FL is an indolent NHL. It arises from germinal centre B cells, and its pathogenesis is incompletely understood. The hallmark is the t(14;18) resulting in bcl2 overexpression; however, it is seen only in about 85% of the cases [11]. Its natural history and prognosis is variable with some patients having waxing and waning painless lymphadenopathy over years while some patients present with rapidly growing lymph node masses or disseminated disease necessitating immediate treatment to relieve compressive symptoms or cytopenias [12, 13].
HT of FL refers to evolution of the low-grade lymphoma to a high-grade lymphoma usually, DLBCL. Incidence of HT is about 1 – 4 % per year [5,6,7]. Clinically patients present with B symptoms (Weight loss, fever, night sweats), rapidly progressive lymphadenopathy, cytopenias, extra nodal involvement, effusions and elevated LDH or hypercalcaemia. It usually portends a poor prognosis. Before the era of rituximab, median survival was around 2 years; however, in the current era, the median survival of around 5 years has been reported [14, 15].
The exact pathobiology of HT is unknown. Two hypotheses are generally considered—divergent evolution of two distinct tumour populations from the original progenitor cell or emergence of an aggressive subclone from FL cells. Transformed FL usually retains the original t(14;18) in addition to additional abnormalities. Mutations of TP53 gene and bcl6 are noted in significant number of cases [16,17,18]. Kridel et al. evaluated samples of transformed FL by gene expression profiling and identified that about 80% transformed FL are germinal B cell type compared to 16% that are activated B cell type and about 24% of them were of double-hit type implying they had mutations in both bcl6 and c-myc genes. However, they could not predict an adverse outcome based on these features [19].
Re-biopsy of a node with suspected HT is the gold standard for diagnosis. The transformed lymphoma may have a germinal centre pattern, but with large cells effacing the follicular pattern. Risk factors for transformation include of higher FLIPI score at diagnosis and grade 3 FL [20]. PET-CT scanning may also aid in diagnosing transformation as transformed FL may have higher SUV uptake. PET-CT also aids in selecting lymph node groups for biopsy [21]. Presence of B symptoms, elevated LDH, beta-2-microglobulin or decreased albumin are also associated with higher risk of transformation [7, 14]. The use of maintenance rituximab may lead to lower rates of transformation [5].
The appropriate management of transformed FL is individualized. Casulo et al. formulated an algorithm for the management of transformed FL. They suggested the confirmation of HT with a biopsy from an FDG-avid lymph node group. In case of a young fit patient, they recommend an anthracycline-based chemotherapy regimen with rituximab, if previously not exposed, followed by consolidation with autologous stem cell transplant (ASCT) or salvage chemotherapy followed by ASCT, if previously exposed to anthracyclines. In older patients, if fit, they recommend considering a similar regimen as in young patients followed by consolidation with radioimmunotherapy or, if unfit, only palliative treatment with lenalidomide [22].
Our patient was initially treated with chlorambucil and prednisolone for 5 years. She was not exposed to anthracyclines or rituximab. She was offered treatment with R-CHOP chemotherapy regimen at transformation. However, in view of financial constraints, she received only 6 cycles of CHOP without rituximab. She had good clinical response; however, she defaulted without a follow-up scan to record the exact response to treatment. ASCT could not be planned as she defaulted. She then presented after 3 years with a diagnosis of follicular lymphoma. In the reported literature, most cases of transformed FL usually relapse with the higher-grade histology. Our case is unique in that at relapse, the histology was of the lower-grade FL.
Xu et al. described two cases of DLBCL which after successful treatment relapsed with FL. In one case, the diagnosis at relapse was pure FL, and in the second case, it was composite lymphoma with FL and DLBCL components [23]. This is a very rare event. We could not find any other cases in which a high-grade lymphoma relapses as follicular lymphoma after treatment. Our case is unlikely to be a case of composite lymphoma as two sites of disease were biopsied at two time points (2015 and 2018) and did not reveal different morphological subsets of disease, i.e., both FL and DLBCL.
A PET-CT should ideally have been done, and this would have helped us identify a lymph node group that would probably contain transformed FL. However, this is unlikely as two sites of disease were biopsied both at initial transformation and at relapse. The probable explanation for this phenomenon is that a subclone of cells transformed to DLBCL and this subset got eliminated with the anthracycline-based chemotherapy. This is a hypothesis derived from extrapolation of the work done by Casulo et al. [22]. It is to be noted that after 6 cycles of anthracycline-based chemotherapy in 2015 at the time of transformation, even though the patient had significant response, residual lymph nodes were palpable. A biopsy at this time point would have helped us know the exact kind malignant cells left after chemotherapy. The low-grade FL cells were probably not eliminated and thus may have contributed to relapse. This is understandable as DLBCL is usually considered a curable lymphoma and FL is not. This hypothesis can be confirmed by gene expression profiling of tissue samples of the biopsy specimen at diagnosis, transformation, post-treatment and relapse.
