Trousseau's Syndrome in 19th Century Qing Dynasty Paintings of Breast Tumors: Early Insights into Cancer and Thrombosis Risk

“No. 35,181, March 25th, 1850. Steatomatous tumor, nineteen and a half inches in circumference. Li Shi, age 43, of the district of Pwanyu, had a steatomatous tumor, which 17 years since commenced just above the clavicle on the left side. When she presented herself at the Hospital, it had attained the abovementioned dimensions, and hung pendulous down into the axilla and over the breast, descending nearly to a level with the umbilicus. Its surface was traversed by large veins…” ([Fig. 1]); so wrote Dr. Peter Parker (1804–1888), a medical missionary and ordained Reverend, in the medical case notes of the 16th report of the Ophthalmic Hospital (present day Second Affiliated Hospital of Sun Yat-sen University, Guangzhou; Guangdong, China). Complementing the surgical description of the breast tumor was a vivid portrait of Madam Li, executed in an oil painting by Lam Qua (1801–1860), a western-trained Chinese painter. Although the primary purpose of the paintings was for visual testimony of Parker's missionary enterprise and medical skills, Lam Qua's rendition of images is a sobering portrayal of human suffering and the affliction of disease in 19th century Qing Dynasty, China.[1] The collaboration of Dr. Parker and Lam Qua reflected in the paintings of Parker's patients capture a pivotal period before the widespread use of photography for medical documentation.

Fig. 1 Portrait number 10 (case number 35,181), Peter Parker Collection, Harvey Cushing/John Hay Whitney Medical Library at Yale University (New Haven, CT). Li Shi, age 43. Left breast tumor with beaded and tortuous superficial chest wall veins (Trousseau's syndrome).

An evaluation of the 80 digitalized portraits from the Peter Parker Collection from the Harvey Cushing/John Hay Whitney Medical Library at Yale University (New Haven, CT) showed 11 advanced stage breast tumors in 30 paintings of adult Chinese women. While the viewer's attention is immediately drawn to these horrific breast tumors, bearing specific features of breast cancer such as ulcerated tumors, skin and nipple ulceration, and multifocal lesions, a second significant pathological diagnosis, should not be missed. Careful observation reveals the appearance of large, beaded, and tortuous superficial veins overlying the breasts of 6 women in the 11 portraits ([Fig. 2]) ([Supplementary Appendix], available in the online version only). Analysis of the appearance of these grossly distended veins and the linking of Parker's clinical notes to these portraits lead to the clinical suspicion that these were superficial migratory thrombophlebitis resultant from breast cancer—an accurate rendition of Trousseau's syndrome in the context of advanced malignancy. The original term, later coined by French physician Armand Trousseau (1801–1867) in 1865 shortly before his death from malignancy, refers to the occurrence of an inflamed and thrombosed vein preceding, or occurring with, the diagnosis of cancer and highlights the profound impact that cancers may have on the hemostatic system. One other differential for a superficial thrombophlebitis would be Mondor's disease. This is a classically self-limiting and benign superficial thrombophlebitis, which involves the superficial veins of the chest wall, namely the superior epigastric vein, thoracoepigastric vein, and lateral thoracic vein. However, Mondor's disease never involves the inner, upper portion of the breast,[2] whereas all six portraits show involvement of superficial veins in that region.

Fig. 2 Portrait number 28 (case number 28,984), Peter Parker Collection, Harvey Cushing/John Hay Whitney Medical Library at Yale University (New Haven, CT). Ho-She, aged 26. Right breast tumor with multifocal lesions, traversed with multiple large veins, some veins having a thrombosed appearance.

The pathogenesis of Trousseau's syndrome (cancer-associated thrombosis [CAT]) in solid malignancies is complex. It involves the interplay of multiple risk factors including hospitalization, surgery, and with patient, tumor and therapy specific factors that culminate in the activation of coagulation, involving all aspects of Virchow's triad.[3] Hypercoagulability is driven by the overexpression of tissue factor by malignant cells and the increased shedding of tissue factor bearing microparticles, which have negatively charged phospholipids that are procoagulant. Increased levels of tissue factor promote activation of factor X, thrombin generation and platelet activation, with raised plasminogen activator inhibitor-1 levels inhibiting fibrinolysis. Endothelial dysfunction is precipitated by inflammatory cytokines, neutrophil extracellular traps, as well as histone and High Mobility Group Box 1 protein release from apoptotic cancer cells. These, together with carcinoma mucins that bind to P-selectin and L-selectin, promote cellular crosstalk and adhesive interactions between endothelial cells, leukocytes, and platelets. Lastly, enlarged tumors can compress veins causing venous stasis, promoting thrombosis.

CAT is the second leading cause of death in patients with cancer, where it is estimated that up to 20% of patients with cancer are affected by venous thromboembolism (VTE) with the highest risk periods during hospitalizations and development of metastatic disease.[4] Treatment of CAT is challenging given the increased rate of VTE recurrence and risk of bleeding complications compared with patients without cancer. In addition to low molecular weight heparin (LMWH), recent randomized trials (SELECT-D, Hokusai VTE-Cancer, ADAM-VTE, Caravaggio) have provided increasing evidence on the safety and efficacy for the use of direct oral anticoagulants (DOACS) in the treatment of CAT. The National Comprehensive Cancer Network,[5] American Society of Clinical Oncology,[6] and International Initiative on Thrombosis and Cancer[7] recommend the use of DOACS or LMWH for a minimum of 6 months for the treatment of CAT, unless contraindicated. Accurate risk prediction for CAT, using validated risk tools such as the Khorana score, is key for an individualized, risk adapted thromboprophylaxis strategy in patients with cancer, targeting higher risk patients and avoiding prophylaxis for those who are low risk.

Just as Lam Qua's medical paintings encapsulate the momentous period of political turmoil and the woeful inadequacies of medical care in 19th century Qing Dynasty, China, major knowledge gaps remain in the prevention and treatment of CAT. The development of formal bleeding assessment tools for CAT with randomized control trials evaluating the use of thromboprophylaxis in hospitalized patients with cancer and the discovery and development of safer and more efficacious anticoagulants are much required to address these unmet clinical needs.

Note

Images from the Peter Parker Collection, Harvey Cushing/John Hay Whitney Medical Library at Yale University (New Haven, CT) are available for public access and research at https://library.medicine.yale.edu/find/peter-parker .

Publication History

Article published online:
09 February 2022

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