Intravascular large B-cell lymphoma as a covert trigger for hemophagocytic lymphohistiocytosis complicated with capillary leak syndrome: a case report and literature review.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.

Plasma circulating tumour DNA is a better source for diagnosis and mutational analysis of IVLBCL than tissue DNA.

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.

A case of cutaneous variant of intravascular large B-cell lymphoma in which dermoscopy revealed telangiectasias associated with erythematous induration.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal, diffuse, large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumen of small blood vessels, with no lymphadenopathy or masses. Herein, we report a cutaneous variant of IVLBCL that is rare in Asia. A healthy 73-year-old Japanese woman presented to our hospital with painful erythematous indurations and telangiectasia of the lower extremities, which was confirmed on dermoscopy. Physical examination revealed no systemic involvement, and laboratory parameters were within normal ranges. No abnormal fluorodeoxyglucose (FDG) uptake was detected on 18FDG positron emission tomography/computed tomography. Histopathological examination revealed proliferation and dilatation of blood vessels in the subcutis layer, occluded by CD20-positive atypical lymphoid cells. Thus, the patient was diagnosed with a cutaneous variant of IVLBCL without systemic symptoms. In conclusion, it is important to confirm telangiectasia using dermoscopy and perform skin biopsies in patients presenting with sudden-onset erythematous induration.

Differentiation Between Disseminated Carcinomatosis of the Bone Marrow From Urothelial Cancer and Intravascular Large B-cell Lymphoma: A Case Report.

This case report describes a rare case of intravascular large B-cell lymphoma (IVLBCL), initially presenting with nonspecific symptoms of fever and fatigue, and tentatively diagnosed as disseminated carcinomatosis of the bone marrow originating from urothelial cancer in an 80-year-old woman. The patient's journey began with symptoms treated as common ailments and progressed through multiple differential diagnoses, including giant cell arteritis, TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) syndrome, and disseminated carcinomatosis of the bone marrow originating from urothelial cancer due to the presence of systemic inflammation, anasarca, and elevated soluble interleukin 2 receptor levels, indicative of an intense immunological response. Despite initial treatments, her condition deteriorated, leading to further investigations that ultimately revealed the presence of malignant cells in the urine and bone marrow, confirming the diagnosis of IVLBCL. This case underscores the diagnostic challenges faced when elderly patients present with systemic inflammation and the critical need for thorough investigation beyond initial impressions. It highlights the importance of considering differentiation between disseminated carcinomatosis of the bone marrow and IVLBCL in the differential diagnosis of persistent inflammation, especially in cases where common causes have been excluded and the primary malignancy is not immediately apparent.

Optimizing random skin biopsies: a review of techniques and indications for intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL), a rare subtype of malignant lymphoma, is diagnosed by observation of intravascular proliferation of tumor cells in samples taken from affected organs. However, diagnosis of IVLBCL is usually difficult due to the lack of mass formation. IVLBCL may be fatal when the diagnosis is delayed, so an accurate early diagnosis is the key to successful treatment. Random skin biopsy (RSB), in which specimens are sampled from normal-appearing skin, has been reported as useful. However, the specific method of RSB remains controversial, with individual institutions using either the punch method or the incisional method. Research has shown that the incisional method has higher sensitivity than the punch method. We discuss whether this difference might owe to the collection of punch specimens from an insufficient depth and whether the punch method might result in false negatives. For RSB, we recommend taking specimens not only from normal-appearing skin, but also from any lesional skin, because lesions may reflect micro IVLBCL lesions. To ensure accurate diagnosis, both dermatologists and hematologists should know the proper method of RSB. This review summarizes the appropriate biopsy method and sites for RSB.

Fatal hemophagocytic lymphohistiocytosis with intravascular large B-cell lymphoma following coronavirus disease 2019 vaccination in a patient with systemic lupus erythematosus: an intertwined case.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

Intravascular large B-cell lymphoma of the eye: Literature review and new findings.

PURPOSE: Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare, aggressive, multi-system disease that can affect the eye. We describe the ophthalmic presentation, multimodal imaging and treatment response of uveal IVLBCL. METHODS: Review and case report. RESULTS: Twenty-five published cases of IVLBCL involving the eye including our own were identified. Of these, 15 patients (60%) had clinically-detectable intraocular involvement, 6 (24%) had extraocular ophthalmic involvement only and 4 (16%) had subclinical, undiagnosed intraocular involvement that was retrospectively detected on post-mortem ocular histopathology. The male to female ratio was 1.08:1 with a mean presenting age of 65.1 ± 11.7 years (range 38-82 years). The majority of cases had bilateral involvement (21/25 patients, 84%). Extraocular manifestations included diplopia, ptosis and ophthalmoplegia. Intraocular manifestations included serous retinal detachment (13/28, 46%), retinal hemorrhages (9/28, 32%), vascular changes (9/28, 32%), retinal pigment epithelial changes (7/28, 25%), thickened choroid (6/28, 21%), vitritis (5/28, 17%), cotton-wool spots (3/28, 10%), and a subretinal lesion (1/28, 3%). Histopathological diagnosis was most commonly confirmed on post-mortem enucleation (8/25 patients, 32%), skin (6/25 patients, 24%) or brain biopsy (6/25 patients, 24%). CONCLUSION: The presence of intra-retinal hemorrhages, cotton wool spots and/or Roth spots help differentiate IVLBCL from other similarly presenting diseases such as central serous chorioretinopathy and Vogt-Koyanagi-Harada disease. New signs not previously described in IVLBCL include macular bacillary layer detachment and hypo-cyanescent spots on ultra-wide field indocyanine green angiography. The diagnosis is elusive and requires tissue biopsy, but systemic chemotherapy and rituximab can lead to rapid improvement of the eye.

[Intravascular Large B-cell Lymphoma Presenting with Lung Adenocarcinoma:
A Case Report and Literature Review].

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive extranodal large B-cell lymphoma, cocurrence in the same organ with other malignancies is very rare, especially in the lung. Here, we report a rare case of lung adenocarcinoma with IVLBCL. The patient was admitted to the hospital due to diarrhea associated with fever and cough. A computed tomography (CT) scan of the chest showed an irregular patchy high-density shadow in the upper lobe of the right lung with ground-glass opacity at the margin. After admission, the patient was given anti-infection treatment, but still had intermittent low fever (up to 37.5 °C). The pathological diagnosis of percutaneous lung biopsy (PLB) was lepidic-predominant adenocarcinoma with local infiltration, which was proved to be invasive nonmucinous adenocarcinoma of the lung with IVLBCL after surgery. This paper analyzed the clinicopathological characteristics and reviewed the relevant literature to improve the knowledge of clinicians and pathologists and avoid missed diagnosis or misdiagnosis.
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Effective management of a rare case of primary renal intravascular large B-cell lymphoma with modified R-CHOP regimen: A case report.

Intravascular large B-cell lymphoma, known for its diverse organ involvement, presents significant diagnostic challenges, particularly when it affects the kidneys. This report highlights a rare case of primary renal intravascular large B-cell lymphoma in a 60-year-old male patient, who presented with persistent fever and renal dysfunction. The case underscores the intricacy of diagnosis and the efficacy of personalized treatment. Following the identification of primary renal intravascular large B-cell lymphoma, a modified R-CHOP regimen was administered, resulting in notable amelioration of symptoms and renal function following the initial treatment cycle. The patient achieved sustained complete remission without any complications after completing five subsequent R-CHOP cycles and two additional cycles of rituximab monotherapy, as confirmed by recent assessments. He is currently under regular follow-up for ongoing monitoring and improvement. This case adds to the limited yet expanding pool of knowledge concerning intravascular large B-cell lymphoma, emphasizing the necessity for personalized therapeutic strategies in atypical presentations. It also highlights the importance of early detection and customized intervention in managing rare lymphoma subtypes with unique organ involvement.

EBV-Positive Intravascular Large B-Cell Lymphoma of the Small Intestine: A Case Report and Literature Review.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma that affects the brain, skin, and bone marrow. We describe the case of a 75-year-old man who was admitted to the hospital after 4 h of stomach aches. A thorough physical examination indicated stomach discomfort and skin discoloration. Laboratory tests revealed thrombocytopenia and elevated lactate dehydrogenase levels. A computed tomography scan of the abdomen revealed that the small intestine wall was thickened, edematous, and necrotic. The necrotic small bowel was surgically removed, revealing many little round, homogenous, and unusual cells in the mesenteric vein. In-situ hybridization revealed that these cells were positive for PAX5, CD20, CD79a, CD10, and BCL2, as well as Epstein-Barr virus-encoded small RNA. After 1 week of hospitalization without treatment, the patient was diagnosed with IVLBCL and died of multiple organ dysfunction syndrome. IVLBCL is a rare illness that affects the small intestine and possibly the gastrointestinal system. It has an insidious start, a fast development, and a dismal prognosis. Knowing its clinicopathologic traits helps in understanding the illness, making an early diagnosis, and preventing rapid worsening.

Intravascular Large B-cell Lymphoma Presenting as Pulmonary Ground-glass Nodules That Progressed Slowly over Several Months with No Overt Symptoms.

A 74-year-old man with no overt symptoms was referred for a chest computed tomography (CT) that revealed multiple bilaterally pulmonary ground-glass nodules (GGNs) with subtle changes in size over eight months. Surgical lung biopsies were performed in the left upper lobe. A pathologic study confirmed the intravascular large B-cell lymphoma (IVLBCL). This lesion was a nodule-like cluster of atypical cells, meaning that it had been localized for several months. Pulmonary IVLBCL may form focal lesions presenting as GGN on chest CT and progress slowly without apparent symptoms.

An autopsy case of intravascular large B-cell lymphoma showing a rapid transition to embolic strokes with occlusion of the major cerebral arteries.

Intravascular large B-cell lymphoma can induce central nervous system manifestations, including strokes, due to small-vessel occlusion caused by lymphoma cells. However, involvement in large-sized vessels is rare. Here, we present an unusual autopsy case of an 88-year-old man showing a rapid transition from multiple strokes due to small vessel occlusion, typical of intravascular lymphoma, to progressive embolic strokes caused by the occlusion of major cerebral arteries. Magnetic resonance angiography demonstrated the major cerebral arteries associated with those multiple progressive strokes, including the right posterior cerebral artery, left anterior cerebral artery, and right middle cerebral artery, but the detectability was poor. A random skin biopsy at the abdomen confirmed the diagnosis of intravascular large B-cell lymphoma. The patient died 106 days after hospitalization despite intensive treatment. An autopsy revealed broad liquefactive necrosis in the area governed by the major cerebral arteries and multiple small infarctions caused by intravascular lymphoma cells in the small-sized vessels. In addition, the major cerebral arteries showed multiple thromboembolism with partial organization and clusters of intravascular lymphoma cells. Notably, those cells were shown aggregated and attached along the vascular wall of the basilar artery, which might have caused focal hypercoagulation in the near vessels. This aggregation might have disseminated widely in the other major cerebral arteries. Moreover, the cluster of intravascular lymphoma cells in the basilar artery was positive for tumor necrosis factor α, and similar histopathology findings were observed in the splenic veins. However, the pathogenesis of this rare phenomenon involving these cells remains unknown. From a clinical perspective, we should consider the possibility that intravascular lymphoma cells may provoke similar progressive embolic strokes.

Distinct FDG PET/CT avidity among newly diagnosed intravascular large B-cell lymphoma patients: a descriptive observational study.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive B-cell non-Hodgkin lymphoma that poses a great diagnostic challenge due to its highly heterogenous clinical manifestations. Although 18F-fluorodeoxyglucose (FDG) is widely used as a diagnostic tool for patients suspected of having lymphoma, as it reveals FDG-avid lesions, the FDG avidity of IVLBCL has not been extensively characterized. Here, we present a comprehensive report of FDG avidity in IVLBCL and its association with clinicopathological features and survival. This descriptive observational study included consecutive patients aged at least 18 years diagnosed with IVLBCL in Peking Union Medical Hospital across 9 years. Among 50 screened IVLBCL patients, 42 had undergone 18F-FDG PET/CT to detect possible lesions for biopsy before pathological diagnosis; their FDG PET/CT (positron emission computed tomography, PET/CT) reports were retrospectively reviewed. The primary endpoint was the clinical description of FDG avidity of newly diagnosed intravascular large B-cell lymphoma and frequency. A total of 73.8% patients showed FDG-avid lesions, with a median SUVmax of 7.4 (range 1-27.7), which was lower than that for other aggressive lymphomas. Clinicopathological features were the same between the FDG-avid group and the non-FDG-avid group, except that the latter had a higher Ki-67 index (median 90% in the nonavid group vs. 80% in the avid group, P = 0.043). The overall survival rate was not different between the PET/CT groups. Our findings demonstrate that FDG PET/CT is a useful diagnostic tool for detecting FDG-avid lesions in IVLBCL patients. A random skin biopsy is essential for assisting in the diagnosis of IVLBCL, even for those with negative PET/CT.

Asian variant intravascular large B-cell lymphoma with highly suspected central nervous system involvement: A case report.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal lymphoma. In particular, the Asian variant of IVLBCL is characterized by hemophagocytic lymphohistiocytosis along with bone marrow involvement. However, central nervous system (CNS) involvement is uncommon in this variant compared to the Western variant. Here, we report a case of typical Asian variant IVLBCL with highly suspected CNS involvement and discuss the nature of the disease and its genetic aberration. CASE SUMMARY: A 67-year-old female patient complained of gradually worsening cognitive impairment. While hospitalized, she developed a high fever and showed marked bicytopenia. Intracranial imaging revealed a suspected leptomeningeal disease. Although no malignant cells were found in the cerebrospinal fluid (CSF), the protein and lactate dehydrogenase levels in CSF were increased. Bone marrow examination revealed an increased number of hemophagocytic histiocytes, and 18F-fluorodeoxyglucose (FDG) positron emission tomography with computerized tomography scan revealed increased FDG uptake in both adrenal glands, the liver, and the right ethmoid sinus. A tissue biopsy showed atypical large lymphoid cells with prominent nucleoli in the vessels, and the tumor cells were positive for CD20, BCL2, BCL6, and IRF4/MUM1. In addition, targeted sequencing identified MYD88, TET2, and PIM1 mutations. Consequently, we diagnosed the patient with the Asian variant of IVLBCL with highly suspected CNS involvement. CONCLUSION: Suspicion of IVLBCL and immediate diagnosis lead to timely treatment. Moreover, careful CNS examination at diagnosis is recommended.

Intravascular large cell B lymphoma presenting as central nervous system pseudo-vasculitis: A rare diagnostic challenge.

Intravascular large B cell lymphoma (IVLBCL) is a very rare subtype of aggressive non-Hodgkin B cell lymphoma characterized by intravascular proliferation of clonal B lymphocytes, classically associated with pulmonary and cutaneous disease and, less frequently, with central nervous system (CNS) involvement. Brain imaging findings are usually non-specific, with evidence of multiple vascular occlusions and stroke as non-specific multifocal abnormalities. We present an exceptionally rare case of IVLBCL in a patient with unexplained inflammatory syndrome with B symptoms and rapidly progressive neurological impairment, with multifocal hemorrhagic and tumefactive brain lesions seen on MRI. We suggest that in this clinical setting, the presence of tumefactive and hemorrhagic lesions should raise suspicion for IVLBCL and lead to the decision to perform a biopsy, which, nonetheless, remains the diagnostic gold standard.

Mononeuropathy multiplex as an uncommon presentation of intravascular lymphoma: A case report.

Key Clinical Message: Although intravascular lymphoma rarely presents with peripheral neuropathy, learning about this presentation can lead to timely diagnosis and improved prognosis in patients with intravascular lymphoma. Abstract: A 64-year-old man presented with asymmetric paresthesia and subsequent weakness of his feet and a 10 kg weight loss over 40 days. Electrodiagnostic studies revealed distal axonal sensory-motor polyneuropathy with ongoing axonal loss. A peroneal nerve biopsy showed intravascular proliferation of CD-20 positive lymphocytes, which suggested intravascular large B-cell lymphoma.

Lactic Acidosis: A Novel Presentation of Intravascular Lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma that preferentially grows intravascularly within the capillaries and often has a fatal course. Most of the patients have advanced and disseminated disease at the time of presentation. It is often arduous to make the diagnosis during the antemortem period due to the multitude of presenting symptoms. We report a case of aggressive IVLBCL which presented with a myriad of complaints and acidosis and had a rapid clinical decline.

Clinical Spectrum, Diagnosis, and Treatment Outcome in Individuals With Intravascular Large B-cell Lymphoma Affecting the Nervous System: A Case Series.

We treated five patients, three females, and two males, with intravascular lymphoma that affected the central or peripheral nervous systems. We reviewed their clinical, laboratory, neuro-imaging, and pathological data and treatment outcomes. The median age of onset was 60 years, with a range of 39 to 69 years. Three patients presented with central nervous system symptoms only, such as confusion, aphasia, seizure, stroke, and ataxia. Three patients presented with systemic lymphoma stage B symptoms, one with peripheral nervous system symptoms, and one with multi-organ failure. Brain imaging revealed white matter lesions, infarcts, hemorrhages, or combinations. Histology showed CD20-positive B-lymphocytes confined to small-size vessels in autopsy or biopsy specimens from the brain or muscle, confirming the diagnosis of intravascular large B-cell lymphoma (IVLBL). The patient with multi-organ failure had diffuse infiltration to the spleen, liver, and kidney. Three patients died within three to four months after the clinical presentation and were diagnosed at autopsy. The other two were diagnosed by biopsy and underwent chemotherapy CHOP-R (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone) or MTX (methotrexate)+Rituximab. The median survival of the chemotherapy patients was 17.5 months, compared to three to four months in those who did not receive chemotherapy. Although IVLBL has distinct pathological features, its clinical presentation can be variable. The patient's best chance for survival depends on the early pathological diagnosis and prompt, aggressive chemotherapy.