High-Grade B Cell Lymphoma with Leukemic Presentation

Clinical history 

42-year-old man with no prior medical history had emergent neurosurgical decompression of a cervical spinal tumor after acute onset of paraplegia. At presentation, he was noted to have marked leukocytosis and was transferred to our institution for treatment of suspected acute leukemia.

Imaging 

No lymphadenopathy or focal PET+ lesions other than the cervical spine lesion.

Complete blood count and differential (reference range)

Peripheral blood and bone marrow morphology

Flow cytometry

Flow cytometric immunophenotyping of the bone marrow aspirate sample showed a large population of monotypic CD10+ B cells.

Immunohistochemical characterization of neoplastic lymphoid cells

Fluorescence in situ hybridization performed on bone marrow

Cytologic and flow cytometric examination of cerebrospinal fluid showed involvement by B cell neoplasm. 

Final diagnosis

High-grade B cell lymphoma with MYC and BCL2 rearrangements with leukemic presentation and central nervous system involvement.

Case Discussion

The pathologist’s view
B cell neoplasms with blastoid morphologic features are further subclassified into B lymphoblastic leukemia/lymphoma, high-grade B cell lymphoma, NOS, and double-hit B cell lymphoma, according to the 2016 WHO classification (1). Using the World Health Organization (WHO)-recommended diagnostic algorithm, the distinction between B lymphoblastic leukemia/lymphoma and the latter two entities is made by assessing the presence or absence of terminal deoxynucleotidyl transferase (TdT) expression.

This patient presents with primarily leukemic, non-nodal disease with numerous circulating blastoid neoplastic cells. Given the clinical presentation and morphologic features, the major differential diagnosis in this case is de novo B lymphoblastic leukemia/lymphoma. This morphologic conundrum is not new; before the age of routine phenotyping confirmed that circulating Burkitt lymphoma cells are mature B cells, they were considered “L3 blasts.” For the pathologist, differentiating mature from immature lymphoid cells is a significant first step in the diagnosis, for which ancillary studies are essential. In this case, initial flow cytometry (FCM) immunophenotypic studies demonstrated markers that support a mature lymphoma cell phenotype: bright CD45 and presence of uniformly bright surface CD20 expression with surface light chain restriction are features not typical of B-ALL. However, FCM also showed dim TdT expression. Given FCM support for a more mature immunophenotype, we performed additional FISH studies that confirmed the presence of concurrent MYC and BCL2 rearrangements and established a diagnosis of high-grade B cell lymphoma with MYC and BCL2 rearrangements (previously “double-hit” lymphoma). Notably, these ancillary FISH studies are not routinely recommended in patients with de novo B-ALL and therefore classification as B lymphoblastic leukemia/lymphoma, NOS based on TdT expression may have led to omission of these studies from the diagnostic workup. In the example presented here, the discrepancy between TdT expression as detected by FCM versus immunohistochemistry is likely attributable to the higher sensitivity of FCM.

There is little guidance on whether TdT expression trumps maturity markers for classification of B cell neoplasms; however, TdT expression has been reported in de novo high-grade B cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements, in “transformed” aggressive B cell lymphomas in patients with known follicular lymphoma, and in other mature B cell lymphomas that acquired TdT expression at relapse (2,3). Awareness of this phenomenon and appropriate disease classification is clinically relevant because it has direct prognostic and management implications (2).

The hematologist’s view

Double trouble: Leukemic phase and CNS involvement in double-hit lymphoma.

The management of patients with high-grade B cell lymphomas with translocations involving MYC and BCL2 or BCL6, colloquially referred to as “double-hit lymphomas” (DHL), is doubly challenging because of their aggressive clinical presentation and poor long-term prognosis after standard immunochemotherapy.

This case is particularly unique because of the one-two punch of a leukemic presentation and central nervous system (CNS) involvement at time of diagnosis. Though bone marrow involvement is relatively common in DHL, leukemic phase presentation with circulating lymphoma in the peripheral blood occurs in only 12 percent of patients and is associated with inferior overall survival (4). Double-hit status and leukemic presentation are likely both associated with risk of secondary CNS involvement (5), found in approximately 10 percent of DHL at diagnosis and also associated with inferior overall survival (4).

How should this critically ill patient be managed in the acute setting? They should be admitted to an intensive care unit for close monitoring. Risk for spontaneous tumor lysis syndrome is high; telemetry to watch for arrythmias, allopurinol, and brisk continuous intravenous fluids as tolerated are important baseline interventions. Rasburicase is likely needed to rapidly lower uric acid levels. Renal replacement therapy may also be required to support the patient through the immediate crisis. Symptomatic leukostasis is typically associated with acute leukemias secondary to large circulating leukemic blasts plugging microvasculature. It is unclear whether this phenomenon can happen with circulating lymphoma cells but, with such significant hyperleukocytosis, we would consider leukapheresis, particularly if the patient has respiratory, cardiac, or nervous system symptoms. Prephase intravenous corticosteroids can be used for cytoreduction while finalizing a definitive treatment plan.

After stabilizing this patient, which systemic therapy regimen should be used? Retrospective (4,6,7) and single-arm prospective (8) studies suggest the superiority of intensive immunochemotherapy regimens such as dose-adjusted rituximab, etoposide, prednisone, vincristine, and cyclophosphamide (DA-R-EPOCH) over standard therapy (R-CHOP). DA-R-EPOCH is an appropriate choice for most DH-L (6), but does not contain agents that adequately penetrate the CNS. Although CNS prophylaxis may include the addition of intrathecal (IT) or high-dose systemic methotrexate depending on the treating institution (9), this patient presented with CNS involvement at diagnosis and requires a strategy to rapidly clear disease in his bone marrow and cerebrospinal fluid (CSF).

The combination of rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with intravenous methotrexate and cytarabine (R-hyperCVAD) is commonly used in the treatment of B cell lymphoid neoplasms that carry a high risk of CNS involvement or relapse (10). This intensive regimen can be difficult for older patients to tolerate, but comes with the benefit of adequate CNS penetration by the inclusion of systemic methotrexate and cytarabine on “even” cycles. If this patient has adequate performance status, we recommend eight cycles of R-hyperCVAD, adding IT chemotherapy with each cycle. For a less fit patient, six cycles of DA-R-EPOCH with IT chemotherapy and mid-cycle systemic methotrexate (11) would be another effective choice.

How should this patient be monitored on therapy? Response assessment during frontline immunochemotherapy in DLBCL is done with a PET/CT scan at baseline, at an interim timepoint during treatment, and at end of treatment to assess for reduction in systemic disease (12). This alone would not be adequate for this patient because he has disease sites not easily detectable by PET/CT. He should have magnetic resonance imaging of the CNS and flow cytometric and cytopathologic assessment of CSF with each dose of IT chemotherapy. He should also undergo bone marrow assessment during and at the end of treatment to ensure marrow involvement has cleared. Flow cytometry on peripheral blood can also be used for disease monitoring. The goal of therapy would be to achieve a complete response (CR) on imaging studies, in the CSF, and in the bone marrow at end of treatment.

Should this patient receive consolidative therapy if he is able to achieve a CR? Generally, patients with DHL who achieve a first CR after intensive immunochemotherapy have good outcomes and do not benefit from consolidative high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT). (13). However, this patient has secondary CNS lymphoma. Outcomes of patients with systemic lymphoma who suffer primary CNS lymphoma (14) or CNS relapse (15) and are consolidated with HDC and ASCT after induction therapy are encouraging. Notably, these studies and others favor the inclusion of thiotepa in the ASCT conditioning regimen for better CNS penetrance. We recommend this patient receive an ASCT with thiotepa-based conditioning in his first CR to maximize chances of long-term remission.

This patient faces numerous hurdles in the short- and long-term that could easily prevent him from achieving a cure. Treatment-refractory or relapsed disease would mean a dismal prognosis. Additional treatment strategies and novel agents are needed for DHL management, and we eagerly await the results of clinical trials in progress.

Read on to discover our other lymphoid cases...

Case 1: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma – Accelerated Phase
Case 2: Lymphoma-Driven Hemophagocytic Lymphohistiocytosis
Case 4: Low-Grade Follicular Lymphoma with Increased Proliferation Index