Non-Neoplastic Diseases Involving the Splenic White Pulp
Reactive Follicular Hyperplasia With Germinal Center Formation
Clinical Features
- •
Occurs at any age; more common in children and younger adults
- •
Caused by a variety of both acute and chronic immunologic stimuli (e.g., bacterial infections, autoimmune diseases including hemolytic processes)
- •
May represent an incidental finding
Gross Pathology
- •
May present with splenomegaly, usually mild to moderate in degree ( Figure 15.1 )
Figure 15.1
Follicular white pulp hyperplasia, gross photograph.
The spleen is enlarged. Small, indistinct pale foci of hyperplastic white pulp are seen on the cut surface and under the capsule.
- •
Prominent white pulp nodularity may be grossly visible
Histopathology
- •
Tripartite variably prominent germinal centers with well-defined marginal and mantle zones
- •
Marginal zones may be expanded in chronic cases ( Figure 15.2 )
Figure 15.2
Marginal zone hyperplasia.
- •
Polarized (dark and light zones) germinal centers with abundant mitoses and tingible body macrophages
- •
Increased number of plasma cells and small plasma cell aggregates in red pulp
Special Stains and Immunohistochemistry
- •
Immunohistochemistry may be useful in differential diagnosis from lymphomatous infiltration
- •
Germinal centers are positive for CD20, CD10, and bcl-6, and negative for bcl-2
- •
Mantle cells are positive for CD20 and bcl-2, may be positive for CD5 and negative for CD43 and cyclin D1
Other Techniques for Diagnosis
- •
Evaluation of light-chain expression by flow cytometry may be complicated by high nonspecific binding; nevertheless, polyclonal pattern is always seen supporting the diagnosis of reactive hyperplasia
Differential Diagnosis
Follicular, Mantle Cell, and Marginal Zone Lymphomas
- •
Neoplastic follicles are less sharply defined, and may coalesce
- •
Reactive follicles have well-defined marginal and mantle zones with polarized germinal centers, tingible body macrophages, and mitotic figures
- •
Neoplastic lymphoid infiltrates are often present in red pulp as well as in periarteriolar lymphoid sheaths (PALS) of white pulp
- •
Immunophenotypic features are dependent on the lymphoma subtype
- •
Histologic features of splenic lymphoid hyperplasia are largely similar to those of nodal reactive follicular hyperplasia
- •
Well-developed germinal centers are considered a normal finding in children and young adults; uncommon in elderly individuals; differential diagnosis includes follicular lymphoma or autoimmune disorders
- •
Localized (nodular) reactive lymphoid hyperplasia is a rare nodular lesion that may grossly simulate lymphoma; histologically, it presents as an aggregation of hyperplastic follicles with typical reactive features
- •
Prominent marginal zone expansion seen in chronic antigenic simulation may resemble marginal zone lymphoma; however, there is no infiltration of the germinal center or red pulp by marginal zone cells and mantle zones are preserved, a feature invariably missing in lymphoma cases
- •
Common findings in patients with splenomegaly associated with systemic lupus erythematosus and rheumatoid arthritis (Felty syndrome) include follicular hyperplasia, plasmacytosis, and red pulp expansion that includes proliferation of CD3+ and CD57-positive cytotoxic T cells, neutropenia, and leg ulcers
Selected References
Burke J.S., Osborne B.M.: Localized reactive lymphoid hyperplasia of the spleen simulating malignant lymphoma: a report of seven cases. Am J Surg Pathol 1983; 7: pp. 373-380.
Burks E.J., Loughran T.P.: Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev 2006; 20: pp. 245-266.
Neiman R.S., Orazi A.: Reactive lymphoid hyperplasia.2nd ed.1999.WB SaundersPhiladelphiapp. 67-84.
Reactive Lymphoid Hyperplasia Without Germinal Center Formation
Clinical Features
- •
Occurs in any age group
- •
Most common pattern encountered in viral infections (infectious mononucleosis, herpes simplex virus), transplant recipients, and immunosuppressed individuals (e.g., steroid-treated immune thrombocytopenic purpura, patients with rheumatoid arthritis on methotrexate) and in functional immunodeficiencies encountered in infants and elderly individuals
Gross Pathology
- •
Modest splenomegaly
- •
Cut surface may be grossly unremarkable
Histopathology
- •
White pulp shows a heterogeneous lymphoid population ( Figure 15.3 )
Figure 15.3
Primary (nonfollicular) white pulp hyperplasia.
Heterogeneous lymphoid population including immunoblasts with open chromatin pattern.
- •
Numerous immunoblasts with open chromatin pattern and prominent nucleoli are seen
- •
Tingible body macrophages may be prominent
- •
Similar proliferation is seen in white pulp surrounding splenic arterioles (PALS)
- •
Transformed lymphocytes may infiltrate splenic trabeculae, predisposing to splenic rupture (e.g., in infectious mononucleosis)
Special Stains and Immunohistochemistry
- •
Immunohistochemistry can be useful in differential diagnosis from lymphomatous infiltration with immunoblastic proliferation (see Differential Diagnosis below)
- •
Immunohistochemical stains and in situ hybridization studies to exclude viral infection (e.g., Epstein-Barr virus [EBV]) may be helpful
Other Techniques for Diagnosis
- •
Evaluation of light-chain expression by flow cytometry shows polyclonal B-cell population
Differential Diagnosis
Diffuse Large B-cell Lymphoma, Immunoblastic Variant
- •
Uniform expansive sheets of immunoblasts favor a diagnosis of diffuse large B-cell lymphoma (DLBCL)
- •
Correlation of histologic findings with clinical history and immunohistochemistry, flow cytometry, or molecular studies for clonality is of great value
Hodgkin Lymphoma
- •
Immunoblastic proliferation in infectious mononucleosis may include Reed-Sternberg–like cells
- •
Reactive immunoblasts are positive for B- or T-cell markers and CD45, and they may be positive for CD30 antigen; however, in contrast to classical Hodgkin lymphoma, immunoblasts are negative for CD15 antigen
- •
Careful examination of the histologic sections with a high-power objective is mandatory; on low-power examination, nonfollicular lymphoid hyperplasia may superficially resemble an unremarkable unstimulated spleen
Selected References
Neiman R.S., Orazi A.: Reactive lymphoid hyperplasia.2nd ed.1999.WB SaundersPhiladelphiapp. 67-84.
Smith E.B., Custer R.P.: Rupture of the spleen in infectious mononucleosis: a clinicopathologic report of seven cases. Blood 1994; 61: pp. 317-333.
Castleman Disease
Clinical Features
- •
Splenic involvement occurs most frequently in multicentric Castleman disease, usually of plasma cell type
- •
Patients with multicentric Castleman disease present with constitutional symptoms such as fever, night sweats, fatigue, and weight loss and frequently show a host of hematologic and immunologic abnormalities (anemia, thrombocytopenia, hypoalbuminemia, and hypergammaglobulinemia)
- •
Multicentric Castleman disease in human immunodeficiency virus (HIV)-positive patients is almost always human herpesvirus type 8 (HHV-8) related. It is associated with HHV-8 in about 40% of HIV-negative cases
- •
Splenic involvement by Castleman disease of hyaline-vascular type is exceptionally rare and poorly documented
Gross Pathology
- •
Modest to moderate splenomegaly
Histopathology ( Figure 15.4 )
- •
Hyaline-vascular type (see Chapter 14 )
Figure 15.4
Castleman disease (mixed type).
Increased plasma cells and hyalinized germinal centers.
- •
Multicentric Castleman disease
- •
Often plasma cell type
- •
Hyperplastic or regressively transformed germinal centers often with hyalinization
- •
Prominent mantle zones with increased numbers of large lymphoid cells with plasmablastic and immunoblastic features within the mantle zone cells and adjacent interfollicular regions
- •
Significant red pulp plasmacytosis
- •
Plasmablasts may form small aggregates in the intrafollicular or perifollicular areas
- •
With disease progression, aggregates of plasmablasts may coalesce to form sheets of lymphoma cells effacing the architecture with progression to DLBCL
- •
- •
Special Stains and Immunohistochemistry
- •
Plasma cells in the red pulp are cIG-A positive, usually polyclonal and negative for HHV-8
- •
Usually negative for EBV; only rare cases resembling germinotropic lymphoma are positive for both EBV and HHV-8
- •
Plasmablasts are positive for immunoglobulin M (IgM), lambda light chain, HHV-8, CD20+/−, CD79a−/+, CD138−, and PAX5– and negative for Epstein-Barr virus–encoded RNA (EBER)
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Reactive Lymphoid Hyperplasia
- •
Hyalinization may be present; however, hyaline-vascular changes associated with follicles characteristic of hyaline-vascular type Castleman disease are not seen
Rheumatoid Arthritis Versus Castleman Disease, Plasma Cell Type
- •
Germinal centers in the white pulp may be hyperplastic
- •
Polyclonal plasmacytosis of red pulp may be prominent
- •
Clinical history and serologic tests are important
- •
Interleukin-6 (IL-6) is important in the pathogenesis of multicentric type of Castleman disease (check serum IL-6 level)
- •
Multicentric Castleman disease (MCD) occurs relatively frequently in individuals with immune deficiencies such as HIV infection or elderly patients with Kaposi sarcoma
- •
Scattered plasmablasts in HHV-8-positive MCD , although monotypic for lambda light chain are polyclonal by molecular studies
- •
MCD with increased number of plasmablasts may progress to HHV-8 positive DLBCL where the sheets of plasmablasts are often monoclonal
Selected References
Cesarman E., Knowles D.M.: Kaposi’s sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Semin Diagn Pathol 1997; 14: pp. 54-56.
Dupin N., Diss T.L., Kellam P., et. al.: HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000; 95: pp. 1406-1412.
Frizzera G.: Castleman’s disease and related disorders. Semin Diagn Pathol 1998; 5: pp. 346-364.
Menke D.M., Tiemann M., Camariano J.K., et. al.: Diagnosis of Castleman’s disease by identification of an immunophenotypically aberrant population of mantle zone B lymphocytes in paraffin-embedded lymph node biopsies. Am J Clin Pathol 1996; 105: pp. 268-276.
Weisenburger D.D.: Multicentric angiofollicular lymph node hyperplasia: pathology of the spleen. Am J Surg Pathol 1988; 12: pp. 176-181.
Common Variable Immunodeficiency
Clinical Features
- •
Presentation may occur from childhood to late adult life
- •
Recurrent infections and autoimmunity
- •
Splenomegaly in subset of patients
- •
Clinical history necessary for adequate interpretation
- •
Increased risk for lymphoma
Gross Pathology
- •
Spleen normal sized to enlarged
- •
May be grossly unremarkable
Histopathology
- •
Variable histologic features dependent on the primary pathogenetic deficiency in lymphoid stimulatory molecules (inducible costimulator, transmembrane activator, and calcium modulating cyclophilin ligand [CAML] interactor or CD19 deficiencies)
- •
Two broad groups:
- •
White pulp hyperplasia (WPH) with reactive follicles, marginal zone hyperplasia, or periarteriolar T-zone hyperplasia
- •
Epithelioid granulomas with or without WPH; granulomas mostly in the marginal zones (rosary-bead distribution) or germinal centers
- •
- •
Immunoblastic proliferation and atypical cells resembling Hodgkin or Reed-Sternberg cells may be present
- •
There may be lymphoid hyperplasia in the red pulp
Special Stains and Immunohistochemistry
- •
Subset of cases may be positive for Epstein-Barr virus–encoded latent membrane protein (EBV-LMP) immunohistochemical stain or EBER in situ hybridization
- •
Reactive follicles are positive for CD20 and CD10 and negative for bcl2
- •
Marginal zone hyperplasia is positive for CD20 and bcl2
- •
Periarteriolar lymphoid hyperplasia of mostly T-cells positive for CD3 and CD4
- •
Polyclonal B-cell population by flow cytometry
Other Techniques for Diagnosis
- •
Polyclonal immunoglobulin gene rearrangement
Differential Diagnosis
Nonspecific Follicular Hyperplasia
- •
Detailed clinical history of immunodeficiency; immunologic and genetic studies
Lymphoproliferative Disorders
- •
Careful clinical history of immunodeficiency must be obtained to avoid misinterpretation of significant immunoblastic proliferation or marginal zone hyperplasia associated with common variable immunodeficiency (CVID) as malignant lymphoma
- •
Often necessary to establish clonality for a firm diagnosis of malignant lymphoma
- •
Histologic features are variable and nonspecific
- •
Include special stains for microorganisms in cases with granulomatous presentation
Selected References
Cunningham-Rundles C., Bodian C.: Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999; 92: pp. 34-48.
Furudoï A., Gros A., Stanislas S., et. al.: Spleen histologic appearance in common variable immunodeficiency: analysis of 17 cases. Am J Surg Pathol 2016; 40: pp. 958-967.
Salzer U., Grimbacher B.: Common variable immunodeficiency: the power of co-stimulation. Semin Immunol 2006; 18: pp. 337-346.
Autoimmune Lymphoproliferative Syndrome
Clinical Features
- •
Rare heritable lymphoproliferative syndrome due to mutations in Fas (CD95), Fas ligand, caspase 8 , or caspase 10 genes
- •
Presents in early childhood, usually in patients younger than 2 years
- •
Generalized lymphadenopathy, splenomegaly, and autoimmunity
- •
Frequent association with immune cytopenias
- •
Increased risk for development of non-Hodgkin and Hodgkin lymphoma
Gross Pathology
- •
Massive splenomegaly
Histopathology
- •
Prominent white pulp with follicular hyperplasia and expansion of marginal zones
- •
Marked expansion of PALS and red pulp due to the infiltration by a mixed population of small T-cells, T-cell immunoblasts, and polyclonal plasma cells ( Figure 15.5 )
Figure 15.5
Autoimmune lymphoproliferative syndrome.
Mixed population of small T-cells, T-cell immunoblasts, and polyclonal plasma cells.
Special Stains and Immunohistochemistry
- •
Double negative T-cells (T-cell receptor [TCR]-αβ positive, CD4 and CD8 negative) are the hallmark of the disease and can be predominantly found in the red pulp
- •
Splenic T-cells are also negative for CD25
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Lymphoproliferative Disorder
- •
Correlation with clinical history and the presence of splenomegaly in infancy is critical to avoid interpretation of an abnormal T-cell population in the spleen as a T-cell lymphoproliferative disorder
- •
Flow cytometric immunophenotyping to look for double negative T-cells (CD4-negative, CD8-negative) in a child with lymphadenopathy and splenomegaly is very helpful to identify autoimmune lymphoproliferative syndrome (ALPS)
Selected References
Lim M.S., Straus S.E., Dale J.K., et. al.: Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 1998; 153: pp. 1541-1550.
Worth A., Thrasher A.J., Gaspar H.B.: Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol 2006; 133: pp. 134-140.
Neoplastic Diseases Involving the Splenic White Pulp
Splenic Marginal Zone Lymphoma
Clinical Features
- •
Most common in middle-aged to elderly patients, without a distinct gender predominance
- •
Presentation with left upper quadrant pain, anemia, and weight loss
- •
Most common type of lymphoma to present with massive splenomegaly
- •
Some cases with autoimmune anemia or thrombocytopenia
- •
Small monoclonal serum IgM/D paraprotein in one-third of cases
- •
Splenic hilar lymph nodes, peripheral blood, bone marrow, and liver involvement are common at presentation
- •
Lacks peripheral nodal involvement
- •
Usually no lymphadenopathy
- •
Association with hepatitis C, cryoglobulinemia, and autoimmunity
- •
Splenectomy may produce long-term remission
Gross Pathology
- •
Prominent lymphoid follicle proliferation producing a miliary pattern of white pulp expansion
Histopathology
- •
Increase in size and number of white pulp follicles with a variable degree of PALS, and red pulp involvement is the rule
- •
Malignant lymphoid cells may form expanded marginal zones or more often show colonization of germinal centers with attenuated mantle zones; combinations of the two patterns are frequently seen ( Figure 15.6A )
Figure 15.6
Splenic marginal zone lymphoma.
A, Histologic section shows expanded marginal zone replaced by tumor cells. B, High-power view shows tumor cells with round nuclei and abundant clear cytoplasm and numerous plasma cells.
- •
A rare “indolent” variant, which closely simulates marginal zone hyperplasia, has been reported; its diagnosis usually requires demonstration of clonality
- •
Red pulp involvement either as diffuse pattern or as lymphoid nodules
- •
Rare cases may display a “red pulp predominant” proliferative pattern
- •
Lymphoma cells are medium-sized with round to oval nuclei and often abundant clear cytoplasm (see Figure 15.6B )
- •
Larger lymphoid cells are usually seen at the periphery of neoplastic nodules
- •
Bone marrow infiltration is the rule; may be intrasinusoidal, interstitial, or multinodular
- •
Peripheral blood may show circulating small lymphocytes with abundant cytoplasm and short polar villi
Special Stains and Immunohistochemistry
- •
Splenic marginal zone lymphoma (SMZL) expresses the B-cell markers CD20, PAX5, and CD79a; CD23, IgD and cytoplasmatic Ig are variable; CD5, cyclin D1, bcl-6, annexin-A1, and CD10 are absent; CD123 and CD103 are also usually negative
- •
MIB-1 shows an annular pattern with increased positivity in marginal zones and germinal centers
- •
Due to the absence of specific markers, the diagnosis of SMZL is based on the absence of immunophenotypic features specific for other lymphoma subtypes
Other Techniques for Diagnosis
- •
By flow cytometry, the expression of B-cell markers (CD19, CD20, and CD22) and clonal surface light chains is seen
- •
Deletion of 7q32 is seen in about 45% of cases
- •
Molecular studies for immunoglobulin gene rearrangements are clonal
- •
No rearrangement of bcl-1 and bcl-2 genes
Differential Diagnosis (also see Table 15.1 )
Splenic Diffuse Red Pulp Small B-Cell Lymphoma
- •
Diffuse involvement of red pulp with almost complete obliteration of white pulp
TABLE 15.1
Morphologic and Immunophenotypic Features of B-Cell Non-Hodgkin Lymphomas With Prominent Spleen Involvement
Morphologic and Immunophenotypic Features
Type of Lymphomas
Architectural Features
Cytologic Features
Immunophenotype Cytogenetics
Chronic lymphocytic leukemia/small lymphocytic lymphoma
White and red pulp involvement; occasional growth centers
Small lymphoid cells with interspersed prolymphocytes and paraimmunoblasts, with or without growth centers
CD20, CD19, CD5, and CD23 positive
Mantle cell lymphoma
White pulp involvement; nodular or mantle zone pattern
Monotonous population of medium-sized lymphocytes with irregular nuclei; blastlike or pleomorphic cells in blastoid variant
CD20, CD19, CD5, FMC7, and cyclin D1 positive; t(11;14)
Follicular lymphoma
White pulp involvement; follicular pattern
Medium-sized lymphocytes with indented nuclei and variable admixture of large lymphoid cells
CD20, CD19, CD10, BCL-6, and BCL-2 positive; t(14;18)
Splenic marginal zone lymphoma
Predominantly white pulp involvement; red pulp infiltrates with scattered cells and nodules of lymphoma cells
Medium-sized lymphocytes with clear cytoplasm, indented nuclei, and large lymphoid cells scattered at the periphery of the nodules
CD20 and CD19 positive, CD43 positive or negative, positive for CD11c, negative for CD103 and CD123; variable positivity for CD25 and CD200
Splenic diffuse red pulp small B-cell lymphoma
Red pulp involvement with (usually) obliteration of the white pulp
Small to medium-sized lymphoid cells with pale or lightly eosinophilic cytoplasm, round and regular nuclei with only occasional small distinct nucleoli; some cases may show plasmacytoid lymphoid cells
Positive for CD20, DBA.44, BCL2, and IgG, often positive for p53, variable positivity for CD11c, CD103, CD123 and IgD, and negative for CD25, CD10, CD23, BCL6, and annexin-A1
Hairy cell leukemia
Predominantly red pulp with pseudosinuses
Medium-sized cells with abundant cytoplasm and cytoplasmic projections
CD20, CD19, CD103, CD25, CD123, CD200, annexin-A1, and CD11c positive
- •
Cutaneous involvement may be present
- •
Bone marrow involvement is often subtle with a predominant intrasinusoidal localization of the atypical lymphoid cells
- •
Strong constant expression of DBA.44 and often of CD11c
Hairy Cell Leukemia
- •
Red pulp involvement with prominent blood lakes
- •
Cells with fine, hairlike cytoplasmic processes may be seen in peripheral blood
- •
Diffuse pattern of bone marrow involvement (vs. nodular in SMZL)
- •
Distinct immunophenotype: B-cells positive for tartrate-resistant acid phosphatase (TRAP), DBA.44, CD25, CD11c, and CD103
- •
BRAF V600E mutation by polymerase chain reaction (PCR)
Hairy Cell Leukemia Variant
- •
Similar to classical hairy cell leukemia but with more pleomorphic cytologic features, including a variably prominent nucleolus and lack of CD25, annexin A1, and BRAF V600E mutation
T-Cell Large Granular Lymphocytic Leukemia
- •
Predominantly a red pulp infiltrate
- •
Distinct T-cell immunophenotype with varying degrees of loss or decreased density of CD7, CD2, and CD3; CD8 and CD57 positive in most cases; aberrant expression of natural killer receptors for class I major histocompatibility complex molecules (of killer cell immunoglobulin-like receptor type, CD158 antigens, and C-type lectin-like CD94 and NKG2 molecules); a minority of cases express CD56, CD16, or both
Hepatosplenic T-Cell Lymphoma
- •
More common in young men
- •
May occur in the post-transplantation setting and after anti-tumor necrosis factor (TNF) therapy
- •
Typically presents with significant hepatomegaly and splenomegaly, abnormal liver function tests, and cytopenias
- •
Diffuse red pulp infiltration by slightly irregular medium-sized lymphocytes
- •
T-cell immunophenotype with surface CD3 and associated γδ TCR, and absent CD5, CD4, and CD8 antigens; CD56 and CD16 are expressed in some cases
- •
Thorough examination of splenectomy specimens with clinical correlation and, if appropriate, with immunohistochemical, flow cytometric, and molecular analysis is mandatory because rare cases of minimal involvement by splenic marginal zone lymphomas have been reported, such as in cases of refractory idiopathic thrombocytopenic purpura (ITP)
- •
Early cases of splenic marginal cell lymphoma may resemble marginal zone hyperplasia; however, in the latter, mantle zones are preserved, a feature invariably missing in lymphoma cases
- •
Subtle lymphomatous infiltrate is also present in the red pulp
- •
Bone marrow involvement is common, often subtle, and intrasinusoidal; sinusoidal infiltrate is best visualized by immunohistochemistry on the marrow core biopsy
Selected References
Ngan B.Y., Warnke R.A., Wilson M., et. al.: Monocytoid B cell lymphoma: a study of 36 cases. Hum Pathol 1991; 22: pp. 409-421.
Piris M.A., Onaindía A., Mollejo M.: Splenic marginal zone lymphoma. Best Pract Res Clin Haematol 2017; 30: pp. 56-64.
Rosso R., Neiman R.S., Paulli M., et. al.: Splenic marginal zone cell lymphoma: report of an indolent variant without massive splenomegaly presumably representing an early phase of the disease. Hum Pathol 1995; 26: pp. 39-46.
Saadoun D., Suarez F., Lefrere F., et. al.: Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity?. Blood 2005; 105: pp. 74-76.
Traverse-Glehen A., Verney A., Baseggio L., et. al.: Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin. Leukemia 2007; 21: pp. 1821-1824.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Clinical Features
- •
Occur predominantly in elderly individuals
- •
Patients present with varying degrees of spleen, peripheral blood, and bone marrow involvement
Gross Pathology
- •
Variable splenomegaly with prominent white pulp (miliary pattern) or more homogeneous diffuse involvement in advanced stages
Histopathology
- •
Diffuse infiltrate of both red and white pulp; no residual germinal centers are present
- •
Neoplastic lymphoid cells are small with a coarse chromatin pattern, inconspicuous nucleoli, and scant cytoplasm ( Figure 15.7 )
Figure 15.7
Chronic lymphocytic leukemia/small lymphocytic lymphoma.
Histologic section shows a neoplasm composed of small uniform lymphoid cells with dense chromatin pattern and scant cytoplasm.
- •
Prolymphocytes and paraimmunoblasts can be intermingled with small lymphoid cells or form ill-defined aggregates; proliferation centers (pseudofollicles) are much less common in the spleen than in lymph nodes or bone marrow
Special Stains and Immunohistochemistry
- •
Neoplastic cells express CD20, CD5, CD23, and CD43
Other Techniques for Diagnosis
- •
Neoplastic cells express CD19, CD5, CD23, and low-density clonal surface light chain, and are weakly positive for CD20 by flow cytometric immunophenotypic analysis
- •
Clonal immunoglobulin gene rearrangement is present
- •
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are derived from recirculating CD5 and from IgM positive and IgD positive or negative B-cells normally present in the peripheral blood
- •
Two groups of CLL/SLL are recognized; this subclassification roughly corresponds to the expression of ZAP-70 and CD38 molecules, which can be quantified by flow cytometry
- •
One type corresponding to the pregerminal center phenotype (naive, showing no mutations in the variable region of immunoglobulin heavy-chain [ V h ] gene)
- •
A second type derived from memory B-cells (post- germinal center, mutated V h gene)
- •
Differential Diagnosis
Splenic Marginal Zone Lymphoma
- •
Predominantly white pulp infiltrate, frequently with marginal zone pattern
- •
Cells are strongly positive for CD20 and surface light chain (flow cytometry) and negative for CD5 and CD23
Follicular Lymphoma
- •
Largely a white pulp distribution with only minimal red pulp involvement
- •
Cytologically composed of a mixture of medium-sized centrocytes and large centroblasts
- •
Cells are positive for CD19, CD20, CD22, CD10, and bcl-2 [ t (14;18)] and negative for CD43, CD5, and CD23
Mantle Cell Lymphoma
- •
Predominantly white pulp involvement with expansion into the red pulp
- •
Uniform small to medium-sized cells with irregular nuclear outlines
- •
Neoplastic cells are positive for CD20, CD19, CD5, CD43, cyclin D1 [ t (11;14)], and FMC7 (flow cytometry) and negative for CD23
Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)
- •
The defining feature is the demonstration of monoclonal IgM protein in the serum, frequently with symptoms related to hyperviscosity
- •
Prominent plasmacytic component or a mixture of plasma cells and plasmacytoid lymphocytes
- •
B-cell–associated antigens, including CD19, CD20, and CD22, are consistently expressed; the surface IgM expression can be demonstrated in all cases, most cases show dim CD25; coexpression of CD5, CD23, and FMC7 have been reported; a minute monoclonal plasma cell component can be identified by flow cytometry in most cases
- •
Molecular analysis for MYD88 L265P somatic mutation represents an additional useful diagnostic tool; the mutation that is present in greater than 90% of LPL cases is only rarely present in other types of small B-cell lymphoma
Prolymphocytic Leukemia
- •
In contrast to small lymphoid cells of CLL/SLL, prolymphocytes are medium-sized atypical lymphoid cells with vesicular nuclei and prominent nucleoli
- •
Patients typically present with high white blood cell counts
- •
Splenomegaly may be massive
- •
CD20 and surface immunoglobulin density are stronger than in typical cases of CLL/SLL; CD5 expression is variable
- •
White and red pulp infiltrate is composed of uniform small lymphoid cells
- •
Modest splenic enlargement usually occurs; most patients whose disease is dominated by massive splenomegaly have mantle zone lymphoma or SMZL rather than SLL/CLL
- •
Richter transformation may present in the spleen; this appears as fleshy, cream-colored tumor nodules similar to the involvement by DLBCL
Selected References
Hollema H., Visser L., Poppema S.: Small lymphocytic lymphomas with predominant splenomegaly: a comparison of immunophenotypes with cases of predominant lymphadenopathy. Mod Pathol 1991; 4: pp. 712-717.
Pangalis G.A., Nathwani B.N., Rappaport H.: Malignant lymphoma, well-differentiated lymphocytic lymphoma: its relationship with chronic lymphocytic leukemia and macroglobulinemias of Waldenström. Cancer 1977; 39: pp. 999-1010.
Treon S.P., Xu L., Yang G., et. al.: MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 2012; 367: pp. 826-833.
Van Krieken J.H., Feller A.C., te Velde J.: The distribution of non-Hodgkin’s lymphoma in the lymphoid compartments of the human spleen. Am J Surg Pathol 1989; 13: pp. 757-765.
Prolymphocytic Leukemia
Clinical Features
- •
Presentation in elderly patients, with male predominance
- •
Marked lymphocytosis (often >100 × 10 9 /L) with more than 55% prolymphocytes
- •
Massive splenomegaly with hypersplenism and resulting cytopenias and the absence of significant lymphadenopathy are common features
Gross Pathology
- •
Massive splenomegaly
- •
Diffuse red pulp infiltration with variable prominence of white pulp
Histopathology
- •
Diffuse red pulp infiltration associated with involvement of the white pulp in most cases
- •
Heterogeneous population of lymphoid cells with a predominance of prolymphocytes characterized by medium size, abundant cytoplasm, and prominent nucleoli ( Figure 15.8 )
Figure 15.8
Prolymphocytic leukemia.
The infiltrate is composed of a heterogeneous population of lymphoid cells, many of which have large nuclei and prominent nucleoli.
Special Stains and Immunohistochemistry
- •
Eighty percent of prolymphocytic leukemia cases are of B-cell immunophenotype and are positive for CD20, with variable coexpression of CD5 and CD23
- •
Twenty percent of cases show T-cell immunophenotype (T-cell prolymphocytic leukemia) with a predominant expression of CD3, CD5, and CD4; loss of T-cell antigens may be seen
Other Techniques for Diagnosis
- •
By flow cytometry, strong expressions of CD20, CD19, FMC7, sIgM, and clonal surface immunoglobulin are seen in most cases
Differential Diagnosis
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- •
Massive splenomegaly is relatively uncommon
- •
Homogeneous population of small lymphoid cells with scant cytoplasm; prolymphocytes are rare
- •
Weaker expression of surface immunoglobulins and CD20, positivity for CD5 and CD23, negativity for FMC7
Splenic Marginal Zone Lymphoma
- •
Significant peripheral lymphocytosis is uncommon
- •
Neoplastic B-cells usually do not have prominent nucleoli
- •
Prolymphocytic leukemia occurs predominantly in elderly males
- •
Massive splenomegaly with significant lymphocytosis and absence of peripheral lymphadenopathy
- •
Characterized by increased numbers of prolymphocytes (large to medium-sized cells with prominent nucleoli) admixed with the small round lymphocytes
- •
Usually B-cell phenotype; variable expression of CD5 and CD23 (both positive in CLL/SLL)
Selected References
Bearman R.M., Pangalis G.A., Rappaport H.: Prolymphocytic leukemia: clinical, histopathological and cytochemical observations. Cancer 1978; 42: pp. 2360-2372.
Lampert I., Catovsky D., Marsh G.W., et. al.: The histopathology of prolymphocytic leukemia with particular reference to the spleen: a comparison with chronic lymphocytic leukemia. Histopathology 1980; 4: pp. 3-19.
Mantle Cell Lymphoma
Clinical Features
- •
Most patients present with widespread peripheral lymphadenopathy, hepatosplenomegaly, and bone marrow involvement
- •
A variant of mantle cell lymphoma with leukemic peripheral blood involvement, no appreciable lymphadenopathy, and sometimes splenic involvement, is now recognized: leukemic non-nodal mantle cell lymphoma; this has a better prognosis than classic mantle cell lymphoma
Gross Pathology
- •
Prominent white pulp in an enlarged spleen
- •
Massive splenomegaly may be seen (>1000 g)
Histopathology
- •
Nodular expansion of white pulp with or without a mantle zone pattern (i.e., lymphoid proliferation surrounding residual germinal centers)
- •
A pure mantle zone lymphomatous growth pattern is rarely seen
- •
Homogeneous population of medium-sized lymphoid cells with irregular nuclear outlines
- •
Blastoid variant of mantle cell lymphoma is composed of blastlike lymphoid cells (lymphoblastoid variant) or of large pleomorphic cells resembling those of DLBCL
Special Stains and Immunohistochemistry
- •
Neoplastic cells are positive for CD20, CD5, cyclin D1 [ t (11;14)], and SOX11 and negative for CD23
- •
The indolent leukemic non-nodal mantle cell variant is negative for SOX11
- •
See Chapter 14 for more detailed information
Other Techniques for Diagnosis
- •
By flow cytometry, the neoplastic cells are positive for CD20 (bright expression), CD19, CD5, monotypic sIg light chain and FMC7, and negative for CD23
- •
The defining feature of mantle cell lymphoma is the presence of t (11;14), the translocation of proto-oncogene cyclin D1 ( bcl-1 ; involved in the regulation of G 1 – to S-phase progression) to the immunoglobulin heavy-chain gene locus
Differential Diagnosis
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- •
Diffuse red pulp infiltration is prominent
- •
Small lymphocytes with some large cells (prolymphocytes and paraimmunoblasts)
- •
Low-density sIg and CD20 positivity; positive for both CD5 and CD23
- •
Lack of staining for cyclin D1
Splenic Marginal Zone Lymphoma
- •
Present with massive splenomegaly without peripheral lymphadenopathy
- •
Expanded, confluent marginal zones can be difficult to distinguish from expanded mantle zones
- •
Neoplastic population composed of medium-sized lymphoid cells with rare admixed large cells
- •
Neoplastic cells do not express CD5 or cyclin D1
Lymphoblastic Lymphoma
- •
Lymphoblasts are positive for TdT and negative for cyclin-D1
- •
Mantle cell lymphoma can present with leukemic peripheral blood involvement and massive splenomegaly
- •
Blastoid mantle cell lymphoma may mimic lymphoblast proliferation or DLBCL
Selected References
Angelopoulou M.K., Siakantariz M.P., Vassilakopoulous T.P., et. al.: The splenic form of mantle cell lymphoma. Eur J Haematol 2002; 68: pp. 12-21.
Banks P.M., Chan J., Cleary M.L., et. al.: Mantle cell lymphoma: a proposal for unification of morphologic, immunologic and molecular data. Am J Surg Pathol 1992; 16: pp. 637-640.
Molina T.J., Delmer A., Cymbalista F., et. al.: Mantle cell lymphoma, in leukaemic phase with prominent splenomegaly: a report of eight cases with similar clinical presentation and aggressive outcome. Virchows Arch 2000; 437: pp. 591-598.
Ondrejka S.L., Lai R., Smith S.D., et. al.: Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica 2011; 96: pp. 1121-1127.
Follicular Lymphoma
Clinical Features
- •
Patients typically present with multifocal lymphadenopathy and bone marrow involvement (stage IV)
- •
About half of patients show splenic involvement, often detected only at the microscopic level
- •
Most cases of follicular lymphoma in the spleen represent secondary involvement; very few cases of primary splenic follicular lymphoma have been reported
Gross Pathology
- •
Uniform expansion of the white pulp nodules (miliary pattern)
Histopathology ( Figure 15.9 )
- •
Uniform multifocal involvement of the white pulp, frequently with small aggregates of lymphoma cells within red pulp
Figure 15.9
Follicular lymphoma.
A, Low-power view shows multiple white pulp tumor nodules. B, The nodules are composed of predominantly centrocytes.
- •
In grades 1 and 2 follicular lymphoma, neoplastic follicles are composed predominantly of small to medium-sized cleaved atypical lymphoid cells (centrocytes) with a variable admixture of large atypical lymphoid cells with vesicular nuclei and multiple nucleoli, mostly attached to the nuclear membrane (centroblasts)
- •
In grade 3 follicular lymphoma, large atypical lymphoid cells predominate
Special Stains and Immunohistochemistry
- •
The immunophenotype reflects the follicle center cell origin of follicular lymphoma
- •
B-cell marker CD20 is positive, along with the coexpression of antigens characteristic for germinal center cells, such as CD10 and bcl-6
- •
Antiapoptotic protein bcl-2 is usually positive
- •
See Chapter 14 for more detailed information
Other Techniques for Diagnosis
- •
By flow cytometry, pan B-cell markers (CD19, CD20) and clonal surface immunoglobulin are present, along with the coexpression of CD10 antigen in most cases; the coexpression of CD10, similar in intensity to that seen in reactive follicular hyperplasia, in association with a relatively low-intensity CD19, is a characteristic feature of follicular lymphoma
- •
Expression of bcl-2 is due to the t (14;18)(q32;q21), which places the bcl-2 gene under a promoter of the immunoglobulin heavy-chain gene; rare cases of bcl-2 protein negative or lacking t (14;18)(q32;q21) in follicular lymphoma, however, do exist (discussed later)
Differential Diagnosis
Reactive Follicular Hyperplasia
- •
Well-defined follicles with distinct marginal and mantle zones, polarization of germinal center into dark and light zones, tingible body macrophages, and mitotic figures
- •
Germinal centers negative for bcl-2
Castleman Disease
- •
Expanded mantle zones
- •
White pulp follicles are variably expanded or atrophic/hyalinized
- •
Red pulp is expanded with large numbers of polyclonal plasma cells
Mantle Cell Lymphoma
- •
Uniform population of small to medium-sized lymphocytes without centroblasts
- •
Cells express CD5 and are generally CD10 negative
- •
Overexpression of cyclin D1
- •
Expression of bcl-2 is not useful in the differential diagnosis
Splenic Marginal Zone Lymphoma
- •
More prominent involvement of red pulp
- •
The expression of markers associated with germinal center origin is not seen
- •
Expression of bcl-2 is seen in most types of indolent B-cell lymphomas; however, when seen in nodular proliferation showing germinal center cell immunophenotype, bcl-2 is diagnostic of follicular lymphoma
- •
About 20% of follicular lymphomas are negative for bcl-2 antigen; in a proportion of these cases, molecular studies (PCR or fluorescent in situ hybridization [FISH] based) may demonstrate the presence of t(14;18) or bcl-6 rearrangement
- •
Predominantly white pulp involvement, but discrete invasion of red pulp is common
Selected References
Gauland P., D’Agay M.F., Peuchmar M., et. al.: Expression of the bcl-2 gene product in follicular lymphoma. Am J Pathol 1992; 140: pp. 1089-1095.
Horsman D.E., Okamoto I., Ludkovski O., et. al.: Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes. Br J Haematol 2003; 120: pp. 424-433.
Howard M.T., Dufresne S., Swerdlow S.H., et. al.: Follicular lymphoma of the spleen: multiparameter analysis of 16 cases. Am J Clin Pathol 2009; 131: pp. 656-662.
Shimono J., Miyoshi H., Kamimura T., et. al.: Clinicopathological features of primary splenic follicular lymphoma. Ann Hematol 2017; 96: pp. 2063-2070.
Diffuse Large B-Cell Lymphoma
Clinical Features
- •
Rare, but accounts for about one-third of lymphomas localized to the spleen at presentation
- •
May arise de novo or represent transformation of low-grade lymphoma
Gross Pathology
- •
Typically presents as large tumor nodules that may coalesce into larger masses randomly distributed in the splenic parenchyma
- •
May show large areas of necrosis
- •
Usually involves hilar and retroperitoneal lymph nodes
Histopathology
- •
Focal large aggregates or sheets of large atypical lymphoid cells with variable cytologic features (centroblasts, immunoblasts) ( Figure 15.10 )
Figure 15.10
Diffuse large B-cell lymphoma.
The tumor cells are large with irregular nuclei and high N:C ratio.
- •
Involves both white and red pulp, effacing the normal splenic architecture
Special Stains and Immunohistochemistry
- •
DLBCL expresses CD20 and CD79a; as in lymph nodes, it may express other antigens of germinal center derivation (bcl-6 and CD10) or of nongerminal center derivation (MUM-1); some cases may be positive for CD5
- •
See Chapter 14 for more detailed information
Other Techniques for Diagnosis
- •
By flow cytometry, DLBCL expresses CD19, CD20, and CD22; most commonly, there is a clonal surface light-chain expression, although cases negative for surface light chains are not uncommon
- •
Immunoglobulin gene rearrangement analysis can be useful (see Chapter 14 for more detailed information)
Differential Diagnosis
Hodgkin Lymphoma
- •
Patients almost always have nodal Hodgkin lymphoma
- •
Splenic involvement is often associated with liver involvement
- •
Typical polymorphous cellular background composed of small lymphocytes, plasma cells, eosinophils, neutrophils, and macrophages with large pleomorphic Hodgkin-Reed-Sternberg cells and their variants
- •
Neoplastic cells are typically negative for CD20, CD45, and CD3 but express PAX-5 (weak) and CD30, with or without CD15
Inflammatory Pseudotumor
- •
Usually a single, well-demarcated whitish mass
- •
Histology shows a polymorphous collection of bland spindle cells and inflammatory cells
- •
Large tumor nodules, often with foci of necrosis
- •
Tumor usually involves hilar and retroperitoneal lymph nodes, with or without peripheral lymphadenopathy
Selected References
Falk S., Stutte H.J.: Primary malignant lymphomas of the spleen: a morphologic and immunohistochemical analysis of 17 cases. Cancer 1990; 66: pp. 2612-2619.
Kobrich U., Falk S., Middeke B., et. al.: Primary large cell lymphoma of the splenic sinuses: a variant of angiotropic B-cell lymphoma (neoplastic angioendotheliomatosis)?. Hum Pathol 1992; 23: pp. 1184-1187.
Kraemer B.B., Osborne B.M., Butler J.J.: Primary splenic presentation of malignant lymphoma and related disorders: a study of 49 cases. Cancer 1984; 54: pp. 1606-1619.
Hodgkin Lymphoma
Clinical Features
- •
Although splenic involvement is not uncommon in cases of nodal-based classical Hodgkin lymphoma, (CHL) true primary splenic Hodgkin lymphoma is exceedingly rare
- •
Nodular lymphocyte-predominant Hodgkin lymphoma rarely involves spleen
Gross Pathology
- •
Focal nodules scattered in spleen parenchyma, often with apparent fibrosis
- •
Occasionally nodules are small, visible only on thin sectioning of the organ
Histopathology ( Figure 15.11 )
- •
Early lesions are found in the T-cell zones of white pulp (PALS) or marginal zones
Figure 15.11
Hodgkin lymphoma.
A, Low-power view shows multiple distinct white pulp tumor nodules. B, The nodules consist of a polymorphous infiltrate, which includes Hodgkin cells, lymphocytes, eosinophils, and epithelioid histiocytes.
- •
Classical Hodgkin lymphoma: typical Hodgkin-Reed-Sternberg cells within a polymorphous background of T-cells, histiocytes, and eosinophils
- •
Nodular lymphocyte-predominant Hodgkin lymphoma: “popcorn” cells characterized by large size and multilobate nucleus with delicate chromatin, within a cellular background of small lymphocytes
- •
Accompanying fibrosis may be prominent
- •
Epithelioid granulomas may be present
Special Stains and Immunohistochemistry
- •
Small lymphocytes are a mixture of CD3-positive T- cells (predominantly CD4-positive helper T-cell) and CD20-positive B-cells; the former usually predominate
- •
Reed-Sternberg cells and their variants are positive for PAX-5 (weak), CD30, and often CD15, and negative for CD45; CD3 and CD20 are usually negative; the latter, however, can be found expressed in a proportion of neoplastic cells with variable staining intensity
- •
Popcorn cells of nodular lymphocyte-predominant Hodgkin lymphoma are positive for CD20 and CD45 and can be surrounded by CD57- and PD-1-positive T- cells (see Chapter 14 for more detailed information)
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Diffuse Large B-cell Lymphoma
- •
Similar to CHL, random distribution of tumor nodules
- •
Composed predominantly of large lymphoid cells
- •
In most cases, neoplastic cells are positive for CD20 and CD45 and negative for CD15
- •
Rare cases of classical Hodgkin lymphoma may be “combined” with DLBCL (composite lymphoma) or rare cases of lymphocyte-predominant Hodgkin lymphoma may show transformation to DLBCL
Anaplastic Large Cell Lymphoma
- •
May form tumor masses or diffusely infiltrate the spleen
- •
Pleomorphic multinucleated large cells with prominent nucleoli may resemble Hodgkin-Reed-Sternberg cells; however, heterogeneous background typical for Hodgkin lymphoma is absent
- •
Neoplastic cells of anaplastic large cell lymphoma express CD30 (strong and uniform), at least a few T-cell markers and anaplastic lymphoma kinase (ALK-1) in a subset but are usually negative for CD15 and PAX-5
Inflammatory Pseudotumor
- •
Usually a solitary mass with whitish cut surface
- •
Tumor localized to the spleen, no lymphadenopathy
- •
Mixture of bland spindle cells, lymphocytes, and plasma cells
- •
Hodgkin-Reed-Sternberg cells are not identified
Splenic Hamartoma
- •
Usually presents as solitary mass with reddish cut surface
- •
Does not involve tissues other than the spleen
- •
Typical red pulplike microscopic appearance
Metastatic Carcinoma or Melanoma
- •
Almost always a previous history of primary tumor
- •
Single or multiple randomly distributed tumor nodules
- •
Microscopy shows sheets of large nonhematopoietic cells (negative for lymphoid antigens)
- •
True primary Hodgkin lymphoma of the spleen is rare (<3% of cases)
- •
Modern radiologic imaging techniques have virtually replaced splenectomy for staging of Hodgkin lymphoma
Selected References
Burke J.S., Osborne B.M.: Localized reactive lymphoid hyperplasia of the spleen simulating malignant lymphoma: a report of seven cases. Am J Surg Pathol 1983; 7: pp. 373-380.
Farrer-Brown G., Bennett M.H., Harrison C.V., et. al.: The diagnosis of Hodgkin’s disease in surgically excised spleens. J Clin Pathol 1972; 25: pp. 294-300.
Lukes R.J.: Criteria for involvement of lymph nodes, bone marrow, spleen and liver in Hodgkin’s disease. Cancer Res 1971; 31: pp. 1755-1767.
Non-Neoplastic Diseases Involving the Splenic Red Pulp
Gaucher Disease and Other Storage Disorders
Clinical Features
- •
Gaucher disease has two major forms: infantile and adult
- •
Infantile form: hepatosplenomegaly and mental deterioration in the first year of life, death in infancy or early childhood
- •
Adult (later-onset) form
- •
Most common form encountered in splenectomy specimens
- •
Highest incidence in Ashkenazi Jews
- •
Insidious onset in late childhood or adulthood
- •
No mental retardation
- •
Pancytopenia may be the presenting symptom
- •
Hepatomegaly, splenomegaly, and adrenal involvement
- •
Bone lesions include pathologic fractures, lytic lesions, and avascular necrosis of the femoral head
- •
- •
- •
Most other inherited metabolic storage diseases have onset in infancy or childhood; all are extremely rare
- •
Non-neuronopathic cases of Niemann-Pick disease may also present in adulthood with clinically significant hypersplenism
- •
Features and differential diagnosis are summarized in Table 15.2
TABLE 15.2
Differential Diagnosis of Storage Diseases With Special Stains and Additional Techniques
Storage Diseases
Stain or Technique
Gaucher Disease
Niemann-Pick Disease
Mucopolysaccharidoses
Glycogen Storage Diseases
Enzyme defect
Glucocerebrosidase (β-glucosidase)
Sphingomyelinase
Varies; multiple types known
Varies; 10 types
Storage product
Glucocerebroside
Sphingomyelin
Varies
Glycogen
Other organs affected
Liver, adrenals, lung, bone; central nervous system in infantile form
Brain, liver, lungs, bone marrow
Central nervous system, tongue, skeleton, liver, cornea, heart valves
Liver, muscle, heart (dependent on type)
Hematoxylin and eosin stain
“Wrinkled silk”
Yellow-green
Clear
Clear
Wright-Giemsa stain
Colorless
Blue-green
Periodic acid–Schiff stain
Positive
Variable
Weakly positive
Positive
Periodic acid–Schiff with diastase stain
Positive
Variable
Negative
Iron
Positive
Negative
Negative
Acid-fast
Negative
Positive
Electron microscopy
Lysosomes with twisted helical tubules
Variably sized residual bodies
Membrane-bound vacuoles with lamellar inclusions
Glycogen granules
Gross Pathology
- •
Diffuse enlargement of the spleen with a pale, dry appearance on its cut surface
Histopathology
- •
Expansion of the red pulp with distention of splenic cords by large pale-stained macrophages ( Figure 15.12 )
Figure 15.12
Gaucher disease.
Gaucher cells occupy the cords of the red pulp. They have abundant cytoplasm and round to oval pale nuclei with uniform nucleoli. This must be distinguished from Langerhans cell histiocytosis, in which the cells are smaller with bean-shaped nuclei. Rarely, macrophages engorged with Mycobacterium avium may resemble Gaucher cells.
- •
Gaucher cells have a characteristic “wrinkled-silk” cytoplasm that often appears brownish in hematoxylin and eosin (H&E)–stained sections and is distinguishable from that of Niemann-Pick cells, which is foamy or bubbly owing to the presence of numerous small clear vacuoles ( Figure 15.13 )
Figure 15.13
Niemann-Pick disease.
A, Low-power magnification. The histiocytes occupy the cords of the red pulp and surround a splenic follicle. B, High-power magnification. The histiocytes have abundant clear multivacuolated cytoplasm and round to oval pale nuclei with uniform nucleoli.
- •
Another important distinction is with ceroid histiocytes, which are smaller, faintly yellow-brown (blue-green in Wright-Giemsa stain), and have a distinctive cytoplasmic granularity; typical ceroid-containing sea-blue histiocytes are encountered in patients with Hermansky-Pudlak syndrome
Special Stains and Immunohistochemistry
- •
See Table 15.2
Other Techniques for Diagnosis
- •
Biochemical analysis of the storage product and determination of the activity of the relevant enzyme in fresh tissue samples are usually necessary for definitive diagnosis
- •
Detection of the specific gene mutations in patients or in at-risk families is now possible in a large number of metabolic diseases
Differential Diagnosis
- •
See Table 15.2
- •
Pancytopenia may be the presenting clinical feature; it may result from hypersplenism and marrow infiltration by the Gaucher cells
- •
Diagnoses in these diseases are made biochemically from peripheral blood, bone marrow, or other tissues
- •
Patients most often have an established diagnosis by the time the pathologist sees the spleen at autopsy or surgery; thus, the need for clinical correlation cannot be overemphasized
Selected References
Barranger J.A., Ginns E.I.: Glucosylceramide lipidoses: Gaucher disease.Scriver C.R.Beaudet A.L.Sly W.S. et. al.The Metabolic Basis of Inherited Diseases.1989, p1677.McGraw-HillNew York:
Elleder M.: Niemann-Pick disease. Pathol Res Pract 1989; 185: pp. 293-328.
Lee R.E., Peters S.P., Glew R.H.: Gaucher’s disease: clinical, morphologic and pathogenetic considerations. Pathol Ann 1977; 12: pp. 309-339.
Hematologic diseases
Extramedullary hematopoiesis
Clinical Features
- •
Extramedullary hematopoiesis (EMH) refers to the accumulation of hematopoietic precursor cells in the spleen
- •
EMH may be divided into two types:
- •
Non-neoplastic EMH that refers to the accumulation in the splenic red pulp of nonclonal hematopoietic precursor cells
- •
A neoplastic form refers to the secondary “spread” to the spleen of a hematologic malignancy capable of manifesting itself as EMH
- •
- •
Non-neoplastic EMH
- •
Normal in the fetus and premature infants
- •
Usually an incidental finding in a spleen removed for some other cause
- •
Typically seen in patients with severe anemia (e.g., thalassemia major) or in cases where a malignant disease (lymphoma, myeloma, metastatic malignancy) replaces the bone marrow (myelophthisic process)
- •
- •
Neoplastic EMH
- •
Often associated with a more marked degree of splenomegaly; in these cases, splenectomy is performed to relieve pain associated with the presence of a large spleen or splenic infarcts or to ameliorate cytopenia due to hypersplenism
- •
Typically occurs in patients with classic myeloproliferative neoplasms, particularly primary myelofibrosis, in which EMH is one of the major clinical manifestations
- •
It is also seen in other myeloproliferative disorders such as polycythemia vera and, rarely, essential thrombocythemia when they progress to “secondary myelofibrosis”
- •
Less frequently, EMH can also be seen in patients with myelodysplastic/myeloproliferative diseases (e.g., chronic myelomonocytic leukemia) and exceptionally, in other types of myeloid neoplasms
- •
- •
In all patients with myeloid neoplasms, splenic EMH needs to be distinguished from extramedullary (splenic) acute leukemia; when the latter is found superimposed on an EMH background, it may represent disease transformation
Gross Pathology
- •
Usually an incidental finding without gross features
- •
May cause diffuse expansion of the red pulp
- •
Rarely causes multiple soft, bulging, dark-red to brown berry-like nodules; these are most often seen in patients with late stage primary myelofibrosis or post–polycythemia vera (or post–essential thrombocythemia) myelofibrosis
Histopathology ( Figure 15.14 )
- •
Cellular infiltrates are seen in red pulp cords or within red pulp sinuses, present in a diffuse or nodular growth pattern
Figure 15.14
Extramedullary hematopoiesis.
A, The red pulp and the vascular sinuses contain trilinear hematopoietic cells with a predominance of erythroblasts and megakaryocytes. B, Extramedullary hematopoiesis in myelofibrosis. Numerous neutrophils accompany abnormal megakaryocytes.
- •
Small clusters of normoblasts are easiest to identify; this is the predominant cell type found in nonclonal EMH. They are most often located intrasinusoidally
- •
Trilineage EMH is most commonly seen in patients with chronic myeloproliferative neoplasms
- •
Identification of megakaryocytes and granulocytic precursors may be facilitated by immunohistochemistry (e.g., CD42b and myeloperoxidase)
Special Stains and Immunohistochemistry
- •
Wright stains (e.g., touch preparations)
- •
Antihemoglobin or glycophorin A or CD71 immuno-staining to highlight the presence of erythroid precursors (erythroblasts)
- •
Antibodies reactive with myeloperoxidase or lysozyme can be used to highlight myeloid cells
- •
Antibodies reactive with platelet glycoproteins such as CD42b or CD61 may facilitate the identification of megakaryocytes
- •
CD34 and CD117 can also be useful in selected cases to identify accumulation of blasts, which may indicate blastic transformation to extramedullary acute myeloid leukemia
Other Techniques for Diagnosis
- •
Usually not necessary; flow cytometry and cytogenetic techniques may be useful to confirm evolution to acute leukemia
Differential Diagnosis
Lymphoid Infiltrate in Red Pulp
- •
Cells are more pleomorphic; nuclei are not as round as normoblasts and have less dense chromatin (that is, have a more visible chromatin pattern) than normoblasts
- •
Cell borders are indistinct
Acute Leukemia
- •
Rapid onset usually with severe cytopenias
- •
Blasts have high nuclear-to-cytoplasmic ratio and display fine chromatin and scant indistinct cytoplasm; however, monoblasts and megakaryoblasts may have more abundant cytoplasm
- •
The formerly used term myeloid metaplasia to indicate EMH is a misnomer; the phenomenon results from entrapment in the spleen (filtration theory) of circulating immature hematopoietic cells
- •
The identification of early extramedullary (splenic) blastic transformation may be challenging, and immunohistochemistry may be invaluable in these cases
Selected References
Neiman R.S., Orazi A.: Functions of the spleen.2nd ed.1999.WB SaundersPhiladelphiapp. 26-38.
O’Malley D.P., Kim Y.S., Perkins S.L., et. al.: Morphologic and immunohistochemical evaluation of splenic hematopoietic proliferations in neoplastic and benign disorders. Mod Pathol 2005; 18: pp. 1550-1561.
Prakash S., Hoffman R., Barouk S., et. al.: Splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms: heterogeneous morphology and cytological composition. Mod Pathol 2012; 25: pp. 815-827.
Hereditary Spherocytosis
Clinical Features
- •
Prominent splenomegaly and anemia
- •
Patients have familial history of hemolytic anemia (autosomal dominant)
- •
Splenectomy in this condition is most often performed in late childhood or early adult years
- •
At a molecular level this disease is heterogeneous, caused by a variety of mutations involving any of several red cell membrane proteins. More often autosomal dominant inheritance; caused by molecular defects in the genes that code for spectrin, ankyrin, band 3 protein, protein 4.2, and other erythrocyte membrane proteins
- •
In hereditary spherocytosis, hemolysis and anemia are relieved by splenectomy, but the underlying red cell defect remains
Gross Pathology
- •
Splenomegaly; usually of moderate degree
- •
Red pulp shows intense congestion
- •
Attenuation of the normal white pulp nodularity
Histopathology
- •
White pulp is normal to atrophic
- •
Red pulp cords are distended, and the sinuses appear empty ( Figure 15.15 )
Figure 15.15
Hereditary spherocytosis.
The red pulp is expanded and shows accumulation of erythrocytes in the splenic cords, hyperplasia of cordal macrophages and sinus lining cell hypertrophy. The sinuses appear relatively empty.
- •
Increased cordal macrophages and hypertrophy of sinus-lining cells
- •
Erythrophagocytosis is hard to see, and hemosiderin deposition is minimal
- •
EMH is not seen
- •
Spherocytic erythrocytes in peripheral blood
Special Stains and Immunohistochemistry
- •
Noncontributory
Other Techniques for Diagnosis
- •
Osmotic fragility test on patient’s red cells
- •
Polyacrylamide gel electrophoresis for molecular subtyping
Differential Diagnosis
Autoimmune Hemolytic Anemia
- •
No family history
- •
Acquired disease
- •
Spleen is of normal size to slightly enlarged
- •
If untreated, the spleen shows significant WPH and red pulp plasmacytosis
- •
Cords are not as distended, and it is easier to detect erythrophagocytosis both in cordal and in sinus macrophages
- •
Hemosiderin deposition and extramedullary erythropoiesis may be prominent
- •
Coombs test positive
Sickle Cell Disease and Variants
- •
Usually autosplenectomy due to multiple infarctions by age 7 years (hemoglobin S [HbSS])
- •
Splenomegaly may be seen in adults with sickle cell variants (e.g., sickle cell and hemoglobin C disease)
- •
Infarcts much more common; organized infarcts are often iron encrusted (these old infarcts are also termed Gamna-Gandy bodies)
- •
Stacked, sickled cells in red pulp
- •
History is important, including ancestry (more common in people of African or Arab ancestry)
Fibrocongestive Splenomegaly
- •
Patients usually have liver disease, often with ascites
- •
Red pulp shows a combination of congestion (due to blood stasis) and fibrosis
