Discussion
In the Western world, IVLBCL is a disease of the elderly, with the median age of diagnosis being 70 years1,2. It is classically poorly understood and appreciated as an aggressive malignancy with dismal outcomes. In historical cohorts, most cases were diagnosed postmortem, although we are increasingly learning more about this elusive disease. IVLBCL is characterized by the exclusive growth of malignant cells in medium-sized blood vessels. Figure 1 is a composite of photographs of our patients’ biopsy specimens, which shows the presence of lymphoma cells within the vasculature of affected organs (skin, liver, thyroid, and bone marrow). As described in our patients, distinct lymphomatous masses are usually not seen3. Symptoms are caused by occlusion of blood vessels, and thus extravascular infiltration of tissues does not occur. IVLBCL commonly presents with fever, weight loss, and deterioration of functional status, which confounds early diagnosis due to the generality of these symptoms. Involvement of specific organ vasculature such as the G.I. tract, endocrine organs, or lungs can produce focal symptoms4,5. The heterogeneity of its presentation further complicates the clinicians’ ability to reach this diagnosis. Traditional diagnostic methods such as PET/CT scans can be inconclusive given the exclusive presence of lymphoma cells inside the vessels. However, focal organ involvement, including bone marrow in cases with heavy infiltration of blood vessels, may be visualized6. In patients with neurological signs and symptoms, MRI brain can show non-specific changes in white matter4,6. As detailed with our patient cohort, bone marrow biopsy, random skin biopsies, or biopsies of specific organs in cases with focal symptoms compose the basis of effective diagnosis7.
IVLBCL has a complex pathophysiology that is not well understood. Malignant cells are invariably positive for CD20; however, T-cells markers such as CD5 can be positive as well. Most cells exhibit a non-germinal center phenotype (BCL-2 and MUM1 positive, CD10 and BCL-6 negative)2,8. Loss of ICAM-1 and integrin β1 expression has been described as a reason for the lack of tumor invasion into surrounding tissues7. Cytogenetics is complex, and implicit genetic mutations have not been identified. An interesting finding in two of our cases was the active use of immunosuppression at diagnosis. In case 2, our patient was on adalimumab for inverse psoriasis, while the patient in case 4 was on tacrolimus/MMF for renal transplant. Withdrawal of immunosuppression was used as an adjunct to chemo-immunotherapy in case 4, which resulted in complete remission of the disease. This raises the question as to whether IVLBCL shares a common underlying mechanism with post-transplant lymphoproliferative disorder (PTLD). It remains unclear if any other comorbidities play a significant role in IVLBCL development or prognosis. Patient comorbidities are listed in detail in table 1.
Despite increasing awareness, IVLBCL remains a rare disorder, and prospective studies regarding treatment regimens and outcomes are lacking. Two out of our four patients had good outcomes with anthracycline-based therapy. In case 1, our patient achieved remission with only one dose of dose-reduced R-EPOCH despite being diagnosed six months from symptoms onset. This case suggests a potentially more indolent cohort that may benefit from aggressive chemo-immunotherapy despite a delayed diagnosis. Outcomes of cases 1 and 4 are similar to reports in the literature, suggesting a median overall survival of 105 months and 5-year survival of 53% with the use of anthracycline-based regimens in IVLBCL6. The addition of rituximab has been associated with improved rates of complete remission and progression-free survival8,9. These outcomes are similar to those seen in DLBCL NOS1. Case 1 contrasts with case 2, where the patient presented with a similar duration of symptoms but rapidly developed malignancy-related complications and died. The time course of this case coincides with the historical portrayal of IVLBCL as an aggressive and fatal disease. The disease is thought to have been too far advanced in this case to allow timely receipt of cancer-directed therapy. Case 3 demonstrated focal end-organ involvement with IVLBCL and with remission achieved upon resection. This patient continued to be in remission despite not receiving any systemic therapy. Maintenance of remission in this case with simple resection of the involved organ may represent a novel approach to managing patients with single organ involvement with IVLBCL. This approach is, however, not an option for more commonly observed bone marrow involving variants. Stem cell transplant after initial induction remains a treatment option, although cannot be offered to many patients due to advanced age at diagnosis and poor ECOG status4. Despite the vast variations in presentation and natural histology of the disease even noted within our case series, the observed potential for improved outcomes hinges on timely diagnosis and early initiation of systemic therapies when indicated.