A Primary Intravascular Synovial Sarcoma Causing Deep-vein Thrombosis and Pulmonary Embolism in a 20-year-old Woman

Primary intravascular synovial sarcoma is a rare malignancy with only a few cases documented in the literature. On presentation, this tumour usually resembles a deep venous thrombosis (dvt) or pulmonary embolism (pe). Here, we report the case of a 20-year-old woman complaining of shortness of breath who had a history of dvt 6 weeks before presentation at our institution. Vascular ultrasound detected a suspicious mass in the right groin, which was identified as a monophasic synovial sarcoma by surgical biopsy. The tumour extended from the right superficial femoral vein into the common iliac vein, profound femoral vein, and great saphenous vein. It caused pe with near-total occlusion of the right pulmonary artery. After initial treatment on the cardiac intensive care unit, the patient was referred to the oncology department for neoadjuvant radiochemotherapy with doxorubicin–ifosfamide according to the Interdisziplinäre Arbeitsgemeinschaft Weichteilsarkome [Interdisciplinary AG Sarcomas] protocol and surgical resection of the tumour. No signs of tumour recurrence were found during the subsequent course of the disease, but the patient died from treatment complications approximately 15 months after initial presentation. This case underlines the importance of screening for malignancies even in young patients presenting with dvt or pe. We also recommend whole-leg compression ultrasonography in patients with suspected dvt or pe (as opposed to venography or simple four-point ultrasound examination in the groin and popliteal fossa) to detect possible underlying causes for thrombosis.


INTRODUCTION
The incidence of venous thromboembolism rises exponentially with age 1 .But even in young patients, serious venous thromboembolism is not uncommon.A German study showed a pulmonary embolism (pe) incidence of 11 per 100,000 in the female population 10-29 years of age, and 6 per 100,000 in the male population 10-29 years of age 2 .
Diagnostic strategies for pe usually include clinical probability scores, testing for D-dimer, echocardiography, and computed tomography or ventilation-perfusion scintigraphy 3 .Ultrasonography of the lower limbs is less important for making the diagnosis, because it detects deep vein thrombosis in only 50% of patients with manifest pe 4 .However, ultrasonography of the lower limbs is crucial in detecting anatomic anomalies leading to deep venous thrombosis (dvt) and embolism.Ultrasonography is readily available in most settings and easy to perform.
In the present case, the findings of a vascular ultrasound study led to the cause of venous thromboembolism in a 20-year-old.

CASE DESCRIPTION
A 20-year-old woman presented at our emergency department with progressive shortness of breath and pleuritic chest pain for about 3 days.She had presented at another hospital 6 weeks earlier with pain in the right thigh, where she was diagnosed with multilevel dvt of the right thigh.Duplex ultrasonography had revealed a clot extending from the superficial femoral vein to the external iliac vein and profound femoral vein.A "nodule" had also been described originating from the proximal superficial femoral vein, which had been interpreted as "clotted venous ectasia." Initial treatment had been certoparin, followed by rivaroxaban 20 mg once daily.No other illnesses were present, and no other medication was taken.A pregnancy test was negative.No family history of dvt or pe was present.An activated protein C resistance ratio of 1.7 suggested heterozygous carrier status for the factor V Leiden mutation.
Despite anticoagulant treatment, the patient's medical history quickly led to a suspected diagnosis of pe.On computed tomography, we found an embolus with near-total occlusion of the right pulmonary artery and extension into segments 4, 6, 8, 9, and 10.The patient was hemodynamically stable, and no signs of right ventricular dysfunction were found on echocardiography.We therefore decided against thrombolysis.The patient was admitted to our intensive care unit and treated with intravenous heparin (adjusted to a partial thromboplastin time of 60-90 seconds).
Subsequent duplex sonography found a thrombus in the right thigh reaching from the distal superficial femoral vein to the common iliac vein, and thrombotic material in the profound femoral vein and the great saphenous vein.We also found a mass in the right groin measuring about 3×4.5 cm which compressed the femoral vein (Figure 1).Arterial Doppler signals could be recorded inside the lesion.
The patient confirmed that she had felt occasional pain in the right leg for about 12 months and had noticed a slowly growing lump in the right groin for about 6 months.The lump had been interpreted as a "muscle swelling" by the family doctors she had seen, and she had been given analgesic medications for it.The differential diagnosis at this time included arteriovenous malformation with thrombus, and sarcoma.
For further differentiation of the mass, magnetic resonance angiography and computed tomography were performed (Figure 2).A neoplastic structure was shown extending from the superficial femoral vein into the common iliac vein, profound femoral vein, and great saphenous vein.Additionally, thrombotic material was found attached to the neoplasm in the common iliac vein.No enlarged lymph nodes were found.
To reach a definitive diagnosis, open surgical biopsy was performed.A blueish tumour approximately 3.5×5 cm embracing the femoral vessels was dissected.A highly vascular piece of tissue was biopsied and sent to frozen-section analysis, which showed a mesenchymal neoplasm.The final pathologic diagnosis revealed a monophasic synovial sarcoma with characteristic SYT1-SSX2 translocation t(X;18).Computed tomography of abdomen and pelvis did not find metastatic disease.
On day 13 after admission, the patient was referred to our oncology department for neoadjuvant radiochemotherapy and surgical resection of the tumour.Throughout the stay on the intensive care unit, the patient remained hemodynamically stable.Shortness of breath was resolved upon referral.
Considering the involvement of large vessels and the desire for limb-sparing surgery in a young patient, a decision for neoadjuvant radiochemotherapy was made.After informed consent, the patient was included in the Interdisziplinäre Arbeitsgemeinschaft Weichteilsarkome [Interdisciplinary AG Sarcomas] registry study and received 4 cycles of doxorubicin (60 mg/m 2 on day 1) and ifosfamide (3 g/m 2 on days 1-3).Cycles were repeated every 3 weeks.Chemotherapy was followed by radiation therapy to the tumour bed using a fractionation scheme of 5×1.8 Gy weekly (total dose: 50.4 Gy).On days 1-2 and 22-23 of the radiation course, the patient received ifosfamide 3 g/m 2 .After neoadjuvant radiochemotherapy, the tumour was completely resected with a wide margin.Regional lymph nodes proved to be free of disease.The femoral artery and vein had to be removed; they were replaced with a polytetrafluoroethylene graft.The patient's postoperative course was complicated by a lymphatic fistula in the groin and impaired wound healing, leading to surgical revisions and flap reconstruction.
Five months after tumour resection, the vascular prostheses had to be replaced with a homograft because of infection.One month later, the patient presented with bleeding in the groin and was readmitted to hospital.During a long and complicated stay, she developed septicemia and died in cardiogenic shock, approximately 15 months after her initial presentation with dvt.
Although her cumulative doxorubicin dose (240 mg/m 2 ) is lower than usual for cardiotoxicity 5 , the combination of septic cardiomyopathy and subclinical anthracyclineinduced cardiotoxicity could have caused the low-output cardiogenic shock in this patient's case.At the time of death, no tumour recurrence was evident.The patient's relatives did not consent to a clinical autopsy.

DISCUSSION
Soft-tissue sarcomas comprise more than 50 different histologic subtypes.Synovial sarcomas constitute one of the more common entities and account for approximately 10% of all soft-tissue sarcomas 6 .Histologically, biphasic synovial sarcomas with epithelial-like cells and spindle cells can be distinguished from a monophasic type with only spindle cells.SYT1-SSX fusion genes resulting from the characteristic t(X;18) translocation can be observed in up to 95% of all synovial sarcomas, making detection of those fusion genes a diagnostic test for this tumour entity 7 .
The name "synovial sarcoma" was originally coined because of some microscopic resemblance to synovial tissue and the frequent presence of these tumours near joints.However, the name is misleading because the tumour can arise almost anywhere in the body.Multipotent mesenchymal stem cells have been proposed as the origin of the malignant cells 8 .
Primary intravascular manifestations of sarcomas are exceedingly rare.Vascular leiomyosarcomas seem to be most common entity, accounting for 0.7% of all malignant soft-tissue tumours in a study from a German sarcoma reference centre 9 .Other primary intravascular sarcomas such as intimal sarcoma or epitheloid hemangioendothelioma are known from case studies.Primary intravascular synovial sarcomas, as in the present case, are extremely rare.A search of the literature revealed only 9 other documented cases (Table i).Of the 10 reported patients (including ours), 8 are women.The age of the patients ranges from 16 years to 54 years, with the predominant age group appearing to be 30-40 years.Histologically, the biphasic tumour type seems to be more common (7 of 10 cases).Pain and swelling in a limb were the most common symptoms; 4 patients presented with shortness of breath, indicating pe or protrusion of the tumour into the right atrium.
The vessels most often affected are the proximal femoral and iliac veins (6 of 10 cases).In 2 patients, the tumour was isolated to the inferior vena cava.Involvement of the superior vena cava and upper limb vessels was reported in only 2 patients.Protrusion of the tumour mass into the right atrium is not uncommon, with 3 documented cases.In another 4 patients, including ours, pulmonary emboli were reported, but the presence of tumour emboli was histologically proven in only 1 patient who died shortly after embolectomy 11 .In the present case, the pulmonary emboli decreased in size after 2 months of anticoagulant treatment, and so we assumed a thrombotic origin and decided against biopsy or removal, which would have put the patient unnecessarily at risk.
Primary treatment options for synovial sarcomas-as for all soft-tissue sarcomas-are wide surgical excision and radiotherapy, often in combination with chemotherapy.Large tumours or tumours in delicate anatomic regions can be treated with preoperative radiotherapy or radiochemotherapy to reduce tumour size and facilitate less-radical surgical techniques.Compared with other soft-tissue sarcomas, synovial sarcomas are regarded as relatively chemosensitive 19 .Regimens containing doxorubicin and ifosfamide seem to be the most effective 20 .
In the present case, neoadjuvant radiochemotherapy with doxorubicin-ifosfamide proved effective and allowed for limb-sparing surgery.However, infection of the vascular grafts caused multiple surgical revisions and hospitalization.An episode of postoperative septicemia ultimately led to the patient's death from a combination of septic cardiomyopathy and anthracycline-induced cardiotoxicity.

SUMMARY
It is well known that malignancies facilitate thromboembolic events by hypercoagulability, pressure, or obstruction of vessels.However, no consensus has been reached on a screening algorithm to detect occult cancer in patients presenting with dvt or pe 21 .The clinician should be aware that cancer might be the underlying cause for thrombosis even in young patients, as in the present case.
The method of choice for diagnosis of dvt is whole-leg compression ultrasonography.In contrast to venography or simple four-point ultrasound examination of the groin and popliteal fossa, whole-leg compression ultrasonography can not only detect thrombosis itself, but also possible underlying pathologies such as soft-tissue tumours.Abnormal vascular ultrasound findings such as "venous ectasia" or "arteriovenous malformation" should always raise suspicion of an intravascular tumour.In the present case, the unusual presence of arterial Doppler signals inside the "thrombus" was a red flag pointing to the diagnosis of intravascular sarcoma.Computed tomography or magnetic resonance angiography is usually the next step, but biopsy should be mandatory.

CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conf licts of interest, and we declare that we have none.

FIGURE 1 2
FIGURE 1 Duplex sonography, axial view, shows the right common femoral artery (arrow).A large circular mass with signs of arterial vascularization is found where the femoral vein is expected.FIGURE 2 Computed tomography image, coronal view, shows a neoplastic mass (arrow) growing inside the right femoral and iliac vein.