Abstract
Background and Clinical Significance: Intravascular large B-cell lymphoma (IVLBCL) is an exceedingly rare and aggressive malignancy characterized by the selective growth of lymphoma cells within blood vessel lumina. This malignancy often presents with non-specific systemic manifestations, making diagnosis challenging. Neurological symptoms and cutaneous findings are typical, whereas thrombotic events are uncommon at the initial presentation. We report a unique case of IVLBCL with MYC and BCL2 rearrangements (“double-hit” genetics), diagnosed following mechanical thrombectomy; Case Presentation: A 79-year-old woman presented with acute right-lower-limb swelling due to extensive iliofemoral deep vein thrombosis. Mechanical thrombectomy was performed, and the histopathological and genetic examination of the retrieved material revealed IVLBCL. Subsequent staging with positron emission tomography-computed tomography (PET-CT) demonstrated an FDG-avid tumor thrombus confined to the right internal iliac vein, without any lymphadenopathy or solid tumor mass. The patient was successfully treated with a combination of systemic chemoimmunotherapy and targeted radiotherapy and remained in complete remission for more than four years after diagnosis; Conclusions: We report a potentially unique case of double-hit IVLBCL diagnosed using endovascular thrombectomy. This underscores the therapeutic and diagnostic potential of mechanical thrombectomy systems in the detection of intravascular malignancies and the critical importance of the routine histopathological examination of all thrombectomy specimens. Despite negative thrombolysis data from the ATTRACT and CAVA trials, mechanical thrombectomy may improve venous hemodynamics and may reduce post-thrombotic syndrome (PTS) in pelvic thrombosis. Here, mechanical thrombectomy followed by right iliac vein stenting achieved excellent technical and clinical outcomes.
Keywords: intravascular large B-cell lymphoma (IVLBCL), MYC and BCL2 rearrangement, deep vein thrombosis, mechanical thrombectomy, case report
1. Introduction and Clinical Significance
Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive subtype of diffuse large B-cell lymphoma characterized by the selective proliferation of neoplastic lymphoid cells within small blood vessels [1,2,3]. While the exact incidence of IVLBCL is unknown, it is estimated to be exceedingly rare, with an estimated incidence of fewer than one case per million per year. The median age at diagnosis is between the sixth and seventh decades. No consistent sex predilection has been demonstrated [1,2,3].
The clinical manifestations of IVLBCL are highly heterogeneous and vary depending on the affected organs. A peculiar aspect of IVLBCL is the lack of lymphadenopathy [1,2,3]. Therefore, diagnosis can be challenging, which is why it is called the oncologist’s “great imitator” [4].
In the WHO Classification of Haematolymphoid Tumours, fifth edition (2024), IVLBCL is recognized as a distinct entity with three primary patterns of presentation in the clinical setting: classic, cutaneous, and hemophagocytic syndrome-associated subtypes [1,3,5,6].
The classic subtype is the most prevalent in Western countries (“Western variant”) and presents with a heterogeneous clinical spectrum. Common manifestations include fever, diverse cutaneous lesions (including painful indurate erythematous eruption, “peau d’orange,” cellulitis, ulcerated nodules, etc.) and multiorgan failure. Central nervous system (CNS) involvement is common, typically resulting in rapidly progressive neurological signs, such as encephalopathy, seizures, or focal deficits such as hemiparesis [1,2,3,6].
The cutaneous subtype is restricted to skin involvement. It occurs primarily in Western populations and is rare in Asian countries. Unlike other forms, it predominantly affects younger women with a good performance status. This variant is less aggressive, presents with fewer systemic symptoms, and is associated with a significantly better prognosis [1,2,3,6].
The hemophagocytic syndrome (HPS)-associated subtype, predominantly seen in Asian patients, classically presents with fever, thrombocytopenia, splenomegaly, and bone marrow involvement [1,2,3,5,6].
Patients often present with laboratory abnormalities such as elevated serum lactate dehydrogenase (LDH; 100%); beta-2 microglobulin; elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); anemia (50–91%); thrombocytopenia (33–60%); leukopenia (30–35%); hypoalbuminemia; altered hepatic, renal, or thyroid function; and/or serum monoclonal protein [2,3,7].
Histopathologically, IVLBCL comprises large atypical lymphoid cells with vesicular nuclei, prominent nucleoli, and a high mitotic rate. It is hypothesized that lymphoma cells often lack essential adhesion molecules, CD29 (β1 integrin) and CD54 (ICAM-1), or exhibit deficiencies in Hermes-3-defined homing receptor antigen. These defects, combined with aberrant chemokine receptor profiles, impair their transendothelial migration. Consequently, these cells become sequestered within the vasculature rather than homing to the lymphoid tissues [1,4,5,8].
We report a case of IVLBCL with concurrent MYC and BCL2 rearrangements (double-hit features) detected by fluorescence in situ hybridization (FISH). This finding is rare in IVLBCL, which typically harbors mutations characteristic of activated B-cell-type lymphomas, particularly MYD88 and CD79B [9,10]. Given the atypical presentation, the intravascular nature was definitively confirmed using elastic van Gieson (EVG) staining to visualize the vascular wall architecture and CD31 immunohistochemistry to demonstrate endothelial-lined lumina. The co-occurrence of an intravascular growth pattern with double-hit rearrangements represents, to our knowledge, an exceptionally rare clinicopathologic scenario and expands the molecular spectrum of IVLBCL.
Finding the right treatment strategy is still a challenge. While standard management relies on rituximab-based regimens such as R-CHOP or R-EPOCH, often combined with CNS-directed therapy such as high-dose methotrexate [1,2,3,9,11], the impact of “double-hit” genetics in guiding therapy for IVLBCL remains poorly defined, with limited disease-specific evidence.
Modern mechanical thrombectomy may occasionally provide an unexpected diagnostic opportunity by yielding thrombus material that can be submitted for histopathological analysis. This can lead to the incidental detection of an intravascular malignancy that might otherwise remain undiagnosed until advanced disease.
This case illustrates a successful therapeutic outcome in this rare and aggressive lymphoma subtype, highlighting the value of early diagnosis, comprehensive molecular characterization, and intensive treatment.
2. Case Presentation
2.1. History
A 79-year-old female patient with good general health and a long-standing history of marathon and ultramarathon running was referred on 8 February 2022 by her general practitioner for clinical and duplex ultrasound evaluation of a progressive swelling of the right leg for 15 days due to suspected deep vein thrombosis (DVT). The patient reported increased swelling and redness of the leg despite daily gym visits. She was otherwise asymptomatic and denied any pain, fever, or night sweats. The 2 kg weight loss was intentional due to intensified physical training; consequently, the patient did not meet the criteria for B-symptoms. She was not on any regular medication and had received three doses of the COVID-19 vaccine.
2.2. Clinical Findings and Imaging
Upon examination, the right leg was found to be significantly swollen and mildly cyanotic. The pedal pulses were palpable bilaterally, and no trophic lesions were observed. There were circumference differences of 5 cm between the thighs and 4 cm between the lower legs. No skin rash or hepatosplenomegaly was observed.
The clinical presentation suggested extensive iliofemoral deep vein thrombosis with features concerning for progression along the phlegmasia spectrum. While the preserved arterial pulses and the absence of severe cyanosis indicated that the condition had not progressed to phlegmasia cerulea dolens (PCD), the mild cyanosis suggested the early involvement of collateral circulation beyond classic phlegmasia alba dolens (PAD).
Laboratory tests revealed mild anemia with a hemoglobin level of 11 g/dL (range, 12–15.5 g/dL) and mild hypocalcemia of 2.03 mmol/L (range, 2.20–2.55 mmol/L). The ferritin level was 25.80 ng/mL (range, 13–150 ng/mL). LDH was slightly elevated at 300 U/L (range, 135–214 U/L). There was no elevation in the CRP level. Duplex ultrasonography confirmed a thrombosis of the right common iliac vein. The common femoral, deep femoral, femoral, and popliteal veins were patent. Contrast-enhanced computed tomography demonstrated extensive thrombosis of the right common iliac vein extending into the inferior vena cava without involvement of the deep venous system of the leg (Figure 1).
Figure 1.
(A) Coronal maximum intensity projection. (B) Coronal CT slice. Note the absence of contrast opacification medium/occlusion in the right common iliac vein extending cauliflower-like (arrow) to the inferior vena cava (arrow) as well as into the left internal iliac vein (*).
Given the extensive iliofemoral deep vein thrombosis with significant limb swelling and high risk of severe post-thrombotic syndrome, mechanical thrombectomy was planned. The patient was bridged with therapeutic anticoagulation for 48 h prior to the intervention.
2.3. Interventional Therapy
The patient was admitted for inpatient care, and therapeutic anticoagulation with heparin was initiated (bolus of 5000 IU, followed by 20,000 IU/24 h). Compression therapy extending from the foot to the groin was administered. Two days later, the patient underwent the endovascular recanalization of the right common and external iliac veins under general anesthesia. Initial phlebography confirmed chronic thrombotic occlusion of the right common iliac vein extending into the distal inferior vena cava (IVC), which remained patent. Extensive collateral vessels were observed (Figure 2a). A temporary infrarenal inferior vena cava (IVC) filter (Celect Platinum; Cook Medical, Bloomington, IN, USA) was deployed via the right internal jugular vein access because of the extension of the thrombus into the inferior vena cava to protect the lungs. Intravenous heparin was administered during the procedure, aiming for a target activated clotting time (ACT) of 250 s, and was monitored intraoperatively. A through-and-through wire was established between the right internal jugular and right common femoral venous access, enabling the controlled advancement of a mechanical thrombectomy system (ClotTriever®, Inari Medical, Irvine, CA, USA) and the protection of the system from the cava filter. Four passes using the device yielded a large quantity of firm white thrombus material with minimal fresh components. Because of its unusual consistency, the extracted material was subjected to histopathological evaluation. Subsequent phlebography revealed a recanalized right pelvic venous axis with a persistent web-like stenosis in the external iliac vein (Figure 2b). After balloon angioplasty using a 14 × 40 mm balloon (Atlas Gold, BD, Franklin Lakes, NJ, USA), a 16 × 60 mm self-expanding stent (Wallstent®, Boston Scientific, Marlborough, MA, USA) was deployed and post-dilated with a 14 × 40 mm balloon, resulting in excellent angiographic patency without residual stenosis or thrombus (Figure 3A–D). Finally, the IVC filter was successfully retrieved through jugular narrowing. The procedure was completed without any complications. Hemostasis was achieved by using purse-string sutures and pressure banding. Therapeutic anticoagulation with intravenous heparin was continued post-interventionally, and the patient was discharged the following day in good condition with continued anticoagulation using dalteparin (2 × 5000 IU daily for 6 weeks), followed by rivaroxaban at 20 mg daily.
Figure 2.
(a) Initial phlebography of the inferior vena cava and iliac veins. Pre-placed vena cava filter (IVC filter) to prevent intraprocedural pulmonary embolism (*). Note the presence of prominent venous collaterals, such as paravertebral collaterals via lumbar veins (yellow arrow), parauterine collaterals (red arrow), and femoro-femoral suprapubic collaterals (blue arrow) due to the occlusion of the common iliac vein. The cauliflower-like protrusion of the tumor into the inferior vena cava can also be seen again (orange arrow). (b) Phlebography of the inferior vena cava and recanalized right iliac vein after mechanical thrombectomy (16F, Inari ClotTriever) with persistent stenosis (arrows). Note the immediate disappearance of the previously described venous collaterals.
Figure 3.
(A,B) Angioplasty with 14 mm balloon due to persistent stenosis after the recanalization of the right iliac vein. This shows a web-like filiform stenosis of the common iliac vein upon inflation (arrow, upper left). (C) Implantation of a self-expanding stent (Boston Scientific Wallstent 16 mm/60 mm) into the common iliac vein. (D) Good result with stenosis-free right pelvic axis. Again, note the absence of venous collaterals in the final image.
2.4. Histopathology and Diagnosis
The histopathological examination of the thrombus (20 × 20 × 3 mm) revealed a large B-cell lymphoma. Immunohistochemistry showed strong and diffuse positivity for the B-cell markers CD20, bcl2, bcl6, and FoxP1, with negative staining for CD3, CD5, CD30, Alk1, TdT, CyclinD1, Melan A, HMB45, and Lu5. The proliferative fraction (Ki-67) was 98%. FISH analysis showed the rearrangement of the BCL2 and MYC genes (“double-hit”), while no BCL6 rearrangement was detected. The EBV (EBER) RNA in situ hybridization results were negative (Figure 4A–D).
Figure 4.
Histopathological examination of the excised thrombus reveals (A) a diffuse infiltrate of a blastic lymphoma in Hematoxylin and Eosin (H&E) staining (×200). (B) The tumor cells are large with vesicular nuclei, prominent nucleoli, and variable amounts of cytoplasm. Immunohistochemistry demonstrates that the lymphoma cells are positive for the B-cell markers (C) CD20 (strong cytoplasmic expression; ×200) and (D) FoxP1 (dense nuclear expression; ×200).
A key diagnostic challenge was the differentiation between IVLBCL and other high-grade B-cell entities, as this case presented an extraordinarily rare integrative profile.
Fibrin-associated large B-cell lymphoma (FA-LBCL) was excluded because it is typically EBV-positive and characteristically presents as non-invasive microscopic aggregates of atypical cells embedded in fibrinous material, without an intravascular growth pattern [6].
Despite the markedly high proliferation rate (Ki-67 index of 98%), a diagnosis of high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS), was inapplicable due to the detection of MYC and BCL2 rearrangements [6].
Immunohistochemistry showed CD10 negativity, BCL6 positivity, and FoxP1 expression, which is associated with a non-GCB phenotype. This immunophenotype is compatible with IVLBCL and is less typical for a B-cell lymphoma with MYC/BCL2 rearrangement (DLBCL), which was considered an important differential diagnosis in this case [6].
Elastic van Gieson staining demonstrated vascular structures with an internal elastic lamina (Figure 5A). While this feature is more characteristic of arteries, it may represent either a small accompanying artery within the thrombectomy specimen or venous remodeling under hemodynamic stress. CD31 immunohistochemistry highlighted the endothelial lining of the affected vessels, supporting that the CD20-positive lymphoma cells were confined within endothelial-lined lumina (Figure 5B). This distinguished the case from DLBCL/HGBL with tumor thrombus or secondary vascular invasion [1,5,6,12].
Figure 5.
(A) Elastic van Gieson (EVG) stain demonstrating a vascular structure with an internal elastic lamina (arrow). While this feature is more characteristic of arteries, it may represent either a small accompanying artery or venous remodeling; ×50 magnification. (B) CD31 immunohistochemistry highlighting the endothelial lining of the vascular wall (arrow); ×50 magnification.
The diagnosis of an IVLBCL with MYC and BCL2 rearrangements was based on the intravascular growth pattern demonstrated by EVG and CD31 staining, a characteristic immunophenotype (CD20+, BCL2+, BCL6+, FoxP1+, CD10−, CD5−, and Ki-67 of 98%), and the absence of extravascular disease or lymphadenopathy on PET-CT. Given the coexisting double-hit genetics and diffuse high-grade morphology, the lesion is best regarded descriptively as an IVLBCL-like, double-hit, large-vessel large B-cell lymphoma rather than being forced into a single WHO-5 or ICC category.
2.5. Management and Treatment
Positron emission tomography-computed tomography (PET-CT) performed three weeks after the intervention revealed a long-segment, highly fludeoxyglucose (FDG)-avid intravascular tumor in the right internal iliac vein (SUVmax 26.1), as well as focal FDG uptake in the collateral venous circulation adjacent to the stent (Figure 6A,B). No nodal or extranodal manifestations were observed. However, owing to the presence of lymphoma cells within the blood vessels, the disease was considered disseminated and, therefore, treated as advanced disease. Complete surgical resection was discussed at the multidisciplinary tumor board but was dismissed because of the extent of disease and expected morbidity. Instead, given the patient’s age (79 years), the absence of nodal or extranodal disease, and the purely intravascular localization, systemic therapy with dose-reduced R-mini-CHOP was initiated on 14 March 2022, followed by consolidative involved-site radiotherapy to the iliac vessels due to the bulky, highly FDG-avid intravascular lesion (SUVmax 26.1). The regimen was exceptionally well tolerated, allowing for gradual dose escalation from cycle to cycle, ultimately reaching near-standard R-CHOP dosing. A total of six cycles of therapy were administered. From 29 March 2022, the patient underwent 3D-conformal external beam radiotherapy of the right iliac region using the IMAT technique (23 × 200 cGy = 4600 cGy; five sessions per week).
Figure 6.
(A) Coronal and (B) axial images of a fused FDG PET-CT scan after mechanical thrombectomy and stent implantation. FDG-avid tumor is found in the right internal iliac vein (arrow).
The radiological assessment of the therapy response was difficult because of the lack of measurable disease. PET-CT at the end of therapy on 13 September 2022, showed no evidence of residual lymphoma.
2.6. Follow-Up
PET-CT performed seven months after the initial diagnosis showed no remaining FDG-avid lesions (Figure 7A,B). At the one-year follow-up, the patient was in excellent clinical condition, continuing an active lifestyle with gym sessions three times a week and running 6–7 km twice weekly. The patient’s weight decreased to 41.8 kg. To date, no recurrent thrombotic events have been reported. Ultrasound follow-up demonstrated a patent stent with rapid flow. Laboratory testing showed that all values were within the normal range, except for mild hypocalcemia and persistent mild anemia. The LDH level, which is considered a surrogate marker of lymphoma activity, was normal. Four years after the intervention and therapy, the patient remained in sustained complete remission.
Figure 7.
(A) Coronal and (B) axial fused FDG PET-CT images after the completion of radiotherapy and immunochemotherapy of the intravascular B-cell lymphoma 7 months after the initial diagnosis. PET-CT shows complete remission without any remaining FDG-avid lesion.
3. Discussion
IVLBCL is a rare and aggressive subtype of non-Hodgkin lymphoma. The diagnosis of IVLBCL remains a major challenge owing to its heterogeneous clinical manifestations, which often lead to diagnostic delays and limit the overall understanding of the disease.
An important minimally invasive procedure for the early detection of IVLBCL is random skin biopsy (RSB). Several studies have recognized the utility of RSB on macroscopically healthy skin for early diagnosis, reporting a sensitivity ranging from 50% to 94.3% [13,14,15]. The higher sensitivity of 90.3–94.3% in the study by Purngpiputtrakul et al. (RSB performed on 209 patients) is most likely due to the use of incisional biopsies with a greater depth of ≥10–12.7 mm [13]. In comparison, Rozenbaum et al. reported a sensitivity of 50% (RSB performed on 50 patients being evaluated for IVL) using a 5 mm depth [14], and Matsue et al. achieved a sensitivity of 77.8% in 111 patients using a standard 4–5 mm biopsy [15]. Across these three studies, the specificity remains consistent, and both the positive predictive value (PPV) and negative predictive value (NPV) are comparable. This demonstrates that obtaining sufficient subcutaneous tissue is crucial, as lymphoma cells preferentially infiltrate subcutaneous capillaries in 89.4% of cases [13]. In contrast, the cohort study by Li Y et al. [3] relied primarily on organ biopsies because most patients were already in an advanced stage of the disease at the time of diagnosis.
In current practice, random skin biopsy with additional bone marrow biopsy is recommended in patients with suspected IVLBCL as part of the initial diagnostic work-up. In our case, the histopathologic diagnosis was incidental, based on the histomorphological examination of the extracted thrombus, and this should be considered standard practice whenever thrombus morphology is atypical or when classical risk factors for thrombosis are absent.
This diagnostic course aligns with individual case reports in which the histopathological evaluation of the thrombus material ultimately provided the decisive diagnosis. For instance, Baker et al. [16] reported on a 70-year-old patient presenting with a tumor-embolic ischemic stroke and left-sided hemiparesis. Due to an atypical thrombus morphology following mechanical thrombectomy, histopathology confirmed a malignant process, although the primary tumor remained occult. Similarly, Isokawa et al. [17] described the case of a 72-year-old patient diagnosed with a fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) based on the histopathology of a thrombectomy specimen following acute lower-limb arterial occlusion. The relevance of systematic thrombus analysis is further supported by larger cohort studies. Aspegren et al. [18] retrospectively analyzed 1008 thrombi retrieved via stent retrievers or aspiration from stroke patients across three different centers. Although histopathology was performed in only 15 cases, significant amounts of extracellular DNA were detected in 6 of these thrombi. In 1–2% of the total cases, unusual histopathological findings such as calcifications, cholesterol deposits, or myxomatous material were observed, offering valuable insights into the underlying cardiovascular pathology. A significant contribution to the understanding of neoplastic emboli was provided by a 17-year retrospective analysis by Bois et al. [19], who investigated 1364 embolectomies in 1103 patients. With a prevalence of 0.8% (11 out of 1364 cases), tumor emboli are rare; however, they represented the initial clinical manifestation of the neoplastic disease in 63.6% of those affected (7 out of 11 cases). Clinically, the majority of these patients presented with limb ischemia, and etiologically, cardiac myxomas were the most common finding.
Our study, with its highly favorable results, reinforces the message that the histopathological examination of embolectomy specimens can provide the crucial and sometimes only clue to an occult carcinoma or other rare pathologies.
The interventional management of iliofemoral and iliocaval thrombosis has become increasingly established in recent years, particularly in cases of extensive thrombosis with impending post-thrombotic syndrome. While randomized trials such as ATTRACT [20] and CAVA [21] did not demonstrate a significant reduction in post-thrombotic syndrome (PTS) with thrombolysis, growing evidence suggests that mechanical thrombectomy combined with stenting may improve venous hemodynamics and relieve the symptoms of pelvic vein thromboses. In our case, mechanical thrombectomy followed by stent implantation into the right common/external iliac vein yielded excellent technical and clinical outcomes with the complete resolution of the initial significant swelling of the right lower extremity. Additionally, the CLOUT Registry [22] (ClotTriever Outcomes) provides valuable real-world data on mechanical thrombectomy systems such as the ClotTriever. Among 500 patients with proximal DVT, the registry demonstrated complete or near-complete (≥75%) thrombus removal in 91.2% of cases with significant symptom relief and low complication rates [22], further supporting the clinical efficacy of this device compared with pharmacomechanical or pharmacological therapies.
This case highlights the importance of interdisciplinary collaboration in modern medicine, in which interventional radiology not only achieves the therapeutic recanalization of vascular obstruction but also provides tissue that may reveal an otherwise unsuspected underlying malignancy.
Modern mechanical thrombectomy systems, such as ClotTriever, now enable the bulk retrieval of intact thrombus material, facilitating detailed histopathological evaluation not feasible with aspiration or thrombolysis techniques. This technological advancement has increased the detection of intravascular tumor manifestations. In our clinical practice, bronchial adenocarcinoma, urothelial carcinoma, and ovarian carcinoma have been diagnosed incidentally during the thrombectomy of the inferior vena cava, pelvic veins, and subclavian vein, supporting the dual therapeutic and diagnostic value of mechanical thrombectomy.
It is the responsibility of vascular surgeons and interventionalists performing the procedure, whether using open surgical or endovascular techniques (including aspiration devices such as Penumbra or AngioJet), to ensure that all retrieved material is sent for pathological analysis.
In addition to its clinical presentation and uncommon diagnostic pathway, the detection of an IVLBCL within a large blood vessel represents a unique clinical feature. The classical definition characterizes the IVLBCL as an extranodal lymphoma that proliferates almost exclusively within small blood vessels, particularly capillaries and postcapillary venules. To the best of our knowledge, only four autopsy cases describing large-vessel involvement have been documented [23,24]. Thus, this represents, to our knowledge, one of the first antemortem diagnoses of a large-vessel IVLBCL and the first reported in combination with double-hit genetics and successful treatment. Table 1 presents these cases in detail, including patient demographics, vessel location, diagnostic method, treatment, and outcomes.
Table 1.
Summary of reported cases of intravascular large B-cell lymphoma involving large vessels.
| Author/Year | Age/Sex | Vessel Location | Clinical Presentation | Diagnostic Method | Treatment | Outcome |
|---|---|---|---|---|---|---|
| Sato et al., 2019—Case 1 [23] | 70s/F | Truncus pulmonalis to pulmonary arteries | Sudden death | Autopsy (bone marrow biopsy positive antemortem) | None (died before treatment) | Sudden death before treatment |
| Sato et al., 2019—Case 2 [23] | 60s/M | Aorta and carotid arteries | Sudden death | Autopsy (skin biopsy positive antemortem) | None (died before treatment) | Sudden death before treatment |
| Sato et al., 2019—Case 3 [23] | 70s/M | Aortic arch | Died during treatment | Autopsy (bone marrow biopsy positive antemortem) | Chemotherapy initiated | Death during treatment |
| Tando et al., 2024—Case 4 [24] | 70s/M | Bilateral middle cerebral arteries, left posterior cerebral artery | Rapid embolic strokes, consciousness disturbance | Autopsy (random skin biopsy positive antemortem) | Chemotherapy initiated | Death on hospital day 13 |
| Current case, 2026 | 79/F | Iliofemoral and iliocaval veins | Extensive iliofemoral deep vein thrombosis | Mechanical thrombectomy (ClotTriever) | R-mini-CHOP + involved-site RT (46 Gy) | Complete remission >4 years |
The histopathological diagnosis of this case also merits a nuanced discussion. The differential diagnostic considerations are detailed in the Section 2.4. The strictly intravascular presentation, in the absence of lymphadenopathy, is characteristic of IVLBCL [1,3,4,5,6]. However, the concurrent presence of MYC and BCL2 rearrangements is uncommon in IVLBCL. This genetic profile is more typical of an HGBL with MYC/BCL2 rearrangement, which commonly manifests as a nodal or extranodal mass rather than an intravascular disease [12]. Neither the fifth edition of the WHO classification nor the ICC classification provides guidance on the diagnostic categorization of cases exhibiting IVLBCL-like morphology alongside a MYC/BCL2 rearrangement. Both classifications define intravascular large B-cell lymphoma and HGBL with MYC and BCL2 rearrangements as distinct entities [5,6,12]. This unique, integrative profile, combining the intravascular growth pattern of an IVLBCL with the genetic signature of an HGBL with MYC/BCL2 rearrangement and FoxP1 expression associated with a non-GCB phenotype, has not been described in recent comprehensive reviews, suggesting that it represents an extremely rare and, to our knowledge, not previously reported combination of features [1,3,12]. We acknowledge, however, that the double-hit genetics and diffuse high-grade morphology overlap with those of a high-grade B-cell lymphoma with MYC/BCL2 rearrangement and that such a lymphoma presenting as tumor thrombus cannot be excluded with absolute certainty based on the available material. The strictly intraluminal confinement demonstrated by CD31 and elastic van Gieson staining, together with the absence of any extravascular mass on PET-CT, supports a genuinely intravascular process; the case is, therefore, best designated as an IVLBCL-like, double-hit, large-vessel large B-cell lymphoma, and we have framed the diagnosis descriptively rather than assigning it to a single WHO-5 or ICC category.
A notable limitation was the absence of bone marrow biopsy and MICM analysis, despite guideline recommendations for routine bone marrow assessment in IVLBCL staging. The diagnosis was established based on thrombectomy specimen analysis, and PET-CT showed no evidence of bone marrow involvement; however, MICM data would have provided additional diagnostic and prognostic information.
As our understanding of IVLBCL is primarily based on a limited number of case reports, this report on the extremely rare involvement of large vessels aims to expand the existing knowledge base. It offers valuable insights into effective diagnosis and treatment strategies for this elusive clinical condition.
Due to the rarity of intravascular large B-cell lymphoma (IVLBCL), there is currently no standard treatment. However, the currently documented clinical evidence indicates that the combination of R-CHOP, high-dose methotrexate, and intrathecal chemotherapy represents the most well-studied treatment option for newly diagnosed cases without CNS involvement at baseline [11].
In the PRIMEUR-IVL study by Shimada et al. [11], a treatment regimen with six cycles of R-CHOP in combination with two cycles of high-dose methotrexate and four doses of intrathecal chemotherapy demonstrated durable efficacy, with a 2-year progression-free survival (PFS) of 76%. Guo et al.’s [25] study highlights the prognostic heterogeneity of IVLBCL. A significant difference in 2-year overall survival (OS) was observed between the clinical subtypes: the classic variant showed significantly better overall survival compared with the hemophagocytosis-associated variant (76.4% vs. 43%; p = 0.007).
In particular, age of >60 years, thrombocytopenia (<150 × 109/L), elevated LDH levels (≥700 U/L), CNS involvement, and the presence of hemophagocytic lymphohistiocytosis (HLH) are considered independent predictors of an unfavorable prognosis [7,11,25].
Our patient responded exceptionally well to sequential radiochemotherapy and remained in complete remission for over four years after the diagnosis, clinically, biochemically, and radiologically. As mentioned in the case presentation, our patient’s LDH level was 300 U/L, which is below the prognostic threshold of ≥700 U/L associated with poor outcomes.
A critical limitation was the absence of CNS staging (cranial MRI and lumbar puncture) and CNS-directed prophylaxis, despite the high CNS relapse risk associated with IVLBCL. At the time of treatment planning, the decision to omit CNS staging was based on the absence of neurological symptoms and on concerns about treatment-related toxicity with high-dose methotrexate. Current evidence supports routine CNS assessment in IVLBCL patients, as demonstrated by the PRIMEUR-IVL trial, which incorporated CNS-directed therapy (high-dose methotrexate and intrathecal chemotherapy) even in patients without apparent CNS involvement at diagnosis, achieving a 2-year cumulative incidence of secondary CNS involvement of only 3% in a cohort of 38 patients (37 eligible) [11]. In retrospect, CNS staging and prophylaxis should have been considered, particularly given the known CNS tropism of IVLBCL.
4. Conclusions
The case underscores several important clinical lessons: (1) the diagnostic and therapeutic potential of mechanical thrombectomy systems in detecting intravascular malignancies, (2) the critical importance of routine histopathological examination of all thrombectomy specimens, and (3) the value of comprehensive clinicopathological correlation when rare genetic findings coexist with atypical clinical presentations.
In conclusion, further research is needed to optimize the diagnostic and treatment strategies. In particular, the investigation of targeted therapeutic approaches based on the specific molecular profiles of IVLBCL offers promising potential.
Abbreviations
The following abbreviations are used in this manuscript:
| CNS | Central nervous system |
| CRP | C-reactive protein |
| DVT | Deep vein thrombosis |
| DLBCL | Diffuse large B-cell lymphoma |
| EBV | Epstein–Barr Virus |
| ESR | Erythrocyte sedimentation rate |
| FISH | Fluorescence in situ hybridization |
| FDG | Fluorodeoxyglucose |
| FA-DLBCL | Fibrin-associated diffuse large B-cell lymphoma |
| HGBL | High-grade B-cell lymphoma |
| IVLBCL | Intravascular large B-cell lymphoma |
| ICC | International Consensus Classification |
| IVC | Inferior vena cava |
| LDH | Lactate dehydrogenase |
| MRI | Magnetic Resonance Imaging |
| PET-CT | Positron emission tomography-computed tomography |
| PTS | Post-thrombotic syndrome |
| R-CHOP | Chemotherapy, combination of five drugs: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone |
| RSB | Random skin biopsy |
| WHO | World Health Organization |
Author Contributions
Conceptualization, N.B. and M.K.; writing—original draft preparation, N.B.; writing—review and editing, N.B., M.K. and S.S.; selection and review of intervention-related images, M.K. and S.S.-U.; selection and review of histopathological images, S.S. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Ethical review and approval of this study were not required by the Ethics Committee Northwest and Central Switzerland (EKNZ) for patients treated at Kantonsspital Baden, because single-case reports are not considered research in our jurisdiction and do not require formal ethical approval. The patient’s information has been completely de-identified.
Informed Consent Statement
Written informed consent has been obtained from the patient to publish this paper.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding Statement
This research received no external funding.
Footnotes
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Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.