No difference in treatment outcome between patients with nodal versus extranodal diffuse large B-cell lymphoma
Background and aim: Diffuse large B-cell lymphoma (DLBCL) has been classified using various parameters, including the site of origin. Studies have reported conflicting outcomes when DLBLC patients were stratified according to the site of origin. This study aimed to investigate the response rate and survival outcomes in nodal versus extranodal DLBCL and compare the results to a region-matched study covering the 1988-2005 period.
Methods: A single-center retrospective cohort study was conducted on all patients diagnosed with DLBCL and treated in a tertiary care hospital in Pakistan during 2014-2019. We calculated the mean and median for continuous variables and frequency and percentages for all categorical variables. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier survival curves. A Cox proportional hazards model was used to determine the hazard ratio (HR) for OS.
Results: Of the 118 patients, 49 patients (41.5%) had nodal disease and 69 patients (58.5%) were diagnosed with extranodal DLBCL. The majority of patients in the nodal and extranodal cohorts presented with stage III and IV disease (73.4% and 62.3%, respectively). A complete response to (immuno)chemotherapy was achieved in 71.4% of nodal DLBCL patients and 65.2% of extranodal DLBCL patients. The 5-y PFS and median PFS in the entire cohort were 0.8% and 17 m, respectively. The PFS and median PFS in the nodal and extranodal DLBCL cohort were 0% and 1.4%, respectively, and 15 m and 19 m, respectively. The 5-y OS and median OS in the entire cohort were 16.1% and 19 m, respectively. The OS and median OS in the nodal and extranodal DLBCL cohort were 8.2% and 21.7%, respectively, and 19 m and 21 m, respectively. Multivariable linear regression revealed that the ABC phenotype (nodal, HR = 1.37, 95% CI = 1.37-3.20; extranodal, HR = 1.65, 95% CI = 1.46-3.17; GBC as reference) and double and triple hit DLBCL (nodal, HR = 1.29, 95% CI = 1.19-2.81; extranodal, HR = 1.87, 95% CI = 1.28-2.43; non-expressors as reference) are independent negative predictors of OS.
Conclusions: DLBCL incidence in the Karachi region has remained comparable but patient composition in the extranodal DLBCL cohort has shifted to predominantly advanced stage. Nodal and extranodal DLBCL were associated with similar PFS and OS profiles and first- and second-line treatment responses. Cell of origin and antigen expression status were independent negative predictors of OS, disfavoring the ABC phenotype and lesions with c-MYC and BCL2 and/or BCL6 overexpression.
Relevance for patients: DLBCL is an aggressive type of non-Hodgkin's lymphoma, however; patients respond well to standard systemic chemotherapy. Extranodal type of DLBCL patients tend to have more residual disease after first-line systemic chemotherapy, but physicians should keep in mind that the subsequent line treatment mitigates its negative impact on survival
[1] Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma Incidence Patterns by Who Subtype in the United States, 1992-2001. Blood 2006;107:265-276.
[2] Shenoy PJ, Malik N, Nooka A, Sinha R, Ward KC, Brawley OW, et al. Racial Differences in the Presentation and Outcomes of Diffuse Large B-Cell Lymphoma in the United States. Cancer 2011;117:2530-40.
[3] Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of Haematological Malignancy by Sub-Type: A Report from the Haematological Malignancy Research Network. Br J Cancer 2011;105:1684-92.
[4] Horesh N, Horowitz NA. Does Gender Matter in NonHodgkin Lymphoma? Differences in Epidemiology, Clinical Behavior, and Therapy. Rambam Maimonides Med J 2014;5:e0038.
[5] Lal A, Bhurgri Y, Vaziri I, Rizvi NB, Sadaf A, Sartajuddin S, et al. Extranodal Non-Hodgkin’s Lymphomas--a Retrospective Review of Clinico-Pathologic Features and Outcomes in Comparison with Nodal Non-Hodgkin’s Lymphomas. Asian Pac J Cancer Prev 2008;9:453-8.
[6] Bakhshi TJ, Georgel PT. Genetic and Epigenetic Determinants of Diffuse Large B-cell Lymphoma. Blood Cancer J 2020;10:123.
[7] Liu Y, Barta SK. Diffuse Large B-Cell Lymphoma: 2019 Update on Diagnosis, Risk Stratification, and Treatment. Am J Hematol 2019;94:604-16.
[8] Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. Blood 2016;127:2375-90.
[9] Herrera AF, Mei M, Low L, Kim HT, Griffin GK, Song JY, et al. Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas have Inferior Progression-free Survival after Autologous Stem-Cell Transplantation. J Clin Oncol 2017;35:24-31.
[10] Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct Types of Diffuse Large B-Cell Lymphoma Identified by Gene Expression Profiling. Nature 2000;403:503-11.
[11] Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse Large B-Cell Lymphoma. Crit Rev Oncol Hematol 2013;87:146-71.
[12] Gandi S, Hernandez-Ilizaliturri FJ. In: Besa EC, editor. Diffuse Large B-Cell Lymphoma (DLBCL). Medscape (English Edition); 2021, 2022.
[13] Jamil MO, Mehta A. Diffuse Large B-cell Lymphoma: Prognostic Markers and Their Impact on Therapy. Expert Rev Hematol 2016;9:471-7.
[14] Aslam W, Habib M, Aziz S. Clinicopathological Spectrum of Hodgkin’s and Non-Hodgkin’s Lymphoma: A Tertiary Care Cancer Hospital Study in Pakistan. Cureus 2022;14:e25620.
[15] Van Leeuwen MT, Turner JJ, Joske DJ, Falster MO, Srasuebkul P, Meagher NS, et al. Lymphoid Neoplasm Incidence by Who Subtype in Australia 1982-2006. Int J Cancer 2014;135:2146-56.
[16] Howell JM, Auer-Grzesiak I, Zhang J, Andrews CN, Stewart D, Urbanski SJ. Increasing Incidence Rates, Distribution and Histological Characteristics of Primary Gastrointestinal Non-Hodgkin Lymphoma in a North American Population. Can J Gastroenterol 2012;26:452-6.
[17] Bobillo S, Joffe E, Lavery JA, Sermer D, Ghione P, Noy A, et al. Clinical Characteristics and Outcomes of Extranodal Stage I Diffuse Large B-Cell Lymphoma in the Rituximab Era. Blood 2021;137:39-48.
[18] Gutierrez-Garcia G, Colomo L, Villamor N, Arenillas L, Martinez A, Cardesa T, et al. Clinico-Biological Characterization and Outcome of Primary Nodal and Extranodal Diffuse Large B-Cell Lymphoma in the Rituximab Era. Leuk Lymphoma 2010;51:1225-32.
[19] Bajwa AA, Khadim MT, Din HU, Ali SS, Jamil U, Khan UA. Immunohistochemical Expression of CD10, BCl6 and MUM1 in Differentiating Diffuse Large B Cell Lymphoma Subtypes. J Coll Physicians Surg Pak 2017;27:621-4.
[20] King JF, Lam JT. A Practical Approach to Diagnosis of B-Cell Lymphomas with Diffuse Large Cell Morphology. Arch Pathol Lab Med 2020;144:160-7.
[21] Kluk MJ, Chapuy B, Sinha P, Roy A, Dal Cin P, Neuberg DS, et al. Immunohistochemical Detection of MYC-Driven Diffuse Large B-Cell Lymphomas. PLoS One 2012;7:e33813.
[22] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: Globocan Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49.
[23] Abid MB, Nasim F, Anwar K, Pervez S. Diffuse Large B Cell Lymphoma (DLBCL) in Pakistan: An Emerging Epidemic? Asian Pac J Cancer Prev 2005;6:531-4.
[24] Vitolo U, Seymour JF, Martelli M, Illerhaus G, Illidge T, Zucca E, et al. Extranodal Diffuse Large B-Cell Lymphoma (DLBCL) and Primary Mediastinal B-Cell Lymphoma: Esmo Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol 2016;27:v91-102.
[25] Bhurgri Y, Pervez S, Bhurgri A, Faridi N, Usman A, Kazi LA, et al. Increasing Incidence of Non-Hodgkin’s Lymphoma in Karachi, 1995-2002. Asian Pac J Cancer Prev 2005;6:364-9.
[26] Roy A, Kar R, Basu D, Badhe BA. Spectrum of Histopathologic Diagnosis of Lymph Node Biopsies: A Descriptive Study from a Tertiary Care Center in South India Over 5½ Years. Indian J Pathol Microbiol 2013;56:103-8.
[27] Almasri NM, Habashneh MA, Khalidi HS. Non-Hodgkin Lymphoma in Jordan. Types and Patterns of 111 Cases Classified According to the Who Classification of Hematological Malignancies. Saudi Med J 2004;25:609-14.
[28] Moubadder L, McCullough LE, Flowers CR, Koff JL. Linking Environmental Exposures to Molecular Pathogenesis in Non-Hodgkin Lymphoma Subtypes. Cancer Epidemiol Biomarkers Prev 2020;29:1844-55.
[29] Hounsome L, Eyre TA, Ireland R, Hodson A, Walewska R, Ardeshna K, et al. Diffuse Large B Cell Lymphoma (DLBCL) in Patients Older than 65 Years: Analysis of 3 Year Real World Data of Practice Patterns and Outcomes in England. Br J Cancer 2022;126:134-43.
[30] Moller MB, Pedersen NT, Christensen BE. Diffuse Large B-Cell Lymphoma: Clinical Implications of Extranodal Versus Nodal Presentation--a Population-Based Study of 1575 cases. Br J Haematol 2004;124:151-9.
[31] Mahmood H, Habib M, Aslam W, Khursheed S, Fatima S, Aziz S, et al. Clinicopathological Spectrum of Diffuse Large B Cell Lymphoma: A Study Targeting Population Yet Unexplored in Pakistan. BMC Res Notes 2021;14:354.
[32] Shi Y, Han Y, Yang J, Liu P, He X, Zhang C, et al. Clinical Features and Outcomes of Diffuse Large B-Cell Lymphoma Based on Nodal or Extranodal Primary Sites of Origin: Analysis of 1,085 Who Classified Cases in a Single Institution in China. Chin J Cancer Res 2019;31:152-61.
[33] Padhi S, Paul TR, Challa S, Prayaga AK, Rajappa S, Raghunadharao D, et al. Primary Extra Nodal Non Hodgkin Lymphoma: A 5 Year Retrospective Analysis. Asian Pac J Cancer Prev 2012;13:4889-95.
[34] Lopez-Guillermo A, Colomo L, Jimenez M, Bosch F, Villamor N, Arenillas L, et al. Diffuse Large B-Cell Lymphoma: Clinical and Biological Characterization and Outcome According to the Nodal or Extranodal Primary Origin. J Clin Oncol 2005;23:2797-804.
[35] Shen H, Wei Z, Zhou D, Zhang Y, Han X, Wang W, et al. Primary Extra-Nodal Diffuse Large B-Cell Lymphoma: A Prognostic Analysis of 141 Patients. Oncol Lett 2018;16:1602-14.
[36] Wang C, Li W, Liu C, He H, Bai O. Analysis of Clinical and Immunophenotypic Features along with Treatment Outcomes of Diffuse Large B Cell Lymphoma Patients, Based on the Involvement of Nodal or Extranodal Primary Sites. Blood Cells Mol Dis 2016;57:42-9.
[37] Kim MK, Bae SH, Bae YK, Kum YS, Ryoo HM, Cho HS, et al. Biological Characterization of Nodal Versus Extranodal Presentation of Diffuse Large B-Cell Lymphoma Using Immunohistochemistry. Clin Lymphoma Myeloma Leuk 2011;11:403-8.
[38] Pai A, Kannan T, Balambika RG, Vasini V. A Study of Clinical Profile of Primary Extranodal Lymphomas in a Tertiary Care Institute in South India. Indian J Med Paediatr Oncol 2017;38:251-5.
[39] Takahashi H, Tomita N, Yokoyama M, Tsunoda S, Yano T, Murayama K, et al. Prognostic Impact of Extranodal Involvement in Diffuse Large B-Cell Lymphoma in the Rituximab Era. Cancer 2012;118:4166-72.
[40] Adams HJ, Kwee TC. Proportion of False-Positive Lesions at Interim and End-of-Treatment FDG-PET in Lymphoma as Determined by Histology: Systematic Review and MetaAnalysis. Eur J Radiol 2016;85:1963-70.
[41] Bhojwani D, McCarville MB, Choi JK, Sawyer J, Metzger ML, Inaba H, et al. The Role of FDG-PET/CT in the Evaluation of Residual Disease in Paediatric NonHodgkin Lymphoma. Br J Haematol 2015;168:845-53.
[42] Harrysson S, Eloranta S, Ekberg S, Enblad G, Jerkeman M, Wahlin BE, et al. Incidence of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Including CNS Relapse in a Population-Based Cohort of 4243 Patients in Sweden. Blood Cancer J 2021;11:9.
[43] Candelaria M, Onate-Ocana LF, Corona-Herrera J, BarreraCarmona C, Ponce-Martinez M, Gutierrez-Hernandez O, et al. Clinical Characteristics of Primary Extranodal Versus Nodal Diffuse Large B-Cell Lymphoma: A Retrospective Cohort Study in a Cancer Center. Rev Invest Clin 2019;71:349-58.
[44] Deng L, Xu-Monette ZY, Loghavi S, Manyam GC, Xia Y, Visco C, et al. Primary Testicular Diffuse Large B-Cell Lymphoma Displays Distinct Clinical and Biological Features for Treatment Failure in Rituximab Era: A Report from the International PTL Consortium. Leukemia 2016;30:361-72.
[45] Zucca E, Conconi A, Mughal TI, Sarris AH, Seymour JF, Vitolo U, et al. Patterns of Outcome and Prognostic Factors in Primary Large-Cell Lymphoma of the Testis in a Survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003;21:20-7.
[46] Ma RZ, Tian L, Tao LY, He HY, Li M, Lu M, et al. The Survival and Prognostic Factors of Primary Testicular Lymphoma: Two-Decade Single-Center Experience. Asian J Androl 2018;20:615-20.
[47] Ryan G, Martinelli G, Kuper-Hommel M, Tsang R, Pruneri G, Yuen K, et al. Primary Diffuse Large B-Cell Lymphoma of the Breast: Prognostic Factors and Outcomes of a Study by the International Extranodal Lymphoma Study Group. Ann Oncol 2008;19:233-41.
[48] Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, et al. Immunohistochemical Methods for Predicting Cell of Origin and Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab. J Clin Oncol 2011;29:200-7.
[49] Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the Molecular Classification of Diffuse Large B-Cell Lymphoma by Immunohistochemistry Using a Tissue Microarray. Blood 2004;103:275-82.
[50] Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, et al. A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy. Clin Cancer Res 2009;15:5494-502.
[51] Nowakowski GS, Czuczman MS. ABC, GCB, and DoubleHit Diffuse Large B-Cell Lymphoma: Does Subtype Make a Difference in Therapy Selection? Am Soc Clin Oncol Educ Book 2015;35:e449-57.
[52] Friedberg JW. Using the Pathology Report in Initial Treatment Decisions for Diffuse Large B-Cell Lymphoma: Time for a Precision Medicine Approach. Hematology Am Soc Hematol Educ Program 2015;2015:618-24.
[53] Phuoc V, Sandoval-Sus J, Chavez JC. Drug Therapy for Double-Hit Lymphoma. Drugs Context 2019;8:1-13.
[54] Zhuang Y, Che J, Wu M, Guo Y, Xu Y, Dong X, et al. Altered Pathways and Targeted Therapy in Double Hit Lymphoma. J Hematol Oncol 2022;15:26.
[55] Nair CK, Kurup AR, Manuprasad A, Shenoy PK, Raghavan V. Pattern of Extranodal Involvement and its Impact on Survival in Diffuse Large B-Cell Lymphoma from a Tertiary Cancer Center in Rural India. J Cancer Res Ther 2021;17:938-42.
[56] Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a Better Predictor of Outcome than the Standard IPI for Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP. Blood 2007;109:1857-61.
[57] Horvat M, Zadnik V, Setina TJ, Boltezar L, Golicnik JP, Novakovic S, et al. Diffuse Large B-Cell Lymphoma: 10 Years’ Real-World Clinical Experience with Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone. Oncol Lett 2018;15:3602-9.
[58] Hui D, Proctor B, Donaldson J, Shenkier T, Hoskins P, Klasa R, et al. Prognostic Implications of Extranodal Involvement in Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Leuk Lymphoma 2010;51:1658-67.
[59] Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term Outcome of Patients in the LNH-98.5 Trial, the First Randomized Study Comparing Rituximab-CHOP to Standard CHOP Chemotherapy in DLBCL Patients: A study by the Groupe d’Etudes Des Lymphomes De L’adulte. Blood 2010;116:2040-5.
[60] Ko OB, Jang G, Kim S, Huh J, Suh C. Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma with Residual Extranodal Involvement. Korean J Intern Med 2008;23:182-90.