Case Presentation

A 69-year-old white woman presented to the emergency department complaining of bilateral swelling and pain in her lower legs that she described as "off and on" for the past 5 days. Doppler ultrasound of the legs did not reveal any evidence of deep-vein thrombosis (DVT) but did demonstrate superficial thrombophlebitis in a multisegmental distribution along the medial aspects of both legs, extending from the calves to the inferior aspect of the thighs. After further inquiry, the patient noted that the pain, tenderness, and prominent varicose veins had started on her right lower leg and then resolved, only to be followed by similar lesions on her left lower leg that eventually extended to her left thigh. The varicose veins were nodular in consistency, with surrounding ecchymosis. The patient was managed medically and then discharged, with instructions to follow up with her regular physician.

Two weeks later she returned to the emergency department, this time complaining of acute, progressively worsening shortness of breath over the past 3 days that was not related to exertion. The thrombophlebitis for which she was seen previously had improved. The swelling on her legs was gone, and the palpable cords were no longer tender. New findings included jaundice; mildly icteric sclera; generalized abdominal tenderness, with slight distention and positive shifting dullness; and multiple, nontender, palpable cords in the distribution of her varicose veins along the medial aspects of both legs, with ecchymoses in different stages of healing (Figure, below).

Figure—Nodular superficial venous thrombophlebitis (arrows) is characteristic of Trousseau's syndrome.

In addition, the patient said she had had no bowel movements for the past 5 days, which she attributed to simple constipation. Spiral computed tomography (CT) of the chest revealed bilateral pulmonary artery embolisms. CT of the abdomen and pelvis revealed diffused peritoneal masses and evidence of omental caking consistent with underlying malignancy. A 2.8-cm mass was also evident on the head of the pancreas. An exploratory laparotomy and omental biopsy revealed adenocarcinoma consistent with primary pancreatic carcinoma. The hematology-oncology department was consulted. After reviewing the poor prognosis with the patient, she decided not to seek further treatment and, instead, opted to be placed into hospice care. She died 3 days later.

Discussion

Trousseau's syndrome is an acquired coagulopathy associated with visceral carcinoma that results in migratory thrombophlebitis. In 1865, Professor Armand Trousseau first described an association between recurrent migratory thrombophlebitis and cancer, a condition from which he subsequently died. Since then, a variety of coagulation abnormalities related to malignancy have been described in the literature, including disseminated intravascular coagulation, thrombotic endocarditis (ie, marantic endocarditis), pulmonary embolism, venous gangrene, and bleeding tendencies. These physiologic phenomena are believed to be secondary to an imbalance in the clotting cascade caused by the underlying malignancy.¹

Trousseau's syndrome is characterized by recurrent superficial thrombophlebitis. Thrombi may occur in the arterial or the venous system. Lesions consist of tender erythematous cords or nodules, typically appearing in the subcutaneous fat of the trunk or extremities. The thromboembolic phenomena are unresponsive to warfarin but can be managed with heparin-based anticoagulation.²

Epidemiology
It is estimated that approximately half of the cases of migratory thrombophlebitis are associated with cancer. The annual incidence of venous thromboembolism (VTE) in patients with cancer is about 1 in 200.³ The presence of a malignant neoplasm increases the risk for VTE by 6.5-fold.⁴ Therefore, in the absence of other causes of hypercoagulability, a search for an occult malignancy is warranted. A review of 260 consecutive patients with symptomatic, venographically proven DVT showed that those without well-recognized risk factors for DVT had a 2.3-fold increased risk for subsequent development of cancer. For those with recurrent idiopathic thrombosis, the risk was increased by more than 17-fold.⁵ A more recent study of more than half a million adult patients with cancer indicated that 2.5% of all patients with unprovoked VTE have occult malignancy.⁶

Various cancers have been associated with Trousseau's syndrome, most often with solid tumors of the adenocarcinoma type. Pancreatic cancer, especially of the body or tail, seems to be associated with the highest risk of migratory thrombophlebitis, but lung cancers are most often reported, probably because of the relatively greater frequency of pulmonary carcinomas. A recent autopsy study that sought to determine the prevalence of Trousseau's syndrome showed that 42% of patients with pancreatic cancer had pulmonary embolism, and that patients with pulmonary adenocarcinoma were at 1.65 times greater risk for pulmonary embolism than patients with squamous-cell lung cancer.⁷

The underlying pathophysiology of Trousseau's syndrome is thought to be chronic subclinical disseminated intravascular coagulation caused by activated procoagulants.⁸ The proposed mechanisms for the induction of a prothrombotic state by tumor cells involve tissue factor expression, as well as direct activation of platelets and several other tumor-related activities.

Diagnosis
The lesions in patients with Trousseau's syndrome may be clinically similar to those seen in a variety of other conditions, including:

• Cellulitis
• Erythema nodosum
• Lymphangitis
• Vasculitis.

Biopsy specimens of involved sites show veins containing occlusive thrombi and an inflammatory infiltrate in the vessel wall. Once the presence of migratory thrombophlebitis is established, the differential diagnosis includes other conditions known to induce hypercoagulable states, including lupus anticoagulant syndrome, Buerger disease, Behçet's disease, and inflammatory bowel disease.

Along with a comprehensive medical history and physical examination, conventional workup in the search for an occult malignancy—including blood tests, chest radiography, upper endoscopy, and CT of the chest, abdomen, and pelvis—can successfully diagnose a primary malignancy in the majority of patients with Trousseau's syndrome. Positron-emission tomography–guided biopsy has also been shown to be an efficient, less invasive, and cost-effective means of diagnosing underlying malignancy in patients with recurrent DVT.⁹

Treatment
Since Trousseau's syndrome is often refractory to vitamin K antagonists, heparin therapy is usually required. Anticoagulation must be continued until the underlying cancer is eliminated, which often also resolves the hypercoagulability. Several case reports support the use of a low-molecular-weight heparin (LMWH), 1 mg/kg every 12 hours or 1.5 mg/kg once daily (enoxaparin sodium [Lovenox]) or 175 IU/kg once daily (tinzaparin [Innohep]), as the primary therapy for malignancy-associated thromboembolic events.^10,11

For patients with advanced malignancy and venous thromboembolism who are willing and able to receive daily injections and have a reasonable quality of life and life expectancy, the use of LMWH is recommended over the use of oral anticoagulants. Treatment should be initiated with LMWH for 3 to 6 months, followed by anticoagulant therapy, to be continued indefinitely or until he cancer is resolved.¹²

Conclusion

Trousseau's syndrome can be easily recognized in patients who have already been diagnosed with cancer, but when the thrombophlebitis is identified first, detection of the cancer is more complex and is therefore often delayed. Patients with idiopathic, especially recurrent, venous thromboembolism or arterial emboli should undergo a thorough workup, including CT, to determine if occult malignancy is present. Resistance to anticoagulation with warfarin but response to heparin in a patient with unprovoked thromboembolism is a clue that underlying malignancy may be present.

References

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