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Diffuse Large B-Cell Lymphoma (DLBCL)

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Differential Diagnosis

Diffuse large B-cell lymphoma (DLBCL) is a type of non-Hodgkin lymphoma (NHL) characterized by abnormally large B-cells in the lymphatic system, which may spread to extranodal organs and tissues. Similar conditions involving lymphadenopathy may present as differential diagnoses to DLBCL. Accurate diagnosis, including the exclusion of other types of lymphomas, is required for best patient outcomes.

Benign Inoculation Lymphoreticulosis

Benign inoculation lymphoreticulosis, also known as cat scratch disease, results in benign lymphadenopathy following a scratch or bite from a cat. It is often caused by bacterial infection with Bartonella henselae.1

Burkitt Lymphoma

Burkitt lymphoma is a B-cell lymphoma associated with Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and chromosomal translocations leading to the overexpression of c-MYC.2 

Burkitt lymphoma is listed in the 2008 World Health Organization (WHO) classification of lymphomas as a gray-zone lymphoma, referred to as “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma.” This designates the ambiguity of differentiating Burkitt lymphoma from DLBCL.3,4 

Normally, Burkitt lymphoma is distinguishable from DLBCL due to the presence of intermediate-size B-cells, appropriate immunophenotyping, an extremely high proliferation index seen with Ki67 staining, and c-MYC chromosomal translocations, although none of these features are exclusive to Burkitt lymphoma.4 

Up to 15% of patients with DLBCL test positive for the c-MYC translocation. Patients with Burkitt lymphoma may demonstrate larger centroblast-like B-cells intermixed with the intermediate lymphocytes commonly found in Burkitt lymphoma, making it difficult to distinguish from DLBCL.3

Researchers identified a unique genetic signature for Burkitt lymphoma using gene expression profiling. Burkitt lymphoma can be differentiated from DLBCL by the overexpression of c-MYC target genes, expression of a subgroup of germinal-center B-cell genes (GCB subtype genes), and low expression of major-histocompatibility-complex class I genes and nuclear factor-kappa B (NF-κB) target genes.5 

Diffuse Mixed Lymphoma

Approximately 6% of all NHLs are diffuse mixed lymphomas characterized by mixed cellular compositions of small and large cells.6 This term is antiquated and applies to NHLs of both B-cell and T-cell origin.7 

Follicular Lymphoma

Like DLBCL, follicular lymphoma is an indolent B-cell lymphoma of grade 1 or 2 that may transform into DLBCL.8 

Follicular lymphoma becomes increasingly more difficult to distinguish from DLBCL at grade 3b, where biopsy samples contain mostly large cells such as centroblasts or immunoblasts. Immunostaining to detect follicular dendritic cells and cytogenetic testing to identify additional chromosomal abnormalities that are usually present in DLBCL may be helpful in diagnosing difficult cases.4

Hodgkin Lymphoma

Classical Hodgkin lymphoma is characterized by the presence of Reed-Sternberg cells, while nodular lymphocyte-predominant Hodgkin lymphoma is characterized by lymphocyte-predominant variants of Reed-Sternberg cells, often called “popcorn cells.” Hodgkin lymphoma rarely affects extralymphatic sites.9,10

Normally, differentiating between DLBCL and Hodgkin lymphoma is straightforward; however, in some cases, features of both DLBCL and classical Hodgkin lymphoma coexist, leading to a second WHO classification as another gray-zone lymphoma referred to as “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma.”4 This unclassifiable cross between classical Hodgkin lymphoma and DLBCL often presents as mediastinal masses with the expression of CD20 and CD79a lymphocytes typically found in DLBCL as well as CD30, CD15, CD3, and CD4 lymphocytes typical of classical Hodgkin lymphoma.4,10

Kikuchi Lymphadenitis

Kikuchi lymphadenitis, also known as Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis, is a benign, self-limiting condition often impacting young women who present with fever, lymphadenopathy, and leukopenia in around 50% of cases. Systemic lupus erythematosus and KFD may co-occur.11 

KSHV-Associated Germinotropic Lymphoproliferative Disorder

There are 4 types of Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8)-associated germinotropic lymphoproliferative disorders: KSHV-multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), KSHV-DLBCL, and germinotropic lymphoproliferative disorder (GLPD).12

Coinfection with KSHV/HHV8 and EBV occurs in PEL and GLPD. PEL is malignant, while GLPD presents with nonmalignant, localized lymphadenopathy and a decreased likelihood of constitutional symptoms. KSHV/HHV8 results in relapsing and remitting episodes of lymphadenopathy, splenomegaly, and constitutional symptoms such as fever, night sweats, and significant weight loss.12 

KSHV-DLBCL typically occurs following HIV infection and MCD. Tumor cells often test positive for CD45, CD20, and MUM1, a terminal B-cell differentiation marker, while testing negative for EBV. KSHV-DLBCL manifests with lymphadenopathy, splenomegaly, and, rarely, extranodal involvement.12

Lymphoblastic Lymphoma

Lymphoblastic lymphoma is an aggressive mature B-cell lymphoma subtype that accounts for 2% of all NHLs.13 Unlike DLBCL, which is characterized by pleomorphic lymphoblasts, lymphoblastic lymphoma presents with monomorphic lymphoblasts, with cell sizes ranging from small to large depending on the individual case. CD10, CD34, BCL2, and terminal deoxynucleotidyl transferase (TdT) are often present in cases of lymphoblastic lymphoma.14 Another histologic feature that is rare in DLBCL, but occurs occasionally in lymphoblastic lymphoma and more commonly in Burkitt lymphoma, is the “starry sky” pattern with scattered tangible body macrophages.14

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is characterized by the overproliferation of lymphocytes associated with EBV infection, and it is categorized as a B-cell lymphoma. Confirmed diagnosis of lymphomatoid granulomatosis requires histological evidence of angiitis, granulomatosis (central necrosis), and polymorphic lymphocyte infiltrates with scattered large lymphoid cells.15 

Unlike DLBCL, histologic findings for lymphomatoid granulomatosis do not include sheets of large B-cells, and they usually involve the respiratory tract. To further differentiate EBV-positive DLBCL from lymphomatoid granulomatosis, more than 50% of lymphoma cells in EBV-positive DLBCL must contain EBV-encoded small RNA.14 

Malignant Anaplastic Large Cell Lymphoma

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) originates in T cells, unlike DLBCL, which originates in B cells. ALK+ ALCL presents with characteristic large, pleomorphic lymphoid cells and a strong immunohistochemical (IHC) staining for CD30, previously called the Ki1 antigen. A hallmark feature of ALK+ ALCL is the horseshoe-shaped nuclei and abundant cytoplasm within the anaplastic large cells, which infiltrate interfollicular T zones and nodal sinuses.10,16

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare type of B-cell lymphoma, accounting for 3% of all NHLs.13

The expression of CD5 most commonly occurs in MCL; however, this is not exclusive to MCL, as around 5% to 10% of DLBCL cases also present with CD5 expression.10,14 

Cytogenetic analysis has revealed that MCL correlates with a translocation at t(11;14), which juxtaposes BCL1 with immunoglobulin heavy chain (IGH) gene sequences in a median of 87% (range, 14% to 99%) of cells.17 This translocation results in the overexpression of the cyclin D1 (CCND1) gene, although in some rare MCL cases, CCND2 or CCND3 translocations may occur.18

Mantle cell lymphoma can be distinguished from DLBCL by testing for cyclin D1 overexpression using IHC testing. IHC testing for cyclin D1 should be performed for B-cell lymphomas with large- or medium-sized B-cells, regardless of CD5 expression. Cyclin D1 overexpression is a sensitive biomarker for MCL, occurring in approximately 98% of MCL cases. In the rare case of cyclin D1-negative MCL, testing for SOX11 transcription factor has been confirmed as a reliable biomarker for both MCL-cyclin D1-positive and MCL-cyclin D1-negative cases.14 

Mediastinal Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a cancer affecting mature B lymphocytes. Gene expression profiling studies indicate that PMBCL and DLBCL are molecularly different and that PMBCL may share more features with classical Hodgkin lymphoma than DLBCL.19 

One such feature is the nuclear localization of the NF-κB subunit c-REL (reticuloendotheliosis viral oncogene). NF-κB target gene signatures differ between PMBCL and DLBCL, with DLBCL gene signatures being more regulated and restricted than those of PMBCL.20,21 

In addition to the overlapping features between PMBCL and classical Hodgkin lymphoma, PMBCL typically occurs in children and adolescents, is localized to the mediastinum, and presents with molecular alterations in JAK2 and programmed death ligands. DLBCL most often manifests in later adult years, can become multifocal, and presents with different gene mutations than PMBCL.22

Sarcoidosis

Diffuse large B-cell lymphoma may occur with or without the comorbid presence of sarcoidosis. Sarcoidosis often predisposes affected individuals to develop lymphoproliferative disorders like DLBCL.23 Sarcoidosis-lymphoma syndrome must be ruled out, as studies have found a predominance of patients with DLBCL who also had sarcoidosis.24

In sarcoidosis, lymph node biopsy histologic findings demonstrate noncaseating granulomas.25

Tuberculosis

In advanced disease stages, DLBCL may present with pleural involvement, so there is an increased probability of misdiagnosis in countries where tuberculosis infections occur more frequently. Lymphoma should be considered over tuberculosis if patients present with pleural effusion and high adenosine deaminase (ADA) activity levels >250 U/L. Surgical biopsy of lung tissue would definitively confirm the diagnosis of either DLBCL or tuberculosis.26 

Mycobacterium tuberculosis would not be present in DLBCL. Patients with DLBCL also would not test positive on the Mantoux tuberculin skin test (TST) or tuberculosis blood test.27,28

Read more about DLBCL diagnosis

References

  1. Catscratch disease (redirected from benign inoculation lymphoreticulosis). TheFreeDictionary.com. Accessed August 10, 2022.
  2. Graham BS, Lynch DT. Burkitt lymphoma. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated October 17, 2021. Accessed August 10, 2022.
  3. Kanbar AH. Burkitt lymphoma and Burkitt-like lymphoma differential diagnoses. Medscape. Updated July 5, 2022. Accessed August 10, 2022.
  4. Hu Y, Yang K, Krause JR. Diffuse large B-cell lymphoma, differential diagnosis and molecular stratification. N Am J Med Sci (Boston). 2011;4(2):67-76. 
  5. Dave SS, Fu K, Wright GW, et al; Lymphoma/Leukemia Molecular Profiling Project. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med. 2006;354(23):2431-2442. doi:10.1056/NEJMoa055759
  6. Foucar K, Armitage JO, Dick FR. Malignant lymphoma, diffuse mixed small and large cell. A clinicopathologic study of 47 cases. Cancer. 1983;51(11):2090-2099. doi:10.1002/1097-0142(19830601)51:11<2090:aid-cncr2820511123>3.0.co;2-g
  7. Diffuse mixed cell lymphoma. National Library of Medicine. Accessed August 10, 2022. 
  8. Getting the facts: transformed lymphomas. Lymphoma Research Foundation. Accessed August 10, 2022.
  9. Hodgkin lymphoma subtypes. Leukemia & Lymphoma Society. Accessed August 10, 2022. 
  10. Singh R, Dubey AP, Rathore A, et al. Diffuse large B-Cell lymphoma-review. J Med Sci. 2018;38(4):137-143. doi:10.4103/jmedsci.jmedsci_147_17
  11. Mahajan T, Merriman RC, Stone MJ. Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis): report of a case with other autoimmune manifestations. Proc (Bayl Univ Med Cent). 2007;20(2):149-151. doi:10.1080/08998280.2007.11928275
  12. Bower M, Carbone A. KSHV/HHV8-associated lymphoproliferative disorders: lessons learnt from people living with HIV. Hemato. 2021;2(4):703-712. doi:10.3390/hemato2040047
  13. NHL subtypes. Leukemia & Lymphoma Society. Accessed August 10, 2022.
  14. King JF, Lam JT. A practical approach to diagnosis of B-cell lymphomas with diffuse large cell morphology. Arch Pathol Lab Med. 2020;144(2):160-167. doi:10.5858/arpa.2019-0182-RA
  15. Kamangar N. Lymphomatoid granulomatosis workup: histologic findings. Medscape. Updated December 31, 2015. Accessed August 10, 2022.
  16. Kaseb H, Mukkamalla SKR, Rajasurya V. Anaplastic large cell lymphoma. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated July 4, 2022. Accessed August 10, 2022. 
  17. Li JY, Gaillard F, Moreau A, et al. Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization. Am J Pathol. 1999;154(5):1449-1452. doi:10.1016/S0002-9440(10)65399-0
  18. Lynch DT, Koya S, Acharya U, Kumar A. Mantle cell lymphoma. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 29, 2022. Accessed August 10, 2022. 
  19. Smith SM. Mediastinal lymphoma: practice essentials. Medscape. Updated May 4, 2022. Accessed August 10, 2022.
  20. Feuerhake F, Kutok JL, Monti S, et al. NFκB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood. 2005;106(4):1392-1399. doi:10.1182/blood-2004-12-4901
  21. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102(12):3871-3879. doi:10.1182/blood-2003-06-1841
  22. Giulino-Roth L. How I treat primary mediastinal B-cell lymphoma. Blood. 2018;132(8):782-790. doi:10.1182/blood-2018-04-791566
  23. Kis A, Eszes N, Tamasi L, et al. Sarcoidosis lymphoma syndrome – the value of PET-CT in the diagnosis. World J Surg Oncol. 2013;11:235. doi:10.1186/1477-7819-11-235
  24. Chalayer É, Bachy E, Occelli P, et al. Sarcoidosis and lymphoma: a comparative study. QJM. 2015;108(11):871-878. doi:10.1093/qjmed/hcv039
  25. Bokhari SRA, Zulfiqar H, Mansur A. Sarcoidosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 8, 2022. Accessed August 10, 2022.
  26. Yang X, Xu X, Song B, Zhou Q, Zheng Y. Misdiagnosis of primary pleural DLBCL as tuberculosis: a case report and literature review. Mol Clin Oncol. 2018;8(6):729-732. doi:10.3892/mco.2018.1601
  27. Adigun R, Singh R. Tuberculosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated January 5, 2022. Accessed August 10, 2022.
  28. Diagnosis of tuberculosis disease fact sheet. Centers for Disease Control and Prevention (CDC). Accessed August 10, 2022.

Reviewed by Kyle Habet, MD, on 8/18/2022.

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