Lymphomas harboring concurrent IGH-BCL2/t(14;18)(q32;q21) and MYC/8q24 translocations, which are referred to as ‘‘double-hit’’ or ‘‘dual-hit’’ (DH) lymphomas, are a group of B-cell malignancies with a heterogeneous cytologic and histologic features. Rearrangements in MYC and BCL2 are extremely rare in B-LBL [4, 5]. Such double-hit B-LBL cases may emerge de novo or through transformation of follicular lymphomas, both of which have been described to have an aggressive clinical course and poor prognosis [2, 6].
In Subramaniyam et al.’s study, the patients with de novo DH B-LBL were adults with a median age of 59 years. They had complex chromosomal abnormalities, in addition to the BCL2 and MYC translocations. The reported median overall survival was 1.5 months (range, < 1–11 months) . Kelemen et al. also found the prognosis of B-LBL with a combined IGH/BCL2 and MYC translocation was poor, with a median survival of five months after the initial diagnosis (range,3–27 months) . The present case was alive at the last follow-up (2020.4.10, six months after the diagnosis).
As to those TdT-positive neoplasms derived from a minority of follicular lymphomas (FL) and characterized by blastoid morphology, the current recommendation in the WHO-2016 scheme is to classify them as B-LBL transformed from follicular lymphoma, which is exceedingly rare as well, with fewer than 10 reported cases. Interestingly, most of these cases were featured with MYC rearrangement in addition to IGH/BCL2 fusion [2, 6, 8–13]. Lymphoblastic transformation of FL is thus proposed to have occurred due to a gain of MYC rearrangement at an early stage of FL lymphomagenesis (immature B-precursor carrying t(14;18)(q32;q21) in the bone marrow),and then the expression of TdT has been interpreted as either a “dedifferentiation” to a lymphoblastic (pre-B-cell) stage of B-cell development or as a re-expression of TdT in B cells due to accumulated somatic hypermutations, a hallmark of germinal center B cells [1, 8–10, 12, 14, 15].
Although TdT is critical in discriminating between TdT-positive LBL and TdT-negative aggressive B cell lymphomas, exceptional cases of either DH/TH-HGBCL with an aberrant expression of TdT have been reported, which could be quite a diagnostic pitfall. Morphology, immunophenotype and key genetic profiles may facilitate the differential diagnose [8, 16, 17].
DH B-LBL should also be distinguished from entities like blastic plasmacytoid dendritic cell neoplasm (BPDCN), blastoid variant of mantle cell lymphoma (MCL), and myeloid neoplasm [3, 18, 19]. Among them, the reported BPDCNs have occurred mainly in elderly with a slight male predominance. The disease tends to involve multiple sites, most commonly the skin, followed by bone marrow and peripheral blood and lymph node. BPDCN is characterized by a diffuse, monomorphous infiltrate of medium-sized blast cells reminiscent of lymphoblasts or myeloblasts. The tumor cells express CD4, CD56, CD43, CD123 and lack expression of TdT, which distinct from LBL .Specific chromosomal aberrations are lacking, but complex karyotypes are common. Moreover, gene expression analysis of BPDCN reveals a unique signature, distinguished from those of myeloid and lymphoid acute leukemia .
As illustrated in the present case, strong expression of CD99 and TdT with lack of expression of CD20 in neoplastic cells has been used as features to support immaturity. Positive for PAX5 and CD79a demonstrated B-cell differentiation. The age of the patient, the location of the lesion, and tumor cells being negative for CD123 and CD56 were not supportive of BPDCNs. MCL-associated markers (CyclinD1, SOX11) were negative, and MPO was not detected, excluding acute myeloid leukemia or B/myeloid acute leukemia, and blastoid variant of mantle cell lymphoma, respectively. Finally, a diagnosis of DH B-LBL was established based on the morphology, immunophenotype, and FISH analysis.
Of note, components of FL might be missed due to the limitations of biopsy. Theoretically, we cannot definitely rule out the possibility of lymphoblastic transformation of FL in this case. However, considering relatively low FDG uptake values and the patient denying oncologic history, there is insufficient evidence (either histologically or clinically) to support the setting of FL. De novo DH B-LBL was thus preferred.
At present, few guidelines regarding DH B-LBL are available in the literature or in the WHO scheme. The optimal clinical management of such patients has not been fully established attributed to the small number of reported cases. Multicenter data is warranted to better make clinicalstrategies on patients with DH B-LBL.