You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1 Gerardo Cazzato + 1532 word(s) 1532 2022-03-01 05:02:27 |
2 format correction Peter Tang Meta information modification 1532 2022-03-02 07:50:10 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Cazzato, G. Non-Hodgkin Lymphomas and Their Microenvironment. Encyclopedia. Available online: https://encyclopedia.pub/entry/20074 (accessed on 13 December 2025).
Cazzato G. Non-Hodgkin Lymphomas and Their Microenvironment. Encyclopedia. Available at: https://encyclopedia.pub/entry/20074. Accessed December 13, 2025.
Cazzato, Gerardo. "Non-Hodgkin Lymphomas and Their Microenvironment" Encyclopedia, https://encyclopedia.pub/entry/20074 (accessed December 13, 2025).
Cazzato, G. (2022, March 01). Non-Hodgkin Lymphomas and Their Microenvironment. In Encyclopedia. https://encyclopedia.pub/entry/20074
Cazzato, Gerardo. "Non-Hodgkin Lymphomas and Their Microenvironment." Encyclopedia. Web. 01 March, 2022.
Non-Hodgkin Lymphomas and Their Microenvironment
Edit
This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12030573

Lymphomas are characteristic tumors surrounded by an inflammatory microenvironment. The cells of the microenvironment are essential for the growth and survival of neoplastic cells and are recruited through the effect of cytokines/chemokines. Lymphomas include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state. Non-Hodgkin lymphomas (NHLs) include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state and are characterized by a great tendency to disseminate towards extra-nodal locations.

inflammatory cells non-Hodgkin’s lymphomas classical Hodgkin’s lymphomas tumor microenvironment

1. Non-Hodgkin Lymphomas (NHLs) and Their Microenvironment

NHLs include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state and are characterized by a great tendency to disseminate towards extra-nodal locations [1]. About 25% of NHLs arise in extra-nodal locations and most of them are present in both nodal and extra-nodal sites. Based on their morphology, immunophenotype, genetic and clinical features, NHLs have been classified into more than 30 different types (Table 1) [2]. NHLs’ histologic features allow us to discriminate between a nodular and a diffuse pattern. In the first instance, the tumor cells aggregate to form large clusters. In the diffuse pattern, no evidence of nodularity or germinal center formation has been observed, and it is characterized by a profound impairment of lymph node architecture [3].
Table 1. Classification of NHLs.

Indolent lymphomas

  • Follicular lymphoma

  • B-chronic lymphocytic leukemia/small lymphocytic lymphoma

  • Lymphoplasmacytic lymphoma

  • Marginal zone lymphoma (nodal, extra-nodal, splenic)

  • T/natural killer large cell granular lymphocyte leukemia

  • T-chronic lymphocytic leukemia/prolymphocytic leukemia

Aggressive lymphomas

  • Mantle cell lymphoma

  • Diffuse large B cell lymphoma

  • Peripheral T-cell lymphoma (unspecified)

  • Peripheral T-cell lymphoma (angioimmunoblastic, angiocentric

  • T/natural killer cell, hepatosplenic γ/δ, intestinal T cell lymphoma)

  • Anaplastic large cell lymphomas

Highly aggressive lymphomas

  • Precursor T or B lymphoblastic leukemia/lymphoma.

  • Burkitt and Burkitt-like lymphoma.

  • Adult T-cell leukemia/lymphoma (HTLV-1+)

2. DLBCL

Diffuse large B cell lymphomas (DLBCL) is the largest group of NHLs, representing 49% of B cell cancers worldwide [4]. The median age of prevalence is seventy years, although it has been diagnosed in young people and rarely in children, with a slight male prevalence [5]. DLBCL is characterized by a high heterogeneity at both the clinical and biological levels because it arises from germinal center B cells at different stages of differentiation associated with recurrent genetic modifications which contribute to the molecular pathogenesis of the disease [6]. On these bases, the DLBCL classification results are very complex and constantly evolving due to heterogenic variants in consideration to morphology, phenotype, genetic anomalies, prognosis and clinical features [7]. DLBCL tumor mass may grow in lymph nodes and/or in other multiple external sites, but the gastrointestinal tract constitutes the most frequent primary tumor site [8]. CD68+ macrophages, tryptase+ mast cells and microvascular density (MVD) have been evaluated in samples derived from DLBCL patients subdivided into two groups. The first group included patients who achieved a complete remission (responders), and the second included patients who never achieved a complete remission or incomplete remission after first-line chemotherapy, and who relapsed within six months (non-responders) [9]. A higher number of both CD68+ cells and microvessels in the non-responders group compared to the responders group has been observed [9]. In DLBCL, a high expression of CD68+ cells has been correlated with a poor prognosis [10]. The higher percentage of tryptase+ mast cells found in the non-responders’ group when compared with the responders’ group positively correlated with the MVD [9], indicating the important role of mast cells in promoting and sustaining tumor angiogenesis in DLBCL. Bulky and residual tumors are considered to increase the risk of relapse in DLBCL patients [11]. To investigate the complex relationships occurring between immune cells, stromal cells, endothelial cells and the tumor cells, the involvement of T cells in the control of bulky and non-bulky DLBCL development and their correlation with mast cells and MVD has been estimated [12]. A significant reduction in CD3+ cells in the TME of bulky compared to non-bulky disease has been reported, suggesting the loss of the immune control resulting in an increased cell proliferation, and consequently to a large tumor cell-mass in bulky DLBCL [12].
Constitutively activated STAT3 is correlated with a more advanced clinical stage and overall poor survival rate of people with DLBCL [13][14]. In addition, STAT3 is strongly activated in ABC-DLBCL and BCL6-negative normal germinal center B cells representing both the second oncogenic pathway in ABC-DLBCL and an additional therapeutic target for treatment [15]. The DLBCL GCB and ABC subgroups of patients have been compared and by means of RNAscope technology a significantly higher number of STAT-3-expressing cells in ABC group as compared to GCB has been shown [16]. Tumor vessels in ABC samples appeared lined by endothelial cells expressing both FVIII and STAT3 signals, while in GCB samples, only few vessels co-expressed FVIII and STAT3 [16]. A higher Ki67 expression in tumor cells and a higher number of CD163+ macrophages in ABC patients as compared with GBC ones has been observed, together with a high density of CD3+ and CD8+ cells, which correlated with STAT3 expression and microvascular density [17]. In the DLBCL TME, the prognostic value of the CD4/CD8 ratio has been associated with both better and worse survival in different studies [18]. No variation in CD4+ cells in ABC with respect to GCB has been observed but a higher CD8+ cell infiltrate in the ABC group associated with a decreased CD4/CD8 ratio [17]. In addition, a higher STAT3 expression is associated not only with CD8+ cells but also with a higher M2 TAM cell infiltration [17].

3. MCL

Mantle cell lymphomas (MCL) represents around 2–10% of NHLs in adults with a median age at diagnosis of 65 years old, principally observed in men more than in women, at a 3:1 ratio. It originates in the lymph nodes although metastasis in the bone marrow, spleen, and gastrointestinal tract are frequently present [19]. The WHO 2016 update about lymphomas distinguished two MCL main subgroups according to the clinical presentation and molecular mutations: classical- and non-nodal-MCL [20]. The first one is characterized by an unmuted immunoglobulin variable region heavy chain (IgHV) and SOX11+ with a blastoid or pleomorphic morphology associated with an aggressive outcome. The second one is characterized by hypermutated IgHV and SOX11-, with an indolent disease course. Here, MCL samples were divided into three histological groups based on SOX11-IHC positivity: “negative” with no staining and 0% of SOX11+ cells; “light” with a weak-moderate staining and 1–39% of SOX11+ cells; and “strong” with a moderate-strong staining and ≥40% of SOX11+ cells [21]. Higher CD4+ and CD8+ T-lymphocyte infiltrates in MCL lymph node biopsies belonging to the strong group compared to the other groups have been demonstrated and correlated with SOX11 intensity and increased angiogenesis [21]. In the strong group, characterized by worse outcomes, CD8+ cells could be involved in the activation of tumor immune evasion processes because CD8+ cells promote the secretion of prostaglandin E2 which consequently induces tumor escape via the Fas signaling pathway [22][23]. Reduced CD68+ and CD163+ TAM in MCL in the strong group compared to the other groups inversely correlated with increased SOX11+ cells and angiogenesis [21]. The p53 expression results were negative or very low in all the samples. The functional loss of p53 induces excessive inflammatory reactions that in turn sustain tumor growth and progression [24]. Although the literature data indicate that STAT3 is constitutively activated and acts by decreasing SOX11, the evaluation of STAT3 mRNA expression did not reveal any variation among the three analyzed MCL group of patients.

4. MZL

Marginal zone lymphomas (MZL) is the second most common subtype of indolent B cell NHL, accounting for 10% of total NHL [25][26][27]. It evolves starting from memory B cells residing in a micro-anatomic compartment of the secondary lymphoid follicles. This compartment is named as the “marginal zone” and it is in mucosa-associated lymphoid tissues (MALT) and in the spleen [28]. The WHO classified MZL as extra-nodal MZL of MALT type, splenic MZL (SMZL), and nodal MZL (NMZL) [29]. About one-third of MZL cases localize it the stomach, but other localization sites include gastrointestinal sites as well as in salivary glands, ocular adnexa, thyroid, lung, skin, breast, and liver [30][31]. MALT lymphoma grows in organs lacking in lymphoid tissue and in which B cells accumulate as a consequence of chronic inflammatory stimuli including Helicobacter pylori, Chlamydophila psittaci, Borrelia burgdorferi infections [32][33][34], as well as in chronic C hepatitis or autoimmune diseases, including Sjogren Syndrome and Systemic Lupus Erythematous [35]. MALT lymphomas in the TME in addition to B cells present the infiltration of T cells, macrophages, and neutrophils. In MZL-MALT lymphoma specimens the inflammatory cells infiltrating the TME have been analyzed and quantified [36]. The results indicate an increased number of CD3+, CD4+ and CD8+ lymphocytes, CD68+, CD163+ macrophages and tryptase+ mast cells in the MALT group samples compared to the healthy ones. In addition, a higher number of CD34+ vessels have been demonstrated in MALT lymphoma samples in a positive correlation with CD8+ cells, underlying the important role of these cells in tumor angiogenesis. Furthermore, the number of CD8+ cells correlated with M2-type macrophages, while tryptase+ mast cells correlated with CD4+ cells, indicating the complex crosstalk between TME-infiltrating cells [36].

References

  1. Campo, E.; Swerdlow, S.H.; Harris, N.L.; Pileri, S.; Stein, H.; Jaffe, E.S. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood 2011, 117, 5019–5032.
  2. Al-Naeeb, A.B.; Ajithkumar, T.; Behan, S.; Hodson, D.J. Non-Hodgkin lymphoma. BMJ 2018, 362, k3204.
  3. Emile, J.F.; Azoulay, D.; Gornet, J.M.; Lopes, G.; Delvart, V.; Samuel, D.; Reynès, M.; Bismuth, H.; Goldwasser, F. Primary non-Hodgkin’s lymphomas of the liver with nodular and diffuse infiltration patterns have different prognoses. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2001, 12, 1005–1010.
  4. Horvat, M.; Zadnik, V.; Šetina, T.J.; Boltežar, L.; Goličnik, J.P.; Novaković, S.; Novaković, B.J. Diffuse large B-cell lymphoma: 10 years’ real-world clinical experience with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone. Oncol. Lett. 2018, 15, 3602–3609.
  5. Smith, S.D.; Chen, A.; Spurgeon, S.; Okada, C.; Fan, G.; Dunlap, J.; Braziel, R.; Maziarz, R. Diffuse large B-cell lymphoma in adults aged 75 years and older: A single institution analysis of cause-specific survival and prognostic factors. Ther. Adv. Hematol. 2013, 4, 349–353.
  6. Schneider, C.; Pasqualucci, L.; Dalla-Favera, R. Molecular pathogenesis of diffuse large B-cell lymphoma. Semin. Diagn. Pathol. 2011, 28, 167–177.
  7. Morin, R.D.; Scott, D.W. DLBCL subclassification: Divide and conquer? Blood 2020, 135, 1722–1724.
  8. Suresh, B.; Asati, V.; Lakshmaiah, K.C.; Babu, G.; Lokanatha, D.; Jacob, L.A.; Lokesh, K.N.; Rudresh, A.H.; Rajeev, L.K.; Smitha, S.; et al. Primary gastrointestinal diffuse large B-cell lymphoma: A prospective study from South India. South Asian J. Cancer 2019, 8, 57–59.
  9. Marinaccio, C.; Ingravallo, G.; Gaudio, F.; Perrone, T.; Nico, B.; Maoirano, E.; Specchia, G.; Ribatti, D. Microvascular density, CD68 and tryptase expression in human diffuse large B-cell lymphoma. Leuk. Res. 2014, 38, 1374–1377.
  10. Cai, Q.-C.; Liao, H.; Lin, S.-X.; Xia, Y.; Wang, X.-X.; Gao, Y.; Lin, Z.-X.; Lu, J.-B.; Huang, H.-Q. High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma. Med. Oncol. 2012, 29, 2317–2322.
  11. Tokola, S.; Kuitunen, H.; Turpeenniemi-Hujanen, T.; Kuittinen, O. Significance of bulky mass and residual tumor—Treated with or without consolidative radiotherapy—To the risk of relapse in DLBCL patients. Cancer Med. 2020, 9, 1966–1977.
  12. Marinaccio, C.; Ingravallo, G.; Gaudio, F.; Perrone, T.; Ruggieri, S.; Opinto, G.; Nico, B.; Maiorano, E.; Specchia, G.; Ribatti, D. T cells, mast cells and microvascular density in diffuse large B cell lymphoma. Clin. Exp. Med. 2016, 16, 301–306.
  13. Ok, C.Y.; Chen, J.; Xu-Monette, Z.Y.; Tzankov, A.; Manyam, G.C.; Li, L.; Visco, C.; Montes-Moreno, S.; Dybkær, K.; Chiu, A.; et al. Clinical implications of phosphorylated STAT3 expression in De Novo diffuse large B-cell lymphoma. Clin. Cancer Res. 2014, 20, 5113–5123.
  14. Zl, W.; Yq, S.; Yf, S.; Zhu, J. High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J. Hematol. Oncol. 2011, 4, 31.
  15. Ding, B.B.; Yu, J.J.; Yu, R.Y.L.; Mendez, L.M.; Shaknovich, R.; Zhang, Y.; Cattoretti, G.; Ye, B.H. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 2008, 111, 1515–1523.
  16. Tamma, R.; Ingravallo, G.; Albano, F.; Gaudio, F.; Annese, T.; Ruggieri, S.; Lorusso, L.; Errede, M.; Maiorano, E.; Specchia, G.; et al. STAT-3 RNAscope Determination in Human Diffuse Large B-Cell Lymphoma. Transl. Oncol. 2019, 12, 545–549.
  17. Tamma, R.; Ingravallo, G.; Gaudio, F.; Annese, T.; Albano, F.; Ruggieri, S.; Dicataldo, M.; Maiorano, E.; Specchia, G.; Ribatti, D. STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas. Leuk. Lymphoma 2020, 61, 567–574.
  18. Xu, Y.; Kroft, S.H.; McKenna, R.W.; Aquino, D.B. Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: A multiparameter flow cytometry study. Br. J. Haematol. 2001, 112, 945–949.
  19. Papin, A.; Le Gouill, S.; Chiron, D. Rationale for targeting tumor cells in their microenvironment for mantle cell lymphoma treatment. Leuk. Lymphoma 2018, 59, 1064–1072.
  20. Swerdlow, S.H.; Campo, E.; Pileri, S.A.; Harris, N.L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.; Salles, G.A.; Zelenetz, A.D.; et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016, 127, 2375–2390.
  21. Annese, T.; Ingravallo, G.; Tamma, R.; De Giorgis, M.; Maiorano, E.; Perrone, T.; Albano, F.; Specchia, G.; Ribatti, D. Inflammatory Infiltrate and Angiogenesis in Mantle Cell Lymphoma. Transl. Oncol. 2020, 13, 100744.
  22. Yang, F.; Wei, Y.; Cai, Z.; Yu, L.; Jiang, L.; Zhang, C.; Yan, H.; Wang, Q.; Cao, X.; Liang, T.; et al. Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling. Cell. Mol. Immunol. 2015, 12, 66–76.
  23. Cai, Z.; Yang, F.; Yu, L.; Yu, Z.; Jiang, L.; Wang, Q.; Yang, Y.; Wang, L.; Cao, X.; Wang, J. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J. Immunol. 2012, 188, 5954–5961.
  24. Uehara, I.; Tanaka, N. Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression. Cancers 2018, 10, 219.
  25. Sumina Sapkota, H.S. Non-Hodgkin Lymphoma—StatPearls—NCBI Bookshelf. Available online: https://www.ncbi.nlm.nih.gov/books/NBK559328/ (accessed on 15 February 2022).
  26. Sriskandarajah, P.; Dearden, C.E. Epidemiology and environmental aspects of marginal zone lymphomas. Best Pract. Res. Clin. Haematol. 2017, 30, 84–91.
  27. Müller, A.M.S.; Ihorst, G.; Mertelsmann, R.; Engelhardt, M. Epidemiology of non-Hodgkin’s lymphoma (NHL): Trends, geographic distribution, and etiology. Ann. Hematol. 2005, 84, 1–12.
  28. Roulland, S.; Suarez, F.; Hermine, O.; Nadel, B. Pathophysiological aspects of memory B-cell development. Trends Immunol. 2008, 29, 25–33.
  29. Bertoni, F.; Coiffier, B.; Salles, G.; Stathis, A.; Traverse-Glehen, A.; Thieblemont, C.; Zucca, E. MALT lymphomas: Pathogenesis can drive treatment. Oncology 2011, 25, 1134.
  30. Singh, R.; Shaik, S.; Negi, B.; Rajguru, J.; Patil, P.; Parihar, A.; Sharma, U. Non-Hodgkin’s lymphoma: A review. J. Fam. Med. Prim. Care 2020, 9, 1834–1840.
  31. Zucca, E.; Bertoni, F.; Stathis, A.; Cavalli, F. Marginal Zone Lymphomas. Hematol. Oncol. Clin. N. Am. 2008, 22, 883–901.
  32. Wang, F.; Meng, W.; Wang, B.; Qiao, L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014, 345, 196–202.
  33. Collina, F.; De Chiara, A.; De Renzo, A.; De Rosa, G.; Botti, G.; Franco, R. Chlamydia psittaci in ocular adnexa MALT lymphoma: A possible role in lymphomagenesis and a different geographical distribution. Infect. Agents Cancer 2012, 7, 8.
  34. Goodlad, J.R.; Davidson, M.M.; Hollowood, K.; Batstone, P.; Ho-Yen, D.O. Borrelia burgdorferi-associated cutaneous marginal zone lymphoma: A clinicopathological study of two cases illustrating the temporal progression of B. burgdorferi-associated B-cell proliferation in the skin. Histopathology 2000, 37, 501–508.
  35. Rotaru, I.; Tanase, A.D.; Nacea, J.G.; Patrascu, S.; Olteanu, O.A.; Pătraşcu, A.M. Heterogeneity among Diffuse Large B-Cell Lymphoma: New Entities in WHO Classification, a First Step in Personalized Therapy. Available online: https://www.researchgate.net/publication/338865198_Heterogeneity_among_diffuse_large_B-cell_lymphoma_new_entities_in_WHO_classification_a_first_step_in_personalized_therapy (accessed on 15 February 2022).
  36. Tamma, R.; Ranieri, G.; Ingravallo, G.; Annese, T.; Oranger, A.; Gaudio, F.; Musto, P.; Specchia, G.; Ribatti, D. Inflammatory Cells in Diffuse Large B Cell Lymphoma. J. Clin. Med. 2020, 9, 2418.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Medicine, Research & Experimental
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Gerardo Cazzato
View Times: 582
Revisions: 2 times (View History)
Update Date: 03 Mar 2022
Table of Contents
    Notice
    You are not a member of the advisory board for this topic. If you want to update advisory board member profile, please contact office@encyclopedia.pub.
    OK
    Confirm
    Only members of the Encyclopedia advisory board for this topic are allowed to note entries. Would you like to become an advisory board member of the Encyclopedia?
    Yes
    No
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    There is no comment~
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    ${ selectedItem.replyTextCharacter }/${ selectedItem.replyMaxCharacter }
    Submit
    Cancel
    Confirm
    Are you sure to Delete?
    Yes No
    Academic Video Service
    Feedback