Extranodal Localization Research Articles

Follicular dendritic cell sarcoma involving the parotid gland with expression of the melanocytic marker PRAME.

Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm arising from follicular dendritic cells (FDC) of lymphoid follicles. While the majority of FDC sarcoma cases arise within lymph nodes, approximately 30% manifest in extranodal sites. Only 4 prior occurrences of intra-parotid FDC sarcomas have been documented. We are reporting a rare case of FDC of the parotid gland in a 65-year-old male with a questionable history of B-cell lymphoma. The patient underwent a right total parotidectomy and bilateral neck dissection. A diagnosis of follicular dendritic cell (FDC) sarcoma was made, with one positive intra-parotid node. The malignant cells expressed the characteristic markers for FDC sarcoma but with positivity of the melanocytic marker PRAME. This is a case of FDC sarcoma with an unusual extranodal localization in the parotid gland. Immunohistochemistry was useful in making a diagnosis although the positivity for the melanocytic marker PRAME was unusual and unreported before.

CORRELATION OF T-CELL LYMPHOMA SUBTYPES WITH ANEMIA AT DR MOHAMMAD HOESIN HOSPITAL PALEMBANG 2018-2022

Lymphoma is divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Among NHL T-cell lymphoma is a rare malignancy of T cells, accounts for 12% of all NHL cases, it is further classified into 53 subtypes by WHO. T-cell lymphoma generally have worse prognosis than those B cells. In 2020 there were 16.125 new cases in Indonesia with 9.024 deaths for all ages and genders. Anemia occurs in some cases of lymphoma, which will make the prognosis of lymphoma worse. This study aims to determine the relationship between T-cell lymphoma subtype and anemia. This observational analytic study utilized a cross-sectional design conducted at the Department of Anatomic Pathology Faculty of Medicine Sriwiaya University/Dr. Mohammad Hoesin Palembang Hospital (RSMH) and the central laboratory of RSMH. The samples from this study were all patients who were diagnosed histopathologically and immunohistochemically as T cell lymphoma at RSMH Palembang from 2018 to 2022. Among 38 samples, T-cell lymphoma predominated in the age group <55 years (73,7%), male gender (73,7%), extranodal location (73,7%), and ENKTCL, nasal subtype (55,3%). Anemia occurred in 60,5% cases and most often it is mild anemia (60,9%). There was no significant correlation between T-cell lymphoma subtype and anemia status (*p = 0.178) and T-cell lymphoma subtype and anemia degree (*p = 0.342). It can be concluded that there is no significant correlation between the T-cell lymphoma subtype and anemia.

A Retrospective Study of 341 Cases of Primary Extranodal Non-Hodgkin Lymphoma of the Head and Neck

Aims: Our goal was to obtain comprehensive and accurate information about primary extranodal non-Hodgkin lymphomas of the head and neck region to contribute to the advancement of medical knowledge in this field. Materiels and methods: We conducted a retrospective study of 341 patients with primary extra-nodal, non-Hodgkin lymphomas of the head and neck, over a period of 7 years from January 2016 to December 2022, in the departments of ENT and Head and Neck Surgery and Hematology, with the help of the department of anatomical pathology of the university hospital Mohammed VI of Marrakech. Results: 341 patients, with primary extra-nodal, non-Hodgkin lymphomas of the head and neck, was included, with an average age of 57 years, and a sex ratio male/female of 2.21 . in more than half of the cases; Waldeyer's ring was concerned; especially palatine tonsils. Type B NHL was the most frequent and involved 308 patients. Diffuse large B-cell lymphoma was the commonly observed histological type, found in 214 patients; followed by a Follicular Lymphoma and Extra-Nodal NK/T‑Cell Lymphoma, Nasal Type. Following the extension workup; patients were all staged according to the ANN ARBOR classification; with a 77.8% of them were localized stages I and II, and of the therapeutically evaluable cases, complete remission was achieved in 112 patients. Conclusion: Our study focused on all extra-nodal localizations of NHL in the head and neck region. Due to the very heterogeneous nature of these tumors, most of the current studies are limited to a specific site of involvement. Nevertheless, our study provides an overall picture; which those specific studies can be based. The management of NHL has evolved considerably in recent years, insisting on the multidisciplinary character to a better management of these patients.

Brazilian Non-Hodgkin T Cell Registry: An Exploratory Analysis of Extranodal Sites

Introduction: T cell lymphomas (NHL-T) account for 10-15% of all non-Hodgkin lymphomas (NHL). They are a heterogeneous group of infrequent neoplasms with a variable clinical course but prevalently aggressive behavior and high mortality rates. Diagnosis is still challenging and there has been little change in the overall prognosis over the last two decades. In spite of IPI (International Prognostic Index) that include extranodal (EN) site in its variables, lack is known regarding EN involvement in nodal peripheral T cell lymphomas- PTCL (PTCL-NOS, TFH and ALCL ALK+/ALK-) location or impact on prognosis). Objective: We aim to evaluate number of extranodal (EN) sites in nodal PTCL lymphomas (PTCL-NOS, TFH and ALCL ALK+/ALK-) and its specific location as a surrogate for overall survival (OS) and progression free survival (PFS). Also generate hypothesis for further molecular analysis. Methodology: Brazil T-cell project is a national, ambispective study of patients with histological diagnosis of PTCL diagnosed from January 2015 to December 2022. Approval for the study was obtained at the coordinating center (Samaritano Hospital - São Paulo) and at each participating center as per the institutional standard before initiation. Those selected for the study were previously untreated patients age ≥ 19 years, with de novo PTCL or natural killer/T-cell lymphoma. At each institution, the local pathologist reviewed the diagnose. Clinical information included coded patient and site identifiers, sex, date of birth, date and site of diagnostic biopsy, sites of disease, EN (location and number), methodology of staging (clinical, CT or Pet) and Ann Arbor stage. Initial therapy and response; details of remission, progression, or relapse; and subsequent therapies, along with survival status and cause of death. Treatment outcome was determined by OS and PFS. REDcap Platform (by Vanderbilt) has been used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. This trial is registered at Clinical trials (NCT03207789). Results: Of 621 registered we selected 198 patients (pts) diagnosed with nodal PTCL with at least one EN involvement [Cohort 1 EN involvement equal to one (148 pts) and Cohort 2 EN involvement ³ 2 (50 patients)]. Considering all 198 pts (Cohort 1 and 2) there was a slight male predominance (63%); median age 53 years; 79% were staged III or IV; 81.5 were IPI 2 or more. Most frequently histology was PTCL-NOS (46%), followed by ALCL ALK+ (32%), ALCL ALK- (12.5%) and TFH (9.5%). The majority had B Symptoms (63%); 37.5% had Bone Marrow infiltration. The chemotherapy most frequently chosen were CHOEP (54.5%) followed by CHOP (19.5%). Transplant was used as consolidation in 20% of the cases. Almost half of patients achieved complete response after first line (44%), although 38% relapsed. Cohort 1 (EN=1) and 2 (EN ³ 2) were similar regarding clinical characteristics, except, for stage III-IV (73% vs 96%; p <.0001); IPI ³ 3 (37.5% vs. 82%; p <.0001) and ECOG (22 vs. 48%; p=.001), respectively. Therefore, translating in a more advanced disease in Cohort 2. The most common extranodal location in Cohort 1 (EN=1) was Skin/ Subcutaneous (35%), followed by gastrointestinal tract (18%) and lung (16%). NHL-T subtypes behaved similarly in this EN exploratory analysis, with a better OS and PFS in ALCL ALK+, followed by ALK- and PTCL-NOS. There was no difference in PFS in Cohort 1 (EN=1) and 2 (EN ³ 2), but there was a slight difference in Overall survival (55% vs. 42% in 12 months; p=0.06), suggesting EN sites involvement assessed by CT and PET-CT as possible surrogate for outcomes in this population. Conclusion: NHL-T is still unmet medical need considering suboptimal outcome in treatment and survival. New biological and clinical finding are still necessary to adequate stratify this group of patients, considering poor performance of IPI and PIT scores. Number and location of EN sites involvement may be a possible surrogate for outcome, which can be a reflect of a distinct biology, that needs further investigation. Registries are of importance considering rarity and poor prognosis of this diseases and an adequate instrument to hypothesis generation.

Prognostic Significance of the Neutrophil/Lymphocyte Ratio in Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis

PROGNOSTIC SIGNIFICANCE OF THE NEUTROPHIL/LYMPHOCYTE RATIO IN DIFFUSE LARGE B-CELL LYMPHOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has stunned up as an easy to use prognostic biomarker in different cancers. Although the exact mechanism remains to be elucidated, reduced infiltration of intratumoral lymphocytes along with the development of neutrophil extracellular traps (i.e., NETosis) has been postulated as endogenous mechanisms for tissue damage and inflammation. We previously reported a NLR ≥4 as independently associated to inferior complete response rates to chemoimmunotherapy and worse survival in Latin American (LATAM) patients with diffuse large B-cell lymphoma (DLBCL; Beltran, Clin Lymphoma Myeloma Leuk, 2020). Here we present a systematic review and meta-analysis on the prognostic value of the NLR in DLBCL. METHODS: A systematic search was conducted using PUBMED, EMBASE and SCOPUS databases up to the most recent date (October 2022). Prospective and retrospective cohorts were reviewed using the diagnosis of DLBCL according to the WHO criteria. The NLR was defined as the ratio between absolute neutrophil and lymphocyte counts in peripheral blood prior to initiating therapy. Two independent reviewers selected the studies and subsequently extracted the data. Clinical variables included gender, age, tumor stage, IPI, presence of B symptoms, serum LDH level, extranodal location, ECOG performance status, treatment regimen, NLR value, Hazard Ratio with its respective 95% confidence interval (CI). Once the quality of the extracted data was verified, a quantitative synthesis of the information was conducted through a meta-analysis-based approach. Additionally, a sensitivity analysis was performed using the leave-one-out method and a NLR cut-off of >4. A meta-regression model was applied to assess the influence of a sample size <200 (based on previous reviews) on the heterogeneity of the results. Primary endpoints were overall survival (OS) and progression-free survival (PFS) rates. Association was reported by Hazard Ratio (HR). Risk of bias was assessed using the Newcastle-Ottawa Scale adapted by Hassan-Murad et al. Data were analyzed using the R program version 4.2.3. RESULTS: Fifteen studies were identified and 4,149 patients were included. Only 3 studies were from Latin America. The median NLR was 4.1 (range 1.5 to 5.54). Thirteen studies with 3,498 patients showed a significant association between NLR and OS (HR: 1.57 [95% CI: 1.3-1.9, I2: 46%; P=0.04]), and 11 studies with 2,660 patients found no association between NLR and PFS (HR: 1.32 [95%CI: 0.8-2.03, I2: 0%; P=0.72]). When reanalyzing the data by region, the NLR was associated to worse OS in Latin American patients (HR: 1.94 [95%CI: 1.14-3.3, I2: 51%; P=0.15]), followed by Europe (HR: 1.79 [95%CI: 1.41-2.27, I2: 0%; P=0.74]) and finally Asia (HR: 1.26 [95% CI: 0.8-1.8, I2: 62%; P=0.02]) Regarding the association between NLR and PFS according to region, Europe (HR: 5.08 [95%CI: 0.7-38, I2: 93%; P<0.001]) and Asia (HR: 1.28 [95CI %: 0.95-1.71, I2: 56%; P=0.03]) did not present an association. We could not perform analysis for Latin America due to only one study was available for analysis. Regarding the cut-off point for NLR, a cut-off of >4 was adversely associated with OS (HR: 1.63 [95%CI: 1.36-1.95, I2: 0%; P=0.46]), and a trend for worse PFS (HR: 1.70 [CI-95%: 1.24-2.33, I2: 51%; P=0.08]). In the sensitivity analysis, when we excluded the results of Jing Wang et al, the heterogeneity disappeared (I2=0%, p<0.01). However, the effect size of the association was not significantly increased (HR: 1.69 [95% CI: 1.46-1.96, I2: 0%; P<0.01]). In the sensitivity analysis for PFS, the results remained stable. The absence of publication bias between studies was confirmed for OS (p= 0.42), but not for PFS (p< 0.0001). A sample size <200 did not influence heterogeneity. DISCUSSION: Our study found the NLT as a relevant prognostic factor for OS in DLBCL patients. The main limitation was the inconsistency of the cut-off values for the NLR in the different studies included, suggesting the need to standardize this cut-off for future research studies. However, a cut-off point >4 could be a promising clinical biomarker for this patient population.

PET/CT Enables Appropriate Staging in Extranodal Marginal Zone Lymphoma

Introduction: PET/CT is the standard-of-care for staging and therapy response assessment in lymphoma. Fluorodeoxyglucose (FDG)-avidity in extranodal marginal zone lymphoma (EMZL) remains controversial with some variability by extranodal location. The current Lugano classification recommends the use of CT scans only in staging and follow-up for EMZL. However, emerging data from small studies have challenged this suggestion. In this study we aimed to determine the ability of PET/CT to detect FDG-avid EMZL during staging work-up. Methods: First, we retrospectively analyzed the University of Miami (UM) MZL database (period 2/2016-1/2023) searching for patients who underwent staging PET/CT. Images were reviewed by expert radiologists to ascertain avidity of tumor and not surrounding tissue, with specific attention to ocular and GI locations; if scans were not available (n=15), we retrieved data from reports (results presented in part at ICML2023). Next, we aimed to validate the initial UM results additionally analyzing data from imaging reports for patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) MZL cohort (period 7/2015-5/2020), excluding LEO patients from Miami to avoid overlap. Patients with high-grade transformation at diagnosis were excluded. For patients with >1 extranodal site, each location was counted independently. We considered FDG-avid disease if SUVmax was ≥2 as this value is commonly observed between mediastinal blood pool (BP) and liver background. To normalize data, we calculated ratios of lymphoma SUVmax versus both BP and liver background, as available. Patients without measurable disease were excluded from analysis. Results: Among 210 patients with EMZL in the UM cohort, 152 had staging PET/CT and were analyzed. Twenty-two patients demonstrated >1 extranodal site providing a total of 187 locations. The LEO cohort included 411 patients from 7 centers, with 235 having available imaging reports. Fifty-two patients in this cohort demonstrated >1 extranodal site providing a total of 306 locations. Disease distribution is depicted in Table 1. Among 187 EMZL locations in the UM cohort, the most common were gastric (n=33, 17.6%), ocular (n=31, 16.6%), lung (n=30, 16%), skin and soft tissue (n=16, 8.6%, each). Similarly, lung (n=63; 20.6%), soft tissue (n=46; 15%), gastric and ocular (n=34 each; 11%) were common locations in the LEO cohort. EMZL demonstrated FDG-avidity (SUVmax ≥2) across all locations with identical values in both cohorts (UM= 78.1% & LEO= 76.5%). FDG-avidity by location is shown in Table 1A & B with salivary gland (100% & 100%), lung (93.3% & 95.2%), soft tissue (93.8% & 100%), and airways (90.9% & 100%) demonstrating high avidity in both cohorts. Contrarily, skin was commonly non-FDG avid (93.8% & 81%). The median size of FDG-avid lesions was 2.4cm (range, 0.7-17.4) in UM and 2.9cm (range, 0.1-12) in LEO cohorts. In patients with >1 extranodal site FDG-avidity was nearly universal across sites (UM=93% & LEO=100%). We observed a significant correlation between lymphoma size and FDG-avidity for UM (r=0.33; P=0.001), and for LEO (r=0.55; P<0.0001). In patients with background FDG-avidity data in the UM cohort (n=150), a BP index and liver index ≥1 detected lymphoma in 79.3% & 71.5% cases, respectively. We were unable to calculate indexes in LEO cohort since only limited data on BP (n=26) and liver (n=19) background was available in imaging reports. Conclusions: This study represents the largest analysis evaluating accuracy of PET/CT to determine initial tumor burden in 387 patients with EMZL. We demonstrate that EMZL is largely an FDG-avid disease across two cohorts, and PET/CT should be included in the staging of these patients while acknowledging possible limited sensitivity in GI locations due to physiologic uptake. Furthermore, we observed that patients with multiple extranodal locations demonstrate uniform FDG-avidity across all sites except for skin involvement. Based on our results we recommend the incorporation of PET/CT into standard staging of EMZL in planned revised Lugano classification guidelines. In those demonstrating initial FDG-avidity, a lower SUVmax threshold of SUVmax ≥2, comparison to mediastinal BP rather than to liver background activity and evaluating for resolution of focal FDG-avidity should be considered to assess treatment response in routine care and clinical trials.

Phase II Clinical Trial of R-CHOP Combined with Lenalidomide in the First-Line Treatment for Patients with High Risk Diffuse Large B Cell Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.

A Population-Based Study on Performance of Clinical Prognostic Models in Patients with Diffuse Large B-Cell Lymphoma Younger Than 70 Years

Background: In diffuse large B-cell lymphoma (DLBCL), the International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) remain the primary prognostic tool for outcome predictions and risk stratification in clinical trials. Several prognostic indices with the same five risk factors included in the IPI have been developed for DLBCL patients, including Revised IPI (R-IPI) and National Comprehensive Cancer Network IPI (NCCN-IPI), showing a decreased prognostic value of the IPI. Additionally, an age-adjusted DLBCL-Prognostic Index (aaDLBCL-PI) developed in patients younger than years combining similar variables (excluding age and stage), but with the addition of albumin, showed better accuracy than the IPI. Younger patients without comorbidities and a history of cancer are typically candidates for clinical trials, but validation studies of prognostic indices in this population are mostly lacking. Aim: This study aimed to compare five clinical models (IPI, aaIPI, R-IPI, NCCN-IPI, and aaDLBCL-PI) in patients with DLBCL younger than 70 years identified from the Danish Lymphoma Registry (LYFO). Methods: Patients diagnosed between 2000 and 2021 and identified through the LYFO were included if they fulfilled the following criteria: 1) newly diagnosed DLBCL; 2) age <70 years; 3) treated with at least one cycle of immunochemotherapy (R-CHOP/R-CHOP-like); 4) availability of all parameters for calculation of all five prognostic models; and 5) no previous/concomitant malignancy (excluding non-melanoma skin cancer). Patients with isolated central nervous system lymphoma were excluded. Discriminatory ability was calculated using the concordance index (c-index), with 1 indicating perfect discrimination and 0.5 indicating random guess. Model fitness was compared with the Akaike Information Criterion (AIC), with the lower values indicating a better fit of a model and the difference ≥10 between models indicating a significant improvement in model fitness. Results: Of 3,184 DLBCL patients younger than 70 years, 2,456 had all parameters available for calculating five prognostic models and were included in the final analysis. The median age at diagnosis was 59 years (range 18-69) with a slight male predominance (n=1,440, 58.6%). Most patients (n=1,619, 65.9%) had advanced (III/IV) stage of disease and were in good performance status 0-1 (n=2,165, 88.2%). More than one extranodal localization was diagnosed in 738 patients (30%), and more than half of our population (n=1,462, 59%) had elevated LDH levels. All models stratified patients into four risk groups except R-IPI, which provided three risk groups. The proportion of patients allocated to the low-risk group according to the IPI, aaIPI, R-IPI, aaDLBCL-PI, and NCCN-IPI were 32.9%, 19.7%, 12.3%, 17.4%, and 15.3%, respectively. The lowest proportion of patients in the high-risk group was identified by NCCN-IPI (6.3%), followed by IPI (14.8%), aaIPI (20.2%), aaDLBCL-PI (22.0%), and R-IPI (40.7%), respectively. The median follow-up was 78.1 months (range 0.2-244 months). As presented in Table 1, NCCN-IPI produced the highest absolute 3- and 5-year difference between high and low-risk groups and was the only model with less than 50% of surviving patients in the high-risk groups in respective survival time points. Moreover, the highest c-index was calculated for NCCN-IPI (0.709), followed by IPI (0.703), aaDLBCL-PI (0.692), R-IPI (0.679), and aaIPI (0.667). NCCN-IPI showed a statistically significant difference in discriminatory ability compared to all models except IPI. The lowest AIC was found in NCCN-IPI (9,231), along with IPI (9,295), aaDLBCL-PI (9,369), R-IPI (9,310), and aaIPI (9,408). When patients aged ≤60 were selected (n=1,328), NCCN-IPI again produced the highest absolute 3- and 5-year difference between high and low-risk groups. Moreover, NCCN-IPI had the highest c-index and lowest AIC (0.758; 3,068) compared to IPI (0.742; 3,118), aaIPI (0.730; 3,124), R-IPI (0.729; 3,109), and aaDLBCL-PI (0.751; 3,110). Conclusion: In this retrospective population-based study investigating 2,456 patients with DLBCL 18-69 years of age, we found NCCN-IPI superior to IPI and, in particular, aaIPI and R-IPI. Therefore, we suggest reporting NCCN-IPI and IPI for risk stratification in future studies and clinical trials.

SPINAL TUMORS-05 CERVICAL DENDRITIC FOLLICULAR SARCOMA: ABOUT A CASE WITH LITERATURE REVIEW

Abstract Dendritic follicular sarcoma (DFS) is a very rare and often poorly known neoplasia. It develops mainly in peripheral lymph nodes at the expense of dendritic follicular cells. However, extra nodal locations were also found in the literature. Diagnosis is often difficult, based mainly on histopathological and immunohistochemical data. There is currently no consensual therapeutic strategy proposed by the National Understanding Cancer Network. The aim of this work is to focus on the various epidemiological, histopathological, immunohistochemical and therapeutic aspects of the follicular dendritic sarcoma. We report the case of a cervical dendritic follicular sarcoma with literature review. This is a 51-year-old patient with no particular pathological history, consulting for a right lateral cervical mass evolving for 5 years without dyspnea, dysphagia, dysphonia, nor other associated signs evolving in a context of apyrexia and general state conservation. The clinical examination had objectified a firm, fixed, painless right upper jugulocarotid mass without inflammatory signs in sight. The cervical MRI had objectified two contigüe lateral cervical tissue masses well encapsulated, well limited necrotic with mass effect on the larynx without vascular enclosing. The patient had benefited from tumor reduction. Histology was in favor of a dendritic follicular sarcoma. Cervical CT was performed 2 months postoperatively which had shown a mixed right lateral cervical mass with thickened wall and hypodense center pushing in and back the primary carotid and forward the internal jugular vein without any sign of invasion locoregional. The patient then benefited from a complete removal of the tumor mass with ligation of the internal jugular vein. The anatomopathological study had objectified a tumor proliferation made of fusiform cells with nuclei augmented of irregular volume, nucleoli presenting moderate atypies without peri nervous engainement or neoplastic vascular emboli. Immunohistochemistry had shown positive antibodies anti-CD23, anti-CD35, anti-vimentin and anti-PS100. The Ki-67 index was positive on 15% of the cells. This profile concluded in a dendritic follicular sarcoma. The post-operative follow-up was simple. The patient was then referred to oncology for complementary radiation therapy. At 6 months no sign of recurrence was noted. Dendritic follicular sarcoma (DFS) is a relatively rare entity derived from dendritic follicular cells, which are B-cell antigen-presenting cells in the germinal centres of lymphoid follicles. It mainly affects the peripheral lymph nodes especially those of the head and neck. However, extra nodal tissues are affected in about 30% of cases especially the pharynx, oral cavity, thyroid gland. The diagnosis of SFD is difficult and often poorly understood, due to its silent symptomatology, extremely varied morphology and aspecific imaging. The main differential diagnoses are inflammatory myofibroblastic tumors, pseudotumoral tumors, interdigitant dendritic cell sarcomas, lymphomas and undifferentiated carcinomas. Diagnosis is mainly based on pathological examination with immunohistochemical complement.

Primary Extranodal Non-Hodgkin Lymphoma of Cheek

Non-Hodgkin’s lymphomas (NHL) comprise a group of extremely diverse lymphoproliferative neoplamas that have a predisposition for extranodal sites. Amongst the extranodal locations rare involvement of oral cavity has been reported and occurrence of these neoplasms on the cheek are thin on the ground. The most commonly encountered is the Diffuse large B-cell lymphoma. The B-cell neoplasms are clonal tumors of mature and immature B cells and the relatedness of B-cell lymphomas to normal B-cell counterparts forms a key aspect in their nomenclature of classification. Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), consists of medium-sized to large B cells with a diffuse growth pattern. This lesion is a morphologically and molecularly heterogeneous entity which does not meet the diagnostic criteria of any specific large B-cell lymphoma neoplasms. Amongst the cases of DLBCL in n the head and neck region involvement of cheek/ buccal mucosa is scarce.

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.

T-lymphoblastic lymphoma of mediastinal lymph nodes with secondary thyroid involvement in an adolescent

Introduction Among tumors of lymphatic tissue, T-lymphoblastic lymphoma is a rare disease, with children and adolescents being affected more often. The thymus, lymph nodes and various extranodal localizations are involved in the tumor process, but no descriptions of secondary thyroid involvement in the tumor process in children with primary lymphoma of other localizations were found in the available literature.The aim of the study was to describe a rare observation of secondary thyroid involvement in mediastinal lymphoma with deciphering of tumor immunophenotype in an adolescent immunomorphological analysis of surgical material.Materials and methods. We analyzed the archived medical records, data of clinical, laboratory, instrumental and morphological studies of non-Hodgkin’s lymphoma of mediastinal lymph nodes with thyroid involvement. Histological examination of the material stained with hematoxylin and eosin followed by immunohistochemical examination with a set of 16 mono- and polyclonal antibodies was carried out 22 years later on the archive paraffin blocks.Results Morphological examination of the thyroid biopsy specimen and resectate of its isthmus made pathological and anatomical conclusion: non-Hodgkin’s lymphoma of the thyroid gland, prolymphocytic variant. Thanks to an adequately planned program of polychemotherapy, it was possible to achieve long-term remission with a 22-year recurrence-free survival rate. The retrospective data of clinical, instrumental, laboratory investigations and the results of immunohistochemical analysis of the archived tissue material with the help of a panel of 16 mono- and polyclonal antibodies were compared and the following conclusion was made: C83.5 (ICD-O code 9837/3) upper mediastinal lymphocytic T-lymphoma with secondary damage of the thyroid gland. Complete remission after polychemotherapy with a 22-year recurrence-free survival.Discussion It was shown that correctly planned treatment on the basis of competent identification of the histo- and cytogenesis of the tumor in the course of well-coordinated teamwork of specialists of different profile (hematologists, pathologists, chemotherapists, etc.) resulted in a favorable outcome. We managed to achieve a long-term remission with no recurrence of the disease for 22 years. By means of immunomorphological analysis, based on the recommendations of new classification of the haemopoietic and lymphoid tissue tumors, at the present stage of medical science development we managed to decode the tumor immunophenotype, which made more concrete, but not refuted the pathological anatomists’ conclusion, made 22 years ago.Conclusion Analysis of the presented case showed that the tumor immunophenotype corresponded to T-lymphoblastic lymphoma with secondary thyroid involvement. In spite of the fact that in this tumor any extranodal localization is possible, in the available literature we could not find any information about secondary involvement of thyroid in tumor process.

Neurolymphomatosis diagnosed on [18F]FDG PET/CT.

Fluorine-18-deoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has been shown to be superior to other conventional imaging modalities in the detection of extra-nodal lymphomatous localizations. Especially in neurolymphomatosis which is rarely encountered in high-grade lymphomas. We report a case of a woman diagnosed with non-Hodgkin lymphoma, whose initial staging with [18F]FDG PET/CT showed increased [18F]FDG uptake along the brachial and sacral plexuses. [18F]FDG PET/CT remains the most appropriate diagnostic tool in these cases, whose prognosis is often poor.

Extranodal Locatio of Lymphoma: Presentation and Evolutionary in Senegalese Patients

Introduction: The frequency of extranodal involvement in lymphoma is not rare, but variously described by authors in Africa. The objective of our work is to describe the profile of patients followed for lymphoma with extranodal locations. Methods: We conducted a descriptive, retrospective and analytic study at the clinical hematology department of Dalal Jamm Hospital, from September 2016 to June 2022. We included patients with a diagnosis of lymphoma immunohistochemistry, with extranodal involvement. The epidemiological, diagnostic, prognostic and survival aspects were studied. Results: Fifty-two (52) patients with extranodal localizations of their lymphoma were included. The mean age was 44.2 ± 17.6 years and the sex ratio was 1.2. The average time to diagnostic was 9.4 ± 3.6 months. We found a performance status ≥ 2 in 65.4% and at least one B symptom in 71.2% of cases. The extranodal manifestations were digestive (19%), cutaneous (17.5%), pleuropulmonary (17.5%), bone marrow (4.8%), thyroid (1.6%), parotid gland (1.6%) and breast (1.6%). Patients presented with Hodgkin’s lymphoma (HL) in 19.2% of cases and non-Hodgkin’s lymphoma (NHL) in 80.8% of cases. At the end of the extension checkup reviews, 61.5% were at an advanced stage and prognostic indices were unfavorable in 32% of patients. Conventional chemotherapy was conducted in 63.5% of patients of which 24 had NHL and 9 had HL. Immuno-chemoterapy was used in 26.9% of patients (13 cases of NHL, 1 case of HL). During the follow-up, we noted only 29.7% of complete remission. The median overall survival was 25.1 months [23.5 - 34.1 months] in HL group and 20.5 months [18.7 - 72.2 months] in NHL patients (p = 0.14). Conclusion: Our study shows that extranodal involvements of lymphomas are various, encountered more during NHL. In our practice, diagnosis is generally made at an advanced stage, with poor response to treatment.

Non-Hodgkin’s Lymphoma Presenting Section as a Soft Tissue Mass on Right Thigh

Non-Hodgkin’s Lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with a greater preference for disseminating to extranodal locations. Prevalence of extranodal involvement in NHL has increased in the past decade, and the sites involved are the stomach, spleen, waldeyer’s ring, Central Nervous System (CNS), lungs and skin. This is a rare case of NHL in a 48-year-old female who presented with solitary exophytic mass with ulceration over the right thigh and erythematous plaque over postaxillary region and enlarged right inguinal and left axillary lymph nodes. Magnetic Resonance Imaging (MRI) of the right thigh showed lobulated mass involving skin and subcutaneous soft tissues without any intramuscular extension suggestive of neoplastic mass. Fine needle aspiration cytology of the inguinal node and biopsy of the right thigh lesion showed features suggestive of NHL. She was treated with three cycles of Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone (CHOP) regimen, but the patient succumbed to death after six months of chemotherapy

Non-Hodgkin's Malignant Lymphomas of the Palatine Tonsils: A Case Report

The palatine tonsils are the first extra-nodal localization of cervicofacial non-Hodgkin's malignant lymphomas. It is a rare localization and most often a type B lymphoma. This case highlights the difficulty of making an early diagnosis, given the non-specificity of clinical and paraclinical signs, and the fact that only anatomopathological examination can confirm the diagnosis. Chemotherapy is the only treatment for chemo sensitive forms of the disease. Prognosis is generally good, depending on sensitivity to treatment and stage of disease.

Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n=33), mantle cell lymphoma (n=7), or Burkitt lymphoma (n=1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P=.025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P=.001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.

Endoscopic diagnosis of a colonic localisation of a mantle cell lymphoma.

Extra-nodal localisations of mantle cell lymphomas are most frequently found in the gastrointestinal tract. It is therefore important for an endoscopist to be familiar with the endoscopic image of a mantle cell lymphoma. In this case series of three patients with colonic involvement of mantle cell lymphoma, we discuss the endoscopic diagnosis.

Predictive Value of Staging PET/CT to Detect Bone Marrow Involvement in Marginal Zone Lymphoma (MZL): An Analysis from LEO MZL Working Group

Introduction: Bone marrow (BM) involvement impacts stage and prognosis in lymphoma, remaining an important factor in risk-stratification scores, including the MALT-IPI. PET/CT is routinely implemented in the staging and response assessment of patients with lymphoma. However, FDG avidity to detect marginal zone lymphoma (MZL) remains debatable. In this study we aimed to assess the predictive value of PET/CT to detect BM involvement and survival implications in MZL using prospectively collected data from the Lymphoma Epidemiology of Outcomes (LEO) cohort. Methods: The LEO cohort is a prospective cohort from 8 academic cancer centers in which patients are enrolled within 6 months of lymphoma diagnosis and followed. We extracted baseline data of MZL patients enrolled in the LEO cohort between 5/2015 and 2/2020. BM biopsy was used as a gold standard for BM involvement. In addition, radiology reports were reviewed for PET/CT-suggested BM involvement. Event-free survival (EFS) defined as time from diagnosis to relapse/progression, retreatment, or death due to any cause and overall survival (OS) defined as time from diagnosis to death due to any cause were estimated by Kaplan-Meier. Results: Of 706 MZL patients enrolled in LEO, 311 (44%) with data on BM status by both biopsy and PET/CT were included in the analysis. Patients’ characteristics were median age 64 (range 24-89) years with most <70 years (n=217, 69.8%), non-Hispanic (n=264, 84.9%) white (n=276, 88.7%), without B symptoms (n=246, 79.1%), and normal LDH (n=185, 59.5%). The most common MZL subtype was extranodal (EMZL, n=208, 66.9%) followed by nodal (NMZL, n=61, 19.6%) and splenic (SMZL, n=42, 13.5%). Stage distribution was as follows: early-stage (I-II; n=134, 43.1%), advanced-stage (III-IV; n=159, 51.1%), and unknown (n=18, 5.8%). BM biopsy was positive in 99 (31.8%) and negative in 212 (68.2%) patients. Across all MZL subtypes, biopsy-proven and PET/CT-suggested BM involvement was present in 11.6% (n=36/311), and positive BM biopsy with negative PET/CT was observed in 20.3% (n=63/311) (EMZL=9.6%, n=20/208; NMZL=31.1%, n=19/61; and SMZL=57.1%, n=24/42). For EMZL, 15.9% (n=33) demonstrated pathologically confirmed BM involvement, and among those patients PET/CT was positive in 39.4% (n=13) and negative in 60.6% (n=20). For NMZL, 50.8% (n=31) demonstrated pathologically confirmed BM involvement, and among those patients PET/CT was positive in 38.7% (n=12) and negative in 61.3% (n=19). Most patients (83.3%, n=35) with SMZL demonstrated pathologically confirmed BM involvement, with positive PET/CT in 31.4% (n=11) and negative in 68.6% (n=24). Considering BM result from biopsy as the standard, PET/CT-based sensitivity and specificity in EMZL, NMZL, and SMZL were 39.4% & 98.9%, 38.7% & 100%, and 31.4% & 100%, respectively. PET/CT-based positive and negative predictive values in EMZL, NMZL, and SMZL were 86.7% & 89.6%; 100% & 61.2%; and 100% & 22.6%, respectively. With a median follow up of 35.4 months there were 70 EFS events and 18 OS events across all MZL subtypes. The 2-year EFS and OS were 81.7% (95%CI 76.8-85.7%) and 96.8% (95%CI 93.9-98.3%), respectively. The 2-year EFS and OS by histology were EMZL= 84.7% (95%CI 78.7-89.1%) & 97.2% (95%CI 93.5-98.8%); NMZL= 69.6% (95%CI 56.1-79.6%) & 96.5% (95%CI 86.9-99.1%); and SMZL= 85.6% (95%CI 70.7-93.3%) & 95.2% (95%CI 82.3-98.8%), respectively. Acknowledging the low number of events and unspecific criteria for treatment selection, those patients exhibiting pathological BM involvement (n= 99) did not show significantly different EFS (p=0.097) (EMZL p=0.48; NMZL p=0.68; and SMZL p=0.75, respectively) or OS (p=0.978) (EMZL p=0.46; NMZL=0.53; and SMZL=0.21, respectively) compared to those without BM disease. Conclusions: While PET/CT may be positive in nodal and some extranodal locations, assessment of BM involvement by PET/CT is characterized by a low sensitivity across all MZL subtypes and low negative predictive value in SMZL, underscoring the limitations of current Lugano criteria in staging MZL. With currently relatively limited follow-up, we did not observe significantly different survival based on BM status.

Extranodal Marginal Zone Lymphomas Show Recurrent Mutations in DNA Repair Genes, Cancer-Associated Proliferative Signaling and NOTCH1 Signaling Pathways, Regardless of Anatomic Site

Extranodal marginal zone lymphomas (EMZL) are usually indolent B cell lymphomas arising in acquired mucosa-associated lymphoid tissue (MALT) as a result of chronic antigen stimulation from infection or autoimmune processes. EMZLs occurring at different MALT sites have shared and unique genetic events including site-associated chromosomal structural changes and mutations. While large scale genetic analyses of EMZL are lacking, previous small studies have shown that EMZL often show activation of NF-κB through chronic stimulation of the B cell receptor and other cooperating genetic events that include somatic mutations, most frequently in TNFAIP3. Here, we report the largest whole exome sequencing (WES) and copy number (CN) analysis to date in EMZL. Formalin-fixed paraffin-embedded (FFPE) samples of EMZL were collected as part of the Atlas of Blood Cancer Genomes (ABCG) consortium. All cases underwent central pathology review by expert hematopathologists and diagnoses were confirmed as defined by the 2016 WHO classification. We defined global CN gains and losses at log2 fold change value of ±0.3, a value used by many CN tools. DNA and RNA WES were performed using the Illumina platform and DNA and RNA reads aligned to the GRCh38 genome and transcriptome, respectively. Exonic variants were identified and filtered using normal samples and population-based databases to identify putative driver mutations which were then aggregated at the gene level. Mutational analysis was done on samples that passed quality filtering. 225 unique diagnostic specimens were collected from 24 academic hematopathology departments. Cases originated from North America (USA and Canada, 86%), Europe (8%), and Asia (Singapore and China, 6%). 72 tumors were excluded due to inadequate mean coverage related to size of the biopsy or its quality. CN analysis and WES to identify non-silent mutations was performed in 153 unique EMZL including ocular adnexal (31), stomach (26), lung (23), salivary gland (23), and other extranodal locations (50). Average patient age was 63 years (range 53-71 years), female: male ratio of 1.6. Mutation calls identified 718 variants (613 missense mutations and 105 truncating mutations) across 59 putative driver genes detected in ≥5% cases across all the anatomic locations. Among the most commonly mutated genes, we detected genes previously reported to be altered by targeted sequencing in EMZL (e.g., SPEN (12%), TNFAIP3 (A20) (8%), CREBBP (8%), TBL1XR1 (7%), and others) confirming our filtering strategy. A total of 44 focal CN alterations (24 gains and 20 CN losses) were detected for our set of recurrently mutated genes. Global CN gains included chromosome 3 (6%), 6p (7%), 8 (3%), 12 (4%), and 18 (5%) and losses in 21p (10%). Previously described tumor suppressor genes such as TNFAIP3 showed a typical pattern of alterations consisting of CN losses (6q23.3 deletion in 6%) and/or mostly truncating mutations (8%). Combining DNA mutations and CN alterations, the number of genetic lesions per tumor sample in the 59 putative driver genes ranged from 1 to 21, with an average load of 4.9 aberrations per case, consistent with previous genetic studies in other types of MZL lymphoma. The most frequent mutations across all sites were IGLL5 (22%), KMT2C (15%), KMT2D (14%), SPEN (12%), PRDM2 (11%), and NCOR1 (10%). Analysis using Elsevier Pathway Collection, BioPlanet 2019 and Go Biological Process 2021 revealed adjusted statistically significant enrichment of aberrations in genes in NOTCH signaling, DNA repair, cancer-associated sustaining of proliferative signaling, cancer associated histone methylation and positive regulation of transcription, by DNA-templated (GO:0045893) and RNA polymerase II (GO:0045944). Many of the mutated genes were previously not reported in EMZL. Some of the mutations were shared by tumors at different anatomic locations while some were more unique. Mutations in TET2, previous reported as specific for thyroid EMZL, were also detected in ocular adnexa, gastric and salivary gland MZL. Mutations in PTPRD, previously suggested as specific for NMZL, were detected also in EMZL. Overall, this analysis of a large number of samples from different anatomic locations further refines the mutational landscape in EMZL and provides novel clues on pathogenesis. More detailed analyses of mutations, CN variations and RNA expression will be presented at the meeting.