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Multimodality Imaging of Tumour Thrombus
Canadian Association of Radiologists Journal xx (2015) 1e9 www.carjonline.org
Abdominal Imaging / Imagerie abdominale
Multimodality Imaging of Tumour Thrombus Saurabh Rohatgi, MD, Stephanie A. Howard, MD, Sree Harsha Tirumani, MD*, Nikhil H. Ramaiya, MD, Katherine M. Krajewski, MD Department of Imaging, Dana Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Abstract Vascular thrombosis occurs commonly in cancer patients. Once the diagnosis of thrombosis is established, it is important to characterize the nature of thrombus, tumoural versus bland, as each have a different prognosis, clinical significance, and management. This review paper discusses the imaging spectrum of tumour thrombus and its clinical significance emphasizing the role of imaging in differentiating tumour from bland thrombus. Resume Les patients atteints de cancer presentent souvent des thromboses vasculaires. Une fois le diagnostic de thrombose etabli, il importe de caracteriser le thrombus (de nature tumorale ou non-tumorale), puisque le pronostic, l’importance clinique et la prise en charge different selon cette nature. Dans cet article de synthese, nous analysons un eventail d’images et l’importance clinique des thrombus tumoraux, en mettant l’accent sur la capacite a distinguer les thrombus tumoraux des thrombus non-tumoraux gr^ace a l’imagerie. Ó 2015 Canadian Association of Radiologists. All rights reserved. Key Words: Thrombus; Tumoural thrombus; Bland thrombus; Imaging
Much has been written about venous thromboembolic disease in literature, but data is sparse on tumour thrombus imaging and its implications. Since the time Trousseau described unexpected or migratory thrombophlebitis as a forewarning of occult visceral malignancy, and Virchow described the triad of stasis, hypercoagulability, and vessel wall injury in the late 18th century, as contributing to thrombosis, the association of thrombosis and cancer has come a long way [1,2]. Tumour thrombus is important in cancer patients, as affected patients have adverse outcomes and surgical planning is more complex. Incidence of tumour thrombus varies depending on the type of cancer. Malignant involvement of the portal vein in hepatocellular carcinoma (HCC) occurs in approximately 35% of cases, is associated with poorer prognosis and is a contraindication to liver transplantation [3]. Incidence of involvement of inferior vena cava (IVC) in renal cell carcinoma (RCC) is reported to be * Address for correspondence: Sree Harsha Tirumani, MD, Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02215, USA. E-mail address: [email protected] (S. H. Tirumani).
between 4%-10% of patients [4]. Depending on the level and extent of tumour thrombus in RCC, surgical planning is altered with rates of adverse events proportionately higher depending on the stage of tumour thrombus with complication rates ranging from 12.4%e46.9% [5]. Identification of tumour thrombosis is challenging, as many patients are asymptomatic, with thrombosis detected on routine staging and follow up scans. Multimodality imaging plays a vital role in the diagnosis of tumour thrombosis using an armamentarium of ultrasound, color Doppler, computed tomography (CT), magnetic resonance imaging (MRI), and combined fluorodeoxyglucose/positron emission tomography/CT (FDG PET/CT) studies.
Imaging Distinguishing tumour thrombus from bland thrombus is important from a management and prognostic standpoint. A high index of suspicion should be kept when dealing with renal cell carcinoma, hepatocellular carcinoma, and lung and pancreatic cancer, known to be associated with tumour thrombus. Irrespective of the site of origin, certain common
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S. Rohatgi et al. / Canadian Association of Radiologists Journal xx (2015) 1e9
Table 1 Imaging features of bland and malignant thrombosis Venous thrombosis Category
Ultrasound and Doppler
Malignant/tumoural thrombus
Bland thrombus
Computed tomography findings
Non contiguous with the primary tumour Homogenous appearing. Normal lumen diameter. No contrast enhancement. No intraluminal vascularity. Continuity of the tumour with the adjacent vein. Contiguity with the tumour mass. Abnormal arterial vascularity. Adherent to the vessel wall. Irregular and expanded venous lumen. Variable degrees of enhancement similar to the primary mass.
features help differentiate malignant from bland thrombus (Table 1). In a subset of patients, both bland and tumour thrombus may coexist [6e8]. Ultrasound and Doppler Findings Tumour thrombus can be distinguished from bland thrombus by identifying continuity of the tumour with the adjacent vein, abnormal arterial vascularity (low resistance arterial signal), and irregular venous lumen expansion [9,10] (Figure 1). Rossi et al. [11] used contrast-enhanced ultrasonography in the characterization of portal vein thrombosis complicating HCC, using enhancing tissue within the vessel lumen in the early arterial phase. This differentiation is particularly important in HCC patients as tumoural involvement of the portal vein deems patients unsuitable for liver transplantation
Magnetic resonance imaging findings Low signal intensity on T2 weighted sequences. No contrast enhancement. Intermediate to increased signal on T2 weighted sequences. Contrast enhancement. Direct extension from the tumour. Vessel lumen expansion.
and often other therapeutic options such as surgical resection and chemoembolization [3,12]. An important pitfall to avoid is cavernous transformation of the portal vein since it can be confused with tumour thrombus. Cavernous transformation is evidenced by the development of prominent periportal collaterals with hepatopedal flow, without the presence of venous expansion or a parenchymal mass seen adjacent to the tumoural thrombus [9] (Figure 2). Typical patients with cavernous transformation develop portoportal venous channels at the porta hepatis in addition to intrahepatic venous channels and portosystemic collaterals [13]. CT Findings An important consideration for the detection of tumoural or bland thrombosis on CT is good bolus of contrast for
Figure 1. An 84-year-old male with pancreatic cancer. (A) Transverse grayscale ultrasound image showing echogenic tumour thrombus with expanded portal vein (PV; arrowhead) and splenic veins (arrow). Transverse color Doppler image showing absence of flow in the PV (arrow,B) and low-resistance arterial waveform seen in the main PV (C).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
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Figure 2. A 62-year-old male with hepatocellular carcinoma (HCC). Transverse color Doppler images showing portal vein thrombosis (arrow,A), with subsequent cavernous transformation of portal vein (B). Note the presence of large collateral vessels adjacent to the portal vein with hepatopedal flow (arrow). Contrast-enhanced axial computed tomography image (C) redemonstrates cavernous transformation of the portal vein (arrow), with HCC mass located separate from the portal vein (arrowhead) and ascites.
optimal opacification of the vessel of interest (ie, portal, jugular, renal veins vs IVC/pelvic veins [9]. The hallmark of thrombus on CT is a filling defect within the vessel lumen on contrast-enhanced scans while on unenhanced scans, thrombi are isoattenuating. Indirect signs of thrombosis include dilatation of thrombosed segment, development of
collateral pathways, end organ damage, and changes in parenchymal perfusion. Once the diagnosis of thrombosis is established, it is imperative to distinguish tumour from bland thrombus. While bland thrombi are homogenous and do not enhance (Figure 3), tumour thrombi are typically contiguous with a
Figure 3. A 46-year-old female with metastatic leiomyosarcoma. Coronal contrast-enhanced computed tomography image shows bland filling defects in bilateral common femoral veins representing bland common femoral deep vein thromboses (arrows).
Figure 4. A 62-year-old male with hepatocellular carcinoma. Axial contrastenhanced computed tomography image shows expanded and enhancing thrombus in the main portal vein (arrow).
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S. Rohatgi et al. / Canadian Association of Radiologists Journal xx (2015) 1e9
Figure 5. A 77-year-old male with hepatocellular carcinoma. (A) Axial contrast-enhanced computed tomography image shows an expanded, heterogeneously enhancing thrombus in the inferior vena cava (arrow). (B) Axial contrast-enhanced computed tomography image shows enhancing thrombus in the right atrium (arrow).
tumour mass, adherent to the vessel wall, and show variable degrees of enhancement, often similar to the primary mass (Figures 4-8). HCC and RCC tumour thrombi typically demonstrate brisk enhancement in the arterial phase of imaging due to the hypervascular nature of these tumours [14]. Given hypercoagulability associated with malignancy, both bland and tumour thrombi may coexist [14] (Figures 9 and 10). Tublin et al. [15] in a retrospective study of 58 patients described CT criteria to distinguish between benign and malignant portal vein thrombosis in patients with cirrhosis. Intra thrombus neovascularity, venous expansion (mean main portal vein diameter greater than or equal to 23 mm), and direct invasion of the portal vein were independently diagnostic of malignant portal vein thrombosis.
Figure 6. A 66-year-old female with adrenal cortical carcinoma. Coronal contrast-enhanced computed tomography image shows a large, heterogeneous, expansile mass arising from the right adrenal gland with invasion into the right hepatic lobe (arrowhead) and inferior vena cava (arrow).
Occasionally, physiologic circumstances may mimic thrombosis. Mixing of opacified and unopacified blood, especially at the junction of 2 vessels, may give the false impression of clot. Additionally, pseudoenhancement secondary to beam hardening after administration of contrast may mimic thrombosis [9]. MRI Findings MRI provides superior soft tissue contrast, is radiation free, and is useful in patients with contraindications to contrast due to availability of flow sensitive sequences. On MRI, bland thrombus appears as a low signal intensity lesion on T2 weighted sequences because of the T2 shortening of blood breakdown products. Tumour thrombus on
Figure 7. A 66-year-old female with lung cancer. Axial contrast-enhanced computed tomography image shows primary lung cancer invading into the left pulmonary artery (arrow).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
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Figure 8. A 79-year-old male with lower extremity perivascular epithelioid cell tumor (PEComa; arrowhead). Coronal (A, B) and axial (C) contrastenhanced computed tomography images show a heterogeneously enhancing tumour thrombus within the dilated left external iliac and common femoral veins (arrows).
the other hand shows intermediate to increased signal characteristics on T2 weighted sequences. Similar to CT, tumour thrombus shows enhancement, direct extension from the tumour, and vessel lumen expansion [6] (Figures 9A, 11-13). Physiologic artifacts may mimic thrombus on MRI. Slow venous flow may increase signal on T2 weighted spin echo
and fast spin echo images, mimicking a thrombus. Turbulent and pulsatile flow can cause intraluminal filling defects on time of flight images. Mixing of opacified and unopacified blood causing artifactual filling defects can be confirmed as such on delayed post contrast sequences, on which the filling defects resolve and vessel homogeneity is demonstrated [16].
Figure 9. A 69-year-old female with metastatic ovarian cancer. Coronal contrast-enhanced magnetic resonance imaging (A) and coronal computed tomography (B) image show coexistent bland (arrow) and tumour (arrowhead) thrombus invading the inferior vena cava.
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S. Rohatgi et al. / Canadian Association of Radiologists Journal xx (2015) 1e9
Figure 11. A 58-year-old male with renal cell carcinoma. Coronal contrastenhanced magnetic resonance image showing enhancing tumour thrombus extending from the renal veins into the inferior vena cava with marked dilatation and expansion (arrow). Figure 10. A 50-year-old male with metastatic rectal cancer. Coronal contrast-enhanced computed tomography images show a liver metastasis invading into the inferior vena cava and right atrium (arrow). A more discrete non enhancing bland thrombus is seen in the right atrium (arrowhead).
Diffusion imaging has recently been used to discriminate between malignant and bland thrombus in the portal vein in patients with hepatocellular carcinoma and tumour thrombus. In a study by Catalano et al. [12] on 25 patients, 15 of 19 malignant thrombi showed similar signal intensity as the primary HCC on diffusion weighted images. The ratio of the apparent diffusion coefficients of the thrombus to the apparent diffusion coefficients of the tumour was 0.998 in the malignant group compared with 2.9 in the bland thrombus group (P ¼ .0003).
Sharma et al. [17], an SUV max cutoff of 3.63 was used to differentiate tumour from bland thrombus, with sensitivity of 71.4% and specificity of 90%. Lee and Khong [8] used an SUV max of 2.25 as a cutoff to differentiate tumour from bland thrombus, and in conjunction with CE CT characteristics could reliably differentiate these with sensitivity of 78%, specificity of 100%, and accuracy of 88%. An increase
FDG PET/CT Findings FDG PET/CT is now an integral part of oncologic imaging, providing both metabolic and anatomical information. Thrombosis may be detected incidentally during a staging scan or may be done to differentiate tumour from bland thrombus. In 2 retrospective series examining tumour thrombus, visual analysis of focal FDG uptake was useful in diagnosing tumour thrombus and no standardized uptake values (SUV) measurements were taken [8]. In a study by
Figure 12. A 62-year-old male with hepatocellular carcinoma (HCC). Axial contrast magnetic resonance imaging showing a large HCC mass (arrowhead) with enhancing thrombus in the adjacent portal vein (arrow).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
Figure: 13. A 63-year-old male with renal cell carcinoma. Coronal contrast magnetic resonance imaging showing extension of tumour thrombus into the renal (arrow) and adrenal veins (arrowhead) in a patient with a left adrenal metastasis.
in FDG uptake is due to high metabolic activity within tumour thrombus (Figures 14). However, inflammatory or infective thrombi could have similar PET imaging appearances, and, in such cases, CT features are helpful in the diagnosis [8,18]. Management Characterization of tumoural from bland thrombus helps guide management. When tumour thrombus complicates a malignancy being considered for surgical resection, tumour thrombus may be treated with surgical thrombectomy with almost no role of anticoagulation. When patients are deemed poor surgical candidates, other alternatives to treat the tumour including antiangiogenic agents
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and various interventional radiology guided procedures are attempted. Imaging is helpful in detecting and delineating the extent of tumour thrombus, therefore aiding in surgical planning. For example, in renal cell carcinoma, if thrombus extends into the IVC beyond the diaphragm, a cardiopulmonary or venous bypass is planned. The tumour is upstaged from T2 to T3 with involvement of the renal veins and T3b with extension into the IVC. Tumoural invasion into the vena cava wall requires resection of the affected segment and vascular reconstruction. There is no role of IVC filter placement in tumour thrombus [4,19]. Accurate reporting is paramount, as tumour thrombi are typically underreported and surgical plans may be significantly altered in these cases. In a retrospective study of nonfunctional pancreatic neuroendocrine tumours, surgical planning was altered depending on the tumour thrombus burden, for example, presence of tumour in the portal vein is a contraindication to distal pancreatectomy [20]. In another patient in this series, a more extensive resection than traditional pancreaticoduodenectomy was performed due to a jejunal vein thrombosis [20]. Interventional radiology and radiation may play a role in the management of hepatocellular cancer with portal vein tumour thrombosis. While portal vein tumour thrombosis has been considered a contraindication to transarterial chemoembolization (TACE) in the past, due to the risk of acute liver failure by such a procedure, a recent report examines the utility of TACE in this setting and demonstrates a survival benefit in TACE-treated patients compared to conservative treatment, 8.67 months versus 1.4 months [21]. Recently, sequential phase 1 and 2 trials using stereotactic body radiotherapy for advanced HCC with malignant thrombus showed sustained local control and higher survival rates as compared to historical controls with a median overall survival of 17 months [22]. Antiangiogenic agents have been used successfully as neoadjuvant therapy for downsizing tumour thrombus to increase surgical resectability. Antiangiogenic agents have
Figure 14. A 63-year-old male with thyroid cancer. (A) Axial post contrast magnetic resonance imaging showing tumour thrombus in the right internal jugular vein (arrow) with contiguous thyroid mass (arrowhead). (B) Coronal images from F-18 fluorodeoxyglucose (FDG)/positron emission tomography/computed tomography showing intense FDG uptake in the right internal jugular vein (arrow) consistent with tumoural thrombus. The avidity is similar to the primary thyroid mass (arrowhead).
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Figure 15. A 62-year-old male with hepatocellular carcinoma on antiangiogenic therapy. Axial contrast-enhanced computed tomography images show an expanded and enhancing thrombus in the main portal vein prior to start of treatment (arrowhead) (A). The posttreatment scan (B) shows resolution of enhancement within the tumour thrombus, now of homogenous low attenuation (arrow), representing a treatment effect.
Figure 16. A 58-year-old male patient with renal cell carcinoma on antiangiogenic therapy. Pretreatment coronal contrast-enhanced computed tomography scan (A) shows a combination of enhancing tumoural thrombus (arrowheads) and low attenuation bland thrombus in the inferior vena cava (arrow). Posttreatment coronal contrast-enhanced computed tomography scan (B) shows resolution of enhancement within the tumour component of the thrombus (arrow), and decreasing tumour burden (not shown).
been shown to decrease the malignant tumour thrombus burden as well as the primary tumour burden, though literature is still limited. In a small series of patients with suspected renal cell carcinoma and IVC thrombus, preoperative sunitinib was utilized with some reduction in tumour burden. Bicavital surgery and cardiopulmonary bypass was avoided in 1 patient [23]. At our institution, we have observed tumour thrombus transforming from an enhancing mass to a low attenuating mass after antiangiogenic therapy (Figures 15 and 16). Conclusion Tumour thrombosis occurs more commonly in renal cell carcinoma, hepatocellular carcinoma, and lung and pancreatic cancer. Traditionally, when feasible, treatment for tumour thrombus is surgical, while medical management is offered for bland thrombus. New approaches are
being evaluated in the treatment of tumour thrombus, with increasing use of antiangiogenic agents and a role for interventional radiology. It is essential for the radiologist to be aware of the imaging differences between tumoural and bland thrombus on various imaging modalities to facilitate surgical planning, management and better patient outcomes. References [1] Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: A qualitative overview and proposed classification system. Ann Intern Med 2003;138:128e34. [2] Lopez JA, Chen J. Pathophysiology of venous thrombosis. Thromb Res 2009;123:S30e4. [3] Piscaglia F, Gianstefani A, Ravaioli M, et al. Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation. Liver Transplant 2010;16:658e67.
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9 [4] Lawindy SM, Kurian T, Kim T, et al. Important surgical considerations in the management of renal cell carcinoma (rcc) with inferior vena cava (ivc) tumour thrombus. BJU Int 2012;110:926e39. [5] Karnes RJ, Blute ML. Surgery insight: Management of renal cell carcinoma with associated inferior vena cava thrombus. Nat Clin Pract Urol 2008;5:329e39. [6] Engelbrecht M, Akin O, Dixit D, Schwartz L. Bland and tumour thrombi in abdominal malignancies: Magnetic resonance imaging assessment in a large oncologic patient population. Abdom Imaging 2011;36:62e8. [7] Lai P, Bomanji JB, Mahmood S, et al. Detection of tumour thrombus by 18F-FDG-PET/CT imaging. Eur J Cancer Prev 2007; 16:90e4. [8] Lee EYP, Khong P-L. The value of 18F-FDG PET/contrast-enhanced CT in detection of tumour thrombus. Clin Nucl Med 2013;38:e60e5. [9] Khosa F, Otero HJ, Prevedello LM, Rybicki FJ, Di Salvo DN. Imaging presentation of venous thrombosis in patients with cancer. AJR Am J Roentgenol 2010;194:1099e108. [10] Tirumani SH, Prasad Shanbhogue AK, Vikram R, Prasad SR, Menias CO. Imaging of the porta hepatis: Spectrum of disease. RadioGraphics 2014;34:73e92. [11] Rossi S, Ghittoni G, Ravetta V, et al. Contrast-enhanced ultrasonography and spiral computed tomography in the detection and characterization of portal vein thrombosis complicating hepatocellular carcinoma. Eur Radiol 2008;18:1749e56. [12] Catalano OA, Choy G, Zhu A, Hahn PF, Sahani DV. Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: Application of diffusion-weighted MR imaging 1. Radiology 2009;254:154e62. [13] De Gaetano A, Lafortune M, Patriquin H, De Franco A, Aubin B, Paradis K. Cavernous transformation of the portal vein: Patterns of intrahepatic and splanchnic collateral circulation detected with doppler sonography. AJR Am J Roentgenol 1995;165:1151e5.
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[14] Catalano O, Nunziata A, di Castelguidone EdL, d’Errico AG. Thrombosis and cancer: Spectrum of multidetector ct findings in oncologic patients with thromboembolic disease. A pictorial review. Acta Radiol 2011;52:730e7. [15] Tublin M, Dodd 3rd G, Baron R. Benign and malignant portal vein thrombosis: Differentiation by ct characteristics. AJR Am J Roentgenol 1997;168:719e23. [16] Rubin GD, Rofsky NM. CT and MR Angiography: Comprehensive Vascular Assessment. Philadelphia, PA: Lippincott Williams & Wilkins; 2009. [17] Sharma P, Kumar R, Jeph S, et al. 18f-FDG PET-CT in the diagnosis of tumour thrombus: Can it be differentiated from benign thrombus? Nucl Med Commun 2011;32:782e8. [18] Sopov V, Bernstine H, Stern D, Yefremov N, Sosna J, Groshar D. The metabolic spectrum of venous thrombotic disorders found on pet/ct. AJR Am J Roentgenol 2009;193:W530e9. [19] Aslam Sohaib S, Teh J, Nargund VH, Lumley JS, Hendry WF, Reznek RH. Assessment of tumour invasion of the vena caval wall in renal cell carcinoma cases by magnetic resonance imaging. J Urol 2002;167:1271e5. [20] Balachandran A, Tamm EP, Bhosale PR, et al. Venous tumour thrombus in nonfunctional pancreatic neuroendocrine tumours. American Journal of Roentgenology 2012;199:602e8. [21] Niu Z-J, Ma Y-L, Kang P, et al. Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumour thrombus: Using a new classification. Med Oncol 2012;29:2992e7. [22] Bujold A, Massey CA, Kim JJ, et al. Sequential phase i and ii trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013;31:1631e9. [23] Horn T, Thalgott MK, Maurer T, et al. Presurgical treatment with sunitinib for renal cell carcinoma with a level iii/iv vena cava tumour thrombus. Anticancer Res 2012;32:1729e35.
Abdominal Imaging / Imagerie abdominale
Multimodality Imaging of Tumour Thrombus Saurabh Rohatgi, MD, Stephanie A. Howard, MD, Sree Harsha Tirumani, MD*, Nikhil H. Ramaiya, MD, Katherine M. Krajewski, MD Department of Imaging, Dana Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Abstract Vascular thrombosis occurs commonly in cancer patients. Once the diagnosis of thrombosis is established, it is important to characterize the nature of thrombus, tumoural versus bland, as each have a different prognosis, clinical significance, and management. This review paper discusses the imaging spectrum of tumour thrombus and its clinical significance emphasizing the role of imaging in differentiating tumour from bland thrombus. Resume Les patients atteints de cancer presentent souvent des thromboses vasculaires. Une fois le diagnostic de thrombose etabli, il importe de caracteriser le thrombus (de nature tumorale ou non-tumorale), puisque le pronostic, l’importance clinique et la prise en charge different selon cette nature. Dans cet article de synthese, nous analysons un eventail d’images et l’importance clinique des thrombus tumoraux, en mettant l’accent sur la capacite a distinguer les thrombus tumoraux des thrombus non-tumoraux gr^ace a l’imagerie. Ó 2015 Canadian Association of Radiologists. All rights reserved. Key Words: Thrombus; Tumoural thrombus; Bland thrombus; Imaging
Much has been written about venous thromboembolic disease in literature, but data is sparse on tumour thrombus imaging and its implications. Since the time Trousseau described unexpected or migratory thrombophlebitis as a forewarning of occult visceral malignancy, and Virchow described the triad of stasis, hypercoagulability, and vessel wall injury in the late 18th century, as contributing to thrombosis, the association of thrombosis and cancer has come a long way [1,2]. Tumour thrombus is important in cancer patients, as affected patients have adverse outcomes and surgical planning is more complex. Incidence of tumour thrombus varies depending on the type of cancer. Malignant involvement of the portal vein in hepatocellular carcinoma (HCC) occurs in approximately 35% of cases, is associated with poorer prognosis and is a contraindication to liver transplantation [3]. Incidence of involvement of inferior vena cava (IVC) in renal cell carcinoma (RCC) is reported to be * Address for correspondence: Sree Harsha Tirumani, MD, Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02215, USA. E-mail address: [email protected] (S. H. Tirumani).
between 4%-10% of patients [4]. Depending on the level and extent of tumour thrombus in RCC, surgical planning is altered with rates of adverse events proportionately higher depending on the stage of tumour thrombus with complication rates ranging from 12.4%e46.9% [5]. Identification of tumour thrombosis is challenging, as many patients are asymptomatic, with thrombosis detected on routine staging and follow up scans. Multimodality imaging plays a vital role in the diagnosis of tumour thrombosis using an armamentarium of ultrasound, color Doppler, computed tomography (CT), magnetic resonance imaging (MRI), and combined fluorodeoxyglucose/positron emission tomography/CT (FDG PET/CT) studies.
Imaging Distinguishing tumour thrombus from bland thrombus is important from a management and prognostic standpoint. A high index of suspicion should be kept when dealing with renal cell carcinoma, hepatocellular carcinoma, and lung and pancreatic cancer, known to be associated with tumour thrombus. Irrespective of the site of origin, certain common
0846-5371/$ - see front matter Ó 2015 Canadian Association of Radiologists. All rights reserved. http://dx.doi.org/10.1016/j.carj.2014.11.001
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S. Rohatgi et al. / Canadian Association of Radiologists Journal xx (2015) 1e9
Table 1 Imaging features of bland and malignant thrombosis Venous thrombosis Category
Ultrasound and Doppler
Malignant/tumoural thrombus
Bland thrombus
Computed tomography findings
Non contiguous with the primary tumour Homogenous appearing. Normal lumen diameter. No contrast enhancement. No intraluminal vascularity. Continuity of the tumour with the adjacent vein. Contiguity with the tumour mass. Abnormal arterial vascularity. Adherent to the vessel wall. Irregular and expanded venous lumen. Variable degrees of enhancement similar to the primary mass.
features help differentiate malignant from bland thrombus (Table 1). In a subset of patients, both bland and tumour thrombus may coexist [6e8]. Ultrasound and Doppler Findings Tumour thrombus can be distinguished from bland thrombus by identifying continuity of the tumour with the adjacent vein, abnormal arterial vascularity (low resistance arterial signal), and irregular venous lumen expansion [9,10] (Figure 1). Rossi et al. [11] used contrast-enhanced ultrasonography in the characterization of portal vein thrombosis complicating HCC, using enhancing tissue within the vessel lumen in the early arterial phase. This differentiation is particularly important in HCC patients as tumoural involvement of the portal vein deems patients unsuitable for liver transplantation
Magnetic resonance imaging findings Low signal intensity on T2 weighted sequences. No contrast enhancement. Intermediate to increased signal on T2 weighted sequences. Contrast enhancement. Direct extension from the tumour. Vessel lumen expansion.
and often other therapeutic options such as surgical resection and chemoembolization [3,12]. An important pitfall to avoid is cavernous transformation of the portal vein since it can be confused with tumour thrombus. Cavernous transformation is evidenced by the development of prominent periportal collaterals with hepatopedal flow, without the presence of venous expansion or a parenchymal mass seen adjacent to the tumoural thrombus [9] (Figure 2). Typical patients with cavernous transformation develop portoportal venous channels at the porta hepatis in addition to intrahepatic venous channels and portosystemic collaterals [13]. CT Findings An important consideration for the detection of tumoural or bland thrombosis on CT is good bolus of contrast for
Figure 1. An 84-year-old male with pancreatic cancer. (A) Transverse grayscale ultrasound image showing echogenic tumour thrombus with expanded portal vein (PV; arrowhead) and splenic veins (arrow). Transverse color Doppler image showing absence of flow in the PV (arrow,B) and low-resistance arterial waveform seen in the main PV (C).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
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Figure 2. A 62-year-old male with hepatocellular carcinoma (HCC). Transverse color Doppler images showing portal vein thrombosis (arrow,A), with subsequent cavernous transformation of portal vein (B). Note the presence of large collateral vessels adjacent to the portal vein with hepatopedal flow (arrow). Contrast-enhanced axial computed tomography image (C) redemonstrates cavernous transformation of the portal vein (arrow), with HCC mass located separate from the portal vein (arrowhead) and ascites.
optimal opacification of the vessel of interest (ie, portal, jugular, renal veins vs IVC/pelvic veins [9]. The hallmark of thrombus on CT is a filling defect within the vessel lumen on contrast-enhanced scans while on unenhanced scans, thrombi are isoattenuating. Indirect signs of thrombosis include dilatation of thrombosed segment, development of
collateral pathways, end organ damage, and changes in parenchymal perfusion. Once the diagnosis of thrombosis is established, it is imperative to distinguish tumour from bland thrombus. While bland thrombi are homogenous and do not enhance (Figure 3), tumour thrombi are typically contiguous with a
Figure 3. A 46-year-old female with metastatic leiomyosarcoma. Coronal contrast-enhanced computed tomography image shows bland filling defects in bilateral common femoral veins representing bland common femoral deep vein thromboses (arrows).
Figure 4. A 62-year-old male with hepatocellular carcinoma. Axial contrastenhanced computed tomography image shows expanded and enhancing thrombus in the main portal vein (arrow).
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S. Rohatgi et al. / Canadian Association of Radiologists Journal xx (2015) 1e9
Figure 5. A 77-year-old male with hepatocellular carcinoma. (A) Axial contrast-enhanced computed tomography image shows an expanded, heterogeneously enhancing thrombus in the inferior vena cava (arrow). (B) Axial contrast-enhanced computed tomography image shows enhancing thrombus in the right atrium (arrow).
tumour mass, adherent to the vessel wall, and show variable degrees of enhancement, often similar to the primary mass (Figures 4-8). HCC and RCC tumour thrombi typically demonstrate brisk enhancement in the arterial phase of imaging due to the hypervascular nature of these tumours [14]. Given hypercoagulability associated with malignancy, both bland and tumour thrombi may coexist [14] (Figures 9 and 10). Tublin et al. [15] in a retrospective study of 58 patients described CT criteria to distinguish between benign and malignant portal vein thrombosis in patients with cirrhosis. Intra thrombus neovascularity, venous expansion (mean main portal vein diameter greater than or equal to 23 mm), and direct invasion of the portal vein were independently diagnostic of malignant portal vein thrombosis.
Figure 6. A 66-year-old female with adrenal cortical carcinoma. Coronal contrast-enhanced computed tomography image shows a large, heterogeneous, expansile mass arising from the right adrenal gland with invasion into the right hepatic lobe (arrowhead) and inferior vena cava (arrow).
Occasionally, physiologic circumstances may mimic thrombosis. Mixing of opacified and unopacified blood, especially at the junction of 2 vessels, may give the false impression of clot. Additionally, pseudoenhancement secondary to beam hardening after administration of contrast may mimic thrombosis [9]. MRI Findings MRI provides superior soft tissue contrast, is radiation free, and is useful in patients with contraindications to contrast due to availability of flow sensitive sequences. On MRI, bland thrombus appears as a low signal intensity lesion on T2 weighted sequences because of the T2 shortening of blood breakdown products. Tumour thrombus on
Figure 7. A 66-year-old female with lung cancer. Axial contrast-enhanced computed tomography image shows primary lung cancer invading into the left pulmonary artery (arrow).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
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Figure 8. A 79-year-old male with lower extremity perivascular epithelioid cell tumor (PEComa; arrowhead). Coronal (A, B) and axial (C) contrastenhanced computed tomography images show a heterogeneously enhancing tumour thrombus within the dilated left external iliac and common femoral veins (arrows).
the other hand shows intermediate to increased signal characteristics on T2 weighted sequences. Similar to CT, tumour thrombus shows enhancement, direct extension from the tumour, and vessel lumen expansion [6] (Figures 9A, 11-13). Physiologic artifacts may mimic thrombus on MRI. Slow venous flow may increase signal on T2 weighted spin echo
and fast spin echo images, mimicking a thrombus. Turbulent and pulsatile flow can cause intraluminal filling defects on time of flight images. Mixing of opacified and unopacified blood causing artifactual filling defects can be confirmed as such on delayed post contrast sequences, on which the filling defects resolve and vessel homogeneity is demonstrated [16].
Figure 9. A 69-year-old female with metastatic ovarian cancer. Coronal contrast-enhanced magnetic resonance imaging (A) and coronal computed tomography (B) image show coexistent bland (arrow) and tumour (arrowhead) thrombus invading the inferior vena cava.
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Figure 11. A 58-year-old male with renal cell carcinoma. Coronal contrastenhanced magnetic resonance image showing enhancing tumour thrombus extending from the renal veins into the inferior vena cava with marked dilatation and expansion (arrow). Figure 10. A 50-year-old male with metastatic rectal cancer. Coronal contrast-enhanced computed tomography images show a liver metastasis invading into the inferior vena cava and right atrium (arrow). A more discrete non enhancing bland thrombus is seen in the right atrium (arrowhead).
Diffusion imaging has recently been used to discriminate between malignant and bland thrombus in the portal vein in patients with hepatocellular carcinoma and tumour thrombus. In a study by Catalano et al. [12] on 25 patients, 15 of 19 malignant thrombi showed similar signal intensity as the primary HCC on diffusion weighted images. The ratio of the apparent diffusion coefficients of the thrombus to the apparent diffusion coefficients of the tumour was 0.998 in the malignant group compared with 2.9 in the bland thrombus group (P ¼ .0003).
Sharma et al. [17], an SUV max cutoff of 3.63 was used to differentiate tumour from bland thrombus, with sensitivity of 71.4% and specificity of 90%. Lee and Khong [8] used an SUV max of 2.25 as a cutoff to differentiate tumour from bland thrombus, and in conjunction with CE CT characteristics could reliably differentiate these with sensitivity of 78%, specificity of 100%, and accuracy of 88%. An increase
FDG PET/CT Findings FDG PET/CT is now an integral part of oncologic imaging, providing both metabolic and anatomical information. Thrombosis may be detected incidentally during a staging scan or may be done to differentiate tumour from bland thrombus. In 2 retrospective series examining tumour thrombus, visual analysis of focal FDG uptake was useful in diagnosing tumour thrombus and no standardized uptake values (SUV) measurements were taken [8]. In a study by
Figure 12. A 62-year-old male with hepatocellular carcinoma (HCC). Axial contrast magnetic resonance imaging showing a large HCC mass (arrowhead) with enhancing thrombus in the adjacent portal vein (arrow).
Multimodality imaging of tumour thrombus / Canadian Association of Radiologists Journal xx (2015) 1e9
Figure: 13. A 63-year-old male with renal cell carcinoma. Coronal contrast magnetic resonance imaging showing extension of tumour thrombus into the renal (arrow) and adrenal veins (arrowhead) in a patient with a left adrenal metastasis.
in FDG uptake is due to high metabolic activity within tumour thrombus (Figures 14). However, inflammatory or infective thrombi could have similar PET imaging appearances, and, in such cases, CT features are helpful in the diagnosis [8,18]. Management Characterization of tumoural from bland thrombus helps guide management. When tumour thrombus complicates a malignancy being considered for surgical resection, tumour thrombus may be treated with surgical thrombectomy with almost no role of anticoagulation. When patients are deemed poor surgical candidates, other alternatives to treat the tumour including antiangiogenic agents
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and various interventional radiology guided procedures are attempted. Imaging is helpful in detecting and delineating the extent of tumour thrombus, therefore aiding in surgical planning. For example, in renal cell carcinoma, if thrombus extends into the IVC beyond the diaphragm, a cardiopulmonary or venous bypass is planned. The tumour is upstaged from T2 to T3 with involvement of the renal veins and T3b with extension into the IVC. Tumoural invasion into the vena cava wall requires resection of the affected segment and vascular reconstruction. There is no role of IVC filter placement in tumour thrombus [4,19]. Accurate reporting is paramount, as tumour thrombi are typically underreported and surgical plans may be significantly altered in these cases. In a retrospective study of nonfunctional pancreatic neuroendocrine tumours, surgical planning was altered depending on the tumour thrombus burden, for example, presence of tumour in the portal vein is a contraindication to distal pancreatectomy [20]. In another patient in this series, a more extensive resection than traditional pancreaticoduodenectomy was performed due to a jejunal vein thrombosis [20]. Interventional radiology and radiation may play a role in the management of hepatocellular cancer with portal vein tumour thrombosis. While portal vein tumour thrombosis has been considered a contraindication to transarterial chemoembolization (TACE) in the past, due to the risk of acute liver failure by such a procedure, a recent report examines the utility of TACE in this setting and demonstrates a survival benefit in TACE-treated patients compared to conservative treatment, 8.67 months versus 1.4 months [21]. Recently, sequential phase 1 and 2 trials using stereotactic body radiotherapy for advanced HCC with malignant thrombus showed sustained local control and higher survival rates as compared to historical controls with a median overall survival of 17 months [22]. Antiangiogenic agents have been used successfully as neoadjuvant therapy for downsizing tumour thrombus to increase surgical resectability. Antiangiogenic agents have
Figure 14. A 63-year-old male with thyroid cancer. (A) Axial post contrast magnetic resonance imaging showing tumour thrombus in the right internal jugular vein (arrow) with contiguous thyroid mass (arrowhead). (B) Coronal images from F-18 fluorodeoxyglucose (FDG)/positron emission tomography/computed tomography showing intense FDG uptake in the right internal jugular vein (arrow) consistent with tumoural thrombus. The avidity is similar to the primary thyroid mass (arrowhead).
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Figure 15. A 62-year-old male with hepatocellular carcinoma on antiangiogenic therapy. Axial contrast-enhanced computed tomography images show an expanded and enhancing thrombus in the main portal vein prior to start of treatment (arrowhead) (A). The posttreatment scan (B) shows resolution of enhancement within the tumour thrombus, now of homogenous low attenuation (arrow), representing a treatment effect.
Figure 16. A 58-year-old male patient with renal cell carcinoma on antiangiogenic therapy. Pretreatment coronal contrast-enhanced computed tomography scan (A) shows a combination of enhancing tumoural thrombus (arrowheads) and low attenuation bland thrombus in the inferior vena cava (arrow). Posttreatment coronal contrast-enhanced computed tomography scan (B) shows resolution of enhancement within the tumour component of the thrombus (arrow), and decreasing tumour burden (not shown).
been shown to decrease the malignant tumour thrombus burden as well as the primary tumour burden, though literature is still limited. In a small series of patients with suspected renal cell carcinoma and IVC thrombus, preoperative sunitinib was utilized with some reduction in tumour burden. Bicavital surgery and cardiopulmonary bypass was avoided in 1 patient [23]. At our institution, we have observed tumour thrombus transforming from an enhancing mass to a low attenuating mass after antiangiogenic therapy (Figures 15 and 16). Conclusion Tumour thrombosis occurs more commonly in renal cell carcinoma, hepatocellular carcinoma, and lung and pancreatic cancer. Traditionally, when feasible, treatment for tumour thrombus is surgical, while medical management is offered for bland thrombus. New approaches are
being evaluated in the treatment of tumour thrombus, with increasing use of antiangiogenic agents and a role for interventional radiology. It is essential for the radiologist to be aware of the imaging differences between tumoural and bland thrombus on various imaging modalities to facilitate surgical planning, management and better patient outcomes. References [1] Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: A qualitative overview and proposed classification system. Ann Intern Med 2003;138:128e34. [2] Lopez JA, Chen J. Pathophysiology of venous thrombosis. Thromb Res 2009;123:S30e4. [3] Piscaglia F, Gianstefani A, Ravaioli M, et al. Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation. Liver Transplant 2010;16:658e67.
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