Tumor Thrombosis: to Anticoagulate or Not to Anticoagulate?

We posted a poll on twitter on 2/14/24 asking the following question:

• Most respondents chose to anticoagulate.
• Decision-making may take into account the following considerations/hypotheticals:
  • In favor of anticoagulation:
    • Prevent propagation of clot.
    • Promote recanalization of the vessel.
  • In favor of no anticoagulation:
    • Unlike bland thrombus, a tumor thrombus generally consists of a viable, healthy tumor that is less likely to embolize.
• Surgical thrombectomy in addition to anti-neoplastic directed medical therapy remain the mainstay of treatment for malignancy with accompanying tumor thrombus.

Below, we will:

• Provide an overview of tumor thrombosis.
• Review the literature concerning treatment, with a focus on anticoagulation.

The bottom line is that the anticoagulation is generally avoided in the setting of tumor thrombosis unless there is evidence of significant concomitant bland thrombus.

Description:

• Cancer-associated thrombosis:¹
  • Venous thromboembolism (VTE):
    • Includes:
      • Deep venous thrombosis (DVT)
      • Pulmonary embolism (PE)
    • Consists of a bland thrombus.
    • Treatment is with anticoagulation.
    • If left untreated, there is a risk for propagation and embolization.
  • Tumor thrombus:
    • Refers to the intravascular extension of a tumor into adjacent blood vessels.
    • Occurs primarily in patients with:
      • Renal cell carcinoma (RCC).
      • Hepatocellular carcinoma (HCC).
    • Often asymptomatic and incidentally detected on routine surveillance imaging.
    • Affects staging and worsens prognosis.
    • Contains organized tumor cells and is believed to be more stable and thus less prone to embolization.
    • In contrast to VTE, risk-benefits of anticoagulation are unclear.

Tumor thrombus by cancer type and vascular location:

• Renal cell carcinoma (RCC):²
  • Prevalence of tumor thrombus 4-10%.
  • Presence of tumor thrombus upstages a tumor from:
    • T2 to T3a for segmental or central renal vein involvement.
    • T2 to T3b for the involvement of the inferior vena cava (IVC), but below the level of the diaphragm.
    • T2 to T3c  for tumor thrombus that extends above the diaphragm or invades the wall of the IVC.
  • Clinical presentation:³
    • May be asymptomatic or may cause a variety of symptoms including:
      • Varicocele
      • Lower extremity swelling
      • Cardiac dysfunction
      • Pulmonary embolism
      • Budd-Chiari syndrome
  • Treatment:
    • Standard treatment is radical nephrectomy with thrombectomy.⁴
    • Surgical planning depends on level involvement with IVC tumor thrombus, including:
      • Level of extension (e.g., below or above the diaphragm).
      • Whether or note there is IVC wall invasion.
    • Expert opinion:
      • According to Agochukwu and Shuch:⁵
        • In a series of patients who underwent nephrectomy and thrombectomy, only 4.4 % of patients⁶ had a preoperative pulmonary embolism.
        • For these reasons, most high volume centers do not routinely anticoagulate patients except in those who present with a pulmonary embolism.
        • We also consider anticoagulation if the imaging studies show a significant amount of bland thrombus on the cephalad extend of the tumor thrombus. In this setting, the tumor thrombus may be more friable and anti-coagulation could be considered until the time of surgery.
      • According to Dason et al:⁷
        • Therapeutic anticoagulation is not indicated for every RCC with IVC thrombus.
        • Indications for therapeutic anticoagulation generally include:
          • Pulmonary emboli
          • Iliofemoral deep vein thrombosis
          • Suspected bland thrombus component of IVC thrombus
          • Significant IVC obstruction
          • Tumor thrombus where subtle progression could increase surgical complexity.
        • Consequences of anticoagulation include:
          • Bleeding
          • Heparin-induced thrombocytopenia
        • For the patient receiving anticoagulation, it is unclear what regimen and dosing is optimal and if bridging is necessary.
        • Patients at particularly high risk of bland thrombus progression or bleeding warrant preoperative admission with a heparin drip to limit their interval off anticoagulation.
      • According to Quencer et al:⁸
        • If bland thrombus is present in addition to tumor thrombus, anticoagulation should be considered.
        • IVC filter placement, however, should be avoided.
      • According to Psutka and Leibovich:⁹
        • Consider anticoagulation in patients with:
          • Completely occlusive tumor thrombus
          • Near-completely occlusive thrombus
          • Recent deep venous thrombosis or embolic event
          • Bland thrombus in addition to tumor thrombus
          • Preoperative therapeutic anticoagulation
        • We advocate the use of low-molecular weight heparin (LMWH) started in the outpatient setting in such cases.
        • Suprarenal IVC filters may be employed in patients with continued pulmonary embolism (PE) despite anticoagulation or in patients in whom anticoagulation is contraindicated.
    • Clinical practice guidelines:
      • European Association of Urology (EAU) guideline on renal cell carcinoma:
        • Treatment of locally advanced RCC:
          • Traditionally, patients with venous tumor thrombus undergo surgery to remove the kidney and tumor thrombus. Aggressive surgical resection is widely accepted as the default management option for patients with venous tumor thrombus.
          • all patients with non-metastatic disease and venous tumor thrombus, and an acceptable PS, should be considered for surgical intervention, irrespective of the extent of tumor thrombus at presentation.
          • No mention of anticoagulation.
      • ESMO clinical practice guideline on diagnosis, treatment, and follow-up of renal cell carcinoma:
        • Locally advanced RCC (T3 and T4):
          • The evidence regarding management of venous tumor thrombus is based on retrospective studies with significant risks of bias and confounding. Resection of venous thrombi is challenging and associated with a high risk of complications. Surgical intervention should be considered, but the most effective approach remains unknown and outcome depends on tumor thrombus level [III].
          • No mention of anticoagulation.
    • Primary data:
      • Retrospective study of 647 patients with RCC:
        • 86 (13.3%) had tumor thrombus at diagnosis.
          • 34 were limited to the renal vein.
          • 37 were limited to the inferior vena cava below the diaphragm.
          • 15 extended above the diaphragm.
        • 20 patients started therapeutic anticoagulation.
        • 45 underwent thrombectomy with/without anticoagulation.
        • During follow-up median 24.0 months:
          • 17 patient with tumor thrombus developed a VTE.
          • 0 developed an arterial thromboembolism (ATE).
          • 11 developed major bleeding.
        • Patients with tumor thrombus (TT) were more often diagnosed with VTE (adjusted HR: 6.61; 95% CI: 3.18-13.73) than non-TT patients.
        • TT patients receiving anticoagulation still developed VTE (HR: 0.56; 95%CI: 0.13-2.48), at the cost of more major bleeding events (HR: 3.44; 95% CI: 0.95-12.42) compared with those without anticoagulation.
  • Prognosis:¹⁰
    • Meta-analysis showed that IVC tumor thrombus is associated with inferior cancer-specific survival.
    • Median survival:
      • Untreated – 5 months
      • Cytoreductive nephrectomy with tumor thrombectomy – 21.5 months

• Hepatocellular carcinoma (HCC):¹¹
  • Sites of tumor thrombosis include:
    • Inferior vena cava
    • Portal vein (most common)
    • Hepatic vein
  • Up to 25% of all patients with cirrhosis have bland portal vein thrombus.¹²
  • HCC patients with any macroscopic vascular invasion are classified as Barcelona Clinic Liver Cancer (BCLC) stage C (advanced stage).
  • Portal vein tumor thrombus:
    • Occurs in 44–66% of patients with HCC.
    • Present at the time of diagnosis in approximately 20% of the patients.
    • Associated with:
      • Development of portal hypertension
      • Liver decompensation
      • Poor prognosis with estimated median survival:
        • 2–4 months without treatment (vs. 16 months in those without thrombus)
        • 9 months in treated patients with segmental portal vein tumor thrombus
        • 4.6 months in treated patients with main portal vein involvement
  • Hepatic vein tumor thrombus:
    • Estimated prevalence of 2–5%.
    • Portends a poorer prognosis with median overall survival of about 5–7 months.
  • Inferior vena cava tumor thrombus:¹³
    • Reported to occur in about 3–4 % cases.
    • Tumor thrombus in the IVC and/or RA is usually classified into 3 types:
      • Type I = IVC tumor thrombus is below the diaphragm
      • Type II = IVC tumor thrombus is above the diaphragm and under the atrium
      • Type III = intracardiac (surgery performed under cardiopulmonary bypass)
    • Extremely poor prognosis of 1–4 months for untreated cases.
  • Treatment:¹⁴
    • In Western countries, surgical resection is rarely performed in the setting of HCC tumor thrombus given poor underlying liver function.
    • Guidelines recommend Sorafenib, a multi-kinase inhibitor, targeting VEGFR, PDGFR and Raf family kinases for BCLC stage C patients.
    • Due to the high rate of recurrence after transplant, the presence of tumor thrombus is considered an absolute contraindication to liver transplantation.
    • The presence portal vein tumor thrombus is considered a relative contraindication to transarterial chemoembolization (TACE) owing to the risk of hepatic necrosis and worsening of liver function.
    • Clinical practice guidelines:
      • According to the AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma:
        • Resection of patients with HCC with macrovascular portal vein tumor thrombus (PVTT) is more controversial because these patients have higher risk of metastatic disease and are typically recommended to undergo systemic therapy.
        • Although most data for hepatic resection in PVTT comes from Asia, limited available data from Western centers support the role of surgical resection in selected patients
        • With significant improvement in systemic therapy for advanced-stage disease, future studies are necessary to best define which subpopulation of patients with multifocal disease or PVTT may benefit from surgical resection. While awaiting these data, extended indications for surgical resection should only be performed in high-volume centers after multidisciplinary discussion.
        • No mention of anticoagulation.
      • According to JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan:
        • Sorafenib is recommended for patients with minor portal vein invasion or portal invasion at the first portal branch (Vp1-3), the new algorithm reflects the consensus that it is not recommended for patients with portal invasion at the main portal branch (Vp4) due to the risk of hepatic failure. However, hepatic arterial infusion chemotherapy (HAIC) is still strongly recommended for patients with Vp4.
        • No mention of anticoagulation.
      • Tumor thrombus not addressed in:
        • Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
        • Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO

• Other tumors:¹⁵
  • Adenoid cystic carcinoma (ACC):
    • Rare and aggressive malignancy.
    • Associated with tumor thrombus in about 25% of patients.
    • Invasion of the wall of the IVC has been reported with ACC.
    • Systemic chemotherapy is the preferred treatment modality.
  • Wilm’s tumor:
    • Accounts for 6% of all childhood cancers.
    • Associated with tumor thrombus in about 35% of patients.
    • Extension into the IVC occurs in up to 10% of cases.
    • If the tumor thrombus appears to be at high risk of embolizing, surgery prior to chemotherapy is preferred.

Pathogenesis:

• A tumor thrombus arises from micro-metastases that establish themselves within the vascular tree, instead of migrating to and colonizing distant organs. From this perspective, a tumor thrombus is often considered the initial stage of tumor metastasis.¹⁶
• Patients with RCC with tumor thrombus are also at risk of bland thrombus formation, often possessing all 3 components of Virchow’s triad:¹⁷
  • A low flow state resulting from venous occlusion
  • A prothrombotic state associated with advanced malignancy
  • An abnormal vascular surface on the tumor thrombus.

Diagnosis

• The diagnosis of tumor thrombus is generally an incidental finding during staging of the disease. 
• Gold standard for diagnosis is biopsy, but this is rarely performed.
• Diagnosis is based mostly on multimodality imaging:
  • For tumor thrombus in renal cell carcinoma, both MRI and CT have high accuracy in:¹⁸
    • Detecting tumor thrombus.
    • Detecting tumor thrombus
    • Assessing its extension
    • Distinguishing it from bland thrombus
  • For tumor thrombus in hepatocellular carcinoma:¹⁹
    • Portal vein tumor thrombus can be diagnosed and differentiated from bland thrombus by many different imaging modalities, including
      • Conventional angiography
      • Color Doppler ultrasound
      • Contrast enhanced ultrasound
      • Contrast enhanced CT scan
      • MRI
      • FDG PET imaging 
  • Ultrasound and doppler findings:²⁰
    • Tumor thrombus can be distinguished from bland thrombus by identifying:
      • Continuity of the tumor with the adjacent vein
      • Abnormal arterial vascularity (low resistance arterial signal)
      • Irregular venous lumen expansion
  • CT findings:²¹
    • Hallmark of thrombus:
      • On contrast-enhanced scans, filling defect within the vessel lumen
      • On unenhanced scans, thrombi are isoattenuating
      • Indirect signs of thrombosis include:
        • Dilatation of thrombosed segment
        • Development of collateral pathways
        • End organ damage
        • Changes in parenchymal perfusion
    • Distinguishing between tumor and bland thrombus:
      • Bland thrombi are homogenous and do not enhance
      • Tumor thrombi are typically:
        • Contiguous with a tumor mass
        • Adherent to the vessel wall
        • Show variable degrees of enhancement, often similar to the primary mass
  • MRI findings:
    • Bland thrombus appears as a low signal intensity lesion on T2 weighted sequences because of the T2 shortening of blood breakdown products
    • Tumor thrombus on the other hand shows intermediate to increased signal characteristics on T2 weighted sequences.
    • Similar to CT, tumor thrombus shows:
      • Enhancement
      • Direct extension from the tumor
      • Vessel lumen expansion

Anticoagulation:

• Expert opinion:²²
  • Across cancer types, guidance on anticoagulation for tumor thrombus is sparse and does not address anticoagulant type or dosage.²³
  • Presence of tumor thrombus is a risk factor for development of bland thrombus (e.g. VTE), which is less stable and prone to embolization.
  • Management of RCC with venous involvement requires consideration of both bland and tumor thrombus burden.²⁴
  • The goal of anticoagulation in the management of TT should be to decrease the occurrence of bland thrombus and thromboembolism, rather than attempting to resolve or decrease the progression of the tumor thrombus itself.
  • This must be weighed against the competing risks of bleeding and cancer-related mortality.
  • Guidelines from major societies do not address the use of anticoagulation in the setting of tumor thrombus, at least in part due to lack of high quality prospective or randomized controlled studies.
  • Although no firm conclusions can be drawn from the currently available retrospective studies, our practice has been to consider the use of anticoagulation in select patients on a case-by-case basis.

• Primary data:
  • Retrospective study of 153 patients with tumor thrombus:²⁵
    • Most common cancers included:
      • Renal cell carcinoma 34.6%
      • Hepatocellular carcinoma 28.8%
    • Most common locations of thrombus included:
      • Portal vein 37.5%
      • Renal vein 32.9%
      • Inferior vena cava 26.3%
    • 26.8% were treated with anticoagulation.
    • 18 patients (11.8%) developed VTE within a 6 month study period after being diagnosed with tumour thrombus:
      • 11 were on anticoagulation (61%)
      • 7 were not (39%)
    • Five patients receiving anticoagulation experienced major bleeding.
    • Mortality was 42.5% at 6 months with no significant difference in survival between those treated with or without anticoagulation
    • Conclusions: In our study, we show that there is no significant difference in survival between patients with tumor thrombus treated with or without anticoagulation. While there is no clear evidence that anticoagulation improves outcomes across all patients with tumor thrombus, further studies are needed to identify subgroups of patients who may benefit from anticoagulation given their increased risk of VTE.

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