Incongruent lymphomas are 2 types of histologically distinct but coexisting in vivo, which can occur in at least 2 different anatomical sites of the body, and are most often seen in peripheral lymph nodes with aggressive lymphoma findings and inert bone marrow findings. In the past, the diagnosis of indolent lymphoma was mostly based on histologic findings alone, but now the diagnosis can also be made based on flow cytometry and molecular biology. Because of the rarity of indolent lymphoma, there is no consensus on its incidence, clinical staging, or treatment strategy. In this article, we review the current literature on indolent lymphoma and discuss the prognosis and treatment strategies.
Introduction
Bone marrow involvement is the primary basis for the diagnosis of inert B-cell lymphoma and, as reported in most studies, is also present in approximately 10-15% of diffuse large B-cell lymphomas, often predicting a poor clinical prognosis. Although peripheral lymph node findings are consistent with bone marrow findings in most cases of lymphoma with bone marrow involvement, there are cases where findings are histologically inconsistent.
It is important to note that inconsistent lymphoma needs to be distinguished from compound lymphoma, which usually refers to lymphomas of different tissue types detected at different anatomic sites, and transformed lymphoma, which usually refers to lymphomas of 2 or more definite tissue types detectable in the same lymph node, and transformed lymphoma, which usually refers to the conversion of inert lymphomas to aggressive lymphomas within the disease process. It is mostly seen in diffuse large B-cell lymphoma.
Diagnosis of Inconsistent Lymphoma
The diagnosis of indolent lymphoma based on histological findings is difficult because there are no uniform criteria. Cell morphology is the main basis for diagnosis, while immunophenotypic and molecular biological characteristics of tumor cells are of great help. With the development of B-cell clonality detection techniques such as immunohistochemistry, flow cytometry, and PCR in recent years, the diagnosis of indolent lymphoma has become relatively easier and easier.
By using genomic techniques, researchers have found that consistent myeloid-involved samples have clear genetic sequences with a low probability of chromosome 7 polysomy or chromosome 6q deletion.
Because there are too few samples with inconsistent bone marrow involvement, it is currently not possible to compare molecular biological differences between them and samples with uninvolved bone marrow. In terms of clonality analysis of incongruent lymphomas, some findings found that two-thirds of cases were clonally associated, some of which were benign pooled lymph nodes, some of which were bone marrow biopsies finding incongruent inert disease, possibly due to conversion of initial inertia to aggressiveness, and the remaining one-third showed a different type of clonality, which implies that incongruent bone marrow involvement may be overestimated (as shown in Figure 1).
For lymph node findings of diffuse large B-cell lymphoma, bone marrow involvement may be histologically consistent with large B-cell infiltration or inconsistent with small B-cell infiltration, the latter suggesting an inert B-cell lymphoma on bone marrow examination. In contrast, histologically inconsistent bone marrow involvement can be clonally related or clonally unrelated compared to intra-nodal diffuse large B-cell lymphoma in molecular biology.
Prognosis of Incongruent Lymphoma
It has been found that overall survival is worse in diffuse large B-cell lymphoma with consistent bone marrow involvement compared to inconsistent bone marrow involvement. In addition, the presence of a large large B-cell infiltrate in the bone marrow suggests a poor overall survival.
There is debate about the recurrence of inconsistent myeloid involvement after initial treatment. A small study that included 13 samples of incoherent bone marrow tissue showed that 7 patients developed relapses, 6 of which occurred within the first 2 years after diagnosis, and all relapses were of the type of primitive large cell lymphoma and not recurrent inert bone marrow disease.
In contrast, other cases reported the opposite result, with a higher percentage of late relapses, more than half of which occurred 2 years after diagnosis, and 7 of the 10 relapsed cases had histologically inert disease. Prior to the advent of rituximab therapy, it was difficult to determine the rate of recurrence of inconsistent disease after diagnosis and whether the clonal type was aggressive or inert after recurrence.
In contrast, after the advent of rituximab therapy, it was found that the majority of relapsed disease types were predominantly aggressive large B-cell lymphomas, and most relapses occurred within the first 2 years after diagnosis.
A recent retrospective analysis of included patients with diffuse large B-cell lymphoma receiving rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP therapy) found that those with consistent bone marrow involvement had poorer overall and progression-free survival compared with those with no bone marrow involvement; those with inconsistent bone marrow involvement had poorer progression-free survival compared with those with no bone marrow involvement, but overall survival was similar.
Similarly, a study that included 133 cases of diffuse large B-cell lymphoma treated with R-CHOP therapy showed that consistent, but not inconsistent, myeloid involvement was associated with poorer overall and progression-free survival. Therefore, inconsistent bone marrow involvement does not serve as an independent prognostic indicator of overall survival or progression-free survival.
Inconsistent bone marrow involvement in inert B-cell lymphoma
Based on current case report statistics, inconsistent bone marrow involvement is generally rare in inert lymphoma, with follicular lymphoma being the predominant type reported, with most bone marrow biopsies being diffuse large B-cell lymphoma and possibly suggestive of being due to transformed disease.
Clinical role of noninvasive PET imaging
A number of studies currently suggest that fluorodeoxyglucose positron imaging (FDG-PET) is highly sensitive in predicting bone marrow involvement in aggressive non-Hodgkin’s lymphoma and less sensitive in predicting bone marrow involvement in follicular lymphoma.
Recently updated guidelines recommend that for most routine stages of diffuse large B-cell lymphoma, routine bone marrow biopsy is not necessary if PET-CT is negative for bone marrow involvement. However, for diffuse large B-cell lymphoma with inconsistent bone marrow involvement, FDG-PET activity in myeloid inert lymphoma is low and does not allow accurate detection of inconsistent disease. Therefore, in some cases of suspected inconsistency, if hematocrit is found, a bone marrow biopsy is required even if the PET-CT examination is negative. The detailed diagnostic process can be referred to Figure 2.
Treatment strategies for indiscordant lymphoma
Currently, there are no randomized controlled trials as well as prospective studies on the treatment strategy for diffuse large B-cell lymphoma in nodes with incoherent inert bone marrow involvement or inert lymph node lymphoma with incoherent aggressive lymphoma with bone marrow involvement.
In general, most diffuse large B-cell lymphoma with inert lymphoma with inconsistent myeloid involvement is often treated with an anthracycline-based regimen such as R-CHOP, and inert myeloid involvement does not affect clinical prognosis in patients receiving aggressive chemotherapy.
For patients with inert lymph node lymphoma and inconsistent aggressive lymphoma on bone marrow biopsy, anthracycline-based regimens are available, but fewer studies are available. The effectiveness of autologous stem cell transplantation for indolent disease cannot be evaluated at this time because the treatment strategy for transformed lymphoma with autologous stem cell transplantation after the first remission period is not well established.
Patients newly diagnosed with diffuse large B-cell lymphoma with consistent bone marrow involvement have previously been reported to be at risk for CNS involvement or relapse, and therefore this group of patients requires periodic cerebrospinal fluid checks to assess for lymphoma involvement and the efficacy of prophylactic CNS-directed therapies. In contrast, patients with intra-nodal diffuse large B-cell lymphoma with incoherent inert bone marrow involvement are not at risk for CNS involvement or relapse and therefore do not require regular cerebrospinal fluid examinations.
In summary
Diffuse large B-cell lymphoma with consistent bone marrow involvement predicts a poorer clinical prognosis and overall survival than bone marrow non-involvement, whereas a new diagnosis of diffuse large B-cell lymphoma with inconsistent inert B-cell lymphoma bone marrow involvement does not have a serious negative impact on clinical prognosis.
FDG-PET, despite its obvious role in diagnosing diffuse large B-cell lymphoma with consistent myeloid involvement, is not as sensitive in detecting inconsistent myeloid involvement. Based on the results of the limited immunoglobulin gene recombination studies available, the majority of the tissue incongruent lymphomas are clonally associated. Subsequent studies will focus on the molecular biology of the incongruity as the main direction and progressively explore the best options for treatment.