History

Introduction

The purpose of this timeline is to define the core historical findings that are common to all present-day leukemias. Our common understanding of leukemia is based upon the differentiation of myeloid from lymphoid cell of origin and whether it is acute or chronic. This gives rise to the four common, well known leukemias: acute lymphocytic or lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous or granulocytic leukemia (CML), and chronic lymphocytic leukemia (CLL).

Leukemia was only recognized within the past 200 years. Gross observations of the blood during life and at autopsy were correlated with the presence at post-mortem of an enlarged spleen or enlarged lymph nodes. Oftentimes, splenomegaly was astutely appreciated as one or two large tumorous swellings in the left abdomen prior to the patient’s demise. Microscopic examination of the blood was critical in defining the presence of increased white cells.

Timeline

Development of Microscopic Research

Sketch of a front and side view of a Leeuwenhoek microscope, next to a photograph of a model of a Leeuwenhoek microscope.

Late 17th Century

Antony van Leeuwenhoek, born in Delft (1632-1723), used a hand-held microscope like the one shown to describe human red blood cells from his hand as globules. McCormick and L’E. Turner describe the microscope as, “essentially a bead of glass mounted in a pin-hole between two plates of soft metal,” with a specimen pin positioned in front of the aperture.

McCormick JB, L’E. Turner G., The Atlas Catalogue of Replica Rara Ltd. Antique Microscopes. Chicago, IL: Replica Rara Ltd., 1975, p.23.
Image adapted from Singer, C. & Underwood, E. A., A Short History of Medicine. Oxford, 1962, p. 127.

Image by van Leeuwenhoek of red blood cells examined under a microscope.

1680

This image, originally printed by van Leeuwenhoek in 1680, is the earliest known image of red blood cells. In 1688, he writes, “The blood is composed of exceeding small particles, named, globules, which, in most animals, are of a red colour, swimming in a liquor, called, by physicians, the serum….These particles, or globules, are so minute, that one hundred of them, placed side by side, would not equal the diameter of a common grain of sand, consequently, a grain of sand is above a million times the size of one such globule.”

Van Leeuwenhoek A. On the circulation of the blood. Philos Trans R Soc Lond B Biol Sci. 1688. Reprinted in Van Leeuwenhoek A, Hoole S. The select works of Antony van Leeuwenhoek: containing his microscopical discoveries in many of the works of nature. London, UK: G. Sidney; 1800, p. 89.
Image from McCormick JB, L’E. Turner G., The Atlas Catalogue of Replica Rara Ltd. Antique Microscopes. Chicago, IL: Replica Rara Ltd., 1975, p. 26.

Early Case Reports

This table of early case reports, adapted from Piller, outlines a series of individual case reports that appeared in the 19th century in which the blood appeared to look milky or pus-like. The following twelve case reports explore these cases in more detail.

Piller GJ. The History and Presentation of Leukaemia 1845-1960. [dissertation]. Open University; 1992.

First page of the Cullen article

1810

Case 1: On June 14, 1810, Sheerness surgeon Peter Cullen saw a 35-year-old male patient named Thomas Halke, who had a sallow complexion, left-sided abdominal pain, and fever. He was treated with aperients (laxatives) and fomentation (hot compress to site of pain). He re-presented on November 24th with more severe pain “chiefly seated about the middle of the left hypochondrium” and a fever. He was bled five times over five days when approximately 58-62 ounces of blood was taken in total. Cullen notes, “the serum of the blood was white, exactly in colour and consistence like milk….The three first bleedings exhibited the same kind of serum as abovementioned; but the two last were natural in appearance.”

Cullen P. Case of splenitis acutus. Edinb Med Surg J. 1811 Apr 1;7(26):169-171.

1825

Case 2: Alfred Velpeau provides a detailed case study (full details) of patient Monsieur Vernis. Vernis developed a hard tumor on his left side, which began to pain him in December, 1825. On February 16, he experienced a left-sided stroke, and he was admitted to the hospital on the 18th, when two large tumors were detected. That night, he cried out, but was unable to say where he felt pain. He died early on the 19th. Of note, the abdomen at autopsy showed that the spleen filled all the hypochondrium on the left side; it weighed ten pounds. The liver was enlarged, and the blood resembled “well-conditioned pus mixed with blackish coloring matter, rather than blood” [translated from French].

Velpeau A. Sur la résorption du pus et sur l’altération du sang dans les maladies. Clinique de perfectionnementRevue médicale française et étrangère. 1827;2:216-240.
Portrait of Velpeau via US National Library of Medicine.

First page of Collineau et al.

1829

Case 3: A 39-year-old hat merchant, thought to suffer from chronic pleurisy, presented with symptoms of dizziness and a heavy aching head. Collineau and Gendrin bled the patient on multiple occasions and applied leeches to him. While the patient’s blood taken on the initial visit exhibited unusual characteristics (full details), later blood samples appeared normal. Collineau and his colleagues were unable to determine a cause for the blood’s unusual properties.

The blood appeared cloudy and light red as it came out of the vein, and became a mottled, whitish-red as it coagulated, eventually forming a small lump swimming in a milky fluid. Heating the liquid coagulated it into an albumen-like lump which could not be identified through chemical testing.

Kampen questions whether this patient was suffering from pneumonia, making it uncertain whether this patient had a leukemia.

Collineau M, Gendrin J, Caventou JB. Observation sur une altération particulière du sang. Journal général de médecine, de chirurgie et de pharmacie françaises et étrangères. 1829;106:67-71.
Kampen KR. The discovery and early understanding of leukemia. Leuk Res. 2012 Jan;36(1):6-13.

First page of Duplay

1833

Case 4: Joséphine Guéris, a 27-year-old seamstress, was admitted to the hospital in December 1833 gravely ill, pale with night sweats and diarrhea and appearing as if she had tuberculosis (full details). She died 2 days later. An autopsy revealed an enlarged liver and spleen. Throughout the body, the blood was described as wine-colored in which dirty yellow flakes were floating, like pus. No cause could be found for the presence of pus in the blood.

Duplay M. Observation d’une altération très grande du sang. Présence d’une quantité très-grande de pus dans le système artériel et veineux, sans origine appréciable, suivie de quelques réflexions sur ce genre d’altération. Arch Gen Med, Paris, II. 1834;6:223-34.

First page of Vidal

1839

Case 5: Marie Charbot, a 44-year-old day worker, medium build, slightly overweight, and pale-faced, presented on June 26, 1839 with a large, firm tumor in her left side, which developed after delivering a stillborn child 17 months earlier. The urine had a whitish deposit and a cloud of mucus. The patient died on July 14.

Autopsy revealed that the patient’s spleen and liver were enlarged, and that the blood was granular and chocolate-colored. An analysis of the blood performed by Donné states that the mucous globules of the blood behaved with ammonia as if they had pus. Vidal concludes that this is a case of splenic leukocythemia.

Vidal E. De la leucocythémie splénique ou de l’hypertrophie de la rate avec altération du sang consistant dans une augmentation considérable du nombre des globules blancs. Gazette hebdomadaire de médecine et de chirurgie. 1856:201–2.

First page of Craigie

1841

Case 6: Peter Campbell, a 30-year-old weaver from Lanark, was admitted on February 24, 1841 to the Royal Infirmary in Edinburgh complaining of “feebleness, impaired health, and diffuse swelling of the belly,” which had lasted for 12 months, and beginning with illness that had symptoms of rheumatism and recurring severe pains on the left side, which resembled cramps. Upon examination, the swelling appears in the left hypochondriac region. He perspired heavily at night. After various treatments, the patient died at 5 AM on April 1.

Autopsy revealed that the spleen was enlarged and that the veins were “filled with clots of grumous blood and clots containing purulent matter and lymph.” Piller suggests that this may have been a case of CLL.

This case was not published until 1845, where it appeared next to a similar case published by Bennett. Craigie and Bennett compared these two cases in their papers.

Craigie D. Case of disease of the spleen in which death took place in consequence of the presence of purulent matter in the blood. Edinb Med Surg J. 1845 Oct 1;64(165):400-413.
Piller GJ. The History and Presentation of Leukaemia 1845-1960. [dissertation]. Open University; 1992.

1844

Case 7: In 1844, in his Cours de Microscopie, Donné describes a case M. Rayer had once treated in which a man in the prime of his life had arteritis, particularly of the lower limbs, which exhibited ecchymosis and gangrenous phlyctenes, among other conditions, and that the patient’s blood had such a high concentration of white globules that Donné was led to believe at the time that the blood was mixed with pus. Later, at the time of his writing, he no longer believed that the white globules were pus, but rather an excess of white blood cells that he posited had failed to transform into red blood cells.

Donné A. Cours de microscopie complémentaire des études médicales: anatomie microscopique et physiologie des fluides de l’économie. J.-B. Baillière; 1844:135-136.
Image adapted from Donné A, Foucault L. Cours de microscopie complémentaire des études médicales: anatomie microscopique et physiologie des fluides de l’économie. Atlas. J.-B. Baillière; 1845: Fig. 20, Fig. 29.

Image from Bennett of colorless corpuscules from the blood of John Menteith

1845

Case 8: John Menteith, a 28-year-old slater who was admitted to the Royal Infirmary in Edinburgh on February 27, 1845 and presented with a tumor on the left side of his abdomen and a “great listlessness with exertion” that had persisted for 20 months. He had first noticed the tumor in June, 1844. After various treatments, the patient died on the morning of March 15.

Autopsy revealed that the blood had coagulated and separated into a dull and granular brick-red portion and a dull, opaque, light yellow portion that resembled “thick creamy pus.” The liver and spleen were enormously enlarged, and the lymphatic glands and heart were also enlarged. Kampen believes that this patient probably suffered from CML.

Bennett JH. Case of hypertrophy of the spleen and liver, in which death took place from suppuration of the blood. Edinb Med Surg J. 1845 Oct 1;64(165):413-423.
Kampen KR. The discovery and early understanding of leukemia. Leuk Res. 2012 Jan;36(1):6-13.
Image from Bennett JH. On leucocythemia, or blood containing an unusual number of colourless corpuscles. Mon J Med Sci. 1851 Jan; 3(13): 17–38.

Image by Virchow, of sections through the cortical substance of human mesenteric glands.

1845

Case 9: Marie Straide, a 50-year-old cook, was admitted on March 1, 1845 to the Charité in Berlin with symptoms of a significantly enlarged and painful spleen, swelling in the lower extremities, and persistent cough with rattling noise in the chest. For the past year, she’d had symptoms of significant swelling in her lower extremities and lower abdomen, chronic violent cough with mucus expectoration, and diarrhea. Over the next few months, she had recurring diarrhea and nosebleeds, and the swelling increased until she could not walk. The patient died on the morning of July 31.

Autopsy revealed that the blood, particularly in the heart, was filled with crumbly greenish yellow-white clots that looked like pus, but the walls of the blood vessels all appeared normal. The lungs were normal except for a slight bronchial catarrh. The liver did not appear significantly abnormal, but the spleen was enormously enlarged.

Virchow R. Weisses blut. Neue Notizen aus dem Gebiete der Natur- und Heilkunde. 1845;36:151-6.
Image from Virchow R, Chance F. Cellular Pathology as Based Upon Physiological and Pathological Histology. Twenty Lectures Delivered in the Pathological Institute of Berlin During the Months of February, March, and April, 1858. London: John Churchill;1860:174.

First page of Fuller and Cantab

1845

Case 10: On December 31, 1845, a man from Chelsea was admitted to St. George’s Hospital in London presenting with symptoms of a tumor in the left hypochondriac region, dyspepsia, headache, occasional vomiting, and diarrhea. His symptoms began approximately 8 months earlier and he had sought no prior treatment for his condition. His condition grew worse and he became slightly jaundiced. The patient died on January 8, 1846.

Autopsy revealed an enormously enlarged spleen and liver. All the blood vessels were dilated and the blood was “grumous and of a peculiarly grey colour.” Examination of blood samples taken at 3 different times before death and once after death revealed that in each instance, the blood contained “a very large proportion of abnormal, granular, colourless globules.”

Fuller HW, Cantab LM. Particulars of a case in which enormous enlargement of the spleen and liver, together with dilation of all the blood vessels of the body were found coincident with a peculiarly altered condition of the blood. London Medical Gazette. 1846 Jun 23;3:123

First page of Weisses Blut (Leukämie).

1847

Case 11: Carl Aug. Schulz, a locksmith from Potsdam, was admitted on June 26, 1847 to the Charité in Berlin with symptoms of enlarged glands in the neck, armpits, and groin and frequent cough with mucus expectoration. The glandular swelling had developed over two years, following pneumonia. The patient’s symptoms increased, and he died on August 2 at 2 PM.

Autopsy revealed massive lymphatic involvement, bronchial catarrh, and the blood in the heart contained a thick, creamy yellow-white pus-like mass. The spleen appeared normal, but the liver was enlarged. Microscopic examination of the white mass found that it was made up of colorless bodies that differed only in number from the elements in lymph nodes.

Piller notes that this paper of Virchow’s is the first to call this newly observed disease “leukemia.”

Virchow R. Zur pathologischen physiologie des blutes. II. Weisses blut (Leukämie). Archiv für pathologische Anatomie und Physiologie und für klinische Medicin. 1847 Oct;1(3):563-72.
Piller GJ. The History and Presentation of Leukaemia 1845-1960. [dissertation]. Open University; 1992.

First page of Zur pathologischen Physiologie des Bluts.

1848

Case 12: Heinrich Hoensch, a 38-year-old carpenter, was admitted on February 28, 1848 to the Charité in Berlin with diarrhea and left-sided abdominal swelling that was not painful when pressed (full details). The patient had a long history of chronic illness. Four years earlier, after a serious cold, he experienced recurring diarrhea and pain in the left side of his abdomen, which began to swell 2 months earlier. He developed nosebleeds and headaches, including a violent nosebleed on March 26 during which he lost more than a quart of blood, as well as fever and a cough with bloody sputum. The patient died on November 2.

Autopsy revealed severe edema of the pia mater and venous hyperemia. While the blood in the capillaries of the brain was normal, the blood in the heart, pulmonary arteries, and veins contained brittle clots of coagulated pus. The spleen was enlarged, but the liver was normal.

Virchow R. Zur pathologischen Physiologie des Bluts. Virchows Archiv. 1849 Oct 1;2(3):587-98.

Image from Bennett of the appearance of a drop of blood taken from patient Barney Tinlay and subjected to various treatments.

1852

In 1852, Dr. John Hughes Bennett published a textbook titled Leucocythemia, or white cell blood, in which he compiled 35 case reports of what he termed leucocythemia; in this text, he objected to Virchow’s term “Leukhemia” on the grounds that the blood was not white and these cases could be confused with a different blood disorder (p.6). This is the first published collection of cases to suggest the existence of leukemia.

Image from Bennett JH. On leucocythemia, or blood containing an unusual number of colourless corpuscles. Mon J Med Sci. 1851 Jan; 3(13): 17–38.

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