A Primary Primitive Neuroectodermal Tumor Arising from Left Subclavian Vein and Extending along Left Brachiocephalic Vein and Superior Vena Cava into Right Atrium Jian Wang, Weici Wang, Yiqing Li, Bi Jin, Miao Yu, Wenqi Liu, Shaohua Yao, Yonggui Liao, and Chenxi Ouyang, Wuhan, China

Primitive neuroectodermal tumor (PNET) is an extremely rare malignancy thought to be derived from fetal neuroectodermal precursor cells. It usually occurs in central and peripheral nervous system or soft tissue and bone, while intravenous or intracavitary PNET is considered as an extremely rare tumor. We reported a case of a 44-year-old woman who presented with the left unilateral facial and neck swelling. Magnetic resonance imaging revealed a tapeshaped solid mass within left subclavian vein, left brachiocephalic vein, superior vena cava, and right atrium; the proximal end proportion occupied almost the entire right atrium with a pedicle flip protruded into the right ventricle. Ultrasonography revealed an irregular hypoechnoic mass arising from the left subclavian vein, which extended along the left brachiocephalic vein and superior vena cava into the right atrium and up to the right ventricle. Positron emission tomography-computed tomography revealed several hypermetabolic thyroid nodules with no evidence of intravenous hyperactive lesion. The patient underwent tumor resection under cardiopulmonary bypass. At 15 days postoperatively, total thyroidectomy and resection of the left subclavian vein were simultaneously performed. The patient received chemotherapy and radiotherapy later. Histologically, the neoplasm displayed small, round, blue cells with hyperchromatic nuclei and scant cytoplasm. The neoplastic cells showed a strong immunopositivity for CD99, synaptophysin, CD56, CD57, and friend leukemia integration 1, thus confirming a diagnosis of the PNET. Histopathological examination of the thyroid showed papillary carcinoma. Thus, this PNET had no definitive organ or tissue of origin, which primarily originated from the left subclavian vein with tumor extension along the superior vena cava to the right ventricle.

Jian Wang and Weici Wang contributed equally to the manuscript. Consent: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Correspondence to: Chenxi Ouyang, MD, PhD, Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Street, Wuhan, Hubei 430022, China; E-mail: [email protected] Ann Vasc Surg 2015; 29: 839.e13e839.e20 http://dx.doi.org/10.1016/j.avsg.2014.12.007 Ó 2015 Elsevier Inc. All rights reserved. Manuscript received: June 22, 2014; manuscript accepted: December 14, 2014; published online: February 25, 2015.

The term ‘‘primitive neuroectodermal tumor’’ (PNET) was first initiated in 1973 by Hart and Earle1 to describe a group of tumors thought to be derived from fetal neuroectodermal cells. PNETs are a group of rare, aggressive, and highly malignant neoplasms with the morphological features of small, round, cell tumors. They may be broadly divided into 2 main categories according to the cell of origin and location: central and peripheral. Central PNETs are derived from the neural tube and involve mainly the brain and the spinal cord. On the other hand, peripheral PNETs are derived from the neural crest and often involve the sympathetic nervous system or soft tissue and bone.2,3 PNETs can also occur in 839.e13

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Fig. 1. MRI showing a tape-shaped heterogeneous tumor inside the lumen of left subclavian vein, left brachiocephalic vein, and superior vena cava (A), extending

into the right atrium with a pedicle protrusion into the right ventricle (B), and producing an incomplete venous obstruction (C).

numerous solid organs such as the kidney, pancreas, uterus, thymus, and cervix. Most of these tumors are diagnosed before the age of 35 years with a slight predominance in male patients. This article describes a rare case of a primary PNET arising from the left subclavian vein with tumor extension through left brachiocephalic vein and superior vena cava into right atrium up to right ventricle in a 44-year-old woman. According to the literature, there are no currently reported cases of intravenous or intracavitary PNET without an organ or tissue of origin.

CASE REPORT A 43-year-old woman presented with a slight left facial and neck swelling symptom for 2-month duration. Medical history and physical examination were unremarkable. Preoperative laboratory values were normal. Magnetic resonance imaging (MRI) revealed an irregularly tapeshaped solid mass within the left subclavian vein, left brachiocephalic vein, superior vena cava, and right atrium (Fig. 1A), in which a 4.7  2.6 cm proximal end occupied almost the entire right atrium with a 1.9  2.6 cm bulging pedicle passed into the right ventricle through the tricuspid valve (Fig. 1B) (see Video, Supplemental

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Fig. 2. Echocardiography showing a large solid mass of hypoechnoic texture filling the entire right atrium (A), bulging into the right ventricle during diastole (B), and causing the mechanical tricuspid valve obstruction or insufficiency (C).

Digital Content 1, which demonstrates the trans-tricuspid movement of an intracavitary right atrial mass). Intravenous tumor was associated with an incomplete venous reflux obstruction (Fig. 1C) (see Video, Supplemental Digital Content 2, which demonstrates the partial obstruction of the superior vena cava). Ultrasonography showed a hypoechnoic lesion arising from the left subclavian vein,

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extending along the left brachiocephalic vein and superior vena cava into the right atrium, occupying a significant proportion of the right atrial volume. Echocardiography confirmed a 5.8  3.8 cm solid mass filling almost the entire right atrium (Fig. 2A) with protrusion into the right ventricle during diastole and retraction into the right atrium during systole (Fig. 2B) (see Video, Supplemental Digital Content 3, which demonstrates the motion of a right atrial mass with heart contraction), resulting in a mechanical tricuspid valve obstruction or insufficiency (Fig. 2C). Positron emission tomography-computed tomography (PET-CT) revealed several hypermetabolic nodules with varying degrees of calcification at the bilateral lobes of the thyroid gland (Fig. 3A, B); nonetheless, no hyperactive lesion coincided with the intravenous and intracavitary mass identified by MRI (Fig. 3C). The patient underwent surgical tumor resection without cardiac arrest under cardiopulmonary bypass. Gross examination revealed a tape-shaped, grayish tan, and fish flesh-like mass measuring 12 cm in length, in which the proximal end portion was well-circumscribed and encapsulated by a dense fibrous layer; nonetheless, the distal end portion was friable and indistinguishable from the surrounding tissue (Fig. 4A). Microscopically, the tumor consisted of undifferentiated small, round, blue-staining cells with hyperchromatic nuclei and scant cytoplasm lying closely packed in sheets without rosette or gland formation (Fig. 4B). Immunohistochemistry (IHC) was positive for CD99 (Fig. 5A), friend leukemia integration 1 (FLI-1) (Fig. 5B), CD56 (Fig. 5C), CD57 (Fig. 5D), and synaptophysin (Fig. 5E), suggesting a diagnosis of the PNET. The mitotic rate was high. The Ki-67 proliferation index was about 20e30% (Fig. 5F). Negativity for smooth muscle actin, smooth muscle myosin heavy chain, CD34, CD31, desmin, CD10, CD117, calretinin, epithelial membrane antigen, pancytokeratin, and S100 excluded the possibility of tumors of smooth muscular, endothelial, lymphatic, epithelial, and glial cell origin. At 1 week postoperatively, echocardiography did not discover any abnormality from intracavitary structure to valve function (see Video, Supplemental Digital Content 4, which demonstrates the complete resection of an intracavitary right atrial mass); nonetheless, ultrasonography revealed the residual tumor thrombus firmly attached to the vessel wall in proximal left subclavian vein (Fig. 6A). At the site of vein narrowing, the blood flow increased in velocity and color flow showed an aliased color Doppler signal (Fig. 6B). Fifteen days later, total thyroidectomy and resection of the left subclavian vein and left internal jugular vein were simultaneously performed under general anesthesia. Silver clips were placed in distal left brachiocephalic vein for adjuvant postoperative radiotherapy. Postoperative histopathological examination of the thyroid specimen revealed typical papillary fronds with fibrovascular core lined by columnar-to-cuboidal tumor cells, with ground nuclei and grooving and abundant cytoplasm and colloid consistent with metastatic papillary thyroid carcinoma (Fig. 7AeD). Intraoperative finding did not support that external tumor

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Fig. 3. PET-CT showing multiple hypermetabolic thyroid nodules (A, B) with no evidence of intravenous hyperactive lesion (C).

locally invaded into the left subclavian vein. One month postoperatively, the patient was started on chemotherapy and radiotherapy. Until her last follow-up examination at 12 months after her surgery, the patient has received a total of 6 cycles of chemotherapy and 27 cycles of radiotherapy. A CT scan after 12 months revealed that venous tumor thrombi were not detected within the left brachiocephalic vein and superior vena cava (Fig. 8A) as well as the right atrium and the ventricle (Fig. 8B), a large left vein acted as a collateral vessel between the left brachiocephalic vein and hemiazygos vein (Fig. 8C), and multiple nodules with a maximum diameter greater than 1.5  1.0 cm were identified mainly within the left upper lung parenchyma raising the possibility of pulmonary metastasis (Fig. 8D). The patient deteriorated rapidly and succumbed to respiratory failure because of pulmonary metastasis 18 months after the initial surgery.

DISCUSSION To our knowledge, this is the first reported case of primary PNET with intravenous origin and tumor extension into the superior vena cava, right atrium, and right ventricle. Most of the reported PNET cases occur with patients in their second or third decades of life. Our patient was unusual 43 years of age at the time of diagnosis. The presenting symptom and clinical sign are generally nonspecific and because of venous obstruction or the dysfunction of tricuspid valve. Our patient complained of a slight facial and neck swelling owing to the insufficient venous reflux. Ultrasonography is the investigation of choice for initial evaluation, which can offer 2dimensional images and comprehend the tumor

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Fig. 4. Photography showing a tape-shaped, grayish tan, and fish-like mass with the distal end portion infiltrating into vessel wall (A). Histopathological examination sections showing a cellular undifferentiated tumor composed of small, round to oval cells with hyperchromatic nuclei and little cytoplasm (B).

location and its growth pattern. CT and MRI help to further characterize the tumor and to assess the extent of tumor spread.4 Application of the full range of diagnostic method is necessary, because a single diagnostic method is not enough to clarify the exceeding rare tumor. The definite diagnosis of primary PNET is made usually postoperatively based on histopathology and the panel of immunohistochemical stains. Histologically, PNET consists of solid sheets and nests of small, round, undifferentiated tumoral cells with scant cytoplasm, oval to round with hyperchromatic nuclei. Immunochemical staining is crucial for the diagnosis. The cell surface glycoprotein MIC2 (CD99) expression was positive in 90e 95% of the PNET cases, while FLI-1 protein was observed as nuclear staining in 84% of the cases.5 Immunohistochemical detection of CD99 together with FLI-1 has proven to be a powerful marker in confirming a diagnosis of a PNET.5 Other helpful

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markers are neuron-specific enolase and vimentin, synaptophysin and S100 protein. Furthermore, cytogenetic studies suggest that PNET is consistently associated with translocation of the long arms of chromosome 11 and 22, t(11:22) (q24:q12) in more than 90% of the tumors.6 Unfortunately, cytogenetic study was not performed in our case because the facilities are not available. Initially, we postulated that the tumor might arise from the neck organ or tissue with vena caval and atrial tumor thrombus. However, various imaging modalities including CT, MRT, ultrasound, and PETCT merely revealed multiple bilateral hypermetabolic thyroid nodules and did not detect any other doubtful primary lesions in the territory of brain, neck, breast, and thorax. More significantly, thyroid histopathology confirmed the diagnosis of papillary thyroid carcinoma, which was entirely inconsistent with clinicopathological feature of intravenous or intracavitary PNET. Accordingly, the possibility that the tumor originates from a definite organ or tissue could be excluded. Grossly, the tumor was welldemarcated and separated from the right atrium, superior vena cava, and left proximal brachiocephalic vein by a dense fibrous pseudocapsule, while it was friable and admixed with the left subclavian vein. Moreover, it was not noted that the external tumor invaded into the left subclavian vein intraoperatively. The tumor appeared to originate from the left subclavian vein and extend along the left brachiocephalic vein and superior vena cava into the right atrium, finally through the atrioventricular valve into the right ventricle. Primary PNETs have been reported to originate from the atrial or ventricular wall, causing intracavitary obstruction or extracardiac compression.7,8 Renal PNETs were reported to be able to invade into the renal vein, extend along inferior vena cava, and finally enter into the right atrium.9,10 Because PNET is a very aggressive malignant neoplasm with a high incidence of local recurrence and distant metastasis, it should be treated with a combination of surgery and chemotherapy. Complete resection of the tumor should be performed if at all feasible. There is a definite curative role for chemotherapy in this tumor, which includes standard regimen with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these 4 drugs alternating with courses of ifosfamide and etoposide.11 In cases where there is an incomplete resection or positive margin or recurrence of the tumor, radiotherapy is strongly recommended. Combination of chemotherapy and radiotherapy with surgery improved 2-year survival rate from 23e44% to 59e67%, and reduced the rate of distant metastasis from 46e65% to 12.5e32%,12

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Fig. 5. Immunohistochemical staining positive for CD99 (A), FLI-1 (B), CD56 (C), CD57 (D), and synaptophysin (E). Nuclear staining for the Ki-67 in about 20e30% tumor cells (F).

which was primarily attributed to eliminate the micrometastases and control local disease. No certain therapeutic protocol has been applied for the PNET patient because of the limited number of reported cases. Accordingly, further studies are needed to find the appropriate treatment protocol. In conclusion, an intravenous and intracavitary PNET is an exceedingly rare tumor. This primary PNET arises from the left subclavian vein and extends along the left brachiocephalic vein and superior vena cava into the right atrium, finally up to the right ventricle. IHC for CD99 and FLI-1 is very valuable in the diagnosis of PNET. A multimodality treatment approach including surgery resection, chemotherapy, and radiotherapy is required. SUPPLEMENTARY DATA Supplementary data related to this article can be found online at doi10.1016/j.avsg.2014.12.007.

REFERENCES 1. Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer 1973;32:890e7. 2. Behdad A, Perry A. Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol 2010;20:441e50. 3. Jimenez RE, Folpe AL, Lapham RL, et al. Primary Ewing’s sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol 2002;26:320e7. 4. Araoz PA, Eklund HE, Welch TJ, et al. CT and MR imaging of primary cardiac malignancies. Radiographics 1999;19: 1421e34. 5. Llombart-Bosch A, Navarro S. Immunohistochemical detection of EWS and FLI-1 proteins in Ewing sarcoma and primitive neuroectodermal tumors: comparative analysis with CD99 (MIC-2) expression. Appl Immunohistochem Mol Morphol 2001;9:255e60. 6. Folpe AL, Hill CE, Parham DM, et al. Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing’s sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 2000;24:1657e62.

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7. Bes¸irli K, Arslan C, T€ uz€ un H, et al. The primitive neuroectodermal tumor of the heart. Eur J Cardiothorac Surg 2000;18:619e21. 8. Thachil A, Saxena A, Choudhary UK, et al. Primary primitive neuroectodermal tumor: an unusual cause of right ventricular intracavitary obstruction in a child. Ann Pediatr Cardiol 2008;1:147e8. 9. Sellaturay SV, Arya M, Cuckow P, et al. Renal primitive neuroectodermal tumor in childhood with intracardiac extension. Urology 2006;68:427.e13e6. 10. Thomas JC, Sebek BA, Krishnamurthi V. Primitive neuroectodermal tumor of the kidney with inferior vena

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cava and atrial tumor thrombus. J Urol 2002;168: 1486e7. 11. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694e701. 12. Saeedinia S, Nouri M, Alimohammadi M, et al. Primary spinal extradural Ewing’s sarcoma (primitive neuroectodermal tumor): report of a case and meta-analysis of the reported cases in the literature. Surg Neurol Int 2012;3:55.

Fig. 6. Ultrasonography showing the residual tumor thrombus adherent to the vessel wall in proximal left subclavian vein (A) and the increased color Doppler flow signal through a lumen region of narrowing (B).

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Fig. 7. Histopathological examination of thyroid showing typical papillary pattern (A and B), ground glass nuclei, groove, colloid and abundant cytoplasm (C and D) indicative of papillary thyroid carcinoma.

Fig. 8. Computed tomography showing no recurrent tumor thrombi within large veins (A) and right heart (B), a collateral vessel between left brachiocephalic vein and

hemiazygos vein (C), and pulmonary nodules of different size mainly in the left upper lung lobe (D).

A Primary Primitive Neuroectodermal Tumor Arising from Left Subclavian Vein and Extending along Left Brachiocephalic Vein and Superior Vena Cava into Right Atrium.

Primitive neuroectodermal tumor (PNET) is an extremely rare malignancy thought to be derived from fetal neuroectodermal precursor cells. It usually oc...
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