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    Topic review

    Follicular Lymphoma and Primary Splenic Lymphoma

    Subjects: Hematology
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    Follicular lymphoma (FL) is a mature B-cell non-Hodgkin lymphoma derived from germinal center B-lymphocytes (centrocytes and centroblasts) that generally has at least a partially follicular/nodular histologic pattern.

    1. Background

    Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL.

    2. Epidemiology of Follicular Lymphoma

    PSL comprise approximately 1% of all malignant neoplasms [1][2], when the disease is restricted to involvement of the spleen and hilar lymph nodes. However, a broader definition also encompassing liver, bone marrow or peripheral blood involvement, but lacking prominent distant adenopathy, is accepted as well.
    Epidemiologically, one study showed the prevalence of PSL to be approximately 62%, where DLBCL was the most common lymphoid neoplasm (25%) followed by splenic MZL (15%) and FL (6%) [3]. Low-grade CD10-positive lymphoproliferative disorders encountered in splenic specimens belong most frequently to the category of FL (either primary or secondary). However, a subset of FL in the spleen represents aggressive disease (equivalent to DLBCL), considering that extranodal FL is most commonly a high-grade lymphoma that may lack expression (or translocation) of BCL2 [4][5]. However, duodenal-type FL represents an exception to this rule, due to an indolent course and constant expression of BCL2 [6].
    The incidence of PSFL is unknown and may be overestimated because the vast majority of FL in the spleen represent secondary disease. In general, PSFL accounts for a small fraction of PSL and only a few case series are available on this entity [7][8][9].
    In general, FL has an incidence of 2.1 per in the United States (SEER Follicular Lymphoma—Cancer Stat Facts (https://seer.cancer.gov/statfacts/html/follicular.html, accessed 16 October 2021), and is less common in eastern Europe, Asia and developing countries [10]. FL is 2–3 times more common in white than in black patients [6][11], and disproportionately affects females. The mean age at diagnosis (including all histologic grades) has been estimated to be 68 years, which is similar to nodal FL [7][8][12][13][14]. PSFL is rarely seen in patients younger than 50 years based on case series [7][8][13].

    3. Clinical Presentation

    Due to the rarity of PSFL, clinical features are incompletely defined. In contrast to nodal FL, most patients present with stage I/II disease [14]. A minority of cases show bone marrow, peripheral blood or liver infiltration [8]. In PSFL, isolated splenomegaly either asymptomatic or accompanied by upper abdominal discomfort is the rule [8]. B symptoms occur in a minority (less than 20%) of cases. Cytopenias (anemia and/or thrombocytopenia) secondary to hypersplenism or rarely due to bone marrow infiltration have been reported [8][13]. In contrast, nodal FL, which may involve the spleen, is usually accompanied by distant lymphadenopathy and more frequent systemic symptoms. The real frequency of PSFL remains to be established. As such, the disease may be incidentally found during work up for other medical conditions [15]. However, pathologic splenic rupture due to massive splenomegaly has been described [16]. Atypical lymphocytosis observed in peripheral blood smears or liver biopsies and/or mild to moderate splenomegaly may be identified incidentally during clinical encounters unrelated to lymphoma work-up in asymptomatic or paucisymptomatic patients. Interestingly, anti-hepatitis C virus (HCV) antibodies were more prevalent in patients with splenic FL compared with nodal FL with splenic infiltration in a study of 17 cases [8].

    4. Treatment and Prognosis

    Treatment of splenic lymphomas is ascribed to its lineage. Based on a few available studies it has been suggested to treat patients with splenic lymphomas with regimens developed for nodal lymphomas, which is particularly true for FL. However, long term outcome data are unavailable given the rarity of splenic lymphomas. Consequently, specific treatment modalities are not formally recommended for PSFL yet [17].
    HCV infection has been more frequently described in PSFL than in nodal FL [8], and anti-viral therapy alone can induce remission of lymphoproliferative disorders [18][19][20], suggesting this option for PSFL.
    Stage I PSFL diagnosed on splenectomy specimen could be subjected to an active observation/expectant management strategy, mirroring guidelines for nodal FL stage I treated with complete surgical removal of the affected lymph nodes [17]. Long treatment-free intervals may be achieved by this approach, while minimizing therapy-related adverse effects. A recent large case series of splenic lymphomas undergoing splenectomy demonstrated that additional chemotherapy after surgery did not impact overall survival (OS) in FL [14], further supporting the practice of expectant management. However, the management of stage I nodal FL remains mired in controversy. While current guidelines still recommend localized radiotherapy, heterogenous alternatives (ranging from vigilance to adjuvant Rituximab monotherapy or immunochemotherapy) are used as evident from prospective observational studies and real-world series [21]. The combination of radiotherapy with systemic treatments (chemotherapy or immunochemotherapy) has been shown to prolong PFS but not OS, and the decision to offer additional treatment remains both patient and physician dependent [22][23]. These concepts have been applied to early PSFL. On the other hand, PSFL presenting with combinations of liver, bone marrow and peripheral blood involvement are expected to behave like advanced FL (stage IV), and the therapeutic choices range from active observation (for low tumor burden asymptomatic disease) to first line immunochemotherapy (for high tumor burden symptomatic disease) [17]. Commonly, combinations of Rituximab with Bendamustine, CHOP or CVP have been used as first line regimens [24][25]. Recently, substituting Rituximab for Obinutuzumab (a type II glycoengineered humanized anti-CD20 monoclonal antibody) in similar chemotherapy combinations was shown to prolong PFS without impacting OS [26].
    Maintenance regimens with anti-CD20 monoclonal antibodies have been applied by several investigators, again prolonging PFS but not OS [27]. The efficacy of maintenance regimens for advanced leukemic disease (as is common in stage IV PSFL) deserves investigation, since lymphocytosis at presentation implies poor prognosis in nodal FL [28][29]. Treatment of relapsed PSFL can also be modelled on nodal FL, where management is influenced by multiple, patient and disease related factors, including the interval between diagnosis and relapse, and documentation of histologic transformation. A growing number of signaling pathway-specific/non-chemotherapy agents and cellular therapies are becoming available for FL, which could change the course of this still incurable disease [30][31]. However, the applicability of these new strategies to PSFL is unknown, and probably dependent on further clarification of specific biological characteristics and pathogenic mechanisms.
    Conclusive data on prognostication of PSFL are not available yet. In the largest series published to date, survival was similar to nodal FL using treatment options ranging splenectomy alone to combined surgery and chemotherapy [13]. It is conceivable that the prognosis of PSFL may be influenced by the stage of disease and prognostic scores usually applied to nodal FL (namely the Follicular Lymphoma International Prognostic Index/FLIPI and FLIP2) [32][33]. However, the clinical outcomes of patients with spleen-confined disease have been similar to those of individuals with disseminated lymphoma [7], which may be explained by a limited sample size.
    When PFSL transforms to aggressive lymphoma, regimens for DLBCL (immunochemotherapy with anti-CD20 antibodies and standard anthracycline-based chemotherapy for at least four cycles in localized stages) are used achieving comparable results.

    This entry is adapted from 10.3390/curroncol28060407


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