Differential diagnosis for splenic B-cell leukemia/lymphoma-unclassifiable.
Splenic B-cell lymphoma/leukemia, which is unclassifiable, includes low-grade B-cell lymphoproliferative disorders that do not fit into any other splenic lymphoid neoplasm based on current WHO classification. Presently, two provisional entities, splenic diffuse red pulp small B-cell lymphoma (SDRPL) and hairy-cell leukemia variant (HCL-v), are the most recognizable members of this group. SDRPL is an uncommon malignancy representing less than 1% of all non-Hodgkin lymphomas. Frequent clinical manifestations include splenomegaly and lymphocytosis. SDRPL is currently considered a diagnosis of exclusion and requires clinical and paraclinical correlation, including blood smear, bone marrow and spleen morphology, and the correct immunophenotype (typically positive for CD20, DBA.44, and IgG; and negative for CD5, CD10, CD23, CD43, annexin A1, CD11c, CD25, CD103, and CD123), and cytogenetic findings. Cyclin D3 is expressed in the majority of SDRPL in contrast to other types of small B-cell lymphomas. HCL-v is a less common disease accounting for 0.4% of all chronic lymphoproliferative disorders. It resembles classical HCL and SDRPL by diffusely infiltrating the splenic red pulp but is considered biologically unrelated. Splenomegaly and atypical lymphocytosis without monocytopenia are common. Distinguishing features of HCL-v include morphology, immunophenotype (the absence of CD25, CD200, CD123, annexin A1, and TRAP), genotype (wild-type BRAF), and prognosis.
- splenic B-cell lymphoma/leukemia unclassifiable
- splenic diffuse red pulp small B-cell lymphoma
- hairy cell leukemia-variant
Splenic B-cell lymphoma/leukemia, unclassifiable, is a rare category of spleen neoplasm with unknown etiology that lacks established, precise diagnostic criteria and remains a diagnosis of exclusion. This category includes the two relatively rare entities of splenic diffuse red pulp small B-cell lymphoma (SDRPL) and hairy cell leukemia variant (HCL-v), which are provisionally recognized in the current World Health Organization (WHO) classification. Other splenic small B-cell lymphomas that do not fit into the current diagnostic scheme can also be part of this category .
2. Splenic diffuse red pulp small B-cell lymphoma
SDRPL is an indolent but incurable non-Hodgkin lymphoma (NHL) composed of small mature B-lymphocytes that involve the red pulp of the spleen, as well as bone marrow and peripheral blood. Therefore, it is usually diagnosed at stage IV . The cell of origin is believed to be an unidentified B-cell precursor. SDRPL was first classified as a provisional entity in the 2008 WHO classification of lymphoid neoplasms  and was later grouped under splenic B-cell lymphoma/leukemia, unclassifiable in the 2016 revision . In the older literature, this entity may overlap with splenic marginal zone lymphoma (SMZL)-diffuse variant, SMZL with diffuse red pulp involvement, and splenic red pulp lymphoma with numerous basophilic villous lymphocytes, which are terms largely abandoned.
The true incidence of SDRPL is unknown, as it is a new part of the spleen lymphoma classification. In general, it has been reported to represent 1–2% of all lymphoid malignancies  and may account for up to 10% of the B-cell lymphomas diagnosed in splenectomy specimens [4, 5]. In a single-center case series of 37 patients, SDRPL reportedly represented 0.5% of all chronic lymphoid malignancies diagnosed by peripheral blood examination . SDRPL has a slight male predominance with a male/female ratio of 1.5–2.5:1. The patients are usually older than 40 years of age with a median age of 65–77 years [6, 7].
2.2 Clinical presentation
Patients with SDRPL usually present with mild lymphocytosis and abdominal pain due to massive splenomegaly. Leukopenia and thrombocytopenia due to hypersplenism and bone marrow infiltration are frequent . Almost all cases are diagnosed at clinical stage IV with involvement of peripheral blood and bone marrow, as mentioned above. Splenic hilar lymphadenopathy is frequently reported. However, peripheral lymph node involvement is very uncommon. B symptoms are reported only in one-third of cases. In a retrospective study of 17 cases with SDRPL, liver involvement was reported in 18% of cases while erythematous and pruritic skin papules were seen in 10% of patients . Concurrent chronic hepatitis B infection has also been described in two cases of SDRPL .
Imaging studies often show diffuse splenic enlargement without discrete splenic lesions, and increased FDG-avidity may be seen on PET/CT . Rarely, normal splenic size/appearance and FDG uptake are present .
Diagnosis of SDRPL rests mainly on the exclusion of other lymphomas by correlating histopathology of spleen and bone marrow/peripheral blood, if available, with ancillary studies assessing immunophenotypic and genetic characteristics, which are not always constant in the literature. Although unequivocal diagnostic criteria for SDRPL are still being developed, generally, the combination of morphology and immunohistochemistry in the correct clinical setting allows definitive categorization. Bone marrow examination showing a purely intrasinusoidal pattern in combination with villous lymphocytosis in peripheral blood smears, together with appropriate immunophenotypic/molecular findings excluding other low-grade B-cell lymphomas, may be sufficient for diagnosis. However, splenic biopsy or splenectomy identifying a diffuse infiltration of the red pulp by neoplastic B cells with a characteristic immunophenotype may also be necessary for unequivocal classification . Genetic studies are increasingly being performed and may facilitate the subclassification of difficult cases or those with limited tissue.
2.3.1 Laboratory findings
The most common laboratory finding in SDRPL is low-grade lymphocytosis (median lymphocyte count of (5.4 × 109/L), which can be a useful diagnostic hint to differentiate it from HCL-v that classically shows higher lymphocytosis. Although not present uniformly among all studies, thrombocytopenia (median platelet count <100 × 109/L) and leukopenia have been frequently reported in SDRPL. However, anemia is a rare finding . Other laboratory results are usually unremarkable except for hepatitis B virus tests .
2.3.2 Morphologic findings
Splenectomy specimens show diffusely enlarged spleen with a homogenous red-brown cut surface (described as “beefy”) and occasional wedge-shaped subscapular infarcts. Spleen nodularity has not been reported in SDRPL cases, and its presence should warn against this diagnosis. However residual lymphoid nodules composed of T-cells may be found .
Splenic histology reveals a purely diffuse pattern of infiltration of the red pulp cords and sinusoids by monomorphous small to medium-size mature B cells with regular ovoid nuclei, clumped chromatin, and pale cytoplasm, which spares the white pulp . Focal plasmacytic differentiation can be present as in other low-grade B-cell lymphomas. Reactive T-cell lymphoid nodules or residual B-cell lymphoid follicles are occasionally present in early disease . Sinusoidal disruption results in erythrocyte collections surrounded by tumor cells, which form the characteristic blood lakes seen in some cases. These so-called true blood lakes tend to be smaller (Figure 1) than those seen in HCL. In contrast, pseudo-blood lakes formed by sinusoidal dilation, which can also be present in other splenic lymphomas, are lined by littoral cells (CD8-positive/CD34-negative) and vascular endothelial cells (CD8-negative/CD34-positive) [7, 10]. The absence of white pulp involvement by follicular or nodular proliferation is a supportive finding to allow correct categorization .
The peripheral blood smear shows villous lymphocytes (Figure 2) in variable degrees, which may be indistinguishable from those present in other small B-cell lymphomas. However, complete circumferential distribution or longer villi should not be seen, in contrast with HCL and HCL-v.
Bone marrow trephine core biopsy typically reveals a predominantly intrasinusoidal infiltration, but occasionally interstitial and nodular aggregates may also be present. This sinusoidal pattern is considered more specific for the diagnosis but is not pathognomonic, and can also be seen in SMZL and HCL-v . Neoplastic lymphoid follicles have not been reported in bone marrow specimens with SDRPL unlike in other low-grade B-cell neoplasms, such as SMZL and follicular lymphoma.
Skin involvement may be seen in advanced cases showing an unspecific patchy peri adnexal/perivascular pattern of infiltration .
2.3.3 Immunophenotypic findings
Based on immunophenotyping, SDRPL belongs to the group of CD5/CD10 double negative B-cell lymphomas, but phenotypic variability has been reported . The classic immunophenotype of the neoplastic cells usually includes positivity for CD19, CD20, IgG, and BCL2; and negativity for CD5, CD23, CD43, cyclin D1, CD10, BCL6, MUM1, CD11c, CD25, CD103, CD123, and annexin A1. DBA.44 is positive in 20–90% of cases [7, 9, 10, 12]. IgD, IgM, CD103, CD11c, CD5, CD123, and CD43 positivity has been described infrequently, although expression of IgD is more commonly associated with marginal zone B-cell lymphoma. A recent study showed cyclin D3 expression in 24 out of 33 (72%) patients with SDRPL . However, this marker is not readily available in most laboratories, limiting its clinical utility. Cases with plasmacytic differentiation commonly show positivity for CD38 and/or CD138, as expected.
Flow cytometry demonstrates restricted B lymphocytes based on the expression of surface light chain immunoglobulins (kappa or lambda), which could be biclonal (IgM and IgG or IgM and IgD) or monoclonal (IgG or IgM alone) based on heavy chain type. In addition, CD103 expression can be detected in up to a third of cases .
2.3.4 Genetic findings
Immunoglobulin heavy chain (
A recent whole-exome sequencing (WES) study identified mutations in the
Since SDRPL is a very rare disease there is a paucity of clinical studies evaluating different management strategies. Therefore, treatment modalities for SDRPL are evolving and usually rely on the experience with other primary splenic lymphomas, such as SMZL. The most utilized therapeutic approaches for SDRPL include splenectomy, rituximab monotherapy, or expectant management. Although splenectomy can achieve durable remission, it is by definition non-curative since residual disease remains in the bone marrow and peripheral blood compartments [7, 12].
Patients with SDRPL as a rule have a chronic clinical course with a median survival compared to those of individuals with SMZL (8–10 years), but significantly superior to those with HCL-v. Although standard treatment is still unavailable, splenectomy is an excellent alternative to producing durable remission in most cases. However, around 25% of patients follow a more progressive course, which may be related to genetic alterations in
Transformation to a large B-cell lymphoma with aggressive behavior has been described rarely [7, 8, 16], and unusual transformation to B-cell prolymphocytic leukemia (B-PLL) is also possible [17, 18].
Future genetic profiling is necessary to discover alterations with prognostic significance in SDRPL, and consequently, molecular testing may be particularly indicated in young patients .
3. Hairy cell leukemia variant
HCL-v is a provisional diagnostic entity in the WHO classification since 2001 and was later included in the broader category of splenic B-cell lymphoma/leukemia, unclassifiable . HCL-v was formally first described by Cawley et al.  as an indolent lymphoproliferative disorder with some resemblance to HCL, but biologically divergent based on the postulated cell of origin (activated late-stage B cell for HCL-v vs. mature B cell of unknown type for HCL). This divergence is reflected in its variant histomorphologic, immunophenotypic, genotypic, and clinical features. Accordingly, HCL-v does not respond well to HCL therapeutic regimens and tends to behave more aggressively .
As in HCL, the spleen, bone marrow, and peripheral blood are usually involved in HCL-v, which commonly present with splenomegaly due to red pulp infiltration. However, absolute lymphocytosis without monocytopenia is the norm, as opposed to the cytopenias, especially monocytopenia, observed in HCL.
HCL-v has an annual incidence of approximately 0.03 cases per 100,000 population . It accounts for 10–20% of lymphoproliferative disorders initially diagnosed as HCL and 0.4% of all chronic lymphoproliferative disorders, accounting for 60–75 new HCL-v cases reported annually in the United States alone . The patients are usually middle-aged to elderly with a slight (1.6:1) male predominance . Although a geographical predilection has not been reported so far, the disease may be more prevalent in Asian populations [21, 22].
3.2 Clinical presentation
The typical initial manifestations, including abdominal discomfort, anemia, bleeding, or infection, are usually related to splenomegaly and/or the presence of cytopenias. In earlier stages of the disease, cytopenias are mainly related to hypersplenism rather than some form of bone marrow failure. A small proportion of cases are identified incidentally by routine hematology (cell blood counts and/or peripheral blood smear reviews) , since leukocytosis (on average 30 × 109/L) with an absolute lymphocytosis and atypical lymphocytes may be detected before the onset of symptoms. However, the absolute number and proportion of monocytes are not decreased in contrast with the usual type of HCL . While thrombocytopenia can be seen in almost half of the patients, anemia is reported in 25% of them . A single institute case series study of 52 patients showed splenomegaly in most (85%) and hepatomegaly in less than a third of the patients. However, lymphadenopathy was rare . Autoimmune hemolytic anemia and extra-splenic involvement (including skin, brain, and terminal ileum) have been reported rarely .
3.3 Morphologic findings
The HCL-v cells display morphologic heterogeneity in the peripheral blood. In most cases, identification of villous lymphocytes is possible, however, the cytoplasmic projections tend to be more polarized, less frequent (Figure 3), and more robust than the typical hair-like long circumferential “pseudopods” of classical HCL. In fact, these projections may be missing completely and when present may be indistinguishable from those seen in SDRPL, SMZL, and HCL. Nuclear features may also be inconsistent and include prominent central prolymphocytoid nucleolus, convolution (instead of round to oval nuclei), and condensed or blastic chromatin, which justifies the published terminology of “hybrid form of HCL” for this entity [1, 24]. Large cells with convoluted nuclei are prominent when HCL-v transforms to high-grade B-cell lymphoma, which is uncommon . In contrast with HCL, insignificant bone marrow fibrosis is detected on reticulin stains, which allows successful aspiration. The lymphomatous burden is usually minimal, vague, and interstitial (Figure 4). However, sometimes an intrasinusoidal growth pattern is present in common with SMZL and SDRPL [26, 27]. Similar to SDRPL and HCL, the splenic infiltrate by neoplastic B cells diffusely expand the red pulp and spares the white pulp, which appears atretic .
3.4 Immunophenotypic findings
A cardinal difference between HCL-v and classic HCL is the absence of expression of CD25, CD200, CD123, and annexin A1 [28, 29, 30]. Immunohistochemical stains (Figure 5), show positivity for CD103, DBA.44 (CD72), and CD11c in most cases, which overlaps with HCL. However, the expression of CD11c and CD103 can separate HCL-v from SMZL and SDRPL. As with any mature B-cell neoplasm, the immunophenotypic profile of HCL-v also demonstrates positivity for pan-B-cell markers (CD19, CD20, and CD22) and is usually strongly positive for surface immunoglobulins expression, most commonly IgG and lambda light chain. In addition, the majority of cases express FMC7 and HLA-DR, one-third expresses CD24 and CD79a, and only a minority express CD10 and CD138. Lastly, CD5 and CD23 have been reported negative in almost every case [19, 21, 28].
3.5 Genetic findings
Although HCL-v shares classic pathologic features with other splenic lymphomas, the signaling pathways involved are different at the molecular level. For instance, alterations in TP53 are more frequent in HCL-v when compared with classical HCL. Likewise,
Additional studies are necessary to clarify the genomic landscape of HCL-v, including further analysis of the reported mutations in U2AF1,
The treatment of HCL-v is challenging due to the rarity of the disease, which has hampered the development of definitive guidelines. Although expectant management (active observation) is an option, most patients will eventually require therapy, ranging from splenectomy to chemoimmunotherapy . Indications for treatment include the development of progressive splenomegaly, rapid increase in lymphocyte count, or symptoms related to cytopenias . Splenectomy alone can lead to long-lasting partial remission in about two-thirds of patients  and maybe the best option because it not only removes the bulk of the disease but also corrects hypersplenism alleviating cytopenias. Moreover, splenectomy followed by Rituximab may be an additional treatment option . HCL-v is resistant to agents effective against HCL, such as cladribine and pentostatin . However, adding rituximab to cladribine as a combination therapy has shown promising results, achieving a complete response in nine of 10 patients, of whom only two showed minimal residual disease (MRD) . Anti-CD22 recombinant immunotoxin, an agent used in refractory HCL, has also been utilized successfully [22, 41]. Alemtuzumab, a monoclonal antibody effective for chronic lymphocytic leukemia with mutated
HCL-v is a treatable but still incurable chronic disease. The median survival is 9 years, and 42% of patients die of unrelated causes. Transformation to large-cell lymphoma is seen in 6% of patients . A study of 35 cases of HCL-v showed a significantly shorter five-year survival in HCL-v compared with SMZL (57% vs. 84%). In contrast, classical HCL has a good response to purine analogs with a five-year and 10-year survival reaching 90%. Poor prognostic indicators in HCL-v include
4. Differential diagnosis
SDRPL and HCL-v must be differentiated from each other and other low-grade B-cell lymphomas/leukemias in the spleen, in particular SMZL, HCL, and lymphoplasmacytic lymphoma (LPL). This task can be a challenge even for experienced hematopathologists since these entities may present clinical and pathologic overlap. Splenomegaly may be the principal clinical finding, and the neoplastic B cells in these four malignancies are generally double negative for CD5 and CD10. In addition, HCL-v displaying prominent nucleoli could be confused with B-PLL. However, clinicopathological correlation, including immunohistochemistry, should allow a categorical differentiation from B-PLL. Salient differential features are highlighted below focusing on distinctions among SMZL, HCL, and LPL (Table 1). Finally, a brief differential between HCL-v and B-PLL are presented.
|Peripheral Blood||Spleen||Bone marrow||Immunophenotype||Chromosomal Aberrations||Altered Genes|
|SDRLP||Polar broad base small villous projections, condensed chromatin||Red pulp, blood lakes (possible)||Intrasinusoidal, interstitial ±,|
|CD25-, CD103±, CD123-, DBA44±, Annexin A1-, Cyclin D3+, IgG+||Uncommon:|
|HCL-v||Circumferential shorter villous projections, prominent nucleoli (subset)||Red pulp, white pulp effacement, blood lakes (uncommon)||Interstitial, Intrasinusoidal, no increased fibrosis||CD25-, CD103+, CD123-, DBA44+, Annexin A1-, TRAP±||del 17p,|
Gain of 5
|HCL||Circumferential long (hairy) projections, oval nucleus, inconspicuous nucleolus||Red pulp, blood lakes (common)||Interstitial, diffuse, prominent fibrosis (dry tap)||CD25+, CD103+, CD123+, DBA44+, Annexin A1+, CD200+, CyclinD1±||Chromosomes 5 and 7 abnormalities|
|SMZL||Polar shorter villi (or similar to SDRPL), condensed chromatin.||White pulp with marginal zone expansion||Nodular±, intrasinusoidal ±, interstitial± (residual follicles)||CD25±, CD103±, CD123-, DBA44±, Annexin A1-, IgD+||Gain of 3q, del 7q|
4.1 Splenic marginal zone lymphoma
The key differentiating trait of classic SMZL from other diseases is nodular involvement of the white pulp frequently showing a microscopic targetoid appearance composed of a darker central zone with small lymphocytes surrounded by a peripheral zone of larger paler marginal zone cells. This pattern is better appreciated on Ki-67 immunohistochemistry. Blood lakes are absent, unlike in SDRPL, HCL, and HCL-v, which all grossly show a characteristic “beefy” red cut splenic surface (correlated with red pulp infiltration and atrophic white pulp). The bone marrow involvement may also be nodular, but interstitial and intrasinusoidal patterns are also common. Notably, well-formed reactive follicles can be seen, which are typically absent in the other entities.
Immunohistochemistry may be of limited value to diagnose CD5/CD10-negative lymphomas due to variable expression of possible differentiating markers. Ideally, both CD25 and CD103 are positive in SMZL and HCL, while CD25 and CD103 are absent in HCL-v and LPL, respectively. In contrast, SDRPL should be double negative for CD25 and CD103. However, this routine clinicopathologic information may be equivocal, and therefore, esoteric testing including cytogenetic and molecular analysis may be necessary. Cytogenetic abnormalities including deletion 7q, trisomy 3q, trisomy 12q, and
4.2 Hairy cell leukemia
Although HCL shares with SDRPL and HCL-v a diffuse pattern of red pulp involvement accompanied by atrophy of the white pulp, its clinicopathologic/molecular features are usually very distinctive. HCL frequently presents with significant pancytopenia and monocytopenia without lymphocytosis. In the contrast, HCL-v and SDRPL are often associated with lymphocytosis without monocytopenia. Bone marrow morphology may show focal or diffuse involvement with characteristic cytology demonstrating round/oval nuclei and somewhat abundant well-demarcated cytoplasm (conferring a “fried-egg” appearance). However, a sinusoidal pattern, which is possible in the other diseases, would make the diagnosis of HCL improbable. Furthermore, significantly increased reticulin fibrosis delineating every neoplastic cell is characteristic and almost always presents in HCL . Immunophenotypically, triple-positivity for CD25, CD103, and CD123 (or quadruple-positivity considering CD11c), is very helpful for solidifying the diagnosis of HCL. In addition, expression of tartrate-resistant acid phosphate and annexin A1 may also be seen, which tend to be negative in the other entities in the differential diagnosis. Of interest, DBA.44 is a nonspecific marker that can also be expressed in SDRPL, HCL-v, and SMZL, limiting its diagnostic power. Finally, the vast majority of HCL cases harbor the
4.3 Lymphoplasmacytic lymphoma
LPL is a bone marrow disease typically recognized by the combination of an IgM gammopathy (with possible hyperviscosity/Waldenstrom macroglobulinemia) and the characteristic
4.4 B-cell prolymphocytic leukemia
B-PLL is an extremely rare disease that may present de novo, mimicking HCL-v. B-PLL shows B cells with prominent nucleoli and without villous projections. However, B-PLL usually follows a more aggressive course with massive splenomegaly and accelerated lymphocytosis above 100 × 109/L. CD103 expression in HCL-v should resolve this quandary. However, due to variable immunophenotypes and genetic profiles, differentiation of B-PLL from HCL-v may be difficult, especially when a splenectomy specimen is unavailable (since B-PLL may show white pulp or red pulp involvement, while HCL-v is restricted to the red pulp) [1, 22, 28]. Specific molecular markers have not been identified yet to resolve this differential diagnosis.
In summary, a review of splenic B-cell lymphoma/leukemia, unclassifiable has been presented, focusing on the differential diagnosis of SDRPL and HCL-v, the two most recognizable members of this group.
Conflict of interest
The authors reported no potential conflicts of interest.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: IARC; 2017
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008
Saboo SS, Krajewski KM, O'Regan KN, Giardino A, Brown JR, Ramaiya N, et al. Spleen in haematological malignancies: Spectrum of imaging findings. The British Journal of Radiology. 2012; 1009:81-92. DOI: 10.1259/bjr/31542964
Shimizu-Kohno K, Kimura Y, Kiyasu J, Miyoshi H, Yoshida M, Ichikawa R, et al. Malignant lymphoma of the spleen in Japan: A clinicopathological analysis of 115 cases. Pathology International. 2012; 62(9):577-582. DOI: 10.1111/j.1440-1827.2012.02844.x
Li M, Zhang L, Wu N, Huang W, Lv N. Imaging findings of primary splenic lymphoma: A review of 17 cases in which diagnosis was made at splenectomy. PLoS One. 2013; 8(11):e80264. DOI: 10.1371/journal.pone.0080264
Traverse-Glehen A, Baseggio L, Bauchu EC, Morel D, Gazzo S, Ffrench M, et al. Splenic red pulp lymphoma with numerous basophilic villous lymphocytes: A distinct clinicopathologic and molecular entity? Blood. 2008; 111:2253-2260
Kanellis G, Mollejo M, Montes-Moreno S, Rodriguez-Pinilla SM, Cigudosa JC, Algara P, et al. Splenic diffuse red pulp small B-cell lymphoma: Revision of a series of cases reveals characteristic clinico-pathological features. Haematologica. 2010; 95(7):1122-1129. DOI: 10.3324/haematol.2009.013714
Kerbauy MN, Fernandes CM, Bezerra ED, Lage LA, Siqueira SA, Pereira J. Splenic diffuse red-pulp small B-cell lymphoma associated with hepatitis B virus: A report of two cases. São Paulo Medical Journal. 2016; 134(4):359-365. DOI: 10.1590/1516-3180.2016.0035130416
Medeiros LJ, Miranda RN. Splenic Diffuse Red Pulp Small B-Cell Lymphoma. Diagnostic Pathology: Lymph Nodes and Extranodal Lymphomas. Second ed. Philadelphia, USA: Elsevier; 2018. pp. 574-581
Ponzoni M, Kanellis G, Pouliou E, Baliakas P, Scarfò L, Ferreri AJ, et al. Bone marrow histopathology in the diagnostic evaluation of splenic marginal-zone and splenic diffuse red pulp small B-cell lymphoma: A reliable substitute for spleen histopathology? The American Journal of Surgical Pathology. 2012; 36(11):1609-1618. DOI: 10.1097/PAS.0b013e318271243d
Traverse-Glehen A, Baseggio L, Salles G, Coiffier B, Felman P, Berger F. Splenic diffuse red pulp small-B cell lymphoma: Toward the emergence of a new lymphoma entity. Discovery Medicine. 2012; 13(71):253-265
Martinez D, Navarro A, Martinez-Trillos A, Molina-Urra R, Gonzalez-Farre B, Salaverria I, et al. NOTCH1, TP53, and MAP2K1 mutations in splenic diffuse red pulp small b-cell lymphoma are associated with progressive disease. The American Journal of Surgical Pathology. 2016; 40(2):192-201. DOI: 10.1097/PAS.0000000000000523
Curiel-Olmo S, Mondéjar R, Almaraz C, Mollejo M, Cereceda L, Marès R, et al. Splenic diffuse red pulp small B-cell lymphoma displays increased expression of cyclin D3 and recurrent CCND3 mutations. Blood. 2017; 129:1042-1045. DOI: 10.1182/blood-2016-11-751024
Baseggio L, Traverse-Glehen A, Callet-Bauchu E, Morel D, Magaud JP, Berger F, et al. Relevance of a scoring system including CD11c expression in the identification of splenic diffuse red pulp small B-cell lymphoma (SRPL). Hematological Oncology. 2011; 29(1):47-51. DOI: 10.1002/hon.957
Jallades L, Baseggio L, Sujobert P, Huet S, Chabane K, Callet-Bauchu E, et al. Exome sequencing identifies recurrent BCOR alterations and the absence of KLF2, TNFAIP3 and MYD88 mutations in splenic diffuse red pulp small B-cell lymphoma. Haematologica. 2017; 102:1758
Wang R-C et al. Villous lymphocytes in splenic large B-cell lymphoma with diffuse red pulp infiltration. International Journal of Hematology. 2019; 109(2):133-134
Hoehn D, Miranda RN, Kanagal-Shamanna R, Lin P, Medeiros LJ. Splenic B-cell lymphomas with more than 55% prolymphocytes in blood: Evidence for prolymphocytoid transformation. Human Pathology. 2012; 43(11):1828-1838. DOI: 10.1016/j.humpath.2012.01.003
Cheng WY, Zhu YM, Cheng S, Chen YS, Shen Y. Development of B-cell prolymphocytic leukemia in a patient with splenic diffuse red pulp small B-cell lymphoma. Leukemia & Lymphoma. 2018; 59(8):1990-1993. DOI: 10.1080/10428194.2017.1405397
Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: A distinct variant of hairy-cell leukaemia. Leukemia Research. 1980; 4(6):547-545
Wang X, Spielberger R, Huang Q. Hairy cell leukemia variant, a new entity of the WHO 2008. Journal of Clinical Oncology. 2011; 29(36):e864-e866
Matutes E, Wotherspoon A, Catovsky D. The variant form of hairy cell leukaemia. Best Practice & Research. Clinical Haematology. 2003; 16(1):41-56. DOI: 10.1016/s1521-6926(02)00086-5
Matutes E. Diagnostic and therapeutic challenges in hairy cell leukemia-variant: Where are we in 2021? Expert Review of Hematology. 2021; 14(4):355-363. DOI: 10.1080/17474086.2021.1908121
Hockley SL, Else M, Morilla A, Wotherspoon A, Dearden C, Catovsky D, et al. The prognostic impact of clinical and molecular features in hairy cell leukaemia variant and splenic marginal zone lymphoma. British Journal of Haematology. 2012; 158(3):347-354. DOI: 10.1111/j.1365-2141.2012.09163.x
Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treatment Reviews. 2006; 32(5):365-376. DOI: 10.1016/j.ctrv.2006.04.010
Zanelli M, Ragazzi M, Valli R, Piattoni S, Alvarez De Celis MI, Farnetti E, et al. Transformation of IGHV4-34+ hairy cell leukaemia-variant with U2AF1 mutation into a clonally-related high grade B-cell lymphoma responding to immunochemotherapy. British Journal of Haematology. 2016; 173(3):491-495. DOI: 10.1111/bjh.13627
Kanellis G, Garcia-Alonso L, Camacho FI, Garcia JF, Mollejo M, Montes-Moreno S, et al. Hairy cell leukemia, blastic type: Description of spleen morphology and immunophenotype of a distinctive case. Leukemia & Lymphoma. 2011; 52(8):1589-1592. DOI: 10.3109/10428194.2011.575488
Cessna MH, Hartung L, Tripp S, Perkins SL, Bahler DW. Hairy cell leukemia variant: Fact or fiction. American Journal of Clinical Pathology. 2005; 123(1):132-138. DOI: 10.1309/8qytyq1clqmhq9cl
Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D. The natural history and clinico-pathological features of the variant form of hairy cell leukemia. Leukemia. 2001; 15(1):184-186. DOI: 10.1038/sj.leu.2401999
Alapat D, Coviello-Malle J, Owens R, Qu P, Barlogie B, Shaughnessy JD, et al. Diagnostic usefulness and prognostic impact of CD200 expression in lymphoid malignancies and plasma cell myeloma. American Journal of Clinical Pathology. 2012; 137(1):93-100. DOI: 10.1309/AJCP59UORCYZEVQO
Matutes E. Immunophenotyping and differential diagnosis of hairy cell leukemia. Hematology/Oncology Clinics of North America. 2006; 20(5):1051-1063. DOI: 10.1016/j.hoc.2006.06.012
Hockley SL, Morgan GJ, Leone PE, Walker BA, Morilla A, Else M, et al. High-resolution genomic profiling in hairy cell leukemia-variant compared with typical hairy cell leukemia. Leukemia. 2011; 25(7):1189-1192
Zhang R, Wu Y, Wang X, Lu X, Li Y, Li S, et al. Difference of genomic copy numbers alterations between hairy cell leukemia-variant and classical hairy cell leukemia: A pilot retrospective study in Chinese. International Journal of Medical Sciences. 2020; 17(3):325-331. DOI: 10.7150/ijms.39307
Laurini JA, Aoun P, Iqbal J, Chan W, Greiner TC. Investigation of the BRAF V600E mutation by pyrosequencing in lymphoproliferative disorders. American Journal of Clinical Pathology. 2012; 138:877-883
Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012; 119(1):192-195. DOI: 10.1182/blood-2011-08-371179
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. The New England Journal of Medicine. 2011; 364(24):2305-2315. DOI: 10.1056/NEJMoa1014209
Waterfall JJ, Arons E, Walker RL, Pineda M, Roth L, Killian JK, et al. High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nature Genetics. 2014; 46(1):8-10. DOI: 10.1038/ng.2828
Dufresne SD, Felgar RE, Sargent RL, Surti U, Gollin SM, McPhail ED, et al. Defining the borders of splenic marginal zone lymphoma: A multiparameter study. Human Pathology. 2010; 41(4):540-551. DOI: 10.1016/j.humpath.2009.09.007
Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R, Duechler M, Gisslinger H. TGF-beta1 induces bone marrow reticulin fibrosis in hairy cell leukemia. The Journal of Clinical Investigation. 2004; 113(5):676-685. DOI: 10.1172/JCI19540
Yoshida T, Mihara K, Sugihara S, Arihiro K, Mino T, Sasaki N, et al. Splenectomy followed by administration of rituximab is useful to treat a patient with hairy cell leukemia-variant. Annals of Hematology. 2013; 92(5):711-713. DOI: 10.1007/s00277-012-1612-1
Kreitman RJ, Wilson W, Calvo KR, Arons E, Roth L, Sapolsky J, et al. Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia. Clinical Cancer Research. 2013; 19(24):6873-6881. DOI: 10.1158/1078-0432.CCR-13-1752
Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. The New England Journal of Medicine. 2001; 345(4):241-247. DOI: 10.1056/NEJM200107263450402
Telek B, Batár P, Udvardy M. Atipusos vonásokat mutató hajas sejtes leukémiavariáns sikeres alemtuzumab- (Campath 1H) kezelése [Successful alemtuzumab treatment of a patient with atypical hairy cell leukaemia variant]. Orvosi Hetilap. 2007; 148(38):1805-1807. DOI: 10.1556/OH.2007.28169
Troussard X, Grever MR. The revised guidelines for the diagnosis and management of hairy cell leukaemia and the hairy cell leukaemia variant. Br J Haematology. 2021; 193(1):11-14. DOI: 10.1111/bjh.17201
Turakhia S, Lanigan C, Hamadeh F, Swerdlow SH, Tubbs RR, Cook JR. Immunohistochemistry for BRAF V600E in the Differential Diagnosis of Hairy Cell Leukemia vs Other Splenic B-Cell Lymphomas. Am J Clin Pathol. 2015 Jul; 144(1):87-93. DOI: 10.1309/AJCP5WVXJ2KTLODO. PMID: 26071465
Flatley E, Chen AI, Zhao X, Jaffe ES, Dunlap JB, Pittaluga S, et al. Aberrations of MYC are a common event in B-cell prolymphocytic leukemia. American Journal of Clinical Pathology. 2014; 142(3):347-354. DOI: 10.1309/AJCPUBHM8U7ZFLOB
Cook JR, Aguilera NI, Reshmi S, Huang X, Yu Z, Gollin SM, et al. Deletion 6q is not a characteristic marker of nodal lymphoplasmacytic lymphoma. Cancer Genetics and Cytogenetics. 2005; 162(1):85-88