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.