Non-germinal Center Phenotype Research Articles

RCHOP Plus High-Dose Methotrexate As First-Line Therapy in Large B-Cell Lymphoma with Testis Involvement

Primary testicular lymphoma (PTL) and diffuse large B-cell lymphoma with secondary testicular involvement (DLBCL-T) are rare subtypes of lymphomas associated with poor prognosis and a high risk of central nervous system (CNS) relapse. The optimal CNS prophylaxis strategy for these subtypes remains uncertain. High-dose methotrexate (HD-MTX) is debated for CNS prophylaxis, but its efficacy in this setting is unknown. This study aimed to retrospectively analyze the use of HD-MTX in combination with chemotherapy (R HD-MTX CHOP) as frontline treatment for PTL and DLBCL-T and to compare the biological characteristics of these two forms of testicular involvement. Data from patients who received R HD-MTX CHOP as first-line treatment for DLBCL-T or PTL between 2010 and 2020 were collected retrospectively. The study included 15 patients, 5 with PTL and 10 with DLBCL-T. The overall response rate was 86%, with 73% of patients achieving complete remission. Treatment-related adverse events were generally manageable, with febrile neutropenia being the most common. Two patients experienced CNS relapse, both from the DLBCL-T subgroup, with a median time of 10.7 months from diagnosis to CNS relapse. None of the PTL patients receiving HD-MTX experienced relapse during the median follow-up of 6.08 years (Figure 1A), compared to 8/10 DLBCL-T (p=0.007). All five PTL cases had a non-germinal center phenotype, while 7 out of 10 DLBCL-T cases were non-germinal center. One DLBCL-T case exhibited high-grade lymphoma. Myc expression was positive in 3 out of 10 patients assessed, of whom all were double expressors. Bcl-2 expression was positive in all 13 assessable patients, while Bcl-6 expression was positive in 6 patients. Myc, Bcl-2, and Bcl-6 rearrangements were assessed in 10 patients and were present in 1 patient who was found to have triple-hit lymphoma. No other patient had double-hit lymphoma or any significant rearrangement. Polysomy of Myc, Bcl-2, and/or Bcl-6 was found in 2 patients. PDL1 expression was observed in one out of six patients analyzed, while no PD1 expression was detected. In 8 out of 15 patients with available tissue material, next-generation sequencing using a panel targeting 43 lymphoid genes was performed. Among these 8 patients, 87% exhibited gain-of-function mutations in MYD88 (MYD88 L265P), and 62% had missense mutations in CD79B at position Y196. Multiple mutations in the PIM1 gene, a known target of aberrant somatic hypermutation, were also observed in 7 patients. Non-recurrent mutations were detected in various genes, including PRDM1, CD58, B2M, CREBBP, CIITA, CARD11, CDKN2A, EP300, CCDND3, FOXO1, IRF4, NFKBIE, and TCF3 (Figure 1B). Ig rearrangement was analyzed in 4/9 patients with available DNA. All 4 were clonal, with distinct but mutated VH segments (sequence identity between 81 and 89%). This study suggests that HD-MTX in combination with RCHOP chemotherapy is highly effective in preventing CNS relapse in PTL but less so in DLBCL-T. DLBCL-T had a higher risk of CNS relapse and poorer outcomes compared to PTL. Further studies are needed to determine the optimal timing and sequence of HD-MTX in DLBCL-T, as well as alternative treatment approaches. PTL and DLBCL-T have distinct clinical presentations and responses to frontline chemotherapy with HD-MTX prophylaxis. PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia & Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia & Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

The Effect of Preemptive Rituximab Treatment in Patients with EBV Viremia after Solid Organ Transplantation on the Development of Post-Transplant Lymphoproliferative Disorder

The association between Epstein-Barr Virus (EBV) reactivation after solid organ transplantation (SOT) and Post-Transplant Lymphoproliferative Disorder (PTLD) is well described. There are currently no guidelines regarding the use of rituximab preemptively in patients with EBV viremia after SOT to reduce the risk of PTLD. We sought to determine whether rituximab in SOT patients with EBV viremia has benefit in preventing PTLD. This retrospective analysis of electronic medical record data identified SOT recipients who experienced EBV viremia post-transplant between January 2010 and February 2023 at Columbia University Irving Medical Center (CUIMC). Data queries were clinically reviewed. Logistic regression analysis was performed to investigate the relationship between predictor variables including rituximab administration, log-transformed EBV peak titer, duration of EBV viremia, and time from SOT to EBV reactivation, with the binary primary outcome of PTLD diagnosis status. The analysis encompassed both univariate and multivariate logistic regression. There were 2,168 patients who met the inclusion criteria of having EBV reactivation after SOT, out of 6,395 total SOT performed at CUIMC during this timeframe. Patient characteristics are described in table 1. The median peak EBV titer was 154 (range: not quantifiable - 5,335,816), the median duration of EBV viremia was 78 days (range: 1 - 6,980), and the median time from SOT to EBV reactivation was 688 days (range: 0-11103). Of the 2,168 patients, 185/2168 (8.5%) received rituximab for indications other than PTLD including EBV viremia, treatment of rejection, antibody desensitization therapy/immunosuppression peri-transplant, and other non-transplant related indications (e.g. lupus nephritis). Of the patients who received rituximab, 182/185 (98.4%) did not develop PTLD. The 3/185 (1.6%) patients who did develop PTLD were all ≤ 20 years-old at time of diagnosis, and had EBER(+), monomorphic PTLD, diffuse large B-cell lymphoma type, with a non-germinal center phenotype, involving the gastrointestinal tract. Two were CD20 positive, all 3 had partial weak CD30 positivity, and all 3 had clonal immunoglobulin heavy chain rearrangements. Among the patients who did not receive preemptive rituximab post-SOT, 195/1983 (9.8%) developed PTLD, whereas 1788/1983 (90.2%) did not. Prior rituximab therapy for any indication in patients with EBV viremia post-SOT was associated with lower risk of subsequent PTLD by univariate analysis (0.14% vs 8.39%, OR 0.15, p = 0.0013, 95% CI 0.048-0.48). Receipt of rituximab (OR 0.12, p=0.0002), log-transformed peak EBV titer (OR 1.10, p<0.0001), and duration of EBV viremia in months (OR 1.01, p<0.0001) were all independently associated with risk for PTLD by multivariate analysis (figure 1). The relationship between time from SOT to EBV viremia was not significantly associated with development of PTLD. This retrospective analysis suggests that administering preemptive rituximab in SOT patients with EBV viremia may lower the risk of developing PTLD. The fact that peak EBV titer and duration of EBV viremia remain associated with PTLD in multivariate analyses suggests that the benefit of rituximab may be independent of the degree or duration of EBV viremia. A prospective analysis of factors such as area under the curve of EBV exposure, HLA status, T cell clonotype diversity, organ type, and immunosuppression type, is needed to better understand individual risks for improved selection of those who would benefit from preemptive rituximab.

Clinicopathologic and mutational profiles of primary breast diffuse large B cell lymphoma in a male patient: case report and literature review

IntroductionPrimary breast lymphoma (PBL) is rare, and most cases occur in female patients, with few reported cases in male patients. The clinical presentation is similar to that of breast cancer, but the condition needs to be well understood, as treatment options and clinical course vary. Hence, we provide a relatively rare case of primary breast diffuse large B cell lymphoma (PB-DLBCL) in a male, including its complete clinicopathological features, radiological findings, genomic mutational profiles, and clinical course.Case presentationA 45-year-old male presented with a lump in his right breast for 1 week and was pathologically diagnosed with breast malignancy after a breast puncture biopsy at the local hospital. He came to our hospital for further treatment and underwent breast ultrasound and systemic positron emission tomography/computed tomography (PET/CT) imaging, followed by right mastectomy and sentinel lymph node biopsy. Histomorphology showed diffuse hyperplasia of tumor cells with clear boundaries and surrounding normal breast ducts. The adhesion of tumor cells was poor with obvious atypia. Immunohistochemical results showed that the tumor cells were positive for CD20, Bcl6, and MUM-1 but negative for CK (AE1/AE3), ER, PR, CD3, and CD10. Forty percent of the tumor cells were positive for c-Myc, and 80% of tumor cells were positive for Bcl2. The Ki-67 proliferation index was up to 80%. The tumor cells were negative for MYC and BCL2 rearrangements but positive for BCL6 rearrangement by fluorescent in situ hybridization. No abnormality was found in the pathological examination of bone marrow aspiration. Therefore, the male was diagnosed with PB-DLBCL, nongerminal center (non-GCB) phenotype, dual-expression type. The sample were sequenced by a target panel of 121 genes related to lymphoma. Next-generation sequencing revealed six tumor-specific mutated genes (IGH/BCL6, TNFAIP3, PRDM1, CREBBP, DTX1, and FOXO1). The patient was given six cycles of orelabrutinib plus R-CHOP chemotherapy and two cycles of intrathecal injection of cytarabine. The last follow-up was on April 13, 2023 (17 months). No recurrence or metastasis was found in laboratory and imaging examinations.ConclusionWe reported a relatively rare PB-DLBCL in a male, non-GBC phenotype, dual-expression type. It is worth mentioning that this case had IgH/BCL6 fusion, nonsense mutations in TNFAIP3, frameshift mutations in PRDM1, and missense mutations in CREBBP, DTX1, and FOXO1. To the best of our knowledge, this case is the first report of genomic mutational profiles of PB-DLBCL in males.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Central nervous system (CNS) relapse still represents an often-fatal event in diffuse large B cell lymphoma (DLBCL). Efforts to prevent it aimed to identify higher risk patients and to administer adequate prophylaxis. In this setting, unmet needs such as the type of prophylaxis (high-dose methotrexate, HD-MTX vs. triple intrathecal therapy) and its timing are still under debate. Hereby, we report our experience of DLBCL patients undergoing CNS prophylaxis with systemic HD-MTX intercalated with systemic chemotherapy. Methods: We retrospectively collected data of DLBCL patients receiving CNS prophylaxis with at least 1 cycle of HD-MTX from 2017 to 2022. The administration of HD-MTX was based on CNS-IPI and on lymphoma histology/clinical presentation in those cases who may not tolerate more intensified chemo-immunotherapy regimens. We performed a Kaplan-Meier analysis to estimate overall survival. Results: Twenty-one patients received HD-MTX. The mean age at diagnosis was 62 years (range 33–77), with 66% of patients over 60 years. The median Cumulative Illness Rating Scale (CIRS) was 8 (range 4–13). At presentation, 76% of patients had advance stage disease (III-IV) with more than 1 extranodal localization in 15 cases. Median IPI and CNS-IPI were 3 (range 0–5) and 3 (range 0–5), respectively. According to immunohistochemistry, a non-germinal center phenotype was shown in 24% and 52% patients had double-expressor profile. Patients received R-CHOP (71%) or R-COMP (29%) associated with variable HD-MTX dose, adjusted on age and comorbidities. At a mean delay of 2 days after R-CHOP, a median number of 3 HD-MTX cycles were administered at a mean dosage of 2 g/mq (range 1–3). Regarding safety, 19% of patients experienced acute renal injury (ARI), among them 2 in patients over 60 years and only one grade 3 ARI. We observed a complete response (CR) in 67% of patients, up to 79% if considering over 60 years. Particularly patients over 60 years were more likely to achieve CR (p = 0.052), even in those who delayed R-CHOP. At a mean follow-up of 24 months, 82% of patients over 60 years patients are alive (Figure 1). A substantial difference in overall survival was seen in patients reaching CR than others (100% vs. 33%) (p = 0.001). Six patients relapsed at a median time of 3 months, among them 4 died from lymphoma. Conclusions: Our report confirms the feasibility of HD-MTX in the treatment of DLBCL patients with high-risk features and high comorbidity burden. Patients over 60 years showed higher rate of complete remission without significant toxicity, independently on chemotherapy delay suggesting a good balance between response and toxicity with MRCHOP/COMP in this setting. Further studies with longer follow-up are needed to draw more definitive conclusions, especially in frail patients such as elderly. Keywords: aggressive B-cell non-Hodgkin lymphoma, chemotherapy No conflicts of interests pertinent to the abstract.

S2150 Triangle of Lymphocytic Colitis, Epstein-Barr Virus, and Lymphoma: Is There Any Association?

Introduction: Epstein–Barr virus (EBV), is linked to range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. EBV-positive diffuse large B cell lymphoma (DLBCL) not otherwise specified is a variant of DLBCL seen in patients without known immunodeficiency or prior lymphoma. In few reports EBV infection was more commonly detected in colonic mucosa of patients with Microscopic Colitis (MC), but it remains unclear if this translates to higher incidence of lymphoma in this subgroup of people. Here, we describe a case of DLBCL in patient with MC associated with EBV infection in context of recent findings. Case Description/Methods: 77-year-old female with history of COPD, diabetes underwent colonoscopy for chronic diarrhea of 4-month duration. She suffered from 3-4 loose stools/day, and had normal celiac panel, fecal elastase, and infectious workup. Colonoscopy was unremarkable except for 4 mm Paris Is polyp in sigmoid colon removed with cold snare. On pathology, the random colon biopsies were positive for lymphocytic colitis along and polyp showed DLBCL (non-germinal center phenotype) along with positive EBV infection (Figure). Discussion: It is widely believed that overall risk of malignancy is not increased in MC. However, theoretically MC should increase risk of lymphoma as it is more likely to be associated with oncogenic EBV than Ulcerative colitis or irritable bowel syndrome (90 % vs 66 % vs 0 % respectively). EBV increases the risk of lymphoma due to protein expression in transformed infected lymphocytes that results in immune evasion and suppression of apoptosis. Earlier studies have shown no evidence of higher risk of lymphoma in MC, however recently Bergman et al. (2021) analyzed data from Sweden´s pathology departments and from the Swedish Cancer Register and included 11758 patients with incident MC and found an increased risk of lymphoma (adjusted HR 1.43 [1.06–1.92]). Studies are needed to explore risk of lymphoma in subgroup of MC patients with EBV infection as inflammation cause by MC and concomitant EBV infection enhance the overall malignant potential. In conclusion, MC may not be as benign entity as it was once thought to be as it is more likely to harbor oncogenic EBV virus. Even diminutive polyps in MC can potentially harbor lymphoma and should be removed and submitted for analysis rather than being discarded.Figure 1.: Colonoscopy image showing small polyp (left) and schematic (right) of triangle between CMV, microscopic colitis and lymphoma error.

Frequency, Histologic, and Prognostic Significance of CD30 Expression in AIDS-associated Diffuse Large B-Cell Lymphoma

Introduction: AIDS-related Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with a variable response to chemotherapy depending on, and not limited to, cell of origin, double/triple hit, or MYC/BCL-2 co-expression status. Similar to DLBCL, AIDS-related DLBCL (ARL) with non-germinal center histology or MYC expression reports poorer response to treatment. In the immunocompetent population CD30+ DLBCL defines a histology with improved survival, however, the characteristics and outcomes of ARL expressing CD30 are not well studied.Methods: We assessed 3 cohorts of ARL. The first cohort, consisted of of an immunohistochemistry tissue microarray (TMA) of 30 ARL patients, followed by two validation cohorts. The first validation was a TMA of 80 ARL, from the AIDS Cancer Specimen Resource. Both TMAs were stained for CD10, BCL6, MUM1, CD20, Ki67, EBER, MYC (by IHC) cut off at 40%, BCL2 (by IHC) cut off 50%, and CD30 (considered positive if any CD30 was expressed on the malignant cells). The third validation cohort was from the County Hospital AIDS Malignancy Project (CHAMP), a prospective database of patients with hematological malignancies and HIV. Of the 100 cases with ARL, only 25 cases were found to have CD30 staining performed, thus only those cases were included. In total, 135 patients diagnosed with ARL were assessed. Cell of origin and germinal (GCB) vs. non-germinal center (NGC) was determined by the Hans algorithm. Statistical differences between groups were analyzed by the fisher exact test. Survival data, when available, was estimated using the Kaplan-Meier method and compared using the log-rank test.Results: Of the 135 ARL, 30% (n=41) were CD30+. Ninety-one% of the cohort was male. EBER was 23% positive in the entire cohort (n=29/126). EBER was positive in the CD30+ vs. CD30- population, 59% (N=17) vs 26% (p<0.01). Despite 59% of the CD30+ population being EBER positive, 92% of the population had a NGC phenotype, 2% was germinal, and 5% had a null phenotype (p<0.01). Of the 86 patients that were CD30-, 88% were GC vs. 12% NGC (P<0.01). The CD4+ T-cell count at presentation was higher in the CD30- cohort with a mean CD4+ T-cell count of 234 vs.164 cells/ul (p<0.05), similar to historical studies demonstrating a similar effect in germinal vs. non-germinal center ARL. Ki67 > 80% was also higher in the CD30- vs the CD30+ cohort 75 vs.60%, (p=0.052). Myc, BCL2, and double expressor lymphomas were identified 59 vs. 57%, 59 vs. 57%, and 31 vs. 28%, respectively, in the CD30+ ARL vs. the CD30- population, none were statistically significant. Survival data was only obtained for 56 of the patients. In the patients treated in the combined anti-retroviral era (ART), there was no difference in survival in the CD30+ vs. CD30- population, 74% (n=18) vs. 84% (n=12) at 5 years (p=0.8). In the 15 patients treated in the early ART era, the OS at 5 years was 48% for the CD30+ vs. 52% (p=0.4), the rest were treated in the pre-ART era.Conclusion: CD30+ ARL in this cohort represents 30% of all ARL evaluated, and presents almost exclusively as a non-germinal center phenotype and has a strong correlation with EBV. While no differences in survival were identified in this study, possible due to the small numbers of patients assessed with survival data, historically, NGC ARL have been shown to have poorer outcomes, by 20-30% in studies with da-EPOCH. As such, the need for better therapies, potentially to overcome these poor prognostic factors, should be studied further. [Display omitted] DisclosuresReid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator.

Clinical Outcome and Prognostic Factors of Patients with Richter's Syndrome: Retrospective Multicenter Study of the Spanish Chronic Lymphocytic Leukemia (CLL) Study Group (GELLC)

Richter syndrome (RS), the development of diffuse large B-cell lymphoma (DLBCL) in the context of CLL, is an uncommon complication with a dismal prognosis. Currently, data on biological and clinical features, and factors predicting the outcome of patients are scarce, and there is still no consensus on the best therapeutic approach for these patients (pts). The aim of this study was to analyze the presenting characteristics, treatment outcomes, and factors predicting for survival in a series of pts with RS from a large population-based cohort of the Spanish CLL Study Group (GELLC).Pts diagnosed with RS during 1988 - 2017 were retrospectively identified in eleven centers of the GELLC group. Only cases with confirmed biopsy-proven RS during follow-up were included. Clinical-biological features at diagnosis of RS, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status detected by in situ hybridization, cell of origin (COO) analyzed by immunohistochemistry, International Prognostic Index score (IPI) and the RS score (Tsimberidou AM et al, J Clin Oncol, 2006), as well as treatment and outcomes, were analyzed.One hundred and twenty-three pts with transformation of CLL to high-grade lymphoma were identified, including 108 classical DLBCL RS, 14 pts with Hodgkin lymphoma (HL), and one case of plasmablastic lymphoma. Median age of the whole series was 66 years (range, 31 to 92 years), and 64% were men. For the DLBCL RS, median time from the diagnosis of CLL to RS development was of 4.7 years (range, 0-24.8 years, with 9 simultaneous diagnosis of CLL and RS), and the median number of prior therapies for CLL/SLL was 1 (range, 0-7). The main clinical characteristics of the pts are shown in table 1. EBV was detected in 12/36 (33%) cases with classical RS and in 9/11 (82%) of patients with HL variant. According to COO the majority of RS tested (20 of 24, 83%) had a non-germinal center phenotype, whereas 19/23 (83%) cases were clonally related to the preceding CLL. Twelve out of 43 pts had 17p deletion or mutation of TP53 in the CLL clone at the time of RS diagnosis.Among the 108 patients with DLBCL RS, data on the treatment for RS was available in 99 patients. Twenty-one patients did not received treatment due to frailty, comorbidities, or poor performance status. Of the 78 patients that were treated for RS, 46 patients received chemoimmunotherapy, mainly R-CHOP (n=44), 29 patients chemotherapy (most commonly CHOP and purine analogue-based therapy), and others (n=3). The overall response rate for the 99 treated patients was 44% (chemotherapy, 24%; chemoimmunotherapy, 60%; P=0.003). A total of 13 patients underwent stem-cell transplantation (SCT), allogeneic SCT (n=7) or autologous SCT (n=6).After a median follow-up for surviving patients of 36 months (range 0.8-160 months), median overall survival (OS) from the time of transformation of CLL to high grade lymphoma was 7.3 months for the entire cohort, 5.7 months for DLBCL RS patients, and 30.8 months for patients with HL variant (P=0.07). Factors associated with shorter OS in the DLBCL RS series included, ECOG PS >1, Hb level < 10 g/dL, platelet count < 100x109/L, LDH > 1.5 UNL, β2-microglobulin > 3mg/dL, prior CLL therapies >1, p53 positive determined by IHQ, and 17p deletion or mutation of TP53 determined in the CLL clone. RS score was also predictive for OS (median OS of 59.5 months [0-1 points], 5.4 months [2 points], 2 months [3 points], and 3 months [4-5 points], p= 0.006); on the contrary, IPI was not discriminative for OS in this series. In addition, RS clonally related presented a median OS of 5.9 months in comparison with 74.8 months for the clonally unrelated RS (p= 0.071). Finally, patients treated with chemoimmunotherapy combinations presented a median OS of 35.4 months, and the 13 patients that could consolidated the response obtained with SCT (autologous or allogeneic SCT) obtained a median OS of 59.5 months.Although clinical outcome of patients with RS is generally poor, chemoimmunotherapy combinations are effective and obtain durable responses in a proportion of patients. RS score and TP53 disruption are predictive of survival. Finally, pts attaining a response should be considered for SCT. Further clinical development with novel promising treatment options is warranted. [Display omitted] DisclosuresDelgado:Abbvie, Jansen, Gilead, Roche: Consultancy, Speakers Bureau.

Guidelines in Clinical Practice: Appraisal of Quality Metrics in the Management of Newly Diagnosed Diffuse Large B-Cell Lymphoma Based on the American Society of Hematology Practice Improvement Module

Background: The National Comprehensive Cancer Network (NCCN) has issued well-established guidelines for the management and treatment of non-Hodgkin's lymphoma (NHL), in particular for diffuse large B-cell lymphoma (DLBCL). In 2014, the American Society of Hematology established practice improvement module (ASH PIM) incorporating quality metrics in six areas: pathologic diagnosis, staging, hepatitis B testing, use of growth factors, vaccination, and fertility counseling. Currently, such practice improvement modules have allowed physicians to monitor the quality of care in their practice, and reiterating the significance of these clinical guidelines. In an appraisal of quality metrics undertaken at Virginia Mason Medical Center (VMMC), Seattle, Washington, we sought to review four of the ASH PIM metrics and several other metrics to assess adherence to treatment guidelines for Diffuse Large B-Cell Lymphoma (DLBCL) and examine the need for institutional improvement.Methods: A longitudinal cohort of all patients who were diagnosed with DLBCL and received treatment at VMMC between January 1st, 2005 to December 31st, 2016 was identified using VMMC's Tumor Registry. Utilizing the electronic medical records, each patient's chart was reviewed for these quality metrics: pathologic diagnosis, staging of lymphoma, hepatitis and HIV serology testing, echocardiogram (ECHO) prior to starting treatment, clymphoma recurrence risk categorization, chemotherapy education, use of Rituximab therapy, G-CSF use, and post-therapy CT or CT-PET scan. Parameters for pathological diagnosis included assessment of expression of CD20, germinal center vs non-germinal center phenotype based on reporting of MUM1, CD10 and BCL-6, fluorescence in-situ hybridization (FISH) and IHC studies for the presence of traslocation/overexpression of c-Myc, BCL-2 or BCL-6, and EBV assessment by EBV-encoded small RNA1 (EBER1) in-situ hybridization. Staging was evaluated based on imaging in the form of a CT or PET-CT scan prior to treatment initiation and if a bone marrow biopsy (BMB) was also obtained. Serology testing for hepatis B (HBV) and hepatitis C (HCV), and HIV was reviewed. Patients receiving anthracycline-based treatments were assessed for having undergone an ECHOcardiogram prior to initiation of treatment. Post-treatment PET-CT was noted based on the presence of an internal report or outside records.Results: A total of 179 patients were included in this analysis. The median age of this cohort was 67 years (range 24 -91 years) and 54% of these patients were male. Pre-treatment viral serologic screening was performed in 87% of patients for HBV, 78% for HCVFISH f and 92% for HIV. All the specimen were uniformly tested for expression of CD20, and the germinal center vs. non-germinal center phenotype was determined in 97% of patients. c-Myc and BCL2/BCL6 data was available in only 32% of patients. For staging, all patients had imaging (CT/PET-CT), while bone marrow was obtained in only 72% of patients. Post-treatment imaging was available in 97% of cases. Additional data analysis of treatment-related quality metrics is underway, and shall be presented at the ASH annual meeting.Conclusion: Performing regular quality assessments by employing standardized metrics provide opportunities to improve the institutional quality of care for patients with newly diagnosed DLBCL, and allows to build and ensure better adherence to evolving NCCN patient-care guidelines ASH PIM. However, performance on the metrics relying on clinical documentation may not be as high as for those relying on objective testing. Whether such quality metrics affect real-time treatment-decisons and patient outcomes needs further evaluation. DisclosuresNo relevant conflicts of interest to declare.

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

Impact of Immunohistochemistry-Defined Cell of Origin and MYC Rearrangements on Outcomes in Patients with PET-Defined Stage I/II Diffuse Large B-Cell Lymphoma Treated with R-CHOP ± Radiotherapy: An International Multi-Center Retrospective Study

Impact of Immunohistochemistry-Defined Cell of Origin and MYC Rearrangements on Outcomes in Patients with PET-Defined Stage I/II Diffuse Large B-Cell Lymphoma Treated with R-CHOP ± Radiotherapy: An International Multi-Center Retrospective Study

Ki67 Proliferation Index in Germinal and Non-Germinal Subtypes of Diffuse Large B-Cell Lymphoma.

IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma. The 2016 World Health Organization (WHO) update on hematopoietic tumors suggested that all DLBCL cases should be subtyped into germinal and non-germinal center phenotypes. Ki67 immunohistochemistry is a maker of cell proliferation and thus is used as a prognostic and predictive marker in various tumors of human body. Only a few studies evaluated the proliferative index of DLBCL subtypes in our population. Therefore, in this study, we evaluated the frequency of subtypes of DLBCL in our population and K67 index in each subtype.MethodsA retrospective observational study was conducted in the Department of Histopathology, Liaquat National Hospital and Medical College, from January 2018 till December 2020, over a period of three years. A total of 101 cases with a histopathological diagnosis consistent DLBCL were included in the study. Immunohistochemical (IHC) stains CD10, B-cell lymphoma 6 (Bcl-6), and multiple myeloma oncogene 1 (MUM1) were applied for the further sub-categorization of DLBCL into germinal center B-cell-like (GCB) and non-GCB subtypes according to the Hans algorithm. The Ki67 index was interpreted in hot spots of the tumor and reported as an average percentage.ResultsOut of 101 DLBCL cases, 47.5% of DLBCL were GCB, while 52.5% were non-GCB subtypes. Bcl-2, Bcl-6, MUM1, c-Myc, CD10, and CD30 expression were noted in 62.4%, 45.5%, 42.6%, 44.6%, 39.6%, and 7.9% cases, respectively. The mean Ki67 index was 72.94±16.69%. The mean Ki67 index in non-GCB-type DLBCL was 77.67±14.80%, which was significantly higher than the mean Ki67 index in GCB-type DLBCL (67.70±17.22%) with a significant p-value (p=0.002). Cervical lymph node was the most common site of DLBCL, while the stomach was the most common extra-nodal site. A significant association of Ki67 index was noted with subtypes of DLBCL. A higher proportion of non-GCB-type DLBCL exhibited greater than 80% Ki67 index than GCB subtype DLBCL. Moreover, a significant association Ki67 index was noted with c-Myc positivity. A higher proportion of c-Myc-positive DLBCL had greater than 80% Ki67 index.ConclusionWe found that non-GCB-type DLBCL had a higher Ki67 index than GCB subtype DLBCL, portending a poor prognostic significance of non-GCB subtype of DLBCL. Moreover, c-Myc expression was associated with a higher Ki67 index.

The Outcome of Diffuse Large B-Cell Lymphoma with CNS Involvement at Diagnosis, Single-Center Experience

Introduction Central nervous system involvement is uncommon in diffuse large B cell lymphoma but always associated with a poor prognosis. We reviewed the risk of CNS involvement at diagnosis, clinical features, and survival outcome of patients with diffuse large B cell lymphoma with CNS involvement. Patients and Methods All patients with diffuse large B cell lymphoma from January 2005 to December 2019 at Princess Noorah Oncology Center were retrospectively reviewed. We included patients 15 years old or over, with biopsy-proven diffuse large B cell lymphoma. Patients with HIV disease, double or triple hit lymphomas, or Burkitt's like lymphomas were excluded. CNS involvement was confirmed by clinical, brain imaging, cerebrospinal fluid flow cytometry or biopsy Results A total of 406 patients with DLBCL were identified. The median age was 58 years. The majority of patients had stage III and IV disease (68%) and had more than one site of extranodal involvement (66%). The majority of the patients had intermediate to high IPI (66%) and elevated LDH (67%). A large proportion of patients had high CNS IPI (36%), and a minority of patients received either intravenous prophylaxis high dose methotrexate (11%) or Intrathecal methotrexate (3%). The majority of patients were treated with R-CHOP chemotherapy (92%). In total, 17 (4%) patients had CNS involvement: 9 patients (2.2 %) at diagnosis and 8 (2%) at relapse. All the nine patients who had CNS involvement at diagnosis had advanced-stage disease except one patient. Six patients had another extranodal involvement. Four out of nine patients had a non-germinal center phenotype, and all four patients had parenchymal rather than leptomeningeal involvement. All the patients received R-CHOP chemotherapy alternating with high dose methotrexate except one patient who received palliative treatment. Five out of nine patients achieved CR and survived. For those patients who had CNS relapse, the median time to relapse was 11.8 months (range 6 to 19 months), and most of the patients experienced a relapse in the first 6-13 months. All patients had an advanced stage, extranodal involvement, intermediate to high CNS-IPI, and only two of them received high dose methotrexate, and one patient received radiotherapy. Only two patients are alive: one patient received high dose methotrexate and high dose Ara C followed by high dose chemotherapy and autologous stem cell transplant. Another patient received salvage R-ESHAP for systemic relapse alternating with intrathecal MTX and waiting for stem cell transplant. The 5-year overall and progression-free survival rates for the entire DLBCL group were 84% and 73 %, respectively. Conclusion CNS involvement in diffuse large B cell lymphoma carries a poor prognosis. Aggressive CNS-directed therapy should be considered, especially in young fit patients. Disclosures No relevant conflicts of interest to declare.

Fibrin-associated diffuse large B-cell lymphoma with plasmacytic differentiation: case report and literature review

BackgroundPrimary cardiac lymphomas are extremely rare entities (< 2% of cardiac tumours) and the most frequent histologic type is diffuse large B-cell lymphoma (DLBCL). Fibrin-associated DLBCL (FA-DLBCL) is a very unusual form of DLBCL associated with chronic inflammation, and only case reports and small series have been described. In the heart, it usually occurs in the context of a cardiac myxoma or cardiac prostheses and it is not bulk forming. These lymphomas frequently present with non-germinal center phenotype and are associated with Epstein-Barr virus (EBV) type III latency.Case presentationWe describe a case of FA-DLBCL arising in a cardiac myxoma, with plasmacytic differentiation and type I EBV latency.ConclusionsAlthough they are very rare, FA-DLBCLs should be known for their diagnostic difficulty, due to its unspecified clinical manifestations, and for their more favourable prognosis, sometimes even without additional treatment after surgical resection.

SUN-915 Diffuse Large B Cell Lymphoma Presents with Femur Fracture and Involvement of Thyroid Gland

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma worldwide. It is an aggressive lymphoma that arises from germinal center or post-germinal center B cells. Patients typically present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen, but may present with a mass lesion anywhere in the body. However, multiple sites of involvement occur less frequently. We report a case of a 74- year-old woman who initially presented to the hospital for evaluation of a right distal femoral fracture which resulted from a fall at home. Lytic lesions were found in the distal femur and proximal fibula. She was also found to have hypercalcemia with a calcium level of 12.2. A CT- guided biopsy confirmed the diagnosis of Diffuse Large B-Cell Lymphoma with non-germinal center phenotype. A radical resection of the right femur was performed, and a distal femoral replacement hinged knee arthroplasty was done successfully. A venous port was also placed for chemotherapy administration. The patient was admitted to inpatient rehab with plans to initiate chemotherapy. 6 weeks later, the patient presented to the emergency department (ED) with a chief complaint of difficulty hearing, ear discomfort, dysphagia, and dyspnea for 3 weeks. These symptoms prompted her medical oncologist to send her to the ED and postpone chemotherapy that was to begin on that day. Physical examination found the patient to have neck fullness, large palpable lymph nodes, and stridor. Upon evaluation she was also found to have impaired renal function (Blood urea nitrogen 41, Cr 3.10), severe hypercalcemia (Corrected calcium 16.2), and hypokalemia (Potassium 2.8). An EKG demonstrated sinus rhythm and non-specific t-wave abnormality. A chest radiograph showed an enlarged thyroid extending into the superior mediastinum. There was also tracheal narrowing, and tracheal deviation to the left. She was admitted to the Intensive Care Unit (ICU) for treatment of hypercalcemia and stridor. The patient was aggressively treated with fluid management. She also received loop diuretics, steroids, and calcitonin. Once stabilized, a fine needle aspiration of the thyroid gland identified further involvement by diffuse B-Cell Lymphoma. The medical oncologist then initiated R-CHOP chemotherapy. The stridor resolved and the patient’s symptoms significantly improved. After two weeks in the ICU she was discharged to a rehab facility where chemotherapy was continued. This is a rare case of rapidly growing non-germinal center DLBCL that presented with involvement of both the bone and thyroid gland causing life-threatening symptoms. Upon reviewing the literature, there has been no documented cases of DLBCL simultaneously involving the bone and thyroid gland. The patient responded well to R- CHOP chemotherapy and continues to receive treatment in an outpatient facility.

Primary Cutaneous DLBCL Non-GCB Type: Challenges of a Rare Case.

Several types of B-cell lymphomas, including both primary cutaneous lymphomas and systemic lymphomas, may affect the skin, with partially overlapping clinical, morphological and immunohistochemical features. Currently, the World Health Organization (WHO) classification of primary cutaneous B-cell lymphomas does not include diffuse large B-cell lymphomas (DLBCL) and considers leg-type DLBCL the only primary cutaneous DLBCL. Here we report the case of a 72-year-old white woman with a primary cutaneous neoplasm comprised of large cells with round nuclei, irregularly clumped chromatin and one or more inconspicuous nucleoli. The immunohistochemistry demonstrated positivity for CD20 and MUM1, with no significant genetic translocations detected by fluorescence in-situ hybridization. After staging, we considered this neoplasm a primary cutaneous DLBCL with a non-germinal center phenotype, not otherwise specified, inconsistent with a leg-type DLBCL. Because of this view, we underscore the need for greater knowledge of the molecular landscape of B-cell lymphomas in order to reconsider the classification of such neoplasms in the skin.

Gastrointestinal (GI) Involvement with Non-Hodgkin's Lymphoma (NHL) Impacts Outcome; A Retrospective Single Tertiary Care Center Analysis of Clinico-Pathologic Characteristics Provides an Alternate Insight to Presentation and Outcome

Introduction Historically, the GI tract is involved in 10-15% of patients with newly diagnosed NHL. Despite being the predominant extranodal site for lymphoma involvement little is known about its pathophysiologic presentation given its overall rarity. Nonetheless its evaluation, diagnosis, prognosis and management is distinct from lymphomas at other sites hence their recognition irrespective of whether being the primary site is prudent. Methods We performed a single center retrospective study of patients to describe clinical characteristics and outcome of newly diagnosed NHL presenting with GI involvement defined by tissue biopsy between January 2003 and April 2019. Descriptive statistics were calculated by Fisher's exact test and Chi2 test for categorical variables and rank-sum analyses for continuous variables. Results We identified 91 patients with one patient presenting with 2 different GI NHL involvement. The median age at presentation was 70 years (range 33-92) and 61 were male. 41 (45%) patients had diffuse large B cell lymphoma (DLBCL) and 5 had concomitant low grade component, 28 (30.8%) mucosal associated lymphoid tissue (MALT) lymphoma, 10 (11%) mantle cell lymphoma (MCL), 4 (4.4%) enteropathy associated T cell lymphoma (EATL), 3 (3.3%) follicular lymphoma, 2 (2.2%) Burkitt's lymphoma and 2 (2.2%) EBV driven lymphoproliferative disorder (LPD). There were 1 case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type. 37 with DLBCL and 2 with MCL had primary GI involvement. Gastric involvement was the commonest site, 43 (55.8%) cases followed by the large intestine, 22 (28.6%). PET-CT scan was done in 42 cases with high grade NHL; GI involvement by FDG avidity was noted in 23 cases and negative in 19 (45.2%). Serum albumin at presentation was available in all patient. Patients with presenting serum albumin &lt; 25 g/L were more likely to die in the first 30-days post diagnosis; p&lt;0.0001. A total of 20 patients died as a result of lymphoma; presenting serum albumin was significantly lower in that group (mean 29 g/L versus 37 g/L; p=0.0077). H pylori status was assessed by either antigen testing in stool and/or histology. This was known in 50 patients and was available by the 2 assessment methods in 31 cases but discordant in 17. A positive result was more likely noted with the antigen test. None of the T-cell LPD were H pylori positive. 12 of the 26 DLBCL and 9 (53%) of the 17 MALT lymphoma patients were H pylori status was known were positive. Nonetheless all H pylori negative MALT lymphoma cases were localized to the stomach and responded to triple eradication therapy and Rituximab monotherapy +/- surgical resection. In the DLBCL cohort, the cell of origin was known in 22 of 39 cases; 17 were non-germinal center phenotype. In the MCL cohort, all patients whom underwent surveillance endoscopies irrespective of symptoms and/or radiologic finding had histologic evidence of GI involvement with lymphoma with only 3 (18%) patients being symptomatic +/- had radiologic finding in keeping with GI involvement. Conclusions Despite the relatively small sample size this real-world data of GI lymphomas outlines some of its recognized features; advanced age at diagnosis, male prevalence and gastric involvement as the commonest site of involvement. Presenting serum albumin &lt;25 g/L was associated with higher 30-day mortality highlighting its relevance and need for its inclusion as a biomarker in risk stratification of NHL where GI tract is involved. There is however several other significant findings not previously recognized; the incidence of GI involvement in MCL is much higher than reported; 100% in all patients whom have undergone endoscopy in our cohort suggesting that GI involvement is a feature of MCL. With only 53% of MALT lymphoma being H pylori positive which is much lower than previously described this renders the prototypical association of H pylori infection in MALT lymphoma pathogenesis void and suggests an alternate etiology. Nonetheless their response to antibiotic therapy with only minimal additional systemic therapy in some indicates that H pylori status does not necessary predict its efficacy and should be considered when treating MALT lymphomas irrespective of H pylori status. CT scans but also PET-CT scans are insensitive in detecting GI involvement even in high grade NHL. Endoscopy with random mapping biopsies even with normal macroscopic GI findings remains the gold standard. Disclosures No relevant conflicts of interest to declare.

Clinical Outcomes of Venetoclax Therapy in Patients with Relapsed/Refractory (r/r) Non Hodgkin Lymphomas (NHL)

Clinical Outcomes of Venetoclax Therapy in Patients with Relapsed/Refractory (r/r) Non Hodgkin Lymphomas (NHL)

Frequency of MYC Overexpression and MYC-BCL2 Double Expression (DEL) in Localized Diffuse Large B-Cell Lymphoma (DLBCL) at a Large Academic Cancer Center

Background:Genetic and functional drivers of diffuse large B-cell lymphoma (DLBCL) have increasingly been used to prognosticate and occasionally even guide treatment for patients with advanced stage DLBCL. In advanced disease, the non-germinal center (non-GC) phenotype, double hit lymphomas (DHLs), and double expression lymphomas (DELs) have poorer outcomes. However, the incidence and impact of these factors on patient outcomes in the limited stage setting is not as well described. In particular, the prevalence of MYC and BCL2 overexpression has not been previously described in the literature for early stage DLBCL. The purpose of our analysis was to determine the incidence of these high-risk factors and analyze if these have an impact on outcomes in patients with stage I-II DLBCL.Methods:We performed a single site retrospective study of patients newly diagnosed with stage I-II DLBCL as defined by the Ann-Arbor staging system. All patients were treated at our institution, between 2011 and 2017. Patients with stage III-IV disease, concomitant follicular lymphoma, primary mediastinal lymphoma, or CNS lymphomas were excluded. The stage-modified IPI was used to categorize patients into different risk categories.Cell of origin (COO) was determined by the Hans criteria. Double expression was defined as overexpression of both MYC (positive ≥50%) and BCL2 (positive ≥70%). Molecular rearrangements of MYC with either BCL2 or BCL6 were used to define DHLs. MYC overexpression, BCL2 overexpression, double (MYC and BCL2) expression, MYC rearrangement, and Ki67 were quantified. Whenever possible, original patient histologic tissue samples were examined if information was not available in the original pathology report.The study examined the impact of these clinical and pathologic factors on progression-free survival (PFS). The impact of prognostic factors was analyzed with the Wilcoxon rank-sum for continuous variables and chi-square tests for categorical variables.Results:A total of 35 patients were identified with stage I-II DLBCL. The median age was 60 years old (range 25-86). Twelve patients (34%) were female. Patient characteristics are summarized in Table 1. Fifteen patients (43%) were treated with chemotherapy alone, while 20 patients (57%) were treated with a combination of chemotherapy and radiation.There were 8 patients (23%) with MYC overexpression and 27 patients (77%) with BCL2 overexpression. Six patients (17%) had double expression. Of the 6 patients who were double expressers, 2 (33.3%) progressed after frontline therapy, while 4 of 25 non-double expressers progressed (16%), although this was not a statistically significant difference. The COO was the non-GC type in 16 patients (45.7%) by Hans criteria. There was 1 patient with MYC rearrangement, and this patient had progression at distant sites. We did not identify any DHLs. There was 1 patient with CNS relapse, but this patient did not have double expression or MYC rearrangement. There was no significant difference in PFS associated with any of our identified clinical and pathological factors.Conclusion:In this retrospective review, we identified the proportion of patients who have high risk genetic and pathologic risk factors. The prognostic impact of the COO in localized DLBCL has been described, and our data support the previously published studies showing no difference in localized DLBCL (Savage et al., Blood 2016 and Johnson et al., JCO 2012). The prognostic impact of DELs has been well described in advanced stage DLBCL; however, the prognostic impact of DELs in localized DLBCL is not well described. To our knowledge, this is the first study reporting the frequency of MYC and BCL2 overexpression in localized DLBCL. While it is difficult to compare rates across trials, the rate of patients with double expression at 17% is lower than the rate of approximately 30% described for advanced stage DLBCL (Johnson et al., JCO 2012 and Hu et al., Blood 2013). Additionally, there was not a significant difference in the risk of progression for DEL versus non-DEL, but this was limited by the small sample size. [Display omitted] DisclosuresGrover:Seattle Genetics: Consultancy. Dittus:Seattle Genetics: Consultancy.

The First 100 Cases of Epstein-Barr Virus-Positive Mucocutaneous Ulcers

In 2016, the World Health Organization provisionally classified Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) as a lymphoid neoplasm under the subcategory of mature B-cell neoplasms. Here we describe a 59-year-old Chinese woman with a long history of recurrent sinus and oropharyngeal infections and was diagnosed initially with EBVMCU and later, diffuse large B-cell lymphoma (DLBCL). She had sought medical attention after a particularly long bout of increased facial pressure and nasal obstruction. As a young adult she had undergone a tonsillectomy, adenoidectomy, and received innumerable treatments for bronchiectasis and recurrent sinopulmonary infections. A sinus computerized tomography (CT) scan showed mucosal thickening and swellings of the left frontal posterior sinus. A subsequent 18fludeoxyglucose (18FDG) positron emission tomography (PET)-CT scan showed a large hypermetabolic mass (standardized uptake value [SUV] 30.6) centered in the left half of the nasopharynx and sinus processes and extending across the mid-line. She underwent an endoscopic turbinate reduction with removal of a polypoid soft-tissue mass. Immunohistochemical studies indicated large atypical lymphoid cells that stained positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and variably for BCL-6, CD15, CD45, and CD79a. The Ki-67 proliferation index was 100% in the atypical cells. Tissue blocks were reviewed locally and at the National Institute of Health and were felt to be most consistent with EBVMCU. She received 4000 cGy involved-field external-beam radiation therapy over 20 fractions. At completion of treatment, no residual abnormalities were identified and no additional adjuvant therapy was pursued.Three years later she presented to medical attention with shortness of breath and a non-productive cough. A PET-CT scan showed whiteout of the left lung and intense 18FDG uptake in a left perihilar nodule (SUV of 18). Bronchoscopy revealed many reactive polypoid bronchial wall masses and a complete collapse of the lower left lobe due to an obstructing mass. The left lower lobe intraluminal mass biopsies however showed EBV-positive DLBCL of non-germinal center phenotype. She received six cycles of conventional R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) and 36 months later she remains cancer free but with persistent bronchial inflammatory nodules and recurrent infections.Using the key words “EBV mucocutaneous ulcers,” “EBV-associated lymphoproliferative disorders,” and “lymphoproliferative disorders,” we identified 100 cases of EBVMCU in the literature. EBVMCU is manifested as a well-circumscribed ulcer typically unifocal (90%) and of the oropharynx (58%), gastrointestinal (GI) tract (20%), and skin (20%). Immunohistochemical studies of the ulcers reveal monoclonal B-immunoblasts staining positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and staining variably for BCL-6, CD15, CD45, and CD79a. EBVMCU is most commonly associated with medication-induced (iatrogenic) immunosuppression (65%), advanced age-associated immunosenescence (27%), and primary (3%) and acquired (3%) immunodeficiencies. The median age for all EBVMCU cases is 68.5 (range, 16 -101) years. Of the 65 cases where medication-induced immunosuppression contributed to EBVMCU, 45 (69%) were in patients greater than 60 years-old. EBVMCU is a predominantly indolent disease reminiscent of post-transplant lymphoproliferative disorders in which conservative strategies are primarily employed with potential escalation to B-cell targeted therapy with or without cytotoxic chemotherapy, resection, and/or radiotherapy. Surveillance for EBVMCU should follow B-cell directed therapies and should be considered in the differential diagnosis in cases of suspected lymphoma relapse. Additionally, other LPDs, including lymphomas, should be monitored after resolution of EBVMCU. Due to overlap of the immunohistochemical profiles and risk factors associated with EBVMCU and other ulcerative LPDs of the oral and sinus cavities, nasopharynx, or GI tract, EBVMCU should be considered in the differential diagnosis to prevent under- or over-diagnosis and their associated potential repercussions. DisclosuresNo relevant conflicts of interest to declare.