Left pneumonectomy for primary lung cancer with Trousseau’s syndrome

Abstract

Trousseau’s syndrome is a paraneoplastic syndrome and a pathological condition that causes cerebral stroke symptoms due to hypercoagulation associated with malignant tumours. There have been many cases of advanced lung cancer, but few reports have described surgery for lung cancer with Trousseau’s syndrome. We encountered a 76-year-old man suspected of having Trousseau’s syndrome associated with lung cancer. He was transferred to our hospital on the second day after the onset. After admission, he was treated with heparin and edaravone, and his condition improved. On the 12th day after the onset, we performed left pneumonectomy and lymph node dissection (ND2a-2). The final pathological results were adenocarcinoma, pathological stage was T4 (tumour size: 77 mm, pulmonary artery invasion) N1(#11, #12u) M0, stage IIIA. He has been recurrence free for 23 months since the surgery. In the future, we need to follow his condition carefully.

Background

Since the pathophysiology of cerebral infarction and pulmonary embolism due to multiple venous thrombosis was first reported by Trousseau,¹ patients with cancer have been known to develop abnormality of the coagulation/fibrinolysis system. Trousseau’s syndrome is a paraneoplastic syndrome and a pathological condition that causes cerebral stroke symptoms due to increased blood coagulation associated with malignant tumours. Generally, in patients with cerebral infarction associated with cancer, the survival time is 4.5 months, and the prognosis is poor.² The prognosis of Trousseau’s syndrome is considered to be even worse.

We herein report a case of successful control of lung cancer associated with Trousseau’s syndrome.

Case presentation

A 76-year-old man was admitted to the previous hospital because of dysarthria and motor paralysis in the left upper and lower limbs. After admission to the hospital, MRI of the head was performed because of the exacerbation of the symptoms. An infarcted lesion was found in the right cerebral hemisphere, and the middle cerebral artery (MCA) region was poorly visualised. Trousseau’s syndrome was suspected for three reasons: (1) no history of heart disease, (2) reopening of right MCA after treatment and (3) a tumour in the upper left lobe on chest CT. He was transferred to our hospital.

Investigation

No major abnormalities were noted in the peripheral blood or biochemistry. Regarding tumour markers, cytokeratin-19 fragment (CYFRA) was elevated to 5.9 ng/mL (normal:<3.5 ng/mL). D-dimer had a high value of 20.2 µg/dL, and fibrinogen degradation products (FDP) had a high value of 12.1 µg/dL. Chest X-ray showed a tumour shadow in the left upper lung field. Chest CT revealed a 77 mm tumour mass in the upper left lobe and partial pulmonary artery (PA) infiltration (figures 1 and 2). On MRI of the head, the right MCA region showed a high signal on T2-weighted and fluid-attenuated inversion recovery imaging, suggesting an infarct lesion from the acute to the subacute stage (figure 3).

Figure 1.

Chest CT shows a 77 mm tumour mass in the upper left lobe.

Figure 2.

On chest CT, the tumour had partially invaded the pulmonary artery (A3).

Figure 3.

Head MRI shows a high signal on T2-weighted imaging in the right cerebral hemisphere region.

Differential diagnosis

No abnormal values were observed in the procaine C activity, protein S antigen amount or anticardiolipin antibody, so diseases that cause abnormal coagulation were negative. And transoesophageal echocardiography showed no obvious source of embolus or patent foramen ovale leading to paradoxical embolism.

Treatment

As treatment, anticoagulation therapy was started, and the dose was adjusted by continuous intravenous administration of heparin to keep APTT at 1.5–2.0 times the reference value. As a brain protectant, edaravone 30 mg was intravenously infused two times a day. A close examination revealed no obvious metastatic lesion except for a tumour in the left hilum and hilar lymph nodes. Therefore, we diagnosed him with clinical stage cT4 (PA infiltration) N1 (#11, #12u) M0, stage IIIA. Since the patient’s symptoms improved, the policy was to conduct surgery prior to chemotherapy.

We started the surgery with a 17 cm posterolateral incision. We determined that A3 was involved in the tumour and that #11LN had extranodal invasion, necessitating left pneumonectomy. The frozen pathological diagnosis was adenocarcinoma. The bronchial stump was blocked with an automatic suture instrument, and then a single ligature was added with two needles of 4–0 proline to reinforce the stump.

The operation time was 219 min, and the blood loss was 130 mL. The pathological diagnosis was adenocarcinoma, T4 (tumour size: 77 mm) N1 (#11, #12u) M0, stage IIIA (figure 4).

Figure 4.

Pathological findings. The tumour was 77×72 mm in size. The postoperative pathological diagnosis was adenocarcinoma with N1 (#11, #12 u) lymph node metastasis (H＆E stain; magnification,×400).

Outcome and follow-up

The drain was removed at one postoperative day (POD), and warfarin was started. The postoperative course was uneventful, and home oxygen therapy was introduced at 11 POD, at which point he was discharged.

Postoperative adjuvant chemotherapy was not performed because the patient’s performance status (PS) was poor. At present, 23 months after surgery, there has been no recurrence, and we are carefully observing him as an outpatient.

Discussion

Trousseau’s syndrome is now defined as an unexpected cancer-related thrombotic event, such as a cerebral infarction or deep vein thrombosis/pulmonary embolism.³ A diagnosis of Trousseau syndrome is often difficult, but latent cerebral infarction that develops in the underlying advanced cancer often has elevated D-dimer activity and can be helpful for making a diagnosis.⁴ The most common type of cerebral infarction in Trousseau’s syndrome is cardiogenic cerebral embolism due to non-bacterial thrombotic endocarditis.⁵ We perform echocardiography, especially transesophageal echocardiography, to exclude cardiogenic cerebral infarction, endocarditis, and paradoxical cerebral infarction associated with patent foramen ovale. It is important to perform a blood test to identify the combination of collagen disease and diseases that cause abnormal coagulation.⁶ In this case, no abnormal findings were observed on an ECG or echocardiography, various autoantibodies were negative, and no abnormalities in coagulation factors were observed. Therefore, Trousseau’s syndrome was considered the cause of cerebral infarction.

There have been few reports of lung cancer associated with Trousseau’s syndrome,^7–13 and only two reports have described the performance of surgery.^{7 13} The median survival time for cerebral infarction in Trousseau’s syndrome is reported to be 4.5 months, and 25% die within 30 days after the diagnosis of stroke.² In cases where anticancer drug treatment is not indicated, the prognosis is even worse because anticoagulant therapy is the only treatment. However, it has been reported that, in cases of Trousseau’s syndrome associated with lung cancer, control of cerebral infarction was able to be obtained by combining anticoagulant therapy with cytocidal anticancer chemotherapy or molecularly targeted therapy.^{7 8 11} Treatment for the primary tumour may thus have an effect on Trousseau’s syndrome. However, no consensus has been established regarding surgery for lung cancer with Trousseau’s syndrome. Nevertheless, we chose salvage surgery instead of chemotherapy in the present patient because of the lack of distant metastases and the improvement in symptoms. If the patient does not receive postoperative adjuvant chemotherapy due to poor PS, we plan to perform chemotherapy in the future if it recurs.

Trousseau’s syndrome requires anticoagulant therapy and treatment for the underlying disease.^{14 15} The initial treatment modalities for cancer-associated thrombosis include low-molecular-weight heparin, unfractionated heparin and fondaparinux. The histological type of lung cancer associated with Trousseau’s syndrome is predominantly adenocarcinoma, especially mucin-producing tumour. Heparin is known to inhibit mucin derived from cancer to form microthrombus by reacting with platelets and leukocytes through selectin.² Warfarin, an oral drug, may have difficulty controlling prothrombin time-international normalized ratio (PT-INR) due to the effects of combined chemotherapy. Warfarin potassium has been reported to be ineffective, as it suggests the presence of coagulation abnormalities that are independent of vitamin K.¹⁵ Furthermore, considering the complexity of cerebral hypercoagulability in Trousseau syndrome, there are many issues to be investigated regarding the effectiveness of direct oral anticoagulants. Therefore, heparin should be used as much as possible to maintain good control. In the present case, we determined that all existing lesions had been removed by surgery, and he started taking warfarin from 1 POD. By 1 month after the operation, his D-dimer level had been normalised.

In conclusion, Trousseau’s syndrome generally has repeated thrombosis and is a condition with a poor prognosis, but it may show a favourable course if it is detected early and effective primary treatment can be performed. We believe that the number of patients following the same course as this report will increase in the future due to dramatic improvements in the efficacy and tolerability of lung cancer therapeutic agents.

Learning points.

• Trousseau’s syndrome, which is often associated with advanced cancer, reportedly has a poor prognosis (median survival time: 4.5 months).

• Trousseau’s syndrome is often found in cerebral infarction of unknown cause, and it is important to distinguish it from other diseases by transoesophageal echocardiography for diagnosis.

• Trousseau’s syndrome requires anticoagulant therapy and treatment for the underlying disease.

• Trousseau’s syndrome may show a good course if detected early and effective treatment of the underlying disease is performed.