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Diagnosis of Splenic B-Cell Lymphomas in the Bone Marrow: A Review of Histopathologic, Immunophenotypic, and Genetic Findings.

Which lymphoma entities constitute the splenic lymphomas (SLs)? The spleen may be involved secondarily by virtually any type of systemic lymphoma originating in the lymph nodes or in an extranodal site; infrequently, lymphomas that are characteristically nodal or extranodal (large B-cell lymphomas, follicular lymphomas, and others) may be entirely restricted to the spleen at diagnosis. (1-3) In these scenarios, the spleen is involved by lymphoma, but these are not typically considered to be SLs. In addition, some T-cell neoplasms, particularly T-cell large granular lymphocytic leukemia and hepatosplenic T-cell lymphoma, characteristically have prominent splenic involvement but will not be considered in this review.

We will restrict our discussion to the following B-cell neoplasms that characteristically exhibit prominent splenomegaly without significant lymphadenopathy: splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), and unclassifiable SLs (including the provisional World Health Organization entities HCL variant [HCL-v] and splenic diffuse red pulp small B-cell lymphoma [SDRPL]). (4) Splenic lymphomas are almost never restricted to the spleen: they almost always exhibit blood and bone marrow involvement. This fact, along with advances in immunophenotypic techniques and the emergence of newly discovered genetic abnormalities, provides an opportunity for pathologists to diagnose these disorders based on the blood and bone marrow findings, with the caveat that some cases will remain difficult to definitively classify in the absence of a splenectomy specimen. The objective of this review is to summarize and compare the blood (Figure 1) and bone marrow (Figure 2) findings for each of these SLs and other lymphoid neoplasms that are included in the differential diagnosis. The immunophenotypic and genetic characteristics of SLs are summarized in Table 1 and Table 2, respectively.

SPLENIC MARGINAL ZONE LYMPHOMA

Splenic marginal zone lymphoma accounts for approximately 20% of all marginal zone lymphomas and 1% to 3% of non-Hodgkin lymphomas. (5) Most patients with SMZL are seen with splenomegaly, lymphocytosis, anemia, and thrombocytopenia. The cytopenias are due to hypersplenism or autoimmune phenomena. Epidemiological investigations have shown an association with hepatitis C infection in a subset of patients. (6)

Blood and Bone Marrow Morphology

Lymphoma cells are often present in the blood and demonstrate various degrees of heterogeneity, ranging from mature lymphocytes with abundant cytoplasm to mediumsized lymphoid cells with plasmacytoid features (Figure 1, A). The presence of large cells is not common and may represent progression or transformation. A subset of circulating lymphoma cells may demonstrate basophilic cytoplasm with short villi, often present at the poles of the cell. The bone marrow is almost always involved in SMZL, even in cases in which the leukemic component cannot be confirmed. Splenic marginal zone lymphoma demonstrates various patterns of infiltration in the bone marrow, typically with a nodular, interstitial, and intrasinusoidal distribution. (7) An anti-CD20 stain highlighting a mixed pattern of bone marrow involvement in a case of SMZL is shown in Figure 2, A.

Immunophenotype

Immunophenotyping assists diagnosis by confirming the presence of monoclonal B-cells that typically lack expression of surface CD5 and CD10. This phenotype, although nonspecific, is helpful to exclude other low-grade B-cell neoplasms such as follicular lymphoma ([CD10.sup.+]), chronic lymphocytic leukemia/small lymphocytic lymphoma ([CD5.sup.+]/ [CD23.sup.+]), and mantle cell lymphoma ([CD5.sup.+]). However, an atypical phenotype does not rule out SMZL because 10% to 25% of SMZLs may express surface CD5. (7,8) In most cases, IgM with or without IgD is strongly expressed, (9) and a subset of neoplastic cells may express DBA.44, CD11c, CD23, CD103, or CD25. (10) Most important, SMZL virtually never exhibits strong coexpression of CD103, CD11c, and CD25 (a feature characteristic of HCL). (11-13)

Genetics

Most SMZLs harbor cytogenetic abnormalities. Deletion in the long arm of chromosome 7 (7q31) is the most common single cytogenetic aberrancy, followed by chromosome 3 gains. (14) Until recently, little was known about the individual gene mutations that underlie the pathogenesis of SMZL. Somatic gain-of-function mutations in NOTCH2 have been described in approximately 25% of SMZLs, and other NOTCH pathway genes are mutated in an additional 10%. (15,16) NOTCH2 signaling is necessary for the development of normal marginal zone B-cells (17,18); the mutations identified in SMZL lead to stabilization of the NOTCH2 protein and increased NOTCH signaling. (19) Mutations and copy number abnormalities of nuclear factor-[kappa]B pathway genes are present in approximately one-third of cases, (16,20) and TP53 deletions/mutations occur. (14,16,21) NOTCH2 mutations and TP53 alterations have been associated with adverse clinical outcomes in SMZL. (14,15,21,22)

Treatment

Management of patients with SMZL depends on the disease status, the severity of the clinical presentation, and the presence of other comorbidities. Asymptomatic patients are often followed up with a watch-and-wait policy. In patients with hepatitis C virus infection, treatment of the viral infection may cause regression of the lymphoma. (6) In symptomatic patients with no history of hepatitis C virus infection, several options are available, including splenectomy, rituximab monotherapy, and immunochemotherapy. (23,24)

HAIRY CELL LEUKEMIA

Hairy cell leukemia is a lymphoid neoplasm that is characterized by diffuse infiltration of the spleen and bone marrow, leading to cytopenias and splenomegaly. The identification of HCL, and the discrimination from other SLs, is critical because the therapeutic approach for HCL is distinct from that of most other B-cell neoplasms.

Blood and Bone Marrow Morphology

Patients with HCL are often pancytopenic, and monocytopenia is a characteristic finding. Typically, the neoplastic B-cells can be identified in the blood; however, they are sometimes few in number and fairly subtle morphologically. Typical hairy cells (Figure 1, B) have round to reniform nuclei without prominent nucleoli and with a moderate amount of pale cytoplasm. The periphery of the cytoplasm exhibits the circumferential, characteristic villiform projections that lend the disease its name. The bone marrow contains an interstitial or diffuse infiltrate of lymphocytes with abundant, pale cytoplasm (Figure 2, B). In some cases, the bone marrow is profoundly hypocellular, so the exclusion of subtle HCL infiltrates should be performed before a diagnosis of bone marrow aplasia in adults. (12)

Immunophenotype

A diagnosis of HCL is typically confirmed by the identification of a characteristic immunophenotype. Hairy cell leukemia expresses bright pan-B-cell antigens and, uniquely among B-cell neoplasms, strongly expresses CD11c, CD25, CD103, CD123, and annexin A1 typical ly. (12,13,25) This characteristic immunophenotype is highly sensitive and specific for HCL.

Genetics

Recently, activating BRAF V600E mutations were identified in classic HCL, occurring in all HCL cases in the initial study (26) and in an early subsequent study. (27) Although the BRAF V600E mutation is commonly present in various neoplasms (colorectal cancer, melanoma, papillary thyroid cancer, Langerhans cell histiocytosis, non-small cell lung cancer, and others), among lymphomas it seems highly specific for HCL. (12,26-29) Although most HCLs are BRAF mutated, a subset of patients with phenotypically classic HCL lack BRAF mutations, (29) exhibit unmutated IGHV4-34 gene use, and have poor responses to conventional therapy. (30)

Treatment

Asymptomatic patients with HCL may be followed up expectantly. When treatment is required, the initial approach to HCL is substantially different from that of other B-cell malignancies. The initial therapy typically consists of single-agent purine analogues such as pentostatin or cladribine, which yield durable responses in most patients. (31-33) Although these standard therapies are generally well tolerated and highly effective in HCL, some patients develop refractory disease. Various therapeutic approaches exist in this setting, (31) and several recent case reports suggest that the BRAF inhibitor vemurafenib elicits dramatic responses in BRAF-mutated refractory HCL. (34-36) The longterm efficacy and appropriate dose schedule for vemurafenib still remains to be established in HCL.

UNCLASSIFIABLE SLs

HCL Variant

Hairy cell leukemia variant is a provisional entity in the World Health Organization classification. (4) As the name implies, HCL-v exhibits some, but not all, of the features of classic HCL, including hairlike cytoplasmic projections.

Blood and Bone Marrow Morphology.--In contrast to HCL, which typically is seen with cytopenias and rare circulating hairy cells, HCL-v often manifests lymphocytosis, and the characteristic monocytopenia observed in HCL is usually not present in HCL-v. Hairy cell leukemia variant cells (Figure 1, C) frequently have prominent nucleoli (prolymphocytic morphology), which is not a feature of typical HCL. (37) Hairy cell leukemia variant may tend to exhibit less extensive marrow involvement than HCL and can have interstitial, predominantly sinusoidal, or diffuse patterns of marrow infiltration (Figure 2, C). (12,38,39)

Immunophenotype.--Much like HCL, HCL-v usually expresses bright pan-B-cell antigens, along with CD103 and CD11c. However, HCL-v typically lacks expression of CD25, CD123, and annexin A1, which are all almost always expressed in classic HCL. (12,25)

Genetics.--Multiple studies (12,26-29) have confirmed that HCL-v lacks the BRAF V600E mutation that is characteristic of HCL. However, downstream mutations of MAP2K1 (MEK1) have been identified in approximately one-third of HCL-vs and in most IGHV4-34-expressing classic HCLs. (40) These findings unify to some extent the pathobiology of HCL and HCL-v because both disorders frequently exhibit activation of the RAS-RAF-MAPK signaling cascade. TP53 deletions seem to be frequent events in HCL-v and could contribute to its more aggressive disease course compared with HCL. (41)

Treatment.--Distinction between HCL and HCL-v has important clinical implications because HCL-v does not respond well to standard HCL single-agent purine analogue therapy (eg, cladribine and pentostatin). (42) Optimal therapy for HCL-v is not established, but some good outcomes have been reported with the addition of rituximab to cladribine therapy. (43) The identification of MAP2K1 mutations raises the possibility of specific inhibition of the MAPK pathway as a novel therapeutic strategy in HCL-v.

Splenic Diffuse Red Pulp Small B-Cell Lymphoma

Splenic diffuse red pulp small B-cell lymphoma is rare and is another provisional entity within the category of splenic B-cell lymphoma/leukemia unclassifiable. (4) The features of this disorder seem to overlap significantly with the entity originally described as splenic lymphoma with circulating villous lymphocytes, as defined by the French-American-British classification. (44,45) However, splenic lymphoma with circulating villous lymphocytes has also been considered to be largely synonymous with SMZL, and precise discrimination of these disorders is challenging. Splenic diffuse red pulp small B-cell lymphoma is uncommon, and so far only a few case series have described the clinicopathologic findings. (46,47) Similar to other splenic B-cell lymphomas, patients often have splenomegaly, moderate lymphocytosis, and variable cytopenias.

Blood and Bone Marrow Morphology.--As the splenic lymphoma with circulating villous lymphocytes terminology implies, circulating lymphoma cells often demonstrate characteristic cytoplasmic villous projections, along with basophilic cytoplasm (Figure 1, D). (46,47) It is important to once again note that cytoplasmic projections are not specific to a particular type of lymphoma, and, as described previously, they can be seen in SMZL, HCL, and HCL-v, as well as other low-grade B-cell neoplasms. Bone marrow involvement has been seen in all reported cases, and the lymphoma seems to show a variable interstitial and sinusoidal pattern of infiltration (Figure 2, D). (7,46,47)

Immunophenotype.--The immunophenotype of SDRPL is typically that of a [CD5.sup.-], [CD10.sup.-], mature B-cell neoplasm. Similar to HCL-v and unlike most cases of SMZL, SDRPL cells frequently express DBA. (44) and IgG; they are less likely to express CD103 than HCL-v, and CD27 is not expressed as frequently as it is in SMZL. (7,46,47)

Genetics.--No definitive recurrent cytogenetic or molecular aberration has been established in this lymphoma. Most studied cases have had normal karyotypes; however, the abnormal cases have abnormalities that overlap with those seen in other SLs such as deletions of 7q and TP53 alterations. (46-48) BRAF mutations have not been reported.

Treatment.--The clinical course of this provisional entity seems to be indolent and even more favorable than that of SMZL. (46) The discrimination between SDRPL and SMZL may not be possible on the basis of only the bone marrow and blood findings (7); however, therapeutic strategies for SDRPL do not differ from those of SMZL, and splenectomy solely to resolve uncertainty in classification is not suggested. (24) Other splenic small B-cell lymphomas not fulfilling the criteria for HCL-v or SDRPL should be diagnosed as splenic B-cell lymphoma, unclassifiable.

Other B-Cell Lymphomas Involving Blood and Bone Marrow Mimicking SLs

Several other B-cell neoplasms can have overlapping features with the SLs and may exhibit involvement of the blood, bone marrow, and spleen.

Lymphoplasmacytic lymphoma (LPL) is often in the differential diagnosis with SMZL because SMZL may exhibit plasmacytic differentiation, and LPL may sometimes be associated with splenomegaly. The LPL infiltrate in the bone marrow contains variable proportions of lymphocytes, plasmacytoid lymphocytes, and plasma cells. The pattern of infiltration in the bone marrow can be diffuse, interstitial, or nodular. The immunophenotype, similar to SMZL, is typically that of a [CD5.sup.-]/[CD10.sup.-] mature B-cell neoplasm.

Detection of monoclonal IgM in the serum is typical in LPL, and monoclonal serum IgM combined with the presence of LPL in the bone marrow defines the clinicopathologic entity of Waldenstrom macroglobulinemia. (49) However, marginal zone lymphomas and other B-cell lymphoproliferative disorders may be associated with an IgM paraprotein, so this finding alone is not fully discriminatory. Recently, somatic mutations in MYD88 were described in a high proportion of LPL cases. (50) MYD88 mutations are infrequent in SMZL and other low-grade B-cell lymphomas, (51,52) and detection of a MYD88 mutation is a useful diagnostic adjunct in the appropriate clinical setting. (53)

B-cell prolymphocyte leukemia (B-PLL) is a somewhat ill-defined, uncommon entity characterized by marked peripheral lymphocytosis composed of more than 55% prolymphocytes (large lymphocytes with a prominent central nucleolus). Splenomegaly and bone marrow involvement are common. (4) Many cases of putative B-PLL have TP53 deletions, (54) and B-PLL is associated with an aggressive disease course. Historically, cases diagnosed as B-PLL have represented a heterogeneous group of diseases: older literature includes cases that now would be considered to be transformed chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma. (55,56) It has also been recognized that some cases of B-PLL are associated with antecedent SMZL, suggesting that many of the remaining cases in the B-PLL category represent transformed SLs. (57) It remains unclear whether B-PLL should be retained as a distinct diagnostic entity.

Other low-grade B-cell lymphomas such as chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, non-SMZLs, and follicular lymphomas may also be included in the differential diagnosis with the SLs. However, typically the immunophenotype, morphology, and other clinical findings help to easily distinguish these entities. Details of the findings in these neoplasms are beyond the scope of this review.

CONCLUSIONS

Morphologic examination and immunophenotyping of blood and bone marrow enable diagnosis of SLs in most patients, without the need for splenectomy. Recognizing HCL, and distinguishing it from HCL-v and other SLs, is critical because of substantially different therapeutic approaches. The genetic basis of SLs is beginning to be uncovered, and genetic testing may contribute to diagnosis in select cases and identify targets for precision therapy.

Please Note: Illustration(s) are not available due to copyright restrictions.

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Amir Behdad, MD; Nathanael G. Bailey, MD

Accepted for publication June 2, 2014.

From the Department of Pathology, University of Michigan Medical School, Ann Arbor.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at New Frontiers in Pathology: An Update for Practicing Pathologists; September 26, 2013; Ann Arbor, Michigan.

Reprints: Nathanael G. Bailey, MD, Department of Pathology, University of Michigan Medical School, 1301 Catherine St, Mail Stop I5242, Ann Arbor, MI 48109 (e-mail: ngbailey@umich.edu).

Caption: Figure 1. Comparison of cytomorphologic findings (Wright-Giemsa stain, original magnifications XI000). A, Splenic marginal zone lymphoma. Mature nuclear features are present, and many cells have abundant cytoplasm. Some villous lymphocytes may also be present. B, Hairy cell leukemia. Circumferential cytoplasmic villous projections are present. The nuclei may have oval or reniform shape with mature chromatin and without prominent nucleoli. C, Hairy cell leukemia variant. Hairy cytoplasmic projections are present, similar to hairy cell leukemia, but nucleoli are prominent. D, Splenic diffuse red pulp small B-cell lymphoma. Cytomorphologic findings can be similar to those of splenic marginal zone lymphoma; however, villous lymphocytes are reportedly more common.

Caption: Figure 2. Comparison of patterns of bone marrow involvement (anti-CD20 immunohistochemical staining, original magnifications X200). A, Splenic marginal zone lymphoma typically exhibits nodular and interstitial marrow involvement, and intrasinusoidal spread may be seen. B, Hairy cell leukemia characteristically exhibits an interstitial or patchy pattern of infiltration. C, Hairy cell leukemia variant often exhibits a marked sinusoidal distribution, as seen in this case, but interstitial involvement similar to that of hairy cell leukemia may also be seen. D, Splenic diffuse red pulp small Bcell lymphoma may exhibit intrasinusoidal, interstitial, or nodular distribution.
Table 1. Comparison of Immunophenotypic Findings in Splenic Small
B-Cell Lymphomas (a)

Variable   CD5   CD10   CD11c   CD25   CD103   CD123   IgM   IgD

SMZL       -/+    -      +/-    -/+     -/+      -      +    +/-
SDRPL      -/+    -       +      -      -/+     -/+    +/-   +/-
HCL-v       -     -       +      -       +       -     -/+   -/+
HCL         -    -/+      +      +       +       +      +     +
LPL        -/+    -       +     +/-      -       -      +     -

Variable   IgG   Annexin A1   DBA.44

SMZL       -/+       -         +/-
SDRPL      +/-       -          +
HCL-v      +/-       -          +
HCL         +        +          +
LPL         -        -          -

Abbreviations: HCL, hairy cell leukemia;  HCL/v, hairy cell leukemia
variant;  LPL, lymphoplasmacytic lymphoma;  SDRPL, splenic diffuse red
pulp small B/cell lymphoma;  SMZL, splenic marginal zone lymphoma;  +,
positive in more than 75% of cases;  +/-, positive in more than 50% to
75% of cases;  -/+, positive in 10% to 50% of cases;  -, negative in
more than 90% of cases.

(a) Data are aggregated from references 7, 9, 10, 12, 13, 25, 37, 46,
47, 53, 58-62.

Table 2. Comparison of Genetic Aberrations
in Splenic Small B-Cell Lymphomas (a)

Variable      Gene Mutation            Associated
                                       Structural
                                       Abnormality

SMZL       NOTCH2 (~25%)          del 7q (~45%); Less
             NF-[kappa]B pathwa     commonly: trisomy
               (BIRC3, TNFAIP3,     3, trisomy 12,
               MAP3K14, IKBKB)      trisomy 18, 17p
               (~33%)               (TP53)
             Rare: MYD88 L265P
SDRPL      Unknown                Uncommon: del 7q,
                                    trisomy 18, del 17p
                                    (TP53)
HCL-v      MAP2K1 (~33%)          del 17p (TP53)
                                    (~33%);
                                    Uncommon: 5q
                                    gain, del 7q
HCL        BRAF V600E (>90%)      Rare: 5q gain, del 7q
LPL        MYD88 L265P (~90%)     del 6q (~45%);
                                    Uncommon: del
                                    13q, del 7q

Abbreviations: HCL, hairy cell leukemia; HCL-v, hairy cell leukemia
variant; LPL, lymphoplasmacytic lymphoma; NF-[kappa]B, nuclear
factor-[kappa]B; SDRPL, splenic diffuse red pulp small B-cell
lymphoma; SMZL, splenic marginal zone lymphoma.

(a) Data are aggregated from references 14-16, 26, 40, 47, 50, 63-65.
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Author:Behdad, Amir; Bailey, Nathanael G.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2014
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