It is well known that patients with advanced malignant disease are at risk of a hypercoagulable condition, and may develop cancer-associated thrombosis (CAT) .
Trousseau syndrome (TS) is a known state of CAT and often occurs in patients with advanced solid cancers . TS is defined as chronic disseminated intravascular coagulation (DIC) associated with non-bacterial thrombotic endocarditis. Recovery is rare in patients with TS and there is no established evidence regarding the effects of anticoagulant treatment on this condition [1,3]. TS is currently used to describe a hypercoagulation disorder in patients with malignancy, similar to CAT [1,3]. TS commonly occurs in pulmonary, digestive, gynecology, or urinary cancer [1,3,4], and no such condition has been reported in a patient with oral cancer.
Here, we described a case of TS in a patient with buccal squamous cell carcinoma (SCC).
In 2017, a 61-year-old Japanese man was referred to an oral and maxillofacial surgeon in Tokai University Hospital, Isehara, Japan, because of trismus and general fatigue. He complained of gradually worsening trismus and a painful ulcerated wound in the right buccal mucosa that had failed to heal for the past 6months. He was on medication for hypertension and had no other specific systemic disease. On physical examination, facial swelling without redness was observed on the middle right side of his face, and trismus was noted (inter-incisor distance was 17mm). Ulceration was observed in the right buccal mucosa, and an indurated mass could be palpated on the skin of his right cheek. Multiple palpable cervical lymphadenopathies were observed. He underwent workup for suspected malignancy of the buccal mucosa. There were no neurological and cardiologic abnormalities.
Laboratory tests on admission showed high white blood cell count (13,400 cells/L) and elevated levels of SCC marker (4.5ng/mL), but did not show any disorder in other tests including blood coagulation tests and tumor markers: cancer antigen (CA) 19-9, 31U/ml; and carcinoembryonic antigen (CEA), 1.0ng/ml.
An incisional biopsy of the right buccal mucosa was performed, which confirmed the diagnosis of SCC. He was given a diagnosis of right buccal carcinoma (T4bN2bM1). Induction chemotherapy was planned, and he was admitted at our hospital. Five days after hospitalization and prior to the initiation of chemotherapy, he experienced aphasia and lost consciousness. He had right hemiparesis with right upper and lower extremities manual muscle test (MMT) grade 0 [5,6], and his National Institute of Health Stroke Scale (NIHSS) was 19 [7,8].
Intravenous recombinant tissue plasminogen activator (t-PA) (alteplase 0.6mg/kg) was administered directly after the MRI scan. Electrocardiogram (ECG), Holter monitoring, echocardiography, and blood culture tests did not show any abnormalities. A head CT on 1, 3, and 7days after onset showed that the infarction in his right MCA area had not recovered. Seven days after the onset of brain infarction, systemic heparinization was started (PT-INR, 1.5 to 2.0). He did not recover from his cerebral infarction and died 16days after admission, 21days after diagnosis, due to pneumonia. A pathological autopsy was not performed as the family did not consent. Family consent was obtained for this case report.
TS was first described in 1865 as migratory superficial thrombophlebitis in patients experiencing cancer . TS commonly occurs in lung (17%), pancreas (10%), colon and rectum (8%), kidneys (8%), and prostate (7%) cancers . This is the first report on TS in a patient with oral cancer or SCC. Recent reports suggested that TS is considered a condition which induces stroke due to the hypercoagulability state associated with malignancy; with non-bacterial and non-circulation thrombotic endocarditis reported as the common causative factor [9,10,11,12]. In this case, although we could not carry out transesophageal echocardiography because of trismus, there were no signs of thrombotic or bacterial endocarditis (normal ECG and echocardiography and negative blood culture). In addition, carotid invasion by the tumor and carotid sheath rupturing was ruled out by Doppler ultrasound given the fact that this is the most common cause of head and neck SCC (HNSCC)-associated cerebrovascular attack [13,14], leading us to the diagnosis of TS in this patient.
TS is described as a chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial emboli in patients with cancer, which often occurs in mucin-positive carcinomas of the lung or prostate. Hypercoagulability is thought to be initiated by mucins produced by the adenocarcinoma, which will then react with leukocyte and platelet selectins to form platelet-rich microthrombi . However, the etiology of TS is not known and multiple factors including thromboplastin-like substances, fibrin deposition, direct activation of factor X by tumor proteases, tissue factor, cysteine protease, tumor hypoxia, tumor-induced inflammatory cytokines, are believed to be responsible for this phenomenon in murine models [11,15,16,17,18] of mucinous carcinoma. Although the present case lacks the typical findings of mucin-producing carcinoma, such as intracytoplasmic mucin or extracellular mucin pools, serum tumor markers CA 19-9 and CA-125 were markedly elevated in the tumor, according to immunohistochemical findings.
Khorana Risk Score criteria for assessing venous thromboembolism in patients with cancer
Site of primary cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphatic system, reproductive organs, bladder, testicular)
Low risk (all other sites)
Platelet count 350,000/l
Hemoglobin level10g/dl or use of red cell growth factors
White blood cell count 11,000/l
Body mass index 35kg/m2
Score (Total points)
Risk of symptomatic VTE
1 or 2
Risk Scoring System of cancer-associated thrombosis criteria for assessing venous thromboembolism in patients with cancer
Age and sex
40 to 80-year-old female
Prior history of VTE
Low VTE propensity
Head and neck, endocrine
High VTE propensity
Lung, gynecologic, sarcoma, metastasis unknown origin
Intermediate VTE propensity
Other cancer subtypes
Score (Total points)
Incidence of VTE
Very low risk
4 to 1
Recovery in TS is slow and there is no established evidence supporting anticoagulant treatment in TS. Controlling the causative tumor and providing immediate systemic anticoagulation are the main steps for the treatment of TS. Systemic heparinization is considered an effective treatment strategy [3,12,22,23].
Based on our experience with this case, further investigations are required to prevent TS in cases of patients with head and neck carcinoma. If a patient has advanced cancer, there must be discussion concerning whether to use anticoagulation therapy to prevent VTE or not, regardless of the tumor primary site and histological type.
- CA:Cancer antigen
- CAT:Cancer-associated thrombosis
- CEA:Carcinoembryonic antigen
- CT:Computed tomography
- DIC:Disseminated intravascular coagulation
- DWI:Diffusion-weighted image
- FDP:Fibrinogen degradation product
- HNSCC:Head and neck squamous cell carcinoma
- IJV:Internal jugular vein
- KRS:Khorana Risk Score
- MCA:Middle cerebral artery
- MMT:Manual muscle test
- MRA:Magnetic resonance angiography
- MRI:Magnetic resonance imaging
- NIHSS:National Institute of Health Stroke Scale
- PET:Positron emission tomography
- PT-INR:Prothrombin time-international normalized ratio
- RSSC:Risk Scoring System of CAT
- SCC:Squamous cell carcinoma
- t-PA:Tissue plasminogen activator
- TS:Trousseau syndrome
- VTE:Venous thromboembolism