Diffuse large B cell lymphomas (DLBCL) is the largest group of NHLs, representing 49% of B cell cancers worldwide [19]. 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 [20]. 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 [21]. 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 [22]. 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 [23]. 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) [24]. A higher number of both CD68⁺ cells and microvessels in the non-responders group compared to the responders group has been observed [24]. In DLBCL, a high expression of CD68⁺ cells has been correlated with a poor prognosis [25]. The higher percentage of tryptase⁺ mast cells found in the non-responders’ group when compared with the responders’ group positively correlated with the MVD [24], 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 [26]. 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 [27]. 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 [27].

Constitutively activated STAT3 is correlated with a more advanced clinical stage and overall poor survival rate of people with DLBCL [31,32]. 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 [33]. 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 [34]. 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 [34]. 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 [35]. In the DLBCL TME, the prognostic value of the CD4/CD8 ratio has been associated with both better and worse survival in different studies [36]. 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 [35]. In addition, a higher STAT3 expression is associated not only with CD8⁺ cells but also with a higher M2 TAM cell infiltration [35].

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 [37]. The WHO 2016 update about lymphomas distinguished two MCL main subgroups according to the clinical presentation and molecular mutations: classical- and non-nodal-MCL [38]. 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 [39]. 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 [39]. 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 [40,41]. Reduced CD68⁺ and CD163⁺ TAM in MCL in the strong group compared to the other groups inversely correlated with increased SOX11⁺ cells and angiogenesis [39]. 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 [42]. 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.

Marginal zone lymphomas (MZL) is the second most common subtype of indolent B cell NHL, accounting for 10% of total NHL [43,44,45]. 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 [46]. The WHO classified MZL as extra-nodal MZL of MALT type, splenic MZL (SMZL), and nodal MZL (NMZL) [47]. 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 [48,49]. 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 [50,51,52], as well as in chronic C hepatitis or autoimmune diseases, including Sjogren Syndrome and Systemic Lupus Erythematous [53]. 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 [13]. 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 [13].