virchow lymph nodes), he did not recognize them as metastases, because he had no notion about metastatic spread of cancer. He described 2 cases of breast cancer with axillary extension and edema of the arm (lymphedema). He assumed that the edema was caused by compression of vessels and nerves in the axilla by cancerous growths.

Morgagni gave account of a patient who had a testicular tumor. To his surprise, at autopsy, there were multiple tumor nodules in the retroperitoneum (metastases). He also presented his necropsy findings in 3 cases of throat cancer, 2 colon cancers, and 2 uterine cervical cancers. In a case of pancreatic cancer, he warned that, because of the deep location of the pancreas, pancreatic tumors seldom were diagnosed during the life of the patient. One additional case he reported was a boy who died with disseminated tumor that appears to be lymphoma at an advanced stage.3

Morgagni is remembered as the most famous clinician-pathologist because of his unique correlation of patients' ailments and postmortem findings and his ability to convince the medical profession that the advancement of medicine rested on clinicopathologic correlation. In addition to tumors, De Sedibus contains hundreds of first descriptions of specific diseases and a dozen eponyms, and it is recognized as the founding work of premicroscopic pathology.

In the second half of the 18th century, the prevailing view was that scirrhus (tumor firm to touch) was different from cancer, and 2 distinct forms were recognized: occult and symptomatic. Occult scirrhus appeared most commonly on the skin, had a long duration, and most often was harmless. Apparently, warts, thickenings, scars, and perhaps condylomas belonged to this category. Symptomatic scirrhus was regarded as hard and ill-defined tumor deep under the skin and in fatty tissues that often degenerated to cancer. Obstruction of vascular outflow and deposit of harmful substances were named as probable causes of scirrhous tumors. Cancers were held different from scirrhus. They could be located anywhere in the body and were caused by accumulation and coagulation of lymphatic serous fluid. It is interesting to note how soon the newly discovered lymph by Bartholin and others in the mid-1600s was added to coagulated blood as the cancer-causing agent. Most of those who accepted the subdivision of tumors into potentially malignant (scirrhus) and malignant (cancer) favored surgical excision over topic application of medications.4 For breast cancer, the recommendation was radical mastectomy.5

Table 1. Chronology of Discoveries, First Descriptions, New Terms, and Other Salient Events
Year Medical History Year World History
1761 Seventeen case reports of cancer and lymphedema of an arm coupled with breast cancer reported 1762 Sandwiches invented in England
1766 Obstruction of vascular flow named cause of cancer 1766 Hydrogen density discovered
1774 Radical mastectomy introduced 1774 Telegraph introduced
1775 Scrotal cancer caused by soot described 1776 American Declaration of Independence
1792 A cancer ward opened in London 1792 US mint dollar coins
1793 Nipple retraction and puckering of skin in breast cancer and botryoid sarcoma of bladder reported 1793 Reign of Terror begins in France
1795 Cancer of lower lip caused by pipe smoking 1795 The French occupy Belgium
1798 The term cancerous dyathesis introduced 1798 Gas lighting in London
1799 Blastema and connective tissue named as source of genesis of all cancers 1799 Rosetta Stone found near Rosetta, Egypt
1805 Postmastectomy lymphedema of arm reported 1804 Napoleon is Emperor
1806 Mycosis fungoides described; proven that cancer is not a contagious disease 1806 Webster published the first American dictionary
1809 Ovariectomy performed; eye tumors described 1809 Excavations at Pompeii
1811 Sarcomas named malignant tumors 1811 Paraguay's independence
1816 A primary carcinoma of lung and colloid carcinoma described; melanosis reported as pigmented cancer 1815 The Americans defeat the British at New Orleans
1822 Skin cancer caused by arsenic described 1822 Liberia founded
1825 Male breast cancer reported 1825 Johann Strauss is born
1829 The idea of hereditary breast carcinoma and the word metastasis introduced 1829 The Smithsonian Institute founded in Washington, DC
1832 Seven cases of Hodgkin disease reported 1833 Britain abolished slavery
1838 Cell theory introduced. Cancers classified and microscopically illustrated 1838 First steamer crosses the Atlantic in 15 days
1843 The term liposarcoma introduced; hematology inaugurated as a new specialty 1843 The world's first night club opens in Paris
1845 Microscopic atlas of pathology published; the terms leukemia and nucleocytoplasmic ratio introduced 1845 Texas and Florida become states of the US
1848 Bence-Jones protein discovered 1848 Revolts in Europe
1850 In situ and infiltrating lobular carcinoma and microinvasion reported and illustrated 1849 Dostoevsky sentenced to death in Russia
1853 Paget disease of breast described; cervical cancer cells observed on smear preparation 1853 First Statistical Congress held in Brussels, Belgium
1854 Bilateral breast cancer described and illustrated 1854 Le Figaro published
1858 The concept that cells come from cells published 1858 Suez Canal Company formed
1859 Surgical classification of cancers printed 1859 Origin of Species published
1863 Detailed microscopic description and illustration of benign and malignant tumors published 1863 Abraham Lincoln signs the Emancipation Proclamation

In 1775, Percivall Pott (1714-1788), English surgeon, without realizing, put a dent into the 4000-year-old theory of causation of cancer. Pott included a short description in his text of Chirurgical Observations on chimney-sweeps with cancer of the scrotum (Fig. 2). He presumed that the cancer was caused by chronic exposure to an environmental agent: soot.6 His observation received wide acceptance and earned him a permanent place in medical history. Pott was actively interested in all sorts of tumors and is credited with the description of Pott tumor—a collection of pus under the pericranium of the scalp (osteomyelitis) as a result of head injury. Regarding cancer, he held that women were more subject to cancer than men. It is puzzling that, despite his original observation that soot was a cancer-causing agent, he continued to adhere to the ancient theory that cancers were caused by the ubiquitous black bile. Parenthetically, in 1779, he gave the classic account of spinal cord compression leading to spinal curvature and paralysis as a result of vertebral tuberculosis. The condition has since been named Pott disease.

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Pott described soot cancer of the scrotum in chimney sweeps in 1775.

Bernard Peyrilhe (1735-1804), French physician, in searching for the cause of cancer, named obstruction of the flow of body fluids—lymph—as the proximate cause of cancer. He believed that stagnation of fluids led to putrefaction and, thus, that ichorous (amorphous and necrotic) matter gave rise to primary and secondary (metastatic) cancers within the body of ailing patients. In an attempt to further his learning about the cause of cancer and its mode of spread, he carried out, in his house, the injection of fluid from a human breast cancer into a dog. Eventually, he had to discontinue his experiment, because his housekeeper objected to the howling of the dog.7

Four noted English surgeons of this era, James Hill, Benjamin Bell (1749-1806), John Pearson, and Joseph Adams (1756-1818), published their books on the signs, symptoms, and surgical treatment of ulcers and cancers8-11 within a few years of the opening of the first cancer ward at the Middlesex Hospital in London in 1792. Those surgeons concurred that cancers and lesions suspected to be cancerous should be removed by generous surgical excision. Pearson warned10 that slowly growing breast cancers had a tendency to contract and, misleadingly, could diminish in size after years of expansion. He then added that retraction of the nipple and puckering of the skin (peau d'orange) were characteristic signs of breast cancer of long duration and required prompt amputation of the breast (Fig. 3).

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In 1793, in his book on cancerous tumors, Pearson described many peculiar features of cancers, including retraction of the nipple and peau d'orange in breast cancer.

The last 2 clinical monographs on cancer published in the 18th century that deserve to be referenced were authored by Samuel T. Soemmerring (1755-1830) and Conrad G. Ontyd. Soemmering reported the association between pipe smoking and cancer of the lower lip.12 Ontyd introduced the term cancerous dyathesis as a precondition to develop cancer from precancerous lesions.13

The hindmost clinician-pathologist, Metthew Baillie (1761-1823) of London, published his systematic treatise in pathology, The Morbid Anatomy of Some of the Most Important Parts of the Human Body (Morbid Anatomy), in 1793, followed by his macroscopic pathology atlas in 1799 as a supplement to his Morbid Anatomy. His dictum was that a successful physician must exercise common sense and cater to the right people. He was the attending physician of the emotionally unbalanced King George III of England, who governed during the American Revolutionary War. Although Baillie did not appreciate the microscope as a useful scientific instrument, his Morbid Anatomy made him famous. It was the first English textbook of pathology and was the first pathology book to be printed in North America. Baillie departed from traditional reporting of pathologic conditions. He described and illustrated pathologic changes according to organ systems and their structures (tissues) as they appeared to the naked eye.14 He described and illustrated common and rare tumors in adults and children. Among the rare tumors, he listed dermoid cyst of the ovary, carcinoma of the stomach in women, carcinoma of the esophagus, osteosarcoma, and polypoid rhabdomyoma (botryoid sarcoma) of the bladder in children (Fig. 4).

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In 1799, in his pathology atlas, Metthew Baillie illustrated a tumor protruding into the bladder and the urethra of a child. He named the tumor rhabdomyoma.

Xavier Bichat (1771-1802), French physician, was not a practicing clinician. He devoted his entire time to postmortem dissections and should be remembered as the first full-time pathologist. Before his untimely death at age 31 years, he wrote and published 4 substantial texts in pathology. The most notable is Traite des Membranes en General et de Diverse Membranes en Particulier.15 Bichat believed that the microscope was an instrument of limited value, because microscopic objects are viewed by everyone differently. It is puzzling how Bichat was able to distinguish more than 20 different types of tissues without microscopic examination. His concept that diseases, including tumors and cancers, occur as the result of pathologic changes in tissues revolutionized medical thinking. He advanced the notion that cancerous tissues are composed of stroma (connective tissue) and parenchyma (epithelial tissue) and initiated the theory that all cancers originate in connective tissue and are the same—scirrhous (firm), encephaloid (soft), and melanoid (pigmented)—regardless of the organ of origin. Bichat introduced the term cellular tissue, meaning that, in tissues and organs, there are empty spaces, pores, which are surrounded by fibers, nerves, and vessels—a concept first described by Robert Hooke in 1665, when he gave the name cells to the tissue spaces in plants. Bichat conceived the idea that the network of these filamentous structures and fibers renders a pathway for cancers into surrounding tissues (local invasion and spreading).

At the close of the 18th century, most physicians thought about cancer as an ominous lesion that spreads gradually and destructively; is ultimately fatal if left untreated; is prone to recur after excision, either locally or at distant site; and causes a nutritional disturbance that leads ultimately to cachexia and death. In general, during the first 2 decades of the 19th century—at the threshold of the microscopic era—numerous noteworthy medical and surgical observations were made and entered into the annals of oncology.

Ulcerated cutaneous tumors and enlarged lymph nodes (cutaneous lymphoma) were described and illustrated by Jean Alibert (1768-1837), the founder of French dermatology,16 in 1806. He named the disease mycosis fungoides (Fig. 5). He also introduced the terms keloid and lupus. James Nooth, an English surgeon, reported17 that he failed to produce any growth by inoculating himself with small pieces of breast cancer. The failure convinced him that, contrary to earlier views,1 cancer is not a contagious disease. Linear extension of cancers (infiltration) between fatty substance (fat cells) was described by macroscopic examination of tissue sections.18 Intraosseous tumors, which are composed partly of bone and partly of soft encephaloid substance (soft tumors), were named osteosarcoma19 by Samuel Cooper (1780-1848), a surgeon in London. He emphasized the importance of the examination by surgeons, the interior of the operative wound, and the surface of every tumor to ascertain that no tumor was left behind. In the same year, James Wardrop (1782-1869), English surgeon, introduced the term fungus hematodes for soft, protruding tumors.20 Having particular interest in diseases of the eye, he noticed that such tumors were common in the eyes of children (retinoblastoma or perhaps orbital rhabdomyosarcoma) (Fig. 6).

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In 1806, Jean Alibert described and illustrated a man with multiple, mushroom-like, eruptions. He called the disease mycosis fungoides. The patient died 5-years later with disseminated tumors and enlarged lymph nodes.

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This is James Wardrop's 1809 illustration of a child with retinoblastoma or perhaps embryonal rhabdomyosarcoma.

John Abernathy (1764-1831), English surgeon, in his Surgical Observations on Tumors, published in 1811, distinguished different types of tumors according to their consistency.21 He considered sarcomas for the first time as malignant new growths that sometimes have a looser texture than carcinomas. According to him, carcinomatous sarcomas (carcinosarcomas) may be located in any organ, but pure sarcomas are located most commonly in vascular and adipose tissues.

In the first book published on cancer in the United States,22 the author condemned the use of arsenic as an anticancer remedy, because it is a toxic substance that may accelerate the local growth and dissemination of cancer by contamination of circulating body fluids (blood and lymph). A decade later, arsenic was identified as a skin cancer-causing agent among workers in copper smelting factories.23 Then, a few years later, arsenic was named as 1 of the most dangerous mineral poisons that should not be used as medication by cancer patients because of absorption into the blood.24

In 1816, Charles Bell (1774-1842), English neurophysiologist and surgeon of the Bell palsy fame, in his Surgical Observations, using Abernathy's concept about sarcomas, introduced the term soft cancer, meaning sarcomas of bone, soft tissues, lymph glands (perhaps lymphomas) and other organs.25 Also in 1816, the first detailed description of a primary lung tumor, probably carcinoma, that was traced to the parenchymal cells (alveolar spaces) by dissection was published.26 Rene Laennec (1781-1826), French physician, is recognized for inventing the stethoscope and introducing auscultation in 1816. It would be a miss not to point out that Laennec also was a very competent pathologist. He was the first to recognize that pulmonary tuberculosis and lung cancer were 2 distinctly different diseases. He named melanosis as a form of disseminated pigmented cancer (melanoma) and introduced the term colloid cancer (mucinous carcinoma), because it reminded him of the substance of the brain.27

Attention was called to the relations between conditions of pelvic organs and breast diseases by Astley Cooper (1768-1841), a London surgeon, because he frequently observed cystic changes in the breast and the ovaries in the same patient. Cooper's interest in breast tumors led him to identify fibroadenoma of the breast as a distinctly benign tumor. He declared that, by injection of mercury, he succeeded in demonstrating lymphatic channels between the breast and the axillary glands. He also was the first to describe and illustrate breast cancer in a man.28

The word metastasis was introduced by Joseph Recamier (1774-1852), a French gynecologist, in 1829. By watching the growth and spread of cancers, he was able to identify with the naked eye blood vessel invasion by cancer. Being familiar with the blood supply of the breast, Recamier favored initial treatment of breast cancer by compression, similar to the treatment 100 years earlier.1 To promote his method, he listed in his book29Recherches sur le Traitement du Cancer the results from treating 100 patients: Thirty patients had successful treatment with compression, 21 patients had no significant improvement, 18 patients had resistance to treatment, 15 patients underwent radical surgery, and 16 patients were incurable and received palliative treatment. In light of these numbers, it should be noted that his diagnosis of cancer was made clinically without the aid of a microscope. Recamier also believed that disposition to breast cancer, and to most other cancers, was hereditary and that there was such a thing as a cancer family.

Case reports of primary cancers of the stomach, intestines, and the orbit30; of the thyroid, lung, and pleura31 (mesothelioma); of the rectum and the urinary bladder32; and of the uterus and the urethra33 were published with recommendations for treatment that ranged from radical surgery to internal or external application of chemicals, such as oxide of bismuth, sulfate of iron, nitric acid, arsenic, and mercury.30, 34 Treating cervical cancer patients with amputation of the cervix or perineal resection, Jacques Lisfranc (1790-1847) of France reported that he had never observed cervical cancer in maidens or nuns, and he conceived the idea that the main cause of cervical cancer was cervical erosion because of pressure, herpes, and leucorrhea.35

After Thomas Hodgkin (1798-1866) failed to obtain clinical privileges at the Guy's Hospital in London, he became the pathologist and curator of the hospital's museum. On dissection of the bodies of deceased patients, he noticed a peculiar association of enlargement of the spleen and lymph nodes in 6 patients. The 6 cases, and 1 additional case he received from Paris, from his friend Jean Lugol (1786-1851), known for his Lugol solution, were presented at 2 consecutive evening sessions of the Medical-Chirurgical Society of London in 1832. The 7 patients ranged in age from 9 years to >50 years, and all were males. Although the cases were published by Hodgkin in a very detailed report with gross illustrations entitled lymphogranuloma malignum36 (Fig. 7), Hodgkin and his cases received very little attention until the year before he died, when the influential pathologist, Samuel Wilks (1824-1911), of the same hospital, gave the name Hodgkin disease to the disseminated, cancerous process that was reported by Hodgkin 33 years earlier. Incidentally, Wilks also introduced the term semimalignant for tumors that appeared to be less than malignant and more than benign (dysplastic or borderline tumors).

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This is the title page from Hodgkin's original article on Hodgkin disease, which was published in 1832.

The year 1838 is 1 of the most momentous years in the history of medicine and biologic sciences. In Berlin, at the Pathology Institute, Theodor Schwann (1810-1882), a physician-physiologist, established the cell theory by demonstrating for the first time that animal and human tissues are composed of microscopic structures: cells.37 In contrast to the cells and cellular tissues described Robert Hook in 1665 and Xavier Bichat in 1799, these were not tissue spaces or empty gaps between fibers, they were real microscopic structures possessing cytoplasm and nuclei. To certain extent, it is most extraordinary that, in the same year, 1838, Johannes Muller, pathologist in chief and Schwann's boss, published his elaborate treatise,38Ueber den feinern Bau und die Formen der krankhaften Geschwulste. In the book, there are nearly 100 gross and microscopic drawings (Fig. 8). Muller described cancers as special groupings of abnormal cells and stroma. He attributed cancer to the formation of new cells in diseased organs with potential to be destructive and to spread to other parts of the body by vascular invasion. He associated cancer with aging and identified tumor necrosis (apoptosis) as a sign of regression. He microscopically distinguished epithelial and connective tissue tumors. Muller divided malignant epithelial tumors for carcinoma simplex (squamous carcinoma), carcinoma alveolare (adenocarcinoma), carcinoma fasciculatum (spindle cell carcinoma), carcinoma medullare (medullary carcinoma), and carcinoma melanodes (malignant melanoma). With regard to malignant connective tissue tumors, Muller described infiltrating fibrous tumors (desmoid tumor and fibrosarcoma), cystosarcoma of the breast, chondrosarcoma, and osteosarcoma of bones.

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In 1838, Johannes Muller illustrated for the first time the microscopic appearance of cancer. (Top) Muller's Figure 14 depicts breast cancer cells. (Bottom) Muller's Figure 17 depicts tumor cells from osteosarcoma of the mandible.

Muller wrote that the examination of microscopic preparations of tumors taught him that cancers are possessed of unique microscopic features, which may serve to identify them; however, it is often difficult to distinguish between benign and malignant tumors. Muller, like everybody else during his time, believed that the source of cancers was the amorphous embryonal blastema, which is scattered throughout the body between normal tissue elements. Thus, as an experimental pathologist, he discovered the cellular nature of the notochord, which was named 25 years later by Virchow as the source of chordoma. Muller also identified the paramesonephric duct (Mullerian duct) and deduced that vestigial nests of this duct may form tumors. His observation resulted in the identification nearly 100 years later of the source of mesodermal mixed tumors of the female pelvic organs. Muller's contributions to embryology, histology, and pathology are many; but he should be remembered best for establishing the cellular nature of benign and malignant tumors.39

At about the same time, in London, the term melanoma was introduced.40 In Boston, John C. Warren (1778-1856) performed the first surgical operation on an anesthetized patient. The patient had a large tumor on the left side of the neck extending along the jaw into the mouth. In his book,41 Warren also described and illustrated resection of an osteosarcoma of the right clavicle in a young man. And, in Philadelphia, a scapulectomy was carried out for a malignant tumor.42

Although many pioneering and distinct microscopic activities took place in 1838, it should not be overlooked that Everard Home (1756-1832), a London surgeon, made the earliest attempt (in 1830) to illustrate the microscopic appearance of a cancer in his monograph.43 Although the magnification is too low and the quality of the picture is less than optimal, there are faint tubules or cell cords discernable on his picture. Home, adhering to Bichat's theory, labeled the cancer cells as lymph globules. Another noteworthy observation was not only that the lymph nodes near the primary cancer may harbor cancerous cells but that spreading of tumor cells to distant parts of the body may occur through the blood vessels.44 Also, 2 observers independently in Germany45 and in England46 observed increased numbers of white blood cells on postmortem dissections that lead to introduction of a new term: leukemia.45 And in Italy, an illustrated case report was published47 illustrating a large, pedunculated tumor called liposarcoma.

It is perhaps not surprising that, within a decade after the announcement of the cell theory and introduction of the microscope into routine use in medicine, several journal articles and 5 textbooks with microscopic illustrations of cancerous tissues and cancer cells were published in France, Germany and England. Gabrial Andral (1797-1876) of Paris, shortly after he described linitis plastica of the stomach, changed his field of interest and studied exclusively the composition of blood. He published the first concise treaty on pathologic hematology48 and introduced the terms anemia and polycythemia. Andral's efforts led to the creation a new field in medicine: hematology.

Julius Vogel (1814-1880) of Germany published the first comprehensive pathology text that contained macroscopic and microscopic illustrations. Among the illustrations are cytologic preparations of sputum and pleural and pericardial effusions and histologic sections of carcinomas of the breast, lung, liver, uterus, and testis.49

Walter Walshe (1812-1892) of London, in his book,50 illustrated several forms of cancer, including the microscopy of alveolar or so-called signet ring cell carcinoma of the stomach. In a classification of malignant tumors, he combined for the first time the results from clinical, macroscopic, and microscopic observations (Fig. 9). With regard to causation of cancer, he named trauma, chronic irritation, smoking, mental affliction, drunkenness, and constitutional predisposition.

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This is a page from Walter Walshe's 1844 classification of cancers with consideration of gross and microscopic features, age distribution, and natural history.

Herman Lebert (1813-1878) of France added a microscopic atlas as third volume to his text in 2 volumes.51 The atlas is known as the first microscopic atlas in pathology. Among the nearly 300 figures, there are 78 illustrations of tumors and cancers, and he gave the name myeloid tumor to neoplasms composed of marrow-like cells (leukemia and giant cell tumor of bone). Lebert demonstrated that there are many different microscopic forms of cancer, even in the same organ, and that malignant tumors are distinctly different microscopically from benign tumors and normal tissues. He described and illustrated enlarged nuclei, macronucleoli, and multiple nuclei as hallmarks of malignant cells. He also demonstrated that cancer cells have an increased nucleocytoplasmic ratio (Fig. 10). Lebert enlarged his atlas a few years later and, in 1851, summarized what was known about cancer in a comprehensive clinical and pathology treatise.52

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This is Plate 21 from Herman Lebert's pathology atlas of 1845 and illustrates cancer cells from (Lebert's Figs. 1-4) a primary gastric carcinoma and hepatic metastases, (Lebert's Figs. 5-7) tumor cells from colloid carcinoma of the colon, and (Lebert's Figs. 8-19) cancer cells from the maxillary antrum.

The last tumor microscopist of the 1840s, John H. Bennett (1812-1875), an English pathologist, was convinced that cancers could be diagnosed with certainty by using the microscope. He cautioned, however, that, with the examination of individual cells alone in fluids, scrapings, and aspirates, the diagnosis is not so certain. According to Bennett, the main problem was that descriptions of the microscopic diagnosis of cancer published in the literature included <500 cases. No wonder, he wrote,53 that cancers are considered incurable when everybody is ignorant of their microscopic nature. Bennett knew that cancers were dependent for their power of growth and extension on the cells they contain.

In 1848, an English physician and part-time chemist, Henry Bence Jones (1814-1873), identified a substance in the urine of a gravely ill elderly patient that precipitated with the addition of nitric acid. The precipitate was soluble in boiling water but reprecipitated after the urine was cooled. At autopsy, multiple hemorrhagic cavities were observed in bones.54 In the late 1800s, the name of Bence Jones was linked eponymically to the protein that he discovered; and, soon after, the disease process was linked to plasma cells, and the terms myeloma and plasma cell myeloma were introduced. Bence Jones' discovery of proteinuria in plasma cell myeloma remained the only biochemical test for cancer until the discovery in the 1970s of carcinoembryonic antigen and alpha-fetoprotein.55 Also in the late 1840s, it was reported56 that the 2 most common sites of melanoma were the eye and the cutaneous tissue and that melanoma was common in gray horses. Benign and malignant meningeal fungous tumors (meningiomas) were described,57 and a New York surgeon concluded58 that treating cancers with medicine does nothing good and that small breast cancers should be treated by wide excision (lumpectomy) and not mastectomy.

The field of oncology was advanced substantially by surgeons and pathologists in the 1850s. A book exclusively devoted to diseases of the breast was published59 by an English surgeon, John Birkett (1815-1904). He introduced the term lobular carcinoma for cancers that surgically or grossly involved 1 lobe (1 segment). He observed microscopically that such tumors consisted of small epithelial round cells, which infiltrated connective tissues (infiltrating lobular carcinoma). Birkett also observed that it was not uncommon for round cells to nest in alveoli (lobular carcinoma in situ). Then, he added that, by chance, epithelial cells could be observed with the microscope escaping through the torn basement membrane (microinvasion) (Fig. 11). Birkett also was familiar with carcinoma of the nipple and areola years before Paget published his observation.

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These are gross and microscopic illustrations of lobular carcinoma of the breast by John Birkett in 1850. The microscopic images (2) show infiltrating lobular carcinoma, (3 and 4) lobular carcinoma in situ, and (5) lobular carcinoma in situ with microinvasion.

Cells obtained for the first time by scraping from a cancerous ulcer of the uterine cervix were described and illustrated as they appeared on a smear preparation.60 Prostate cancer was described as a nodular, firm tumor that could be touched with a finger on rectal examination and could be distinguished from benign hypertrophy.61 The term epithelioma was introduced for noninvasive cancers (carcinoma in situ) arising from skin and mucous membranes.62 Early detection of cervical cancers by physical examination under proper visualization was furthered.63 Although the optimal treatment of cancer continued to be debated, internal medical therapy (chemotherapy) was highly recommended in selected cases.64

Three surgeons, James Paget (1811-1899) of England, Alfred Velpeau (1795-1867) of France, and Samual D. Gross (1805-1884) of the United States, combined knowledge of pathology and cancer surgery that became known as operative pathology or surgical pathology. The second volume65 of Paget's Lectures on Surgical Pathology, published in 1853, contains 590 pages with 71 illustrations on tumors (Fig. 12). He divided cancers into scirrhous or firm tumors and into medullary, villous, colloid, melanoid, and hematoid forms. Paget was familiar with mitosis of cancer cells and looked upon it as an unfavorable sign. He called mitosis, very aptly, endogenous development of nuclei. He gave the first hint, 21 years before formal reporting66 of the breast disease that is eponymically known as Paget disease, by describing and illustrating a breast carcinoma extending to the skin and involving the nipple. He also was familiar with the transformation of a pigmented mole of the skin to malignant melanoma and was convinced that cancer cells, even in single forms, had characteristic microscopic features and could be distinguished from benign cells.

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The second volume of Paget's book is devoted to tumors and cancers.

Velpeau specialized in treating breast cancer. He recognized 3 principal forms of breast cancer: scirrhus (firm), encephaloid (soft), and fibroplastic (semisolid). Velpeau compared cancer with a parasite that is constantly reproducing itself and destroys healthy tissue. In his book, Traite des Maladies du Sein, published in 1854, he summarized his experience with over 2000 breast tumors.67 He treated breast cancers by radical surgical excision, but he also used internal and external remedies, because he believed that surgical procedures alone very seldom cured the patient. Velpeau opposed the compression method for cancer, but he used it for fibroadenoma and other benign conditions, such as cystic changes. In his book, he provided the first clinical and microscopic description and illustration of bilateral breast cancer (Fig. 13).

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This is Plate 8 from Alfred Velpeau's 1854 treatise on breast diseases: (Bottom) Figure 1 illustrates bilateral mammary carcinoma involving the nipples and the skin of the chest wall, and (Top) Figure 2 illustrates the microscopy of cancer cells.

Gross was a practicing pathologist for more than 20 years before he changed his field of interest to surgery. Actually, he wrote 3 pathology textbooks—an orthopedic pathology text,68 a general pathology book,69 and a urologic pathology treatise70—before publishing his 2-volume treatise,71A System of Surgery; Pathological, Diagnostic, Therapeutic, and Operative, in 1859 (Fig. 14). All 4 of his books are remembered as the first American texts on the subjects they covered. Gross was familiar with the clinical and pathologic aspects of various forms of malignant tumors. He listed the differences between 2 groups of malignant tumors: carcinomas and sarcomas. He indicated that carcinomas were diseases of adults and, overall, were less bulky, less fast growing, and less dangerous than sarcomas. He made this distinction at a time when most physicians regarded sarcomas as benign tumors. Gross characterized malignant tumors as those capable of destroying not only the tissues and organs in which they arise but also the life of the patient. However, despite his diagnostic acumen in pathology and surgery, he adhered to the prevalent view—which still lingered on from the 1700s—that cancer cells were formed of amorphous material (blastema) and that blastema bore faint resemblance to malignant cells in its physical, chemical, and microscopic composition. It is a paradox that, although Gross believed that a surgeon could not be successful without knowing pathology, he opposed needle biopsy of tumors and regarded the microscope as an auxiliary instrument.72

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This is the title page from the enlarged and revised edition of Gross' surgical text in 2 volumes.

Gross was not alone in his view about the limited use of the microscope and the importance of blastema in the genesis of cancer. Carl Rokitansky (1804-1878), an Austrian pathologist, never used a microscope, remained strictly a gross pathologist, and continued all of his life to promote the theory of the genesis of cancer by metamorphosis from fluid blastema. Rokitansky divided tumors into homeoplastic (benign) formations and heteroplastic (malignant) growths.73 He admitted that it often was very difficult to distinguish between the 2. To him, sarcomas were benign new growths that always remained local affections and were curable by local excision. He believed that primary cancer of the peripheral nerves (malignant nerve sheath tumor) was always incurable. Conversely, he recognized for the first time that the degree of malignancy (grade) of carcinomas, even in the same organ, was not always the same and that not all carcinomas were incurable. Rokitansky knew about carcinoma of the renal pelvis in adults and renal carcinoma in children (later named Wilms tumor). He also recognized that villous-polypoid new growths in the intestines could be cancerous lesions.

The phenomenal speed with which the medical use of the microscope spread in Europe from 1838 to the 1850s called for a conclusive and authoritative summation of the cell doctrine. It was Rudolph Virchow (1821-1902) of Germany who fulfilled the expectation. Virchow, as a former associate of Johannes Muller in Berlin—the venue where the cell theory was introduced in 1838—and his numerous macroscopic and microscopic contributions to pathology eminently qualified him to summarize the state of the art of cellular pathology and tumor pathology.

He outlined his views in his 2 illustrated books,74, 75Die Cellularpathology and Die krankhaften Geschwulste, published in 1858 and 1863, respectively. By introducing his dictum that all cells come from cells74 signaled the end of the 2000-year-old humoral theory and the 100-year-old blastema theory. Virchow believed that every pathologic lesion consisted of cells deriving from pre-existing cells that depended for their function on intracellular chemical changes. After Rokitansky, he divided all new growths into 2 types: homologous and heterologous. Homologous growths, mostly benign tumors, were represented by an increase in size and number of cells of the type that are present in normal tissues. Heterologous tumors were mostly malignant and consisted of new forms of cells that did not exist in normal tissues.

After reviewing the pathology of benign conditions, in his texts, Virchow described and illustrated the macroscopic and microscopic appearance of malignant tumors, always with attention to the distinguishing features of benign and malignant tumors. The malignant tumors named by Virchow are far too many75 to consider for inclusion in this review. It seems that no known malignant tumor escaped his attention, and he added several new entities, such as cancroids (keratinizing squamous carcinoma) of the lip and the uterine cervix, gelatinous (mucinous) carcinomas of different organs, squamous and glandular carcinoma of the lung, myxoma of the abdomen (pseudomyxoma peritonii), myxoma of soft tissues (myxoid liposarcoma), fibrous and myogenic sarcomas, and physalopherous chordoma. Virchow regarded some of the gastric carcinomas as hereditary and recognized gliomas as infiltrating primary tumors of the brain. Shortly after he introduced the term leukemia45 in 1845, he began to divide leukemias into a splenic form (myeloid leukemia) and a lymphatic form (lymphocytic leukemia) according to the origin of the white corpuscles that formed the tumor. He accepted the discovery of others that cancers spread through lymphatic and blood vessels; however, to make it complete, he added his discovery: perineural invasion. Virchow, just like some other investigators before his time, was not without fault. Until his death, he held onto his mistaken concept of the origin of epithelial tumors, carcinomas, from connective tissue cells and not from the surface epithelium. His mistake contributed to the death of at least 1 patient with adverse impact on world history.76

To conclude, during the second-half of the 18th century, detailed, gross descriptions of tumors by pathologists aided surgeons in establishing the outlines of operative surgery for tumors. Because, during the first half of the 19th century, most surgeons and other practitioners embraced microscopic pathology with enthusiasm, this provided impetus to pathologists to accelerate their microscopic work on the fine details of tumors. The combined efforts of pathologists, surgeons, and other physicians resulted in the creation of 3 distinct new fields in medicine: microscopic pathology, surgical oncology, and hematology. These efforts were not without exception, but, overall, they resulted in definition of the microscopic differences between benign and malignant cells. Furthermore, the efforts of all concerned established—once and for all—that epithelial tumors, including carcinomas, arise from pre-existing epithelial cells and that the source of connective tissue tumors, including sarcomas, is pre-existing connective tissue cells.

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