The World Health Organization (WHO) 2008 classification established a new provisional entity, the splenic diffuse red pulp small B-cell lymphoma (SDRPL). Subsequently, it was included in the revised 2016 WHO classification, where SDRPL was included in the splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U) category (Swerdlow SH, et al., 2016). SDRPL is a rare disease defined by diffuse involvement of the splenic red pulp by an infiltrate of small B-lymphocytes. Dissemination in bone marrow as well as the identification of hairy cells in the peripheral blood are also characteristic features of SDRPL. Other indolent lymphomas with spleen involvement include splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), and a variant from HCL (HCL-v), encompassing the differential diagnosis. The last one is also considered an SLL-U. Due to the significant overlap between SDRPL and those previous diseases, differential diagnosis is challenging (Suzuki T, et al., 2020). Thus, the clinical course, histologic samples, immunophenotype and molecular features are essential for its diagnosis. Splenectomy is needed for diagnosis and is the first-line treatment approach. SDRPL presents a good prognosis represented by long-term survival rates; however is an incurable disease (Vig T, et al., 2018).

The pathogenesis is obscure with no risk factors or definitive genetic aberration described; contrary to SMZL ( NOTCH2 25%), HCL ( BRAFV600E >90%), or HCL-v ( MAP2K1 33%) (Vig T, et al., 2018). Nevertheless, in a recent study, the mutational status of 23 SDRPL patients was performed, highlighting an expression of cyclin D3 (in some cases due to somatic mutations in the PEST domain of CCND3 gene) (Curiel-Olmo S, et al., 2017). Furthermore, being described the association between hepatitis B virus (HBV) and other B-cell non-Hodgkin lymphomas (NHL); some authors have hypothesized the same association with SDRPL. Two patients diagnosed with SDRPL were also infected by HBV, supporting that chronic stimulation of HBV can promote B-cell proliferation allowing the expansion of malignant cells (Kerbauy MN, et al., 2016).

SDRPL is a very uncommon lymphoma, accounting for

The clinical course is benign although at diagnosis the vast majority of cases present IV Ann Arbor stage with splenomegaly (massive in some cases) and frequently, bone marrow involvement. On the other hand, B symptoms or enlarged lymph nodes are less common (Julhakyan HL, et al., 2016). As a leukemic neoplasm, it could be presented in peripheral blood with low lymphocytosis and the typical villous lymphocytes which may represent >50% of peripheral lymphocytes. Leukopenia and/or thrombocytopenia may be present, whereas anemia or monocytopenia are less frequent (Mollejo M, et al., 2020; Piris MA, et al., 2017). Skin lesions as erythematous and pruritic papules have been also reported in 10% of cases (Kanellis G, et al., 2010).

Histologic evaluation is imperative for SDRPL diagnosis, with characteristic features in spleen and bone marrow samples. As stated in the disease term, spleen involvement is restricted to the red pulp. Which is conformed by the splenic sinusoid and splenic cord. In the latter: erythrocytes, lymphocytes, dendritic cells and macrophages are observed. SPLL-U and HCL are the lymphomas that will impair this red pulp. In contrast, in the white pulp a cylindrical contour around the central artery is conformed by lymphocytes and is infiltrated in SMZL (Suzuki T, et al., 2020).
The spleen histology shows a monomorphic infiltrate composed by lymphocytes with regular nuclei, compact chromatin and pale cytoplasm. Some of them small-sized, other medium-sized. Specific blood lakes coated by malignant cells could be observed. This infiltrate involves diffusively the red pulp cord and sinusoids and obliterating/atrophying the white pulp. In addition, residual T-cell lymphoid nodules may be observed in the white pulp (Martinez D, et al., 2016; Vig T, et al., 2018). The immunohistochemical stains are positive for CD20, CD79a, PAX5, and DBA-44 (CD72); and negative for tartrate-resistant acid phosphatase, CD3, CD5, CD10, CD11c, CD23, CD25, CD103, CD123, Cyclin D1 and Annexin A1 (Vig T, et al., 2018). The infiltrative pattern and the immunohistochemical examination establish the distinction between HCL, SMZL and SDRPL; however compared to HCL-v those results are not absolute, indeed some authors assume that this 2 entities could be actually the same disease (Julhakyan HL, et al., 2016).
The bone marrow impairment caused by SDRPL cells is defined by intrasinusoidal infiltration that could be accompanied by nodular and interstitial irruption. The absence of lymphoid follicles differs from SMZL cases (Piris MA, et al., 2017).
Phenotype
Along with clinical and histological features is necessary for the exclusion of other B-cell lymphomas. Furthermore, same as the pathology setting, the immunophenotype will not differentiate between HCL-v and SDPRL in all cases. The malignant cells express IgG, CD20 and DBA-44 (CD72) while are negative for the same antigens like in immunohistochemical studies (CD3, CD5, CD10, CD11c, CD23, CD25, CD103, CD123, Cyclin D1 and Annexin A1) (Piris MA, et al., 2017).

IGHV genes are involved in SDRPL cases since somatic hypermutation in them is reported in 70-80% cases (Martinez D, et al., 2016). Deletions on 7q and del(17p) as well as trisomy of chromosome 3 and trisomy 18, have been reported, nevertheless are uncommon (Traverse-Glehen A, et al., 2008). Mutations in TP53, NOTCH1, MAP2K1, BRAF and SF3B1 have also been observed in a small number of cases (Martinez D, et al., 2016). As mentioned before, expression of cyclin D3 is reported in a higher number of cases, being warranted further studies to demonstrate if could be a hallmark finding in SDRPL (Curiel-Olmo S, et al., 2017).

Treatment is based on isolated cases since large series of patients are uncommon. Splenectomy is the standard of care and needed for diagnosis in most cases (Traverse-Glehen A, et al., 2012). Watch & wait strategy is also applicable in the less frequent cases of diagnosis without splenectomy. Compared to other splenic lymphomas as SMZL, HCL and HCL-v, SDRPL is reported to be more resistant to chemotherapy, thus is not the preferred approach (Vig T, et al., 2018). Rituximab, an anti-CD20 monoclonal antibody, may be a reasonable option since malignant cells usually express CD20 (Traverse-Glehen A, et al., 2012).

Despite the benign course of the disease is not curable. However, a 5-year survival rate of 93% has been reported, demonstrating its good prognosis (Kanellis G, et al., 2010). Inferior survival in specific subgroups has also been reported since cases with mutations in NOTCH1, MAP2K1 and TP53 have shorter progression free survival (Martinez D, et al., 2016).