Case study 45.1
A 62-year-old woman presents to the hospital with abdominal pain and leg swelling and is found to be in renal failure with bilateral hydronephrosis. Cystoscopy reveals an external mass compressing the bladder, and biopsies show bladder wall infiltration by a diffuse population of uniform and medium-sized lymphoid cells with slightly irregular nuclei, fine chromatin, small nucleoli, and small amounts of cytoplasm. Immunoperoxidase studies reveal that the neoplastic cells are CD20-positive B-cells that co-express CD10, B-cell lymphoma-6 (BCL6), and BCL2; the neoplastic cells are negative for CD5, CD30, CD34, and TdT. The Ki67 proliferation index is approximately 95% in the neoplastic cells. Staging studies reveal advanced-stage disease with extranodal involvement, including bone marrow and bladder wall involvement. Her lactate dehydrogenase (LDH) level is elevated at 764 U/L (ULN 231 U/L).
In 2008, the WHO created a provisional diagnosis for lymphomas that shared features between, but were distinctive from, BL and DLBCL, a so-called gray zone lymphoma or B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (B-UNC/BL/DLBCL). These lymphomas differ morphologically from DLBCL in that the neoplastic cells are generally of intermediate to large, rather than large, size with a high proliferation rate as expressed by the Ki67 index; they are also uniformly CD10 positive by immunohistochemistry. They differ from BL in that the cells are more variable in size, are often BCL2 positive and can be BCL6 variable, and have a slightly lower Ki67 index (≤90%). These lymphomas have historically been called many different things, including “non-Burkitt,” “atypical Burkitt,” and “Burkitt-like” lymphoma, making them difficult to study. Although this category is defined by morphologic and genetic features, gene expression profiling (GEP) has likewise identified a group of lymphomas with an expression profile between those of BL and DLBCL. This group is not synonymous with B-UNC/BL/DLBCL, but the two do overlap, suggesting that B-UNC/BL/DLBCL is not a unique entity but rather a group of distinct lymphomas, including true BL, DLBCL, and unclassifiable lymphomas, which require further characterization. Although potentially heterogeneous, these lymphomas generally carry a poor prognosis with high International Prognostic Indices (IPIs) and frequent extranodal sites; this characterization may be driven by a few particularly poorly behaving subtypes of this diagnosis.
• What additional pathologic testing would you ask for given this diagnosis?
Since 1993, the IPI has been the best tool to predict how patients with aggressive non-Hodgkin’s lymphoma (NHL) will do following multiagent, anthracycline-containing chemotherapy, and later immunochemotherapy. It separates low-, intermediate-, and high-risk disease based on a patient’s age, LDH, performance status, number of extranodal sites of disease, and disease stage, and correlates closely with response to therapy, progression-free survival (PFS), and overall survival (OS). Although we have discovered additional prognostic factors in these diseases, none have proven to be more powerful than this index. However, as we learn more about the genetic events associated with these lymphomas, we have developed new tools to identify patients with particularly high-risk aggressive NHL. Specifically, detection of multiple concurrent chromosomal translocations, most often involving the MYC–8q24 and the BCL2–18q21 loci, has been shown to identify a particularly high-risk group of patients with aggressive B-cell NHL with a poor prognosis. While the partner locus for BCL2 translocations is almost always the immunoglobulin heavy-chain (IgH) locus on chromosome 14, MYC translocation may involve this or other loci. This observation was first noted in pathology samples from patients with small noncleaved, non-Burkitt (Burkitt-like) lymphoma, many of whom would fall within the provisional WHO category of B-UNC/BL/DLBCL. Within this group, patients with the dual translocations of MYC and BCL2 had a poor prognosis with no patients alive at one year in one series. This was in contrast to patients with an isolated MYC translocation or other cytogenetic abnormalities, of which 32% and 25% were alive at 2 years, respectively. Further investigation of these translocations in DLBCL found that dual translocations are present in up to 12–14% of cases, and are similarly associated with a poor prognosis. B-UNC/BL/DLBCL appears to be enriched for these dual translocations, or “double-hit” lymphomas, with approximately 30–45% of cases co-harboring MYC and BCL2 translocations. While the majority of double-hit lymphomas do fall into this diagnostic category, not all B-UNC/BL/DLBCL are double-hit lymphomas. Double-hit lymphomas with this histology appear to have a particularly poor prognosis, even compared to double-hit DLBCL, with a median OS of 4 months compared to 3 years, respectively.
The overexpression of MYC and BCL2 or BCL6 can be accomplished by mechanisms other than translocations involving a gene with a constitutively active promoter like the immunoglobulin loci, and data suggest that these mechanisms are likely biologically and prognostically relevant. The development of reproducible and accurate MYC immunochemical stains has allowed for the identification of lymphomas that overexpress MYC and correlate highly with the presence of a MYC translocation. Furthermore, the presence of high MYC staining by immunohistochemistry was associated with inferior outcomes among DLBCL treated with R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone). More recently, a number of independent groups have investigated the use of both MYC and BCL2 immunochemical stains to identify patients with overexpression of both of these proteins. When using prespecified values to define overexpression, each group was able to identify 70–90% of patients with cytogenetically confirmed dual translocations, which were associated with an expectedly poor prognosis. Dual IHC positivity, however, identified additional patients without dual translocations but with increased staining, or overexpression, of both MYC and BCL2, and these patients likewise had a poor prognosis similar to lymphomas with dual translocations or intermediate between these lymphomas and DLBCL without MYC and BCL2 translocations or protein overexpression. While fluorescent in situ hybridization (FISH) cytogenetics identifies double-hit lymphomas in 12–14% of DLBCL, dual IHC-positive lymphomas appear to account for approximately 30% of DLBCL. Immunohistochemical analysis of protein expression, then, may represent a more biologically relevant measure associated with prognosis than a specific type of genetic aberration. DLBCL with an activated B-cell (ABC) phenotype is known to be associated with a worse prognosis compared with germinal center B-cell lymphomas (GCB), and the ABC phenotype, while rarely harboring a MYC and/or BCL2 translocation, is enriched for MYC and BCL2 overexpression and dual IHC positivity, and perhaps this reflects the worse prognosis in this group. Interestingly, dual IHC positivity and dual translocations in these studies appear to be prognostically significant independent of IPI, which is in opposition to what has been previously reported. Because these immunohistochemical and cytogenetic changes are associated with older age, more advanced disease with frequent extranodal involvement, and an elevated LDH, the number of patients with immunohistochemical and/or cytogenetic double-hit lymphomas and a low IPI is small, making these data difficult to interpret. It should be noted that the prognostic significance of dual IHC positivity has not been studied specifically in B-UNC/BL/DLBCL.
FISH cytogenetics for a MYC and BCL2 translocation are ordered and reveal a t(8;14) and a t(14;18), consistent with a double-hit lymphoma.
• What front-line therapy would you offer this patient?
There has been no systematic investigation of the treatment of B-UNC/BL/DLBCL or double-hit lymphomas. Prior to the creation of the 2008 WHO provisional category and the discovery of the prognostic impact of these multiple chromosomal translocations, many of these lymphomas often were described as B-cell lymphomas with high-grade features, or Burkitt-like lymphomas, and front-line treatment consisted of a number of therapeutic regimens of varying intensities chosen at the discretion of the treating physician. These regimens included Burkitt-like therapies like modified Magrath with R-CODOX-M/IVAC (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone, methotrexate, ifosfamide, and cytarabine), R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, adriamycin, dexamethasone, methotrexate, and cytarabine), dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and R-CHOP. No prospective data exist to support the use of more intensive chemoimmunotherapy regimens over R-CHOP, the gold standard regimen for DLBCL. However, three groups have looked at the impact of intensified chemotherapy regimens on outcomes specifically for B-UNC/BL/DLBCL in a retrospective fashion. These analyses are limited in that they are retrospective, involve patients diagnosed prior to the creation of this diagnostic category (and so likely included patients whose disease did not meet the criteria for this category), and are of small size. Each did show, though, that a more intensive regimen (R-hyper-CVAD, R-CODOX-M, dose-adjusted R-EPOCH, or a slightly altered modified Magrath regimen) resulted in an improvement in overall response rate (ORR) and PFS over patients who received R-CHOP +/− central nervous system (CNS) prophylaxis (ORR 86% versus 57%, 4-year PFS approximately 50–65% versus 0–30%).
Another group retrospectively examined the outcomes following intensive therapy (R-hyper-CVAD or R-CODOX-M) compared with R-CHOP in 53 patients with aggressive B-cell lymphoma with high-grade features whose MYC cytogenetic status was known. Interestingly, in this group only, just over half had a high-risk IPI and well under half had involvement of more than one extranodal site, suggesting this was a lower-risk group than has previously been described for B-UNC/BL/DLBCL. Among all patients, there was no difference in overall survival between R-CHOP and more intensive regimens, with approximately 50–60% of all patients alive at 4 years; this relatively good overall survival rate is widely different from what has been reported in other series and perhaps reflects that this is a better-risk group than other B-UNC/BL/DLBCL cohorts. While not significant, there was a trend toward patients with a MYC translocation doing worse, with approximately 40% alive at 4 years. Within the group of patients with a MYC translocation, those treated with higher-intensity regimens had a significantly longer PFS (P = 0.036) and a trend toward longer OS than those treated with R-CHOP. Finally, the BCL2 translocation status was known for 35 of these patients, and among patients with dual translocations, there was a nonsignificant trend toward a shorter PFS and OS compared with patients with an isolated MYC translocation. This suggests that perhaps it is the double-hit lymphomas within the larger category of B-UNC/BL/DLBCL that drive the poor prognosis seen, and perhaps it is these patients who might benefit from more intensive upfront chemotherapy regimens like modified Magrath, R-hyper-CVAD, or dose-adjusted R-EPOCH. Data of MYC translocation-positive DLBCL treated with dose-adjusted R-EPOCH on the phase II studies out of the National Cancer Institute (NCI) are promising; in this study, nine patients (8%) were known to harbor a MYC translocation and had a 4-year event-free survival (EFS) of 83%. This regimen is currently being explored further in BL and MYC translocation–positive DLBCL in a multicenter US Intergroup trial.
At the present time, there is not sufficient evidence to suggest that all patients with B-UNC/BL/DLBCL should be treated with regimens more intense than R-CHOP chemotherapy. This is a heterogeneous group of patients with varied prognoses and natural histories, some of whom may do very well with standard R-CHOP chemotherapy. There is a general consensus, however, that for dual translocation, or now perhaps dual IHC, positive aggressive B-cell lymphomas, many of which are B-UNC/BL/DLBCL, chemoimmunotherapy with R-CHOP is not sufficient. The difficulty is that there is no compelling prospective evidence to show that more intensive regimens improve outcomes in this group. These patients thus should be encouraged to participate in clinical trials, like the US Intergroup trial of dose-adjusted R-EPOCH discussed here. In the absence of a clinical trial, our practice has been to treat younger (<60 years), fitter patients with dual translocation–positive aggressive B-cell lymphomas with modified Magrath and older (>60 years), more frail patients with dose-adjusted R-EPOCH in the upfront setting. Due to the documented high risk of CNS recurrence in these patients, we add CNS prophylaxis in the form of intrathecal chemotherapy to the treatment of patients being treated with dose-adjusted R-EPOCH. Agents that target BCL2 and a MYC-driven protein, aurora A kinase, are currently in development and may prove useful in these double-hit lymphomas, and these patients should be considered for clinical trials when available. How to manage the dual IHC-positive but translocation-negative patients is even less clear at this time and requires further study. We continue to treat these patients with R-CHOP chemotherapy.
This patient is treated with six cycles of dose-adjusted R-EPOCH with intrathecal chemotherapy given as CNS prophylaxis on four occasions. Mid- and posttreatment positron emission tomography–computed tomography (PET–CT_ scans confirm a complete response to chemoimmunotherapy, and a posttreatment bone marrow biopsy shows no evidence of disease.
• Is there a role for a consolidation strategy for this patient?
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17: Management of Therapy-Related Myeloid Neoplasms
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71: Secondary Brain and Spinal Cord Tumors
