—  SHORT COURSE #39  —

Neoplastic Disorders Of The Spleen

Section 4 - Lymphoid Hyperplasia in the Spleen

Attilio Orazi
Dennis P. O'Malley


Various benign conditions that affect the splenic white or red pulp can simulate hematopoietic malignancies [Table 4-1]. In this section, we will cover various benign hyperplasias with emphasis on those that simulate malignancies [Table 4-2].

Reactive Follicular Hyperplasia
Reactive follicular hyperplasia with formation of germinal centers , seen in evolving immune responses, is usually easily recognized as benign [1, 2]. However, follicular hyperplasia with prominent germinal centers occasionally needs to be distinguished from follicular lymphoma. As in lymph node, there are several criteria which help distinguish between benign follicular processes and malignant [Table 4-3].

A rare entity that may grossly simulate lymphoma is known as localized (nodular) reactive lymphoid hyperplasia. The area of nodular hyperplasia appears quite distinct from adjacent normal spleen and may raise the suspicion of lymphoma. Histologically, this is formed by focal aggregation of hyperplastic follicles, which have typical, benign features [3].

Marginal Zone Hyperplasia
The marginal zones may become expanded, a phenomenon which has been referred to as splenic marginal zone hyperplasia [1, 2, 4, 5, 6, 7]. In some studies, a marginal zone layer thicker than 12 cells has been (arbitrarily) defined as "hyperplasia" [6]. Marginal zone hyperplasia usually occurs in association with follicular hyperplasia. It may be occasionally impossible on morphologic grounds alone, to distinguish these reactive changes from cases of indolent marginal zone lymphoma [4, 8]. Features that can help distinguish the two conditions are listed below in Table 4-4. It is important of being fully aware of any underlying condition which may be associated with the presence of hyperplastic marginal zones such as ITP, systemic lupus erythematosus or other chronic autoimmune disorders.

Reactive follicular hyperplasia, without germinal center formation , which is characteristic of infectious mononucleosis as well as herpes simplex and other viral infections, can simulate Hodgkin lymphoma and non-Hodgkin lymphoma [1, 2]. The white pulp in these conditions lacks germinal centers and, on low-power examination, resembles the immunologically unstimulated spleen [1, 2, 12]. Higher power examination, however, reveals reactive changes including the presence of lymphocytes in varying stages of transformation, including small and large lymphocytes and immunoblasts. Transformed lymphocytes/immunoblasts also proliferate around the splenic arterioles and may infiltrate the subendothelial zones of the trabecular veins and the connective tissue framework, resulting in splenic rupture in extreme cases [13]. These morphologic findings are often present in viral infections (e.g. infectious mononucleosis) and are rarely seen in malignant lymphoma. Steroid-treated immune thrombocytopenic purpura and autoimmune hemolytic anemia also may show this pattern of lymphoid reaction activation [14] due to the atrophy of follicular germinal centers caused by this type of treatment. Also, there may be reduction of the marginal zones and mantle zones as well.

Castleman Disease
Occasional cases of Castleman disease of both the hyaline-vascular and the plasma-cell type have been reported to occur in the spleen, but are very rare [16]. The plasma cell (PC) type is usually multicentric and has been associated with human herpes virus-8 (HHV-8). It represents the majority of cases reported in the spleen [15, 16]. They have features typical of the plasma cell variant, although there may be admixed atrophic follicles with hyaline-vascular germinal centers. Some cases may show expansion of the marginal zones infiltrated by plasma cells [17]. Importantly, PC Castleman has polyclonal plasma cells. In rare cases of the hyaline-vascular type, grossly visible masses composed of hyperplastic nodules of white pulp surrounded by dense fibrous tissue were seen.

T-cell Hyperplasia
(Slide #1) T-cell hyperplasia is occasionally encountered in the spleen and may be a cause of white pulp expansion. There are varied etiologies that can cause selective expansion of the white pulp T-cell compartment including congenital or acquired immunodeficiencies (ex. Common Variable Immunodeficiency, Hyper IgM syndrome) and autoimmune conditions. Morphologically, these can simulate white pulp involvement by lymphoma. Only after basic immunohisto-chemical staining (CD3, CD20), is the expansion of the T-cell compartment appreciated. The PALS may be thickened to a degree that is similar to the size of germinal centers. There is typically a mixture of small T-cells and larger transformed T-cells (immunoblasts). White pulp (follicular) expansion is not common in T cell lymphomas in the spleen. Extensive panels of T-cell reactive antibodies may be necessary for evaluation, to rule out the possibility of an unusual population of T-cells or an aberrant immunophenotype. In addition, PCR for T cell gene rearrangements may provide important diagnostic help.

Nodular T-cell hyperplasia simulating a peripheral T-cell lymphoma can be rarely observed in patients treated with phenytoin [18].

Autoimmune Lymphoproliferative Syndrome
A rare disorder that can mimic lymphoma in the spleen is autoimmune lymphoproliferative syndrome ( ALPS), a hereditable disorder usually due to mutations of the CD95 (Fas) gene [19], which presents in early childhood (less than 2 years of age). ALPS is characterized by lymphoid hyperplasia, splenomegaly and autoimmune manifestations. The spleen is frequently enlarged up to ten times its normal size. Histologically, the PALS and red pulp are disproportionately expanded, due to a markedly increased number of T cells. These cells consist of a mixture of small lymphocytes and immunoblasts and are negative for both CD4 and CD8. In addition, the red pulp has an increase in polyclonal plasma cells. The white pulp shows variable degrees of follicular hyperplasia often with enlarged marginal zones. This finding is not seen in most patients because of previous treatment with steroids. Patients with this disorder have an increased risk of developing both Hodgkin and non-Hodgkin lymphomas.

Table 4-1: Benign Conditions that may result in Splenomegaly
  1. Immune reactions
    1. Florid follicular hyperplasia

    2. Marginal zone hyperplasia

    3. Mantle cell hyperplasia (hyperplasia of 'primary' follicles)

    4. Immunoblastic proliferations

  2. Vascular congestion
    1. Portal hypertension

    2. Splenic vein obstruction

    3. Hepatic vein obstruction

    4. Due to liver disease

    5. Due to congestive heart failure

  3. Congenital immunodeficiency
    1. Common variable immunodeficiency

    2. Autoimmune lymphoproliferative syndrome

    3. Selective IgA deficiency

    4. Hyper-IgM syndrome

    5. Others

  4. Infectious
    1. Viral
      1. EBV/Infectious mononucleosis

      2. HIV/AIDS

      3. Other viruses

    2. Bacterial/Rickettsial
      1. Sepsis

      2. Endocarditis

      3. Bartonella henslae (bacillary angiomatosis)

      4. Typhoid

      5. Other bacteria or rickettsia

    3. Mycobacterial
      1. Tuberculosis

      2. M. avium-intracellulare

      3. Leprosy

      4. Mycobacterial spindle cell tumor

    4. Fungal
      1. Histoplasmosis

      2. Blastomycosis

      3. Cryptococcus

      4. Coccidioidomycosis

    5. Other Parasitic/protozoal
      1. Malaria, including "tropical splenomegaly"

      2. Leishmaniasis

      3. Schistosomiasis
  1. Other Autoimmune conditions
    1. Autoimmune hemolytic anemia

    2. SLE

    3. Connective tissue diseases

    4. Immune thrombocytopenic purpura

  2. Disorders of the reticuloendothelial system
    1. Storage diseases
      1. Gaucher's disease

      2. Niemann-Pick disease

      3. Mucopolysaccharidoses

      4. Amyloid

      5. Other storage disorders

    2. Hemophagocytic syndromes


  3. Langerhans cell histiocytosis Castleman disease
  1. Red blood cell disorders
    1. Membrane defects
      1. Hereditary spherocytosis

      2. Hereditary elliptocytosis

    2. Enzyme defects
      1. G6PD

      2. Pyruvate kinase deficiency

      3. Others

    3. Hemoglobinopathies
      1. Qualitative (e.g. Sickle cell disease - Hgb SS, others)

      2. Quantitative (e.g. Thalassemia)

    4. Foreign antigens - transfusion

  2. Other systemic disorders
    1. Uremia

    2. Sarcoidosis

    3. Liver disorders

  3. Increase in hematopoietic elements
    1. Due to cytokine treatment

    2. Extramedullary hematopoiesis (non-neoplastic)

  4. Non-hematopoietic lesions
    1. Cysts

    2. Hamartomas

    3. Inflammatory pseudotumors



Table 4-2: Hyperplasia of the Spleen
CELL TYPE PATTERN FINDINGS EXAMPLE(S)
B-cell Follicular Typical findings of follicular hyperplasia. Numerous causes Numerous etiologies including autoimmune causes such as ITP and hemolytic anemias.
Localized (nodular) Rare. Focal nodule(s) that mimic lymphoma grossly but have benign features microscopically.
Marginal zone Expansion of marginal zone layer. Numerous causes including ITP and autoimmune disorders. Occasionally prominent enough to confuse with SMZL. Clinical, immuno stains and molecular testing may be necessary to differentiate. Autoimmune conditions.
Mantle cell Rare. Proliferation of 'primary', unreacted follicles or expansion of mantle zone. Expansion of B-cells after steroid treatment and Castleman Disease.
T-cell Immunoblastic; maybe associated with follicular hyperplasia without germinal centers Proliferation of large, transformed lymphocytes. Can be seen in both the white pulp (PALS) and in the red pulp. May mimic large cell lymphoma. Immunoblasts may infiltrate capsule and large vessels. May mimic large cell lymphoma. Viral etiologies, most classically associated with infectious mononucleosis (acute EBV infection).
Expansion of PALS Periarteriolar white pulp is expanded. Includes a mixture of small and larger cells. Occasionally, intermixed plasma cells. Inherited types of immunodeficiency (hyper IgM, CVID, selective IgA deficiency), drug reaction including dilantin.



Table 4-3: Morphologic Comparison of Follicular lymphoma and Follicular Hyperplasia
Criteria Follicular Lymphoma Follicular Hyperplasia
Increase in follicle density Yes Yes
Back-to-back follicles Yes No
Lack of tingible-body macrophages Yes No
Mantle zone Poorly formed or absent Present
Follicle polarization Not present Often present
Dysplastic/abnormal cytology Yes No



Table 4-4: Marginal Zone Hyperplasia versus Marginal Zone Lymphoma
Features MZH MZL
Expanded MZ (>12 cell layers) Yes Yes
Numerous B-cells in PALS No Yes
Follicles 3 layers
(Normal Tripartition) 		Loss of layers; often uniform single layer
Red Pulp No increase in red pulp B-cells Often has clusters of red pulp B-cells
Clonality No Yes
Kappa/lambda Polyclonal Monoclonal
Ki67 Normal secondary follicles with high proliferation Colonized follicles have low proliferation in neoplastic cells



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