Extranodal Sites Research Articles

Clinical characteristics and treatment outcomes of Chinese diffuse large B-cell lymphoma patients in the era of rituximab (2005–2018)

BackgroundRituximab combined with cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R–CHOP) regimen has improved the survival of diffuse large B-cell lymphoma (DLBCL) patients worldwide, compared with CHOP alone. Several limitations were seen in previous studies of Chinese DLBCL patients treated with R–CHOP or R-CHOP-like regimens. This study aimed to investigate the clinical characteristics and treatment outcomes of Chinese DLBCL patients treated with the standard first-line treatment. MethodsClinical data were collected from DLBCL patients who received frontline R–CHOP or R-CHOP–like regimens at the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College (CHCAMS) between January 1, 2005, and December 31, 2018. The treatment outcomes were compared with those of patients diagnosed with DLBCL between 2004 and 2017 and who received immunochemotherapy from the United States Surveillance, Epidemiology, and End Results (SEER) database. Survival rates were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis of progression-free survival (PFS) and overall survival (OS) was performed using Cox proportional hazard regression. ResultsOverall, 1084 patients from the CHCAMS and 4013 patients from the SEER database were included in the study. As of April 30, 2022, the median follow-up period for the CHCAMS group was 87.3 (range: 0.5–195.4) months. For the CHCAMS group, the 5-year PFS and OS rates were 61.7% (95% confidence interval [CI]: 58.8–64.7%) and 70.6% (95% CI: 67.8–73.4%), respectively. For the SEER group, the 5-year OS rate was 66.5% (95% CI: 65.0–68.0%), which was inferior to that of the CHCAMS group (P ​< ​0.001). After adjusting for clinical factors and treatment, no significant difference was observed in the OS between the CHCAMS and SEER groups (P ​= ​0.867). In the CHCAMS group, multivariate analysis showed that an Eastern Cooperative Oncology Group performance status score ≥2, presence of B symptoms, Ann Arbor stage III–IV, elevated serum β2-microglobulin levels, and bulky mass were independent adverse prognostic factors affecting PFS and OS (P ​< ​0.05). Additionally, patients aged over 60 years, elevated lactate dehydrogenase levels, and more than two extranodal sites were independent adverse prognostic factors for OS (P ​< ​0.05). Local radiotherapy was significantly associated with better PFS (P ​< ​0.001) and OS (P ​= ​0.001). ConclusionAfter adjusting for clinical and treatment-related factors, no significant difference was observed in the 5-year OS rate between Chinese DLBCL patients treated with standard first-line treatment and those from the SEER database.

Strong Coexpression of Transcription Factors PU.1 and Oct-2 in Rosai-Dorfman Disease.

Rosai-Dorfman disease (RDD) is a rare disorder characterized by the accumulation of large S100 protein-positive histiocytes that typically exhibit emperipolesis. The recently reported expression of Oct-2 in RDD histiocytes led us to explore whether PU.1, a transcription factor that is required for monocyte and B-cell development, could similarly function as a diagnostic marker in RDD. We evaluated the expression of PU.1 and Oct-2 using immunohistochemistry in 19 patients diagnosed with RDD involving nodal, extranodal, and cutaneous sites. Both PU.1 and Oct-2 were positive in all cases studied, with a strong intensity of staining in 84% of cases in which more than 50% of the lesional cells were positive. In three patients, both markers showed weak to moderate intensity of staining. Two patients had concomitant RDD and Langerhans cell histiocytosis in which PU.1 stained both types of histiocytes while Oct-2 stained only the RDD component. PU.1 emerged as a robust marker with crisp nuclear staining in RDD histiocytes as well as in engulfed inflammatory cells. Strong coexpression of PU.1 and Oct-2 is a useful diagnostic marker in differentiating histiocytic/dendritic cell proliferations.

TET-2 mutations predict poor outcomes and are associated with unfavorable clinical-biological features in PTCL, not otherwise specified and angioimmunoblastic T-cell lymphoma in Brazilian patients.

Nodal peripheral T-cell lymphomas [nPTCL] constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation play a central role in their pathogenesis. However, the mutational landscape involving epigenetic regulators has never been reported in Latin American patients and their prognostic impact remains controversial. From 2000 to 2019, 59-Brazilian patients with nPTCL were eligible for screening mutations in the IDH-1, IDH-2, RHOA, TET-2 and DNMT3A genes by Sanger sequencing at Formalin-Fixed Paraffin-Embedded samples [FFPE] of diagnosis. We reported the frequency, distribution and potential prognosis of these mutations. With a median follow-up of 3.70 years, estimate 2-year OS and PFS were 57.1% and 49.2%, respectively. Mutations in the IDH-1 gene were not found, mutations in the IDH-2 occurred in 3.4% (2/59), RHOA in 23.7% (14/59), TET-2 in 50.8% (30/59) and DNMT3A in 62.7% (37/59). RHOA gene mutations were more frequent in PTCL, NOS and AITL (p= 0.06). Almost half of the patients had more than one mutation in concomitance, particularly RHOA-mut and TET-2-mut. Mutations in RHOA (p= 0.030) and TET-2 (p= 0.046) were associated with high-tumor burden. In the non-ALCL subgroup (PTCL, NOS and AITL) TET-2 mutations were associated with decreased 2-year PFS [HR: 2.22, p= 0.048]. Likewise with lower overall response rate [ORR] (p= 0.048) and unfavorable clinical features, as bulky disease (p= 0.012), ECOG ⩾ 2 (p= 0.032), B-symptoms (p= 0.012), ⩾ 2 extranodal sites compromised (p= 0.022) and high-risk Prognostic Index for T-cell lymphoma (p= 0.005). Mutations in RHOA, TET-2 and DNMT3A were frequent in Brazilian patients with nPTCL. TET-2 mutations were associated with lower ORR for CHOP-like chemotherapy, decreased PFS and unfavorable clinical-biological characteristics in non-ALCL (PTCL, NOS and AITL). Further studies using a larger cohort may validate our findings.

INCIDENTAL PRIMARY PULMONARY DIFFUSE LARGE B-CELL LYMPHOMA

INCIDENTAL PRIMARY PULMONARY DIFFUSE LARGE B-CELL LYMPHOMA

ABCL-088 Subgroup Analysis in RE-MIND2: An Observational, Retrospective Cohort Study of Tafasitamab + Lenalidomide Versus Systemic Therapies in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Tafasitamab+lenalidomide (LEN), a chemo-free immunotherapy for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), demonstrated efficacy in autologous stem cell transplant-ineligible patients in the single-arm L-MIND study (NCT02399085). RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient cohorts treated with other systemic therapies. Prolonged overall survival (OS) with tafasitamab+LEN was detected compared to a cohort of pooled systemic therapies (PST), bendamustine+rituximab (BR), rituximab+gemcitabine+oxaliplatin, polatuzumab vedotin+BR (pola-BR), and rituximab+LEN (R2). Comparable OS was detected versus CD19 chimeric antigen receptor T-cell therapies (CAR-T). However, limited information is available on the comparative effectiveness of tafasitamab+LEN in specific subpopulations. This study aimed to determine the relative effectiveness of tafasitamab+LEN versus other treatments for R/R DLBCL in clinically relevant patient subgroups in the absence of head-to-head trials. The L-MIND cohort was matched with RE-MIND2 patients using estimated propensity score-based 1:1 nearest neighbor matching balanced for a minimum of six covariates. Sensitivity analyses were conducted. The study was conducted at academic, public, and private hospitals in Europe, North America, and the Asia-Pacific region. Patients were ≥18 years old with histologically confirmed DLBCL and ≥2 prior systemic therapies for DLBCL, including ≥1 anti-CD20 therapy. Data are presented for tafasitamab+LEN versus PST, versus pola-BR, versus R2, and versus CAR-T. Hypothesis-generating analyses were conducted for patient subgroups of number of extranodal sites (ENS) (0-1 vs. ≥2) and elevated lactate dehydrogenase (LDH) (yes vs. no). The primary endpoint was OS. Of 3,454 patients enrolled, 961, 106, 106, and 149 were treated with PST, pola-BR, R2, and CAR-T, resulting in 76, 24, 33, and 37 matched pairs for patients receiving tafasitamab+LEN, respectively. Hazard ratios for OS for patients with ≥2 ENS were 0.803, 0.524, 0.478, and 1.459, and for patients with elevated LDH were 0.627, 0.585, 0.420, and 1.663, for comparisons of tafasitamab+LEN versus PST, pola-BR, R2, and CAR-T, respectively. There was a trend towards favoring tafasitamab+LEN in most patient subgroups. The combination may be associated with improved OS versus selected systemic therapies for certain patients with high-risk disease. These analyses are not powered for statistical comparison and should be interpreted with caution. Funding: MorphoSys AG.

S3701 Necrotic Ulcer From Diffuse Large B-Cell Lymphoma

Introduction: Diffuse B cell lymphoma is a non-Hodgkin’s lymphoma that mainly occurs within the lymph nodes. However, about 40% of the time it occurs in extranodal sites. The most common sites are within the gastrointestinal tract, especially within the stomach and ileocecal regions. We present a case of a patient with diffuse large B Cell lymphoma within the cardia of the stomach. Case Description/Methods: A 69-year-old male with a past medical history of diffuse large B cell lymphoma was admitted for active melena. Further workup revealed a hemoglobin of 5.6 g/dL with a baseline around 10 g/dL, as well as a BUN of 67 mg/dL. Aside from mild tachycardia the patient was otherwise hemodynamically stable. He had received K Centra and one unit of blood in the emergency room. A CT angiogram of the abdomen showed recurrence of diffuse large B cell lymphoma with multiple lymph node stations in the pancreas, left kidney, and associated vasculature. Ultimately, the patient underwent an endoscopy. A necrotic ulcer measuring 5 cm in the cardia of the stomach with pigmented material on the surface indicating recent bleeding. Multiple biopsies were taken of each of these ulcers to rule out underlying malignancy. The pathology report revealed that the chronic ulcer in the cardia of the stomach was diffuse large B cell lymphoma and no evidence of Helicobacter pylori. The patient was treated with pantoprazole and Carafate. Their hemoglobin remained stable after 3 units of packed red blood cells and the patient was discharged. However, it was advised for them to follow up outpatient with hematology and oncology however he has since elected for hospice (Figure 1). Discussion: Diffuse large B cell lymphoma is the most common type of non-Hodgkin's lymphoma. The stomach is the most common extranodal site involved in non-Hodgkin's lymphoma representing up to 65% of all GI lymphomas. In these patients, symptoms may include dyspepsia, nausea, and vomiting. Primary gastric lymphoma is the most common extranodal lymphoma but only accounts for 2-8% of all stomach cancer. Thus, our case of diffuse large B lymphoma in the cardia of the stomach is a rare entity. Most patients are treated with conservative management like chemotherapy or immunotherapy. One retrospective study showed the use of R-CHOP to have a high remission rate. Surgical intervention is usually reserved for lesions that cause perforation, obstruction, or intractable bleeding. Our case would have required surgical intervention had the bleeding continued.Figure 1.: 5 cm necrotic ulcer found on retroflexion in gastric cardia.

ABCL-200 Primary and Secondary Extranodal Diffuse Large B-Cell Lymphoma: A Single-Center Survey from India

Approximately 30% of all non-Hodgkin lymphoma (NHL) cases arise from extranodal sites and almost half of them have diffuse large B-cell lymphoma (DLBCL) histology. Not only does the extranodal presentation require a site-specific diagnostic or therapeutic approach, but there is geographical variability in the overall frequency of extranodal presentation as well. To estimate the distribution of sites of extranodal DLBCL in patients treated at a tertiary care center in north India. This retrospective study was conducted at Dr. Bhim Rao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. Case files of patients (age >18 years) diagnosed with DLBCL at our institute between 2014 and 2018 were retrospectively studied and their sites of disease involvement were surveyed. A total of 550 patients were diagnosed with DLBCL during the study period, including 244 (44.3%) with nodal disease, 224 (40.7%) with extranodal involvement, and 82 (14.9%) with primary extranodal disease. A total of 306 (55.63%) patients have extranodal involvement, either primary or secondary. Among patients with primary extranodal DLBCL (n=82), the most common sites were gastrointestinal (n=36, 43.90%); the stomach was the most common region followed by the central nervous system (n=11, 13.4%), bone (n=8, 9.7%), head and neck area (n=7, 8.5%), breast (n=6, 7.3%), testis (n=4, 4.8%), and liver (n=4, 4.8%). The less commonly involved sites included the spleen (n=2, 2.4%), and one patient (1.2%) each had involvement in the prostate, pancreas, adrenal, and ovary. Bone was the most common site of secondary extranodal involvement observed in 32% of patients followed by gastrointestinal involvement in 30% of cases. Parallel to the incidence of DLBCL, the incidence of extranodal involvement, including primary and secondary extranodal presentation, is high in India. Bone is the most common site for secondary extranodal involvement, and the upper gastrointestinal system (stomach) is the most common site of primary extranodal lymphoma.

Low Incidence of Central Nervous System (CNS) Relapse of Diffuse Large B-Cell Lymphoma despite Limited Use of Intrathecal Prophylaxis

Diffuse large B cell lymphoma (DLBCL) is the commonest sub type of non-Hodgkin's lymphoma (NHL) accounting for 30–50 % of NHL cases. Around 2% to 10% of patients with diffuse large B-cell lymphoma (DLBCL) experience central nervous system (CNS) relapse after initial therapy which is associated with a poor prognosis and most often a fatal outcome. The incidence of CNS relapse can vary from <1% in younger, good-risk patients, to around 30% in patients with multiple risk factors, however, the relapse risk was reported to be lower in the rituximab era in some studies. Moreover, optimal modality of CNS prophylaxis remains to be defined, with both systemic and intrathecal (IT) chemotherapy being widely used. As the incidence of CNS relapse and type of prophylaxis used varies in different reports, it is important to study this risk in different populations to implement optimal prophylaxis strategies. The Objectives of this study was to evaluate the incidence of CNS relapse in DLBCL patients at our institution and to study risk factors and the type and role of CNS prophylaxis. We retrospectively analyzed patients diagnosed with DLBCL at King Khalid University Hospital, Riyadh, from January 2011 to June 2019. Data were collected from computerized hospital information system and from the files of the patients. Variables studied included age at diagnosis, stage at diagnosis, international prognostic index (IPI) and CNS-IPI score, site(s) of extra-nodal involvement, type of chemotherapy received, CNS prophylaxis and CNS relapse. CNS prophylaxis was administered on the basis of presence of high-risk features like presence of ≥2 extranodal sites, involvement of bone marrow, bone, testes, nasopharynx and paranasal sinuses. Patients with presence of CNS involvement at diagnosis and primary CNS lymphoma were excluded. A total of 101 patients were diagnosed with DLBCL during the study period. There were 58 males and 43 females with a median age of 56 (range: 16-87) years. Ann Arbor stage of I-IV was assigned in 9, 21, 17 and 50 patients, respectively. The lung was the most common extranodal site involved in 27 (26.7%) patients, and liver and bone marrow involved in 20 (19.8%) patients each. Gastrointestinal tract was involved in 9 (8.9%) patients, kidneys in 5 (4.95%), breast in 4 (4%), and testis and adrenal in 2 (2%) patients each. Twenty-five (24.75%) patients had high risk CNS-IPI score, 44 (43.5%) had intermediate risk score and 32 (31.7%) had low risk score. Ninety-four (93%) patients received R-CHOP chemotherapy while rest of the patients received other types of chemotherapy, mostly a milder regimen (R-CVP), because of comorbidities and poor performance status. Sixteen patients received CNS prophylaxis, which was IT methotrexate (MTX) ± cytarabine/hydrocortisone in all patients. Nine of 25 (36%) patients with high-risk CNS-IPI score did not receive CNS prophylaxis. After a median follow up of 36 months (range 4-114), 2 (2%) patients developed CNS relapse and died shortly after this diagnosis. Both the patients with CNS relapse had high risk CNS-IPI score and did not receive CNS prophylaxis. CNS relapse of DLBCL was uncommon in this patient population despite limited use of IT CNS prophylaxis in high-risk patients. Low incidence of CNS relapse in many high-risk patients despite limited use of IT prophylaxis may be related to rituximab use and/or other factors. Our data indicate that IT CNS prophylaxis may be adequate for DLBCL patients at high risk of CNS relapse.

HIGH TUMOR MUTATION BURDEN IN EPIGENETIC REGULATORY GENES PREDICTS DECREASED OVERALL SURVIVAL IN NODAL PERIPHERAL T-CELL LYMPHOMAS

Nodal peripheral T-cell lymphomas (nPTCL) constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation, such as IDH2, DNMT3A, TET2 and RhoA , play a central role in their pathogenesis. Tumor mutation burden (TMB) has emerged as a prognostic biomarker in numerous solid neoplasms. Furthermore, TMB reflects the process of clonal evolution, with progressive acquisition of additional molecular-genetic abnormalities. Recent studies were capable to establish a relationship between TMB and response to anti-cancer treatments. In 2021 Fachi et cols. established a correlation between high TMB in epigenetic regulatory genes and higher response rates to 5-azacytidine and romidepsin in nPTCL. However, the potential prognostic impact of epigenetic TMB remains unknown in nPTCL. Based on this premise, here we aimed, in a pioneering way, to search for a correlation between epigenetic high TMB and adverse prognosis in nPTCL. This is a retrospective, observational and single-center study, involving 59 patients with nPTCL diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2000 to December 2019. FFPE diagnostic tumor samples were submitted to Sanger sequencing with a target-panel, involving IDH2, DNMT3A, TET2 and RhoA genes to search for recurrent mutations. The median age was 50 years (IqR 38-61), and 57.6% (34/59) were male. Thirty-nine percent (23/59) had bulky disease ≥ 7 cm, 83% (49/59) had B-symptoms, 94.9% (56/59) had advanced stage III/IV, 27.1% (16/59) had ECOG ≥ 2, 27.1% (16/59) had ≥ 2 extranodal sites involved by lymphoma, and 55.9% (33/59) had intermediate-high/high-risk IPI. Seventy-six percent (45/59) received up-front therapy with CHOP-like regimens (CHOP or CHOEP), 23.7% (14/59) experienced radiotherapy, and 33.3% (20/59) were consolidated with ASCT. With a median follow-up of 3.7 years (95% CI: 0.9-12.4), the estimated 2-year OS and PFS were 57.1% (95% CI: 45.5-70.4) and 49.2% (95% CI: 34.0-59.2), respectively. Missense, non-sense or frameshift mutations in the IDH2 gene were observed in 3.3% (2/59) of cases, DNMT3A in 3.3% (2/59), RhoA in 23.7% (14/59) and TET2 in 37.2% (22/59). Among the 59 patients included, 23/59 (38.9%) had no mutations in the target-genes, 25/59 (42.4%) had 1 mutation, and 11/59 (18.6%) had two or more mutations. Therefore, the cases were categorized into low TMB (< 2 mutations) [n = 48/59 – 81.3%] or high TMB (≥ 2 mutations) [n = 11/59 – 18.7%]. The median overall survival was 51.4 months (95% CI: 0-124.1) for low TMB and only 3.1 months (95% CI: 3.1-15.2) for high TMB, p = 0.08. The estimated 2-year OS was 64.3% (95% CI: 50.6-78.0) for low TMB and 36.4% (95% CI: 8.0-65.0) for high TMB. Similarly, median progression-free survival was 13.3 months (95% CI: 0-29.4) for low TMB and 6.3 months (95% CI: 0.9-11.6) for high TMB, p = 0.319. The estimated 2-year PFS was 46.1% (95% CI: 20.0-72.1) for low TMB and 25.0% (95% CI: 17.5-67.5) for high TMB. In a pioneering way, we demonstrated that the high epigenectic TMB, defined by the presence of 2 or more mutations involving epigenetic regulatory genes, was associated with decreased overall survival in Brazilian patients with nodal PTCL. Although preliminary, these data support the potential impact of epigenetic TMB as a prognostic biomarker in nPTCL.

S3738 Agent Orange as a Possible Cause of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Introduction: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma was first described in 1983 as the most common extranodal site of non-Hodgkin lymphoma. Helicobacter pylori (H. pylori) infection is implicated in 90% of all gastric MALT lymphoma cases. Agent Orange (AO), with traces of oncogenic 2,3,7,8-tetrachlorodibenzo-p-dioxin, has also been classified as a causative agent in non-Hodgkin lymphoma, which includes gastric MALT lymphoma. Here we report a case of H. pylori negative gastric MALT lymphoma in a patient with history of significant AO exposure. Case Description/Methods: A 75-year-old Caucasian male veteran who served in the Vietnam War with significant AO exposure, as well as history of chronic gastroesophageal reflux disease, was referred for endoscopy to evaluate a reported history of un-staged Barrett’s esophagus 5-years prior but with two subsequent normal endoscopies at an outside facility. He noted symptoms of burning chest pain and dyspepsia following large meals, all of which were worsened with spicy foods and improved with omeprazole. Family history was negative for a history of gastric cancer, and he had a 25-pack year smoking history but quit 20 years prior to presentation.Initial esophagogastroduodenoscopy (EGD) revealed abnormal folds in the gastric fundus and erythema in the gastric antrum, but otherwise normal exam including normal duodenum and esophagus. Random gastric biopsies and biopsies of the abnormal folds were consistent with gastric MALT lymphoma, negative for H. pylori and t(11;18)(q21;q21). Repeat EGD 1 month later for further sampling demonstrated identical findings (Figure 1A). Stool testing for H. pylori antigen was also negative. The patient was referred to oncology and after staging imaging was found to have stage IE gastric MALT lymphoma. He was treated with involved site radiation therapy and EGD 3 months later showed both endoscopic and pathologic resolution (Figure 1B). Discussion: The 10% of cases of H. pylori negative gastric MALT lymphoma have an unclear etiology, although dysregulation of nuclear factor-kappa B (NF-κB) principally via translocations t(11;18)(q21;q21) is thought to be a potentially causative genetic alteration. In this patient, neither H. pylori nor the common t(11,18) genetic alteration were present. Given AO is implicated in non-Hodgkin lymphoma and the most common site of extranodal non-Hodgkin lymphoma is the gastric mucosa, AO exposure should be considered a risk factor for development of gastric MALT lymphoma.Figure 1.: (A) EGD demonstrating abnormal gastric mucosa with prominent gastric fundus folds seen on retroflexion during EGD prior to ISRT (radiation) therapy. (B) Post-radiation EGD demonstrating resolution of the abnormalities seen with the pre-treatment EGD including disappearance of the prominent gastric fundus folds.

AGE 75 YEARS, CLINICAL STAGE III/IV, NEUTROPHILIA AND HIGH LYMPHOCYTE/MONOCYTE RATIO PREDICT DECREASED OVERALL SURVIVAL IN ELDERLY PATIENTS WITH DLBCL, NOS OLDER THAN 70 YEARS

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with a wide clinical and biological diversity, as well as a heterogeneous prognosis. It especially affects the elderly population, with an increasing incidence with advancing age. The DLBCL of elderly (≥ 60 years) and very-elderly (≥ 80 years) patients has numerous particularities, including high-risk molecular-genetic findings, greater association with Epstein-Barr (EBV) virus infection, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. Therefore, alternative therapeutic strategies have emerged for these patients, including immunochemotherapy in reduced doses and regimens without anthracyclines. Based on this premisse, the current study aims to describe clinical and laboratory characteristics, assess outcomes, determine survival predictors and compare responses and toxicities in a large cohort of elderly patients with DLBCL, NOS older than 70 years. This is a retrospective, observational and single-center study, involving 185 patients with DLBCL, NOS aged ≥ 70 years, diagnosed and treated at the Department of Hematology, University of São Paulo, Brazil, from January 2009 to December 2020. The median age at diagnosis was 75 years (70-97) and 58.9% (109/185) were female. Comorbidities were prevalent, including 19.5% (36/185) of immobility, 28.1% (52/185) of desnutrition, and 25% (46/185) of polypharmacy. Advanced clinical stage (III/IV) was observed in 73.6% (134/185), 48.6% (90/185) had bulky disease ≥ 7 cm, 63.2% (117/185) had B-symptoms, 76.2% (141/185) had ≥ 1 extranodal site involved by lymphoma, 67% (124/185) had intermediate-high/high-risk IPI, and 52.3% (57/109) had GCB-like phenotype detected by IHC. Ninety-eight percent of patients (182/185) received at least one line of therapy, 65.9% (120/182) underwent cytoreduction, 50.5% (92/182) received intrathecal CNS chemoprophylaxis, and 41.8% (76/185) experienced radiotherapy. The R-miniCHOP elderly regimen had a lower overall response rate (ORR) (p = 0.040), however patients in this group had unfavorable clinical and laboratory characteristics, including higher rates of hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013) and NCCN-IPI ≥ 3 (p = 0.002). For the entire cohort, ORR was 68.1% (95% CI: 60.8-74.8), 13.2% (95% CI: 8.6-18.9) were chemorefractory, early-mortality rate (< 100 days) was 18.7% (95% CI: 13.3-25.1), and overall mortality rate was 52.4% (97/185). With a median follow-up of 6.3 years (95% CI: 5.5-6.7), the estimated 5-year OS and PFS were 50.2% (95% CI: 42.4-57.5) and 44.6% (95% CI: 37.0-51.9), respectively. In multivariate analysis, age ≥ 75 years [HR 2.22, p = 0.001], advanced-stage III/IV [HR 2.36, p = 0.003], neutrophilia ≥ 7.0 × 109/L [HR 2.25, p = 0.001] and lymphocyte/monocyte ratio > 4 [HR 1.98, p = 0.01] were associated with decreased overall survival. Similarly, age ≥ 75 years [HR 2.33, p < 0.001], stage III/IV [HR 2.38, p = 0.002], B-symptoms [HR 1.62, p = 0.032], LDH ≥ 1.5 x UVN [HR 1.09, p = 0.047], neutrophilia [HR 2.25, p = 0.001] and high lymphocyte/monocyte ratio [HR 2.08, p = 0.005] predicted poor PFS. In the largest real-life Latin American cohort including patients with DLBCL, NOS older than 70 years, age ≥ 75 years, advanced clinical stage III/IV, neutrophilia and high lymphocyte/monocyte ratio were independent predictors associated with decreased overall survival.

TCL-276 Outcome of NK/T-Cell Lymphoma - Retrospective Analysis from a Tertiary Care Cancer Center.

Extra-nodal natural killer (NK)/T-cell lymphoma is a rare, distinctive clinicopathologic entity with an aggressive clinical course. High expression of multidrug-resistant (MDR) P-gp on NK lymphoma cells renders this disease resistant to anthracycline-based chemotherapy regimens. Over the years, based on retrospective analysis and phase II studies, regimens with L-asparaginase and non-MDR drugs have been used. To evaluate the outcome of patients with extra-nodal NK/T-cell lymphoma treated in a tertiary cancer care center in India from 2012 to 2021. Retrospective, observational, single-center study. Hematolymphoid Department, Tata Memorial Hospital. From January 2010 to December 2021, all consecutive patients with NK/T-cell lymphoma were analyzed. Relapse-free survival and overall survival. A total of 78 patients with a diagnosis of extra-nodal NK/T-cell lymphoma were treated from 2010 to 2021. Amongst them, 56 (71.8%) were male, with a median age of 40 years (15-71 years). The most common presenting symptom was nasal swelling (9%), followed by dysphagia (3.8%). B symptoms were present in 35 patients (45%). Only 5% had HLH anytime during the treatment. One-third of the patients had an ECOG performance status >1. Nasal type constituted 80% of the cohort, regional node was involved in 60%, distant node was involved in 28%, 33% had more than 1 extra-nodal site involved, 23% had bulky disease, and 40% had advanced stage (stage 3-4) at presentation. EBV LMP1 was positive in 19 patients (24%). EBERISH was available in 9 patients, of which 7 were positive. Fifteen patients received treatment prior to presentation to our center (CHOP in 10 patients). At our center, the SMILE chemotherapy protocol was administered to 52 patients (66.7%). Consolidative radiation therapy was administered in 43 patients (55.1%). The best radiological response of CR was achieved in 49 patients (62.8%). After a median follow-up of 30 months, 30 (38.5%) patients relapsed and 30 (38.5%) died. Median relapse-free survival was 45 (95%CI: 5.1-84.8) months. Overall survival at 36 months was 53.4% (95%CI: 41.7%-68.4%). The outcome of NK/T-cell lymphoma in our cohort is comparable to the outcomes found in the literature.

Primary intraosseous Rosai-Dorfman disease: An analysis of clinicopathologic characteristics, molecular genetics, and prognostic features.

BackgroundRosai–Dorfman disease (RDD) is a rare histiocytic proliferative disorder of uncertain pathogenesis. Most patients present with proliferation in the lymph nodes manifesting as adenopathy; however, RDD may primarily arise in a variety of extranodal sites, including the bone, which is a great challenge in the diagnosis. The clinicopathological characteristics and prognostic features of primary intraosseous RDD have not been well characterized.MethodsWe retrospectively analyzed the clinicopathologic and prognostic features of four cases of primary intraosseous RDD during the past 10 years in our hospital, with a review of an additional 62 cases with complete follow-up data from the literature.ResultsPrimary intraosseous RDD was identified in 0.14% (4/2,800) of total bone biopsies performed at our institution over the study period. According to our retrospective analysis, a total of 18 cases of primary lymph node, skin, or other non-osseous site-based RDD were diagnosed in our hospital. The ages of the 66 total patients ranged from 1.5 to 76 years, with a median age of 25 years. There were 31 male and 35 female patients, with a male-to-female ratio of 0.89:1. Primary intraosseous RDD occurred most often in the bones of the extremities (60.6%, 40/66), with the proximal tibia being the most common location; 39.4% (26/66) of the cases arose in the axial skeleton, predominantly in the vertebra and craniofacial bones. Solitary masses and multiple tumors were present in 84.8% (56/66) and 15.2% (10/66) of the cases, respectively. Pain of the affected area was the most common presenting symptom. Radiographically, the lesions were lytic with well-defined and usually sclerotic margins. Immunohistochemistry showed that large histiocytes from patients with RDD were positive for OCT2, in addition to S100 and CD68. Molecular tests were performed in seven reported cases and four of our cases. All the 11 cases were non-decalcified. PCR results showed that there were no BRAF-V600E, KRAS, or NRAS mutations in primary intraosseous RDD; only one case with both RDD and Langerhans cell histiocytosis showed BRAF-V600E mutation. The survival data showed that 22.7% (15/66) of the patients experienced recurrences or developed RDD at distant sites during the follow-up period (median follow-up, 13 months; range, 1–106 months). The 5-year progression-free survival (PFS) of the patients with primary intraosseous RDD was 57.5%. We found that there was a significant difference in PFS between female and male patients (p = 0.031). However, there was no statistically significant difference in PFS between patients with solitary masses and multiple tumors (p = 0.698). Similarly, no statistically significant differences in PFS were found between the different age groups (p = 0.908) or tumor locations (p = 0.728).ConclusionPrimary intraosseous RDD is an extremely rare disease. The diagnosis of RDD may be quite challenging because of its non-specific clinical presentation and imaging. Immunohistochemistry showed that large histiocytes were positive for OCT2 in addition to S100 and CD68, which may be helpful for differential diagnosis. Molecular detection showed that RDD may be related to the MAPK pathway, though these results are also ultimately not specific. The pathogenesis of RDD is yet to be elucidated, but recent studies suggest possible clonality of hyperproliferative histiocytes.

Patient-Derived Xenograft and Cell Line Models of Human Primary Cutaneous Diffuse Large B-Cell Lymphoma-Leg Type

Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is a rare and aggressive malignancy, mostly occurring on the leg of elderly women (Willemze et al., 2019). PCDLBCL-LT harbors an activated B-cell‒like diffuse large B-cell lymphoma (ABC-DLBCL) signature and is enriched for mutations involving the toll-like receptor, B-cell receptor, and NF-κB pathways (Pham-Ledard et al., 2012; Zhou et al., 2018). The high frequency of MYD88L265P mutation in combination with those of CD79B and PIM1 relates these lymphomas to the MCD/C5 subset of diffuse large B-cell lymphomas, which includes ABC-DLBCL occurring in extranodal sites (Danilov et al., 2022).

Abstract A15: Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL)

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and in 30-40% cases can present or relapse at extranodal sites. Primary extranodal DLBCL (EN-DLBCL) is defined as disease presenting as clinically dominant extranodal masses with no or only minor nodal disease. EN-DLBCL is predominantly of the activated B-cell (ABC) and less commonly of germinal center B-cell (GCB) like DLBCL subtype. We aimed to identify genetic characteristics of EN GCB-DLBCL to gain insights into extranodal tropism and aggressive clinical behavior. Methods: Patient data was collected via retrospective chart review. Inclusion criteria consisted of pathologically confirmed diagnosis of GCB-DLBCL by the Hans algorithm, extra-nodal involvement at diagnosis or relapse, and availability of next-generation sequencing (NGS). Overall (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Results: Fifteen patients were identified. The median age at diagnosis was 64 years (range 33-89) and majority were men (62.5%). Two patients had purely nodal disease at presentation that relapsed at EN sites, while the remainder (13/15) had predominantly EN disease. EN sites included central nervous system [CNS] (n = 5), bone marrow (n = 4), epidural (n=4), bone (2), paranasal sinus (1), testes (1), stomach (n = 2), lung/pleura (n=2), and liver (n=3). Nine patients had disease in multiple EN sites. All patients had advanced stage disease and median IPI score was 3 (range 3-4). On FISH/cytogenetic analysis, two patients had MYC and four patients had BCL2 rearrangements. Copy gains in BCL6, BCL2 and MYC were seen in 2, 1 and 4 patients respectively. No patients had evidence of MYC and BCL2 and/or BCL6 rearrangements (double hit). TP53 deletion was seen in 1 patient. On NGS, prominent gene mutations identified were KMTD2 (8/15, 53%), TP53 (5/15, 33%), TNFRSF14 (4/15, 27%), and evidence of aneuploidy with abnormalities in chromosome 12 (5/15, 33%), chromosome 6 (4/15, 27%), and chromosome 8 (4/15, 27%), including both losses and gains of function. Notably, MYD88 (3/15, 20%), CARD11 (2/15, 13%), and IRF4 (2/15, 15%) mutations, representative of BCR/TLR4 pathway activation and NF-kB signaling were seen at initial presentation. All patients were treated with chemo-immunotherapies incorporating CNS prophylaxis and 2 patients received salvage CAR T-cell therapy. Median OS was 1.3 years and median PFS was 11.3 months. Nine patients (63%) progressed, with CNS relapses in 5 and of these, 7 patients died. Conclusions: This study shows that EN GCB-DLBCL is molecularly similar to EN ABC-DLBCL; specifically, activation of NF-kB pathway signaling through gene mutations involving the MCD (MyD88/CD79B) cluster is prominent, and this potentially enables extranodal tropism. The complex karyotype and TP53 mutations may contribute to chemoresistance and aggressive disease biology. Our results provide valuable molecular information and can aid in personalizing treatment strategies for this uncommon, aggressive DLBCL subset. Citation Format: Akshat Patel, Brian Lue, Kiran A Kumar, Farrukh T Awan, Jeffrey Gagan, Weina Chen, Praveen Ramakrishnan Geethakumari. Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL) [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A15.

A Multicenter Study of Clinicopathology and Immunohistochemical Distinction between Adult and Pediatric Large B-Cell Lymphoma

Introduction: Pediatric DLBCL is considered a homogenous group and has superior outcomes compared to adults. This study investigated the clinical pathology and immunohistochemical distinction between adult and pediatric large B-cell lymphoma. Methods: A cross-sectional study of 314 NHLs with the morphology of diffuse pattern, large B-cell, and CD20 expression was investigated. Results: Of 314 cases, there were 6 cases of pleomorphic MCL (all in adults), 19 cases of Burkitt lymphoma (all in children), and 289 cases of DLBCL. Pediatric DLBCL had many striking differences: More frequency in extra-nodal sites; a higher proportion of centroblastic morphology; a predominance of GCB-type; a high proliferation rate; an infrequency of Bcl2 protein expression, and a lack of double-expresser lymphoma. Conclusions: Our study demonstrated the significant biological differences between adult and pediatric DLBCL.

Extranodal risk sites for CNS lymphoma: Review, good practice guide and the new SIHMIR paradigm shift

Category: Other

MALT LYMPHOMA IN PAROTID GLAND ASSOCIATED WITH SJÖGREN'S SYNDROME

Mucosa-associated lymphoid tissue (MALT) lymphoma is a subtype of non-Hodgkin lymphoma, often affecting the parotid glands in Sjögren syndrome (SS). MALT lymphoma is an indolent disease frequently located in mucosal or nonmucosal extranodal sites. A 63-year-old woman complained of a nodular growth near her ear. Upon palpation, a nodular mass was observed in proximity to the anterior lobe of the left parotid gland. She reported dry mouth feeling lasting 2 years, hoarseness, dryness of the eyes and vaginal mucosa, tiredness, and body pain. Parotid ultrasonography and magnetic resonance imaging, minor salivary gland biopsy, and ophthalmologic evaluation were obtained. After 2 inconclusive ultrasound-guided needle biopsies, the lesion was removed by partial parotidectomy. Immunohistochemical analysis showed B-cell MALT lymphoma in the parotid gland, associated with SS. The patient was referred to a hematology oncologic center for evaluation and follow-up was established every 6 months.

Hodgkin lymphoma of skin masquerading as inflammatory breast carcinoma - A rare case report

Hodgkin’s Lymphoma is a B- Cell neoplasm occurring in lymph nodes and extra-nodal sites. Among the latter, skin involvement is a rare phenomenon with a very low incidence rate. Cutaneous involvement of Hodgkin’s Lymphoma may have varied clinical presentations from erythematous papules to ulcers. However, a thorough search in histology shows the classic RS cells which are diagnostic of Hodgkin’s lymphoma, but this needs a high degree of suspicion. Presentation of Hodgkin Lymphoma, in an elderly female patient of 60 years of age bearing erythematous skin changes over breast which made a clinical suspicion of inflammatory breast carcinoma, is presented here.

Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations

AbstractNodal peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with cytotoxic phenotype is overall rare, with most reports coming from Asia. Given its elusive pathobiology, we undertook a clinicopathological and molecular study of 54 Western patients diagnosed with PTCL, NOS expressing cytotoxic molecules, within a lymph node. More commonly males (M/F-2,6/1) with median age of 60 years were affected. Besides lymphadenopathy, 87% of patients had ≥1 involved extranodal site. High-stage disease (III-IV), International Prognostic Index >2, B symptoms, LDH level, and cytopenia(s) were observed in 92, 63, 67, 78, and 66% of cases, respectively. Ten patients had a history of B-cell malignancies, one each of myeloid neoplasm, breast or prostate cancer, and 4 others had underlying immune disorders. Most patients (70%) died, mostly of disease, with a median overall survival of 12.7 months. Immunophenotypically, the neoplastic lymphocytes were T-cell receptor (TCR) αβ + (47%), TCR-silent (44%) or TCRγδ+ (10%), commonly CD8 + (45%) or CD4-CD8- (32%). All except one had an activated cytotoxic profile, and 95% were subclassified into PTCL-TBX21 subtype based on CXCR3, TBX21, and GATA3 expression pattern. Seven patients (13%) disclosed EBER + tumor cells. Targeted DNA deep-sequencing (33 cases) and multiplex ligation-dependent reverse transcription-polymerase chain reaction assay (43 cases) identified frequent mutations in epigenetic modifiers (73%), including TET2 (61%) and DNMT3A (39%), recurrent alterations affecting the TCR (36%) and JAK/STAT (24%) signaling pathways and TP53 mutations (18%). Fusion transcripts involving VAV1 were identified in 6/43 patients (14%). Patients with nodal cytotoxic PTCL, NOS have an aggressive behavior and frequently present in a background of impaired immunity, although the association with Epstein-Barr virus is rare. The recurrent alterations in genes involved in DNA methylation together with genes related to cytokine or TCR signaling, suggest that co-operation of epigenetic modulation with cell-signaling pathways plays a critical role in the pathogeny of these lymphomas.