Intravascular Diffuse Large B-cell Lymphoma Research Articles

A rare case report of Intravascular Diffuse Large B cell Lymphoma presenting as subcutaneous nodules

Intravascular diffuse large B-cell lymphoma is a rare entity where the large lymphoma cells are seen within the vessels. The difficulty is in its diagnosis, as it can have varied presentations affecting multiple systems. Here, we present the case report of a woman with intravascular diffuse large B-cell lymphoma who presented with subcutaneous nodules.

Multicenter Retrospective Study of Features and Outcomes of Patients with Intravascular DLBCL Treated at Academic Institutions within the United States

Multicenter Retrospective Study of Features and Outcomes of Patients with Intravascular DLBCL Treated at Academic Institutions within the United States

Differential Diagnosis of Suspected MYD88 Wild-Type Waldenstrom's Macroglobulinemia Includes Other Malignant and Non-Malignant IgM Secreting Entities, Including Frequent Cases of IgM Myeloma

MYD88 mutations are present in 95% of patients with Waldenstrom's Macroglobulinemia (WM), and permit diagnostic discrimination from other overlapping IgM-secreting B-cell malignancies. However, such diagnostic discrimination can often be difficult among suspected WM patients with wild-type MYD88 (MYD88WT), and can result in either diagnostic misclassification or mistreatment. We therefore examined a relatively large cohort of patients with suspected MYD88WT WM, and performed a systematic review of their clinical, pathologic and laboratory studies. Sixty-four patients with suspected MYD88 wild-type WM were identified. All had a monoclonal IgM protein, and bone marrow (BM) disease involvement. AS-PCR testing for MYD88 L265P mutation, and exclusion of non-L265P mutations by Sanger sequencing was performed to confirm MYD88WT status utilizing CD19-selected and unselected BM mononuclear cells (Xu et al, Blood 2013). WHO and WM consensus guidelines were used to establish clinicopathological diagnosis.Forty-six (71.8%) patients fulfilled WHO and WM consensus criteria for WM. Their median BM involvement was 37.5% (range 5-95%), serum IgM was 2,980 (range 160-9,000 mg/dL), and hemoglobin was 11 (range 4-15.5 g/dL). Sixteen (35%) and 13 (28%) had adenopathy and splenomegaly, respectively. Principal reasons for diagnosis included anemia (50%), and/or other cytopenias (13%), peripheral neuropathy (13%), adenopathy (8%), symptomatic hyperviscosity (5%), and renal failure (5%). At a median follow-up of 5.4 years, 31 (67%) patients required therapy. Notably, 7 (15.2%) MYD88WT patients were diagnosed with diffuse large B-cell lymphoma (DLBCL) during the follow-up period. Eleven (24%) patients died, 4 due to DLBCL transformation. Among the other MYD88WT patients, 7 (10.9%) had IgM multiple myeloma (IgM MM). Their median BM disease involvement was 60% (range 10%-80%), with a predominant plasma cell infiltrate. In 3(43%) patients, both clonal B-cells and plasma cells were detected, while clonal plasma cells alone were observed in the other 4 patients. FISH testing of BM mononuclear cells showed t(11;14) in 5 patients; t(14;16) in one patient; and normal cytogenetics in one patient. The median serum IgM level was significantly higher at 8,375 (range 2,530-12,000 mg/dL) versus MYD88WT WM patients (p=0.016). One (14%) patient had both adenopathy and splenomegaly. Principal reasons for diagnosis included anemia (100%), and symptomatic hyperviscosity (43%). With a median follow-up of 2.4 years, all patients required treatment and one died of myeloma. Findings consistent with marginal zone lymphoma (MZL) were observed in 6 (9%) patients. Their median BM involvement was 10% (range 5-25%), and three (50%) had detectable clonal B-cells by BM flow cytometry. Their median serum IgM level was 1,642 (95-2,800 mg/dL), and was not significantly different versus MYD88WT WM patients. Adenopathy and splenomegaly were present in 4 (67%) and 2 (33%) patients. With a median follow-up of 3.8 years, 4 (67%) required therapy, and all remain alive. For 3 (4.6%) patients, the findings favored a diagnosis of IgM MGUS with plasma cell infiltration. The median BM involvement for these patients was 5% (range 5-8%) with flow cytometry demonstrating clonal plasma cells. The median serum IgM level for these patients was 1,846 (range 1,262-2,390 mg/dL), and did not differ versus MYD88WT WM patients. With a median follow-up of 2.5 years, none progressed or received treatment, and are alive. In one patient, the findings favored the diagnosis of CLL while another patient had intravascular DLBCL. The serum IgM level was 1,822 and 355 mg/dL respectively. The BM disease burden was 5% in both patients. The CLL patient remains alive without treatment, while the patient with DLBCL required therapy and remains alive. No DLBCL transformation was observed among non-WM cases. Our findings show that up to 30% of suspected MYD88WT WM cases have an alternative clinicopathological diagnosis that includes both malignant and non-malignant entities. IgM MM was frequently present among suspected MYD88WT WM cases, and presented with very high serum IgM levels, symptomatic hyperviscosity and chr. 14 translocations. Patients with MYD88WT WM disease had a high incidence of DLBCL transformation that contributed to a third of deaths. The findings highlight the importance of diagnostic discrimination among suspected MYD88WT WM cases. DisclosuresTreon:Pharmacyclics: Consultancy, Research Funding. Castillo:Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

Asymptomatic pink nodules on a 28-year-old patient

Asymptomatic pink nodules on a 28-year-old patient

Pulmonary Intravascular Large B-cell Lymphoma in a Patient Administered Methotrexate for Rheumatoid Arthritis.

A 70-year-old woman with rheumatoid arthritis undergoing methotrexate (MTX) treatment presented with dyspnea and a subfever. Computed tomography (CT) revealed a diffuse minimal ground-glass appearance in both lungs and splenomegaly. The gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen. The lung biopsy specimen revealed the presence of CD20-positive atypical lymphocytes in the small pulmonary vessels. The patient was diagnosed with pulmonary intravascular diffuse large B-cell lymphoma (IVLBCL) and exhibited spontaneous regression after MTX was discontinued. This report describes a rare case of MTX-associated lymphoproliferative disorder expressing pulmonary IVLBCL.

Hepatic intravascular diffuse large B-cell lymphoma with synchronous metastatic colorectal adenocarcinoma

Hepatic intravascular diffuse large B-cell lymphoma with synchronous metastatic colorectal adenocarcinoma

Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge.

Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT) 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT) 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH) 1231 IU/L. Except for a positive DNA test for Epstein–Barr virus (EBV) infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL) is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH, and about 65% are anemic. About 20% have hepatic and renal dysfunction. The treatment consists of systemic chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (CHOP-R) and central nervous system prophylaxis. Retrospective data suggests that, with treatment, 51% to 82% of the patients achieve a complete remission and 27% to 56% are alive at 2-year follow-up. Conclusion. IVLBCL is a difficult diagnosis to make as the disease remains confined to the vascular lumen. It may be associated with certain viral illnesses, and this association needs to be explored further. It is important to consider this diagnosis in the appropriate settings because patients may achieve durable remissions with therapy.

Uncovering a Covert Enemy: Systemic AL Amyloidosis Associated With Intravascular Diffuse Large B-Cell Lymphoma

IntroductionAL amyloidosis, precipitated by the deposition of immunoglobulin light chains in various organs, is generally secondary to the benign or malignant proliferation of clonal plasma cells. Reviews from large amyloid centers show that approximately 2-3% of AL amyloidosis is associated with an underlying non-Hodgkin lymphoma (NHL). Of the non-Hodgkin lymphomas, lymphoplasmacytic lymphoma (LPL) is most commonly associated with systemic AL amyloidosis. Systemic NHL-associated AL amyloidosis tends to feature a high level of IgM paraproteinemia and a predilection for several different organ tropisms. Here we report the unique case of a 71-year-old male with an insidious course of hypotension and worsening renal failure of unknown etiology, who was ultimately diagnosed post-mortem with AL amyloidosis associated with an intravascular large B-cell lymphoma (IVLBCL). Case DescriptionA 71-year-old white male presented to the hospital after a fall. His medical history included type II diabetes, spinal stenosis, and a 30-pack-year smoking history. Over the past few months, he noticed a steady decline in functional status. On admission, he was hypotensive with bilateral 2+ pitting lower extremity edema. Laboratory evaluation revealed leukocytosis, anemia, and acute kidney injury with elevated creatinine and blood urea nitrogen. Urinalysis showed 30 mg/dL of protein, along with the presence of white and red blood cells and moderate bacteria. Enterococcus was subsequently cultured from the urine. A chest X-ray revealed small bilateral effusions. The patient was treated for urosepsis with antibiotics and vasopressor support in the intensive care unit. His hypotension improved initially, but over the next 3 weeks his course was complicated by recurrent episodes of hypotension, altered mental status, and worsening renal function. An exhaustive laboratory workup was negative for infection, and a transthoracic echocardiogram showed no significant findings. Further evaluation included a normal cortisol stimulation test and TSH level, but a serum protein electrophoresis showed 0.13 g/dL of monoclonal IgM lambda immunoglobulin (Figure A) with a urine protein electrophoresis showing a low level of lambda free light chains. Abdominal fat pad biopsy was negative for amyloid. The patient's condition continued to deteriorate, and he died on hospital day 29 with no clear diagnosis. Post-mortem examination revealed a CD20+, lambda restricted intravascular diffuse large B-cell lymphoma involving the kidneys, prostate, a cecal polyp, and lungs (Figure B). Sections of lung tissue revealed scattered areas of extracellular eosinophilic material that stained brick red with Congo red staining (Figure C) and displayed apple green birefringence under polarized light (Figure D). Similar findings in the heart and kidneys were consistent with systemic amyloidosis. Bone marrow analysis showed normal trilineage hematopoiesis with no evidence for involvement by lymphoma or plasma cell neoplasm. [Display omitted] DiscussionThis case exhibits the first reported association of two rare and diagnostically challenging disorders: intravascular large B-cell lymphoma (IVLBCL) and systemic AL amyloidosis. Patients with IVLBCL often present with nonspecific symptoms secondary to small vessel occlusion and subacute deterioration in performance status, as was the case with our patient. Our patient's underlying intravascular NHL with systemic AL amyloidosis proved difficult to diagnose with his low-level IgM paraproteinemia serving as the only clue to the cause of his illness. The negative fat pad biopsy added to the diagnostic difficulty, but was not surprising due to the low sensitivity of the test in detecting systemic amyloidosis. In addition, diagnosing intravascular lymphoma is difficult as patients present with nonspecific findings and often without lymphadenopathy, making post-mortem diagnosis common. Thus, this case sets a precedent for intravascular diffuse large B-cell lymphoma provoking the onset of systemic AL amyloidosis – a covert, morbid, and diagnostically challenging combination. Disclosures:No relevant conflicts of interest to declare.

FDG‐PET guided diagnosis of vaginal intravascular diffuse large B‐cell lymphoma

A 76-year-old woman presented with a 6-month history of progressive bilateral lower limb weakness, anorexia and weight loss and the recent onset of urinary and faecal incontinence with saddle anaesthesia. There was no palpable lymphadenopathy. Urgent magnetic resonance imaging (MRI) ruled out spinal cord or cauda equina compressive lesions. Blood tests showed a raised lactate dehydrogenase (LDH) and erythrocyte sedimentation rate with an IgM paraprotein of 7 g/l; immunoglobulins were otherwise normal. Cerebrospinal fluid analysis showed a reactive lymphocytosis on morphology and by flow cytometry. Bilateral bone marrow aspirates and trephine biopsies were normal. Computed tomography (CT) was entirely normal but a repeat MRI with gadolinium showed enhancement of lumbosacral nerve roots suggestive of infiltrative disease. [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) showed diffuse uptake in the uterus, cervix, vagina and numerous groups of lymph nodes throughout the body. The FDG-PET findings led to a vaginal mucosal biopsy, which showed subepithelial capillaries packed with neoplastic lymphoid cells (left) expressing CD20 (right), CD79a and CD5 with a Ki-67 index of 100%; the histological features were those of intravascular diffuse large B-cell lymphoma (DLBCL). At the time of diagnosis the patient had a performance score of 4 and she remained an inpatient. She received twice weekly intrathecal methotrexate, followed by one cycle of CVP (cyclophosphamide, vincristine and prednisolone combination chemotherapy). Rituximab was given 1 week later due to the high risk of tumour lysis syndrome, which has been reported previously. Unfortunately she developed neutropenic sepsis and died 2 weeks after diagnosis. Despite extensive prior investigations it was the results of the FDG-PET scan that eventually guided the biopsy site. The lack of solid lesions makes routine CT and MRI unhelpful in diagnosing this rare subtype of extranodal DLBCL; approximately 50% of patients are diagnosed at autopsy. This case highlights how the nonspecific and diverse symptoms, in the absence of significant lymphadenopathy, can result in critical delays in diagnosing this clinically aggressive lymphoma and how the use of FDG-PET scanning in such patients can guide the biopsy site.