Characteristics and outcomes of incidentally diagnosed diffuse large B‐cell lymphoma and implications for cancer screening
Authors: Suheil Albert Atallah‐Yunes, Matthew J. Rees, Raphael Mwangi, Robyn L. Kuchler, Grzegorz S. Nowakowski, Thomas M. Habermann, Yucai Wang, Carrie A. Thompson, Andrew L. Feldman, Matthew J. Maurer, James R. Cerhan, Stephen M. Ansell, Thomas E. Witzig
Journal: American Journal of Hematology (2024)

Differences in characteristics and outcomes between incidental and symptomatic presentations of Large B-Cell Lymphoma. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in the world and most cases present with stages III/IV disease.1-3 These patients usually palpate a mass, develop pain, or have abnormal blood tests at the time of a routine exam leading to imaging, biopsy, and the diagnosis. Alternatively, while undergoing radiologic studies or diagnostic procedures for preventive cancer screening or other systemic symptoms, some patients may have adenopathy detected, which subsequently leads to a diagnosis of DLBCL. We refer to this group as incidental lymphoma or lymphoma diagnosed before symptoms or signs (DB4SS). The outcomes and disease characteristics such as stage and international prognostic index (IPI) score in DB4SS DLBCL have not been previously studied. We hypothesized that the DB4SS DLBCL cases would be earlier stage and have a better prognosis. These questions are relevant given the ongoing studies of multicancer early detection tests (MCEDT) that use blood from asymptomatic individuals to detect methylated DNA markers (MDM) for a variety of cancers including lymphoma.4 MCEDT have been developed based on recent methylation research in normal cells and various cancers. A key finding is that normal tissue exhibits DNA methylation patterns that are organ/tissue-specific with little interpatient variation. Cancer cells, on the contrary, have different methylation patterns, and research into each cancer type has led to the discovery of methylation patterns unique to specific types of cancer.5-8 These methylation markers are now being tested prospectively for early discovery of cancers including DLBCL. It remains unclear whether early detection of DLBCL in asymptomatic individuals by these new molecular assays will matter with respect to outcomes such as the type of treatment, number of cycles, complications, need for salvage treatments with their accompanying morbidity (and even mortality), and second cancers.9 This area of early detection warrants study in DLBCL given that it is the most common type of NHL and is curable. Additionally, discovering DLBCL at lower stages, when patients are asymptomatic and without organ dysfunction, may lead to better outcomes, require fewer cycles of chemoimmunotherapy, and reduce the downstream need for expensive and potentially toxic therapies such as transplant, Chimeric Antigen Receptor T-cell (CAR T cell) therapy, and bispecific antibodies.1, 2, 10-13 In order to begin to address whether incidental diagnosis of DLBCL matters in terms of disease characteristics and outcomes, we investigated staging and outcome differences between patients with DLBCL DB4SS to those presenting with signs and symptoms due to their lymphoma. We performed a retrospective analysis of patients with newly diagnosed large B-cell lymphoma enrolled into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) from 2002 to 2015. This study received approval by the Mayo Clinic Institutional Review Board. Patient medical records of the Mayo component were reviewed to assign mode of diagnosis (DB4SS vs. symptomatic). We examined disease characteristics and outcome data according to the mode of diagnosis (DB4SS vs. symptomatic) in Mayo Clinic Rochester patients only. DB4SS was defined as asymptomatic DLBCL discovered incidentally after a procedure/imaging performed for medical reasons unrelated to lymphoma, abnormal laboratory tests, or a clinical health care professional palpating a mass undetected by the patient. We describe continuous variables using mean and median, while categorical values are described using frequencies and proportions. Event-free survival (EFS) was the time from diagnosis to relapse, progression, retreatment, or death from any cause. Overall survival (OS) was defined as the time from diagnosis to death from any cause. We compared EFS and OS outcomes between DB4SS patients and those presenting with lymphoma-related signs and symptoms using Kaplan–Meier curves. Differences between the two groups were assessed using the log-rank test. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), measuring the relative risk of events occurring in the two patient groups. All statistical analyses were performed using R/RStudio version 4.2.2 and SAS version 9.4 M5. We reviewed records from 1140 patients diagnosed with DLBCL (90.6%), high grade B-cell lymphoma (2.4%) or primary mediastinal B-cell lymphoma (7.0%) and summarized their characteristics in Table 1. 7.5% (85/1140) of patients met criteria for DB4SS; 92.5% (1055/1140) presented with lymphoma related signs or symptoms. In the DB4SS group, 67.5% (65/85) were diagnosed after imaging or a diagnostic/surgical procedure performed for medical reasons unrelated to lymphoma; 14.1% (12/85) due to a lab finding; and 9.4% (8/85) after a clinical health care professional incidentally identified a lump or a mass. The DB4SS patients compared with the symptomatic group were more likely to have stages I/II (62% vs. 39%, p < .0001), lower IPI score (p = .025), lower incidence of multiple extranodal organ involvement (15.5% vs. 29.8%, p = .025), and lower frequency of elevated lactate dehydrogenase (LDH) levels (40.8% vs. 55.4%, p = .014). The median follow-up time was 152.3 months in the DB4SS group and 123.7 months in the group with lymphoma-related symptoms or signs. There was no difference in EFS between the two groups on univariate (HR = 1.08, 95% CI = 0.8–1.45; p = .61) or multivariable analysis adjusted for IPI (aHR = 0.97, 95% CI = 0.72–1.31; p = .85). Also, there was no difference in OS on univariate (HR = 0.98, 95% CI = 0.72–1.34; p = .91) or multivariable analysis adjusted for IPI (HR = 0.87, 95% CI = 0.64–1.19; p = .39) (Figure 1). As expected, patients with stage I/II disease had significantly better EFS and OS compared to those with stage III/IV disease (p < .0001). However, there were no significant differences in EFS (HR = 0.92, 95%CI = 0.60–1.40; p = .69) or OS (HR = 0.85, 95% CI = 0.54–1.33; p = .48) between the DB4SS group and the symptomatic stages I/II group. Similarly, among patients with stage III/IV disease, there were no significant differences in EFS (HR = 0.97, 95% CI = 0.64–1.48; p = .89) or OS (HR = 0.88, 95% CI = 0.65–1.36; p = .56) between the two groups. The median time from diagnosis to treatment (DTI) was significantly longer in the DB4SS group (21 days, IQR 12–34) compared to the group presenting with lymphoma-related symptoms (15 days, IQR 9–24) (p = .0014). While anthracycline-based chemoimmunotherapy can cure DLBCL, ~40% experience relapse or are refractory with upfront therapy making DLBCL a potentially lethal disease.14 Despite this potential lethality of DLBCL and it being the most common NHL in the world, asymptomatic lymphoma is not screened for in the general population. The reasons include the low overall prevalence of DLBCL, impracticality of imaging techniques with lack of validation for lymphoma screening, and the historical absence of blood tests with high sensitivity for detecting lymphoma due to technical and biological factors. The field of cancer screening is in an exciting new phase with the evaluation of MCEDT that utilize MDM assays on blood samples from patients without known cancer.5, 6 The Galleri test was designed to serve as a MCEDT for over 50 types of cancer, some of which (like DLBCL) lack a screening test. PATHFINDER, a nonrandomized clinical trial, applied the Galleri test in 6662 asymptomatic participants older than 50 years with no known cancer.4 Participants also underwent routine cancer screening tests. Among individuals available for analysis, Galleri detected circulating free DNA (cfDNA) signal alterations in 92 patients (1.4%), 35 of whom were subsequently diagnosed with 26 different kinds of cancer. The test demonstrated 97% accuracy in detecting the origin of the cancer. The positive predictive value (PPV) of the test was 38% with a specificity of 99.1%. The rate of true positive test was 73%. The study concluded that a MCEDT is feasible.4 In the PATHFINDER study, 12 lymphomas were detected including 8 with early-stage disease (4 stage I, 4 stage II). In another study (Witzig TE et al. ASCO 2022), blood assays utilizing MDM have been shown to detect evidence of lymphoma in the blood in 80% of DLBCL cases. In our study, we characterized the DB4SS group as a surrogate for what potentially could be found with a MCEDT. We show that in DLBCL, the DB4SS group is more likely to be lower stage and have a lower IPI score. If indeed, MCEDT were in widespread use this could identify more patients with early-stage, favorable DLBCL. This would have potential impact on the type and number of chemoimmunotherapy treatments. Even the discovery of asymptomatic stage III/IV disease is important as the risk for tumor lysis and complications due to organ infiltration or compression could potentially be reduced. The impact of the early discovery in this study did not impact EFS or OS in either Stages I/II or III/IV. This suggests that MCEDT in lymphoma may not meet the high bar of requiring an OS benefit.9 However, the DB4SS patients in this study may be different than those discovered by MCEDT. While our cohort of incidentally diagnosed patients had no better OS but better prognostic features, some of these patients still had abnormal laboratory findings or exhibited an enlarged lymph node or a mass that was felt incidentally by a health care provider. On the contrary, incidental molecular detection may capture a higher proportion of patients who present even earlier without exhibiting any signs of lymphoma on blood work up or physical exam; thus, it would be interesting to learn from large MCEDT studies underway if a MCEDT-discovered DLBCL has an even better EFS/OS than the DB4SS group we describe. Although prior studies demonstrated better outcomes when DLBCL is diagnosed at lower stages and IPI scores,1, 2, 13 this may not be the sole reason to look forward to discovering DLBCL at an earlier stage and prior to symptom onset. For example, detecting DLBCL at an earlier stage may alter treatment strategies as some patients with stage I-II disease are candidates for receiving fewer number of chemoimmunotherapy cycles based on evidence from FLYER, S1001, and the SWOG S8736 studies.10-12 This holds significant importance in some vulnerable patient populations such as the elderly, immunocompromised patients and individuals who have previously received anthracycline-based treatments for other malignancies such as breast cancer. In our cohort, DLBCL patients with incidental detection were more likely to have normal LDH levels at diagnosis which may suggest a lower tumor burden since LDH level can be a reliable surrogate marker for tumor burden.15 Detection of DLBCL when it is less bulky and with lower tumor burden may help reduce the risk of certain complications such as spontaneous and treatment-related tumor lysis syndrome (TLS). Organ dysfunction caused by tumor bulk such as kidney injury due to ureter compression by lymphoma or liver dysfunction due to hepatobiliary infiltration may lead to treatment delays and dose adjustments which may potentially be avoided if lymphoma was detected at an earlier stage. Additionally, some procedures such as ureteral stent placement may be less needed. The treatment landscape of DLBCL has been revolutionized by the introduction of cellular therapy agents including CAR T cells and bispecific antibodies. These are approved for refractory/relapsed disease; however, detecting DLBCL even earlier presents new opportunities for these types of therapy especially for elderly patients who cannot tolerate frontline chemoimmunotherapy. Indeed, studies incorporating bispecific antibodies in the frontline treatment of frail patients are ongoing (NCT05207670). The strengths of our study lie in the large sample size of patients with aggressive B-cell lymphoma included in this report. The relatively low number of patients who presented incidentally (7.5% of the cohort) was expected, and it will take larger groups of these patients from the ongoing MCEDT studies to fully characterize their outcomes. We also did not have information on the number of cycles of treatment, number of downstream treatments, nor incidence of TLS that occurred. These are important metrics that if proven to be reduced would support MCEDT in DLBCL. In addition, the retrospective nature and the time period of presentation (2002–2015) are limitations to our study given the new treatments now approved in DLBCL. In conclusion, while our study demonstrates that incidental detection of DLBCL is associated with earlier stage and more favorable prognostic features, this did not translate into a significant difference in survival outcomes compared with symptomatic patients. However, the potential for MCEDT to detect DLBCL even earlier at a molecular level, before any clinical or laboratory abnormalities arise, remains an exciting avenue for future research. Further investigation of MCEDT is warranted to determine whether early DLBCL detection can lead to improved outcomes, refined treatment strategies, and reduced treatment-related complications. TEW and SAAY came up with the conception and design of the study. SAAY, MJR, and RK collected and assembled data. RM analyzed and interpreted data. All authors provided expert input, interpretation of the data, and approved the final version of the manuscript. Supported in part by the University of Iowa/Mayo Clinic Lymphoma SPORE CA97274, U01 CA195568, and the Predolin Foundation Biobank at Mayo Clinic. The authors declare no conflict of interest. Data is available upon reasonable request.