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Semin Thromb Hemost 2024; 50(05): 790-793
DOI: 10.1055/s-0043-1777303
Letter to the Editor

Insights into Cancer-Associated Thrombosis from Leukemia (“Leucocythemia”) from the 19th Century: The Untimely Death of the Scottish Slater John Menteith

Bingwen Eugene Fan
1   Department of Haematology, Tan Tock Seng Hospital, Singapore
2   Department of Laboratory Medicine, Khoo Teck Puat Hospital, Singapore
3   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
4   Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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“That the blood may be loaded with a multitude of cells, exactly resembling those of pus that such blood may circulate in the human subject for months, or even years, without destruction to life, and that this condition is always associated with disease in those organs….”

So mused English physician and pathologist, Dr. John Hughes Bennett (1812–1875) in his 1852 review “On Leucocythemia, or Blood Containing an Unusual Number of Colourless Corpuscles.”[1] Widely credited with first describing leukemia as a blood-related disease, which he termed leucocythemia—from λευκóς (white), κύτος (cell), and αίμα (blood), literally white cell blood—Bennett hypothesized that an excess of leucocytes in the absence of infection or inflammation was due to a primary systemic blood disorder.

John Menteith, a young 28-year-old Scottish male slater, was Bennett's index case of leucocythemia. On February 27, 1845, Menteith was admitted to the Royal Infirmary of Edinburgh under the care of Dr. Robert Christison (1797–1882). Menteith suffered from a chronic, progressively enlarging left hypochondrial tumor and generalized lymphadenopathy. Significant diarrhea on March 10 was treated with a combination of castor oil and opium pills. Fever on March 13 was medicated with tinctures of ammonia, morphine solution, spring water, and a quarter ounce of syrup every hour. This was followed by Menteith's sudden demise on March 15. Bennett, performing the autopsy 4 days later, discovered massive hepatosplenomegaly, extensive lymphadenopathy, and blood clots within the blood vessels. Light microscopy of the coagulated blood revealed numerous colorless corpuscles in the arteries and veins. His findings were published in the Edinburgh Medical and Surgical Journal titled “Case of hypertrophy of the spleen and liver which death took place from suppuration of the blood,”[2] where he attributed Menteith's death to “pus in the blood,” opining that the pus cells were formed liquor sanguinis (within the blood vessels), without phlebitis or inflammation. In 1851, Bennett abandoned his former view of suppuration of blood in his review,[1] renaming Menteith's case as “Case 1—Leukocythemia Discovered after Death; Hypertrophy of the Spleen, Liver and Lymphatic Glands,” stating that “we can have little doubt that the colorless corpuscles are formed in the lymphatic glands, and from thence find their way into the blood.” An evaluation of Bennett's detailed observations provides new clinical insights into the mechanisms of Menteith's death.

From the history of intractable diarrhea, fever, and increased white blood cells, it is plausible that sepsis could have been a cause for Menteith's death. However, a review of Bennett's autopsy report provides remarkable evidence of multivessel thrombosis that has never been identified in existing medical literature. The postmortem findings state, “On removing the dura mater, the veins which empty themselves into the longitudinal sinus were considerably engorged, especially posteriorly…” with the lithograph of the brain ([Fig. 1], panel “[Fig. 1] ”) showing the marked distension of the superior sagittal sinus from thrombosis causing widening of the longitudinal cerebral fissure. On further dissection, “The lateral ventricles were found healthy, contained no serum, and the choroid plexus was perfectly normal…The substance of the brain itself was throughout healthy. All the sinuses at the base of the cranium gorged with the red coagulum,” describing thrombosis of the transverse and sigmoid sinuses. As there were no autopsy findings of trans-tentorial herniation, focal mass effect or hemorrhage, the presence of an extensive cerebral venous thrombosis, while likely to contribute to significant morbidity, remains a less probable cause of death.

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Fig. 1 Extensive, multivessel thrombosis, with superior sagittal sinus thrombosis (panel “[Fig. 1]”), thrombosis in the inferior vena cava (panels “Fig. 3” and “Fig. 4”) with embolism to the right auricle (panel “[Fig. 2]”). (From Explanation of Plates, Page 132, Leucocythaemia, or White Cell Blood in Relation to the Physiology and Pathology of the Lymphatic Glandular System. Edinburg: Sutherland and Knox; 1852.) Captions for double plate: “Drawn by N. Stewart, 1851”; “Lithog. by J. Gellathy, Edin.”

Further findings of thrombosis are found in the description “In the right cavities of the heart, pulmonary artery, venae cavae, vena azygos, external and internal iliac vein, and many of the small veins leading into them, it was firmly coagulated, and formed a mould of their size and form internally. On section, the yellow coagulum of the blood was observed to occupy all the ramifications of the pulmonary artery….the right auricle much distended, and gorged with a firm coagulum…the right ventricle and pulmonary artery were similarly distended; portions of the clot closely embraced the columnae carneae, but were in no place adherent. The coronary arteries and veins were normal…the femoral veins, after passing under Poupart's ligament, were empty and perfectly healthy as far down as the Sartorius muscle. The external and internal iliac veins, as well as the pelvic veins, were full and distended…In the aorta and external arteries were a few small clots, resembling those found in the veins. These vessels, however, were comparatively empty.” Here, features of iliac and pelvic venous thrombosis, right ventricular thrombosis with ventricular distension, and pulmonary embolism are described. Lithographs showing a right auricle thrombus ([Fig. 1], panel “[Fig. 2]”) and a thumb-sized inferior vena cava thrombus ([Fig. 1], panel “Fig. 3”) support these descriptions. The pulmonary emboli had likely originated from thrombi within the inferior vena cava ([Fig. 1], panel “Fig. 4”) and pelvic veins. Menteith's case remains the sole presentation of extensive thrombosis documented in Bennett's review, where in the analysis of the post-mortem reports of other cases of leucocythemia, features of multivessel thrombosis were not described.

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Fig. 2 Illustrations of the microscopic examination of blood cells of John Menteith (From Page 11, Leucocythaemia, or White Cell Blood in Relation to the Physiology and Pathology of the Lymphatic Glandular System. Edinburg: Sutherland and Knox; 1852.)

The subtype of Menteith's chronic leukemia has been highly speculated, with some proposing that Menteith suffered from chronic myeloid leukemia (CML)[3] [4] or chronic lymphocytic leukemia (CLL).[5] Here, correlation of antemortem and postmortem findings suggest the latter as more probable. First, the symptoms that Bennett documented, “that twenty months ago he was affected with great listlessness on exertion, which has continued to this time. In June last he noticed a tumour in the left side of the abdomen, which has gradually increased in size…since then, several other small tumours have appeared in his neck, axillae, and groins” provide clues to the pernicious nature of the disease. The presence of chronic fatigue, symptomatic splenomegaly, and generalized lymphadenopathy implies the existence of an underlying chronic hematologic malignancy. Second, urinalysis performed on March 1 was described as “Urine…natural in colour, acid to litmus. Sediment presents cubic crystals under the microscope, disappears almost entirely on the addition of aqua potassae, but is unaffected by nitric acid. The filtered urine is not affected by aqua potassae, and yields only a slight white haze when boiled.” This suggests hyperuricosuria with typical cubic urate crystals, which dissolve on urinary alkalinization with aqua potassae (potassium hydroxide) and remain on acidification with nitric acid. Hyperuricemia, with resultant hyperuricosuria, is associated with advanced cases of CML and CLL, where the tumor burden is high; however, this finding is nonspecific and can be seen in patients without malignancy. The observation of a “slight white haze upon boiling” suggests the presence of Bence–Jones proteinuria, a condition associated (but not specific) with B cell lymphoproliferative disease. In this context, urinary light chain paraproteins tend to precipitate at 40 to 60°C, redissolve at 100°C, and reappear upon cooling. However, alternatives such as the precipitation of urinary phosphates or proteins cannot be excluded.

Third, prominent findings of massive hepatosplenomegaly accompanied by generalized, conglomerative lymphadenopathy were found on autopsy. Bennett wrote “The liver enormously enlarged from simple hypertrophy. Its structure throughout healthy…The spleen also enormously enlarged from simple hypertrophy…It weighed seven pounds twelve ounces. It measured in length fourteen inches…The lymphatic glands were everywhere much enlarged. In the groin they formed a large cluster, some being nearly the size of a small hen's egg, and several being that of a walnut. The axillary glands were similarly affected…the mesenteric glands were of a whitish colour, some as large as an almond nut.” Massive hepatosplenomegaly can be a presenting feature in both CML and CLL. Although generalized lymphadenopathy can be seen in cases of extramedullary involvement during the accelerated or blast phases of CML, it is more of an exception than a common occurrence, with these clinical features more prevalent in patients with chronic lymphoproliferative disease.

Lastly, Bennett provides morphological descriptions and microscopic illustrations of the blood cells seen. These were interpreted by Kampen[4] as morphologically resembling CML. However, one important caveat is that Menteith's blood cells were examined during the postmortem period, and not while he was alive. Postmortem interpretation of blood cells is challenging because autolytic changes begin immediately after death. In a study evaluating the morphological changes of blood cells of cadavers kept at 4°C with postmortem timings of up to 270 hours, significant morphological changes in many leucocytes occurred rapidly after death, with lymphocytes appearing to be most resistant to autolysis.[6] In Bennett's description, “The corpuscles varied in size from the 1/80th to the 1/120th of a millimetre in diameter; they were round, their cell-wall granular…”[1] ([Fig. 2], panels “[Fig. 1]” and “[Fig. 2]”). From his account, the white blood cell diameters measured between (1/80th mm) 8.3 and (1/120th mm) 12.5 µm. In comparison, the diameter of myelocytes ranges from 10 to 18 μm, segmented neutrophils 10 to 15 μm, and mature lymphocytes 7 to 15 μm.[7] As the autopsy was performed 4 days after death, there is a high likelihood of autolysis of the white cells. Hence, the white cells Bennett documented were probably a combination of the more resilient smaller lymphocytes, with crenated or apoptotic granulocytes, rendering the microscopic findings unreliable in reflecting the true cellular pathology. In summary, Menteith suffered from a chronic leukemia, with microscopic findings of increased white blood cells of indeterminate morphology due to postmortem autolysis, and clinicopathological findings favoring a CLL. Other potential etiologies include CLL with Richter's syndrome, aggressive B cell follicular lymphoma, blastoid mantle cell lymphoma, and T cell leukemia/lymphoma.

In conclusion, a hypercoagulable state resulting from malignancy, combined with venous stasis due to prolonged bed rest and dehydration from diarrhea and fever, represents significant risk factors for thrombosis. These may have collectively triggered an acute disseminated intravascular coagulopathy, leading to extensive multivessel thrombosis, culminating in a sudden and fatal pulmonary embolism.

Still today, both leukemia and cancer-associated thrombosis pose significant health risks when left undiagnosed or untreated. Bennett's case of leucocythemia and cancer-associated thrombosis provides a rich historical lens through which we can gain insights into the diagnostic challenges that physicians of the 19th century grappled with when encountering unfamiliar diseases. Dr. Rudolf Virchow (1821–1902), Bennett's contemporary, contributed significantly to the current-day knowledge of these two conditions. Virchow's identification and naming of “leukemia” as a blood disorder, characterized by him as “leukämie” in 1847, garnered widespread acceptance, over Bennett's leucocythemia. In 1856, Virchow defined the pathophysiology of pulmonary embolism, establishing it as a cause of death.[8] Through the 19th century, artists have chronicled the harrowing phenomenon of cancer-associated thrombosis,[9] which, even today, ranks as the second most common cause of death among cancer patients. This condition results from a multifaceted interplay of factors that culminate in the formation of blood clots in individuals with cancer. Virchow's triad of hypercoagulability, decreased venous flow, and vessel wall damage form the basis of the pathophysiology of cancer-associated thrombosis, with mechanisms such as increased thrombin generation[10] and the overexpression of procoagulant proteins like tissue factor, podoplanin, plasminogen activator inhibitor-1, and protein disulfide isomerase providing a deeper understanding of thrombogenesis. The pioneering discoveries by Virchow and Bennett's fascinating postmortem findings of thrombosis and leukemia continue to serve as a source of inspiration for clinicians and researchers. They form an important foundation in our understanding of these diseases, with further research efforts in the management of cancer-associated thrombosis required to integrate novel risk factors and molecular markers for enhanced risk assessment,[11] optimization of anticoagulation duration, and prevention of recurrence and major bleeding.

Data Availability Statement

The data that support the findings of this study are available in Wellcome Collection at https://wellcomecollection.org/works/avrzy3fm.




Publication History

Article published online:
04 December 2023

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