An autopsy case of Trousseau’s syndrome with tumor thrombosis in unknown primary squamous cell carcinoma of the head and neck

Abstract

Trousseau’s syndrome (TS) and tumor thrombosis (TT) are known as cancer-associated thrombosis with poor prognosis. TS is extremely rare in patients with squamous cell carcinoma. In this study, we report an unknown primary squamous cell carcinoma of the head and neck (SCCHN) patient with TS and TT in pulmonary artery definitely diagnosed by autopsy. A 73-year-old man had a past surgical history for unknown primary SCCHN and lung metastases. Three years after the initial surgery, the patient had multiple cerebral infarction, deep venous thrombosis in the legs and mediastinum metastases. Our diagnosis was TS and treatment with chemotherapy and unfractionated molecular heparin started. It could help control the hypercoagulative state and cancer progression, but finally, he died from progressive disease (mediastinum metastases and pulmonary embolism) five years after the initial surgery. An autopsy revealed multiple metastases and thrombosis in the pulmonary artery with squamous cell carcinoma microscopically. Although there is no established treatment for managing TS, intensive therapy such as a combination of chemotherapy and anticoagulant therapy can be effective in improving hypercoagulation therapy. In addition, an autopsy should be considered for patients with thrombosis to distinguish between TS and TT.

Introduction

Trousseau’s syndrome (TS) was first described as migratory superficial thrombophlebitis associated with patients with malignancy [1]. Recently, TS is considered a hypercoagulative disorder associated with malignant tumors. However, it is difficult to diagnose TS except by autopsy because cancer-associated thrombosis (CAT) may be caused by other diseases such as tumor thrombosis (TT) [2]. TS often occurs in patients with adenocarcinoma in the lung, pancreas, or ovary, but rarely in those with squamous cell carcinoma [3, 4]. To the best of our knowledge, the present case is the first case of TS with TT in unknown primary squamous cell carcinoma of the head and neck (SCCHN). In this case, despite the prediction of poor prognosis in TS cases, intensive treatment could control the hypercoagulative state and cancer progression, leading to prolonged survival.

Case report

A 73-year-old Japanese man with manual dexterity deficit for 2 days was referred to the department of neurosurgery and hospitalized for evaluation and treatment. The patient had a past surgical history for unknown primary SCCHN (pT0N3b) and lung metastases (two times). The treatment for the patient’s unknown primary SCCHN was radical neck dissection and tonsillectomy followed by postoperative chemoradiotherapy three years ago. p16 immunohistochemistry and Epstein–Barr encoding region in situ hybridization (EBER-ISH) were negative for tumor cell nuclei in the metastatic lymph node. The chemotherapy regimen was two courses of cisplatin (CDDP), and a total radiotherapy dose of 60 Gy was given. Isolated lung metastases occurred twice at one year and two years after the initial surgery, at which point, he underwent thoracoscopic surgery and partial pneumonectomy, respectively. Five months before onset of the cerebral infarction in this report, positron emission tomography–computed tomography (PET–CT) showed no relapse and no metastases. The patient had other thrombosis risk factors: hypertension and smoking, since he smoked 2 packs of cigarettes per day from age 20 to 70.

At admission, diffusion-weighted magnetic resonance imaging (DWI-MRI) revealed multiple cerebral and cerebellar infarctions in bilateral and both anterior and posterior circulation territories (Fig. 1). Examinations including a 12-lead and Holter electrocardiogram showed normal results. Laboratory tests revealed elevation of D-dimer (10.3 µg/ml). Transthoracic and transesophageal echocardiography revealed no thrombus. Ultrasonography of limbs showed deep vein thrombosis (DVT) in the left soleal vein. Contrast-enhanced computed tomography (CT) showed metastatic enlargement of mediastinal lymph nodes (Fig. 2a). We diagnosed the hypercoagulability as TS because of the progression of the malignant tumor. Therefore, we planned to start combination treatment, such as chemotherapy and anticoagulation therapy.

Fig. 1.

DWI-MRI showed multiple cerebral and cerebellar infarctions in different circulation territories

Fig. 2.

Contrast-enhanced CT showed a multiple metastases in mediastinal lymph nodes at the cerebral and cerebellar infarction (arrows); and b,c progression to mediastinal lymph nodes, occluding the superior vena cava and brachiocephalic vein (arrow), and pulmonary embolism in the right pulmonary artery (arrowhead)

The patient received intravenous unfractionated heparin (UFH) therapy during his hospitalization, followed by subcutaneous UFH as anticoagulation therapy. On the 43rd day after the cerebral infarction, he began chemotherapy which combined CDDP, 5-fluorouracil and cetuximab. During the combination treatment, D-dimer test results were within normal limits and there was no thrombosis event. Even though three courses of the chemotherapy followed by three courses of cetuximab and paclitaxel reduced the tumor size, metastases in mediastinal lymph nodes progressed again. Seven months after the onset of the infarction, the patient was started on nivolumab every two weeks. CT was conducted every 3 months and revealed that the tumors were stable disease. There was no side effect related with nivolumab. However, 14 months after starting on nivolumab, the patient suddenly had difficulty breathing, and contrast-enhanced CT showed progression to mediastinal lymph nodes, occluding the superior vena cava and brachiocephalic vein due to tumor compression resulting in superior vena cava syndrome, and pulmonary embolism (PE) in the right pulmonary artery (Fig. 2b,c). D-dimer test result was elevated to 3.9 µg/ml. After a prolonged period of 63 months from the initial surgery, the patient received palliative care in the last 2 months of his life.

A postmortem autopsy was performed with the approval of the patient’s family. A microscopic examination revealed metastases of squamous cell carcinoma in the following: paratracheal, mediastinal, and abdominal para-aortic lymph nodes, lymphatic vessels invading the thyroid and adrenal gland, and organs such as the heart and lung. Cardiac metastasis was located at the origin of the pulmonary artery on the surface macroscopically (Fig. 3a,b) and invaded the cardiac muscle microscopically (Fig. 3c). There were multiple thrombus in the superior vena cava and pulmonary artery (Fig. 4a), and some of them included squamous cell carcinoma (Fig. 4b). There was the lymphangiosis carcinomatosa in the right middle and lower lobes of lung. There was no primary squamous cell carcinoma and metastases in the brain. Unintentionally, prostate cancer was detected, which was a microinvasive adenocarcinoma (pT2aN0).

Fig. 3.

The macroscopic and microscopic findings of cardiac metastases show a, b cardiac metastasis located at the origin of the pulmonary artery on the surface macroscopically (arrows); and c squamous cell carcinoma invading cardiac muscle microscopically

Fig. 4.

The microscopic findings of thromboembolism in the pulmonary artery show a thromboembolism without cancer; and b thromboembolism with squamous cell carcinoma

Discussion

As it is widely known, some patients with malignancy are under a hypercoagulable state and at risk of CAT. This could lead to a major cause of death, excluding death from cancer itself [5]. TS is defined as a paraneoplastic syndrome that causes a hypercoagulative syndrome in patients with malignancy [6]. The incidence of CAT is various in patients suffering from different histological types of malignant disease. In an epidemiological study, adenocarcinoma had the highest risk factor for hypercoagulation, and the overall incidence rate of thrombosis in cancer patients was 1.08%. CAT was observed in 0.43% of patients with head and neck cancer, exhibiting a lower rate than the other malignancies [7]. Despite no obvious clinical criteria for the diagnosis of TS, the term TS is considered a hypercoagulative disorder in patients with malignancy. Therefore, a clinical diagnosis is currently defined as a hypercoagulative state and cancer progression. However, the definitive diagnosis is made by autopsy because the diagnosis of tumor thrombosis in living patients is extremely difficult [8, 9].

In this case, we diagnosed first thrombosis event of multiple cerebral infarction and DVT as TS clinically and also diagnosed PE as TS in an antemortem examination. It was because the patient had elevated D-dimer indicating general hypercoagulation and his simultaneous cancer progression which was not apparent from previous PET–CT. As a result, the autopsy on the patient revealed cardiac metastases and tumor thrombosis in the pulmonary artery. However, we consider the first thrombosis event as TS in the end because the autopsy did not show brain metastasis. We also thought that the second thrombosis event was TS with TT because there was mixed thrombus in pulmonary artery both with and without squamous cell carcinoma revealed by autopsy. TT is considered as one of the end-stage manifestations of wide variety of malignancies and is frequently observed in renal cell carcinoma, Wilms tumor, adrenal cortical carcinoma, and hepatocellular carcinoma [10]. Because TS and TT are rare in SCCHN and have similar characteristics associated with tumor progression and elevation of D-dimer, it is often difficult to diagnose the cause of thrombosis between TS and TT in the antemortem examination [11].

To treat and prevent the progression of TS, active treatment including chemotherapy and anticoagulation therapy immediately after diagnosis should take priority because cancer can induce hypercoagulability and tumor thrombosis depends on cancer progression [2, 12]. Although a limited number of drugs are approved for the treatment of recurrent or metastatic SCCHN in Japan, immune checkpoint inhibitors such as nivolumab and pembrolizumab has been added as treatment option and demonstrated prolonged overall survival [13, 14]. However, we have to pay attention to CAT because some chemotherapeutic agents have a possible risk for chemotherapy-related CAT [15]. As anticoagulation therapy, low-molecular-weight heparin (LMWH) is recommended for TS. However, in Japan, subcutaneous LMWH injection cannot be used because it has not been approved, so we used subcutaneous UFH [12]. In this case, the patient went through many kinds of aggressive chemotherapy and subcutaneous UFT treatment for long periods because we suspected hypercoagulation due to TS. In spite of the poor prognosis of CAT and unknown primary SCCHN, the patient was able to survive longer than similar patients previously reported [16, 17].

Conclusion

TS should be diagnosed as soon as possible, with radical treatment such as chemotherapy and anticoagulation therapy performed after the diagnosis. Intensive treatment can help control the hypercoagulative state and cancer progression. Although TS has to be diagnosed clinically, an autopsy must sometimes be considered for a detailed diagnosis.

Funding

This work was supported by JSPS KAKENHI (Grants-in-Aid for Early-Career Scientists) Grant Number JP19K18808.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

It was deemed to be unnecessary for this case report.

Informed consent

Written informed consent was obtained from the patient’s family for publication of this case report and accompanying images.