—  SHORT COURSE #26  —

Hematopathology Diagnoses Too Easy to Miss!

III. Specific Benign Entities that Can be Easily Misdiagnosed as a Lymphoma

Marsha Kinney, James Cook and Steven Swerdlow


Reactive lymphoid hyperplasia can be confused with malignant lymphoma particularly when there is marked alteration of nodal architecture, the presence of large atypical lymphocytes, or abnormal expansion of a lymphoid population that is usually present in small numbers giving a false impression of clonal expansion of a neoplastic population. The best defense against making the wrong diagnosis is being aware of entities and the circumstances where difficulties can arise. The first two cases are examples of unusual lymphoid proliferations that arise predominantly in pediatric patients or young adults and may be confused with neoplastic processes.

Case 1

Diagnosis:
Autoimmune Lymphoproliferative Syndrome (ALPS)

Clinical History:
2 year-old male with diffuse lymphadenopathy, splenomegaly, anemia (HCT = 28.8%) and thrombocytopenia (97 thou/uL). WBC = 4.4 thou/uL with 43% lymphocytes. Serum protein electrophoresis revealed polyclonal hypergammaglobulinemia.

Morphology:
This case illustrates the typical morphologic features in the enlarged lymph nodes in ALPS. There is marked paracortical expansion by lymphocytes in varying stages of activation. There is a mixture of small lymphocytes, medium-sized lymphocytes, immunoblasts, and polyclonal plasma cells. The lymphocyte cytoplasm varies from clear to eosinophilic. Numerous mitotic figures are present. Some histiocytes with apoptotic material are seen but are decreased compared to other lymphoproliferative processes with a high mitotic rate. B-cell follicles are present but compressed by the T-cell proliferation.

Other morphologic features have been described in ALPS but are not seen in this case. Florid follicular hyperplasia and focal changes of progressive transformation of follicle centers (60%) or atrophic follicles similar to those in Castleman's disease (40%) may be present. [1] Prominent postcapillary venules in the interfollicular regions are seen in some cases. Approximately 40% of patients have S-100+ histiocytic proliferations resembling sinus histiocytosis with massive lymphadenopathy (SHML). [2] Features of SHML in ALPS are associated with male predominance, younger age at presentation, and families with more cases of ALPS; no differences were seen in race, prior splenectomy, autoimmune disease, and autoantibodies.

Immunophenotype:
The key to making a diagnosis of ALPS is the expansion of an unusual population of CD4-CD8- a b T-cells. The immunophenotype in this case is typical of ALPS:

Positive: CD2, CD3, CD5, CD43, CD45RA, CD57, Beta-F1 (TCR protein, ab ), TIA-1, Perforin, HLA-DR

Negative: CD4, CD8, CD16, CD25, CD45RO, CD56, CD34, TDT

Contributor:
This case was kindly contributed by Ellen J. Schlette, M.D., The University of Texas, MD Anderson Cancer Center, Houston, TX.

Background and Clinical Features:
ALPS, also known as Canale-Smith syndrome, was originally described in 1967 as a rare chronic lymphadenopathy simulating malignant lymphoma. [3] Since that time only a few hundred patients have been reported. [4] Patients with ALPS have mutations in the FAS apoptotic pathway resulting in chronic lymphoproliferation and a breakdown in immunologic tolerance. [5, 6, 7] There is a slight female predominance and patients usually present within the first five years of life (median age 1-2 years) with generalized lymphadenopathy, splenomegaly, hepatomegaly in approximately 50%-70%, peripheral lymphocytosis, hypergammaglobulinemia, and autoantibodies and sometimes overt autoimmune disease. Rare cases present with lymphadenopathy at birth suggesting the process began in the prenatal period. In severe cases, pulmonary infiltrates may be seen. [8] ALPS has rarely been diagnosed in adults [9] and should be suspected in adult patients with chronic lymphoproliferation and autoimmune symptoms that do not fit precisely into a specific disease category. ALPS has been described in multiple races but predominantly occurs in whites. Skin inflammation (urticaria, angioedema, and pruritic erythematous maculopapular rash) have been rarely reported in ALPS; the lesions show a perivascular  lymphohistiocytic infiltrate, numerous CD1a+ histiocytes in the epidermis and lack double negative T-cells. [10]

Autoimmune manifestations occur in approximately 40%-70% of patients and include thrombocytopenia, hemolytic anemia and less commonly neutropenia or glomerulonephritis. [11, 12] Anti-neutrophil antibodies and antiplatelet antibodies are seen in 46% and 35% of ALPS patients, respectively, but there is no correlation with clinical neutropenia or thrombocytopenia. [13] Other serologic abnormalities include positive direct Coombs test, alloantibodies, and IgG and/or IgM antibodies to cardiolipin, and a Factor VIII inhibitor. [14, 15] Despite the relatively frequent presence of anti-cardiolipin antibodies, thrombotic or embolic events are rare. [16] Other autoimmune disorders include Guillain-Barré syndrome, uveitis, arthritis, hepatitis, diabetes, urticarial rashes, and vasculitis. Typical SLE is not seen; anti-DNA antibodies can be present in ALPS II but not ALPS 0 or ALPS Ia. Recent studies have shown that 58% of children with Evans syndrome (autoimmune destruction of at least two peripheral blood cells types) have increased double negative T-cells and defective FAS mediated apoptosis, [17] indicating that many cases are likely ALPS.

Note: See Table 1 from Jackson, 1999 [6] and Table 2 from Sneller, 2003 [16] for a summary of clinical features reported from two large series.

The diagnostic criteria for ALPS are summarized in Table 1.

Table 1. Diagnostic Criteria for ALPS

Required Features:
1. Chronic non-malignant lymphoproliferation (lymphadenopathy; splenomegaly)

2. Defective in vitro FAS-mediated lymphocyte apoptosis

3. > 1% TCR a b+, CD3+, CD4-, CD8- cells in peripheral blood or lymphoid tissue

Supporting Features:
1. Autoimmune antibodies/autoimmune disease

2. Mutations in FAS gene, FAS ligand gene, or caspase 10 gene

3. Family history of ALPS

It should be mentioned that another disorder with autoimmunity and lymphoproliferation has been described (Dianzani autoimmune/lymphoproliferative disease, DALD). These patients lack expansion of double negative T-cells and have defective apoptosis to both anti-FAS monoclonal antibody and ceramide, in contrast to patients with ALPS who only have defective apoptosis to the anti-FAS monoclonal antibody. These patients have over expression of the cytokine osteopontin (OPN). In vitro excess exogenous OPN decreased activation induced T-cell death. [18, 19]

Pathology of Other Extranodal Sites:
The spleen in patients with ALPS is markedly enlarged (620-856 grams, normal pediatric spleen weight approximately 50-60 grams) and shows expansion of the red pulp by the same population of CD4- CD8- αβ+ T cells. The white pulp shows follicular hyperplasia with prominent marginal zones. Liver biopsies show infiltration by double negative T-cells, extramedullary hemopoiesis (if significant cytopenias are present), and some show signs of hepatitis with piecemeal necrosis, intense inflammation, numerous plasma cells, and evidence of micronodular cirrhosis.

Bone marrow may show erythroid or megakaryocytic hyperplasia in response to cytopenias and variable numbers of double negative T-cells, plasma cells, and eosinophils. The bone marrow has interstitial clusters and sheets of large atypical double negative T-cells and may be confused with lymphoblastic leukemia. [1] Peripheral blood absolute lymphocyte counts vary from patient to patient and range from normal or mildly elevated to up to 12,328. [1] Lymphocytes undergoing apoptosis can be seen on peripheral blood smears. [8] Approximately 16% of ALPS patients have eosinophilia with increased peripheral blood leukocytes of multiple lineages, increased serum IgE and higher mortality from infection. [20] These patients have more severe cytopenias leading to splenectomy.

Pathogenesis:
ALPS results from defects in the FAS/FAS ligand apoptotic pathway. [4, 7, 21] FAS (CD95) is a 43kd type 1 transmembrane receptor and a member of the TNF receptor family. FAS is widely expressed on many cells whereas FASL is present primarily on T-cells. The normal role of this pathway is to maintain lymphocyte homeostasis by elimination of activated T-cells, to suppress autoreactive T-cell clones, and to help in eliminating virally infected cells. Binding of FAS-FASL results in receptor trimerization and clustering of the intracellular death domain. The cytoplasmic protein FADD (FAS associated death domain) is activated and triggers the activation of caspase 8 and 10 and ultimately caspase 3 with subsequent apoptosis. See Figure 1. [4]

Figure 1. Normal Fas mediated lymphocyte apoptosis (Corresponds to Figure 1 in Rieux-Laucat, 2003 [4])


It was shown in 1992 that ALPS patients shared similarities with two mouse models of autoimmunity, lpr and gld, [22, 23] with mutations equivalent to genes encoding CD95 (FAS/APO1) and CD95L (FASL) in humans. [24] Classification of ALPS is based on the type of mutation (See Table 2). [7] Most cases have heterozygous mutations in the apoptosis antigen 1 (APT1)(TNFRSF6) gene (chromosome 10q24.1) encoding the FAS molecule (ALPS Ia). See Figure 2.  [4]

Table 2. Classification of Autoimmune Lymphoproliferative Syndrome7, 23

Subtype Mutation/Defect Frequency Age of Onset Other
Type 0 Homozygous FAS gene (TNFRSF6) Very rare Prenatal/newborn
Type Ia Heterozygous FAS gene (TNFRSF6) 74% Childhood
Type Ib Fas ligand gene (TNFSF6) <1% Adult Features of SLE; lacks DN T-cells
Type Im Somatic mutation of TNFRSF6 ~ 2%
Type II Caspase 10 ~ 2%
Type III Undefined; most are sporadic 24%-33% Childhood ? acquired defects in other lymphocyte apoptotic pathways; normal FAS-mediated apoptosis
Type IV NRAS mutations Very rare Childhood Suppression of mitochondrial BIM mediated apoptosis associated with cytokine withdrawal; lacks expansion of DN T-cells

DN = double (CD4-CD8-) negative

Figure 2. Defects in FAS-FASL signaling in ALPS Patients (Corresponds to Figure 2 in Rieux-Laucat,2003 [4]) and in caspase 8 deficiency (CED); see Figure 1, reference Su, 2008. [7]
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Sixty percent of mutations are localized within the death domain and one third affect the extracellular domain of FAS. See Figure 3. [6 ]

Figure 3. Mutations in the FAS(TNFRSF6) Gene in ALPS Patients (Corresponds to Figure 1 in Jackson, 1999 [6])
figure2

Mutations in the intracellular domains result in the synthesis of a FAS protein that is expressed on the cell surface but at a lower level. Mutations in the extracellular domains lead to absence of FAS protein on the cell surface or it is rapidly degraded. The mutant FAS protein exerts a dominant negative effect and inhibits the normal FAS protein. Some relatives of ALPS patients have the same mutations but are asymptomatic therefore showing a variable penetrance of the mutation. The strongest penetrance is seen in intracellular domain missense mutations where the penetrance is about 90%. The mutant protein exerts a dominant-negative effect on the function of wild-type CD95 interfering with recruitment of FADD/MORT1 resulting in high penetrance. Mutations that lead to truncation of the intracellular domain have roughly 75% penetrance and those mutations in the extracellular domain have only 30% penetrance. Mutations in the extracellular or transmembrane domain of CD95 result in haploinsufficiencywith decreased production of the membrane receptor. [25] No correlation is seen between the mutations, the magnitude of the apoptotic defect, and the clinical severity of the syndrome. This partial clinical penetrance suggests that a second event is associated with the FAS mutations to induce an overt ALPS Ia syndrome. As mentioned earlier some relatives of ALPS patients that lack FAS mutations have a slight increase in double negative T-cells suggesting that the second event may be independent of FAS-mediated apoptosis. [26] Homozygous null mutations of FAS result in a complete FAS deficiency (ALPS 0) and are very rare.

As gld mice have defects in the FASL gene (TNFSF6), it is predicted that some ALPS patients would as well. This has been called ALPS Ib and is very rare. It was defined based on a patient with systemic lupus erythematosus and chronic lymphoproliferation. The phenotype, however, did not fulfill the criteria of classical ALPS, as double negative T-cells and splenomegaly were absent. The lack of expression of this phenotype suggests that FASL is more important for human than murine development and results in an embryonic lethal phenotype or it leads to another different phenotype (such as immune deficiency) or another severe disease masking the diagnosis of ALPS, or that mutations in FASL do not show recognizable abnormalities. A recent report of a patient with a heterozygous FAS-L mutation with features of ALPS but with associated hypogammaglobulinemia and granulomatous inflammation has been published. [27] The mutant FAS-L interfered with the function of wild-type FAS-L.

Patients with ALPS II have the typical clinical and immunologic features of ALPS but have defects in caspase 10. Caspase 8 mutations, previously called ALPS IIb, have been reclassified as "caspase-8 deficiency state" (CEDS). [7] Caspase 8 mutations have some features of ALPS, but lack DN T-cells and also show immunodeficiency and defects in activation of B-cells and T-cells suggesting caspase 8 may be involved in early signaling after receptor engagement. [28, 29] These patients suffer from recurrent HSV infections and bacterial sinopulmonary infections and have poor response to vaccinations. Immunodeficiency is caused by failure to form a caspase-8 dependent NFkB gene transcription factor signaling complex distinct from DISC.

Rieux-Laucat et al. have investigated over 30 patients with hypergammaglobulinemia and increased double negative T-cells that show normal in vitro activation of the FAS pathway (ALPS III). [4] These patients theoretically may have a defect in another lymphocyte apoptotic pathway such as Trail-R, DR3, or DR6. However, the same group of investigators has more recently shown that some of these patients do indeed have mosaic heterozygous FAS mutations and support reclassification of such patients to ALPS type I or type Im. [30] These patients have a normal in vitro response to FAS-induced apoptosis due to a normal population of activated T-cells that lack FAS mutations. Activating mutations in NRAS that augment RAF/MEK/ERK signaling decreases the proapoptotic protein BIM causing ALPS-like abnormalities and are now classified as ALPS IV. [7, 31]

ALPS patients have normal apoptotic responses to steroids, anti-metabolites, and some infectious agents suggesting other apoptotic pathways are intact.

Immunophenotype/Immunology:
On paraffin immunoperoxidase staining of nodal tissue the paracortical T-cells are predominantly CD4-CD8- αβ T-cells with normal expression of CD3 and CD5. Only a few CD4+ T-cells are present in the interfollicular areas and most CD4+ T-cells are in the germinal centers of the B-cell follicles. The double negative T-cells express the cytotoxic granule associated proteins TIA-1 and the NK-associated protein detected by CD57. Granzyme B and perforin are decreased in the double negative T-cells but are present in CD8+ T-cells and in CD4+ T-cells. [32] Staining for EBV is usually negative.

By flow cytometric analysis on tissue, ALPS patients predominantly have increased numbers of TCR a b + CD4-CD8- T cells, constituting 27%-54% of the mononuclear cells and 51%-78% of αβ T-cells. [1, 33] Other lymphoid populations are increased as well and include TCR γδ TCR+ CD4-CD8- T-cells, CD8+ T-cells, CD3+ HLA-DR+ T-cells, CD8+ CD57+ T cells, total B-cells and CD5+ B-cells. CD3+ CD25+ T cells are decreased primarily due to a reduction of CD4+ CD25+ T-cells. [26] Rare ALPS patients with an accumulation of CD4-CD8- T-cells expressing the γδ T-cell receptor rather than the a b T-cell receptor have been described. [34]

In the peripheral blood, the percentage of CD3+ T-cells is normal with a relative decrease in CD4+ T-cells compared to CD8+ T-cells. Polyclonal B-cells are increased (20%-43%) and a high percentage express CD5 (50%-92%). [1] Relatives with FAS mutations but without criteria for the diagnosis of ALPS also have expansions of CD8+ T-cells, TCR αβ+ CD4-CD8- T cells, and TCR γδ TCR+ CD4-CD8- T-cells. It is interesting that family members with no mutation and no features of ALPS have small, but significant expansions of CD8+ T-cells, both double negative T-cell subsets and CD5+ B-cells. [26]

The CD4-CD8- αβ T-cells are HLA-DR+ but often lack expression of CD25 the alpha chain of the IL-2 receptor, generally a marker of activated T-cells. The CD4-CD8- αβ T-cells also express CD57 and CD45RA. These results suggest that the double negative T-cells may have lost CD8 or CD4 expression after antigen encounter. Although somewhat debatable, most evidence indicates loss of CD8. [35] Although a few recent studies suggest that the CD4-CD8- T-cells are not clonally related to CD4+ or CD8+ T-cells. [36] From a functional standpoint, the T-cells in ALPS are skewed toward a Th2 phenotype with production of IL-4, IL-5, IL-6 and decreased expression of IFN- g and IL-12. [37] ALPS patients have increased serum IL-10; the double negative T-cells secrete very large amounts of FASL and IL-10. [37, 38] The elevated IL-10 may be produced by the expanded monocyte/macrophage population see in ALPS. [5] Excess production of IL-10 likely promotes the proliferation of autoimmune B-cells [39] as IL-10 can increase BCL-2 expression. Polyclonal hypergammaglobulinemia is due to increased IgG and IgA, and IgM is usually decreased. Polyclonal B-cell hyperplasia with expansion of CD5+ B-cells is noted. IL-10 also inhibits IL-12 thereby promoting a Th2 bias.

Treatment, Course and Prognosis:
Longitudinal follow-up of ALPS Ia patients has shown significant decrease in lymphoproliferation over time, even in the absence of treatment. [40, 41] This may be due to development of alternative pathways of lymphocyte apoptosis or decrease of influx of naïve T and B-cells compared to early childhood. Hypergammaglobulinemia, elevated double-negative T-cells, and autoimmune phenomena persist throughout life, however. The major determinants of morbidity and mortality are the severity of autoimmune disease, post-splenectomy sepsis, and lymphoma. Patients (approximately 5%) have died from causes directly related to ALPS, but follow-up is relatively short since the entity has only recently been recognized. [16]

Treatment has included steroids, intravenous immunoglobulin and/or immunosuppressive drugs, and chemotherapy that only give transient clinical improvement. [7, 42] Splenectomy should be avoided but may be necessary in some patients to control the cytopenias. Recent studies have shown a response to the anti-malarial drug Fansidar (sulfadoxine/pyrimethamine) that induced apoptosis in lymphocytes through the mitochondrial pathway and a marked decrease in interleukin-10 levels [43] but severe hypersensitivity reactions can occur with Fansidar and further information is needed before this becomes routine treatment. [16] Bone marrow transplantation has been performed rarely in patients with homozygous mutations in the FAS gene and severe disease. [42] Recent murine studies have demonstrated efficacy of rapamycin [44] but await further studies in humans. Inhibitors of the Notch signaling pathway (important in double negative T-cell transition in T-cell development and in T-cell activation) have been tested with some success in murine models. [45 ]

Apoptosis Defects and the Development of Lymphoma:
ALPS patients have a 51x and 14x increased frequency, respectively, of developing Hodgkin lymphoma (HL)(particularly lymphocyte predominant HL) and non-Hodgkin lymphoma (NHL). [41, 42, 46, 47, 48, 49, 50, 51] Approximately 3% of ALPS patients develop lymphoma, usually as adults with Straus et al. reporting an average age at onset of 28 years. [47] Most ALPS associated lymphomas have developed in patients with Type Ia ALPS with intracellular death domain mutations. [7] One patient with ALPS and a large B-cell lymphoma was found to have a perforin gene mutation in addition to a FAS mutation, [52, 53] suggesting additional mutations may be necessary for the development of lymphoma. The diagnosis of lymphoma in an ALPS patient should be made with caution, however, as one patient with type II ALPS and recurrent bacterial infections developed a monoclonal IgG/lambda immunoblastic proliferation with a clonal IgH rearrangement that resolved after antibiotic therapy alone. [54]

Somatic mutations of the FAS and CASP10 gene (chromosome 2q33-34) have also been reported in 11% and 14.5%, respectively, of NHL and include low and intermediate grade B-cell and T-cell lymphomas. [55] Hodgkin lymphoma has FAS mutations in 10%-20% of patients. Somatic mutations in FAS may play a role in the association of lymphoma with autoimmune disease. [46]

Differential Diagnosis:
The differential diagnosis includes benign and malignant T-cell proliferations that arise from CD4- CD8- T-cell populations or cause paracortical expansion of lymph nodes and/or involvement of the liver or spleen. See Table 3.

Precursor T-cell lymphoblastic leukemia/lymphoma occurs in children and young adults, usually presents in the bone marrow and/or thymus and can involve the lymph nodes and spleen. Nodal involvement shows infiltration of the paracortex (with some preservation of follicles) by a homogeneous population of blasts (high nuclear to cytoplasm ratio and scant cytoplasm) with a high mitotic rate, and a "starry sky" pattern may be present. Infiltration of the capsule is often seen. The cells have variable expression of CD4 and CD8, with the earliest stage of differentiation being CD4-CD8-, followed by CD4+, CD8+ and finally CD4+ or CD8+. The nuclei are TdT+ and CD34 is often expressed. HLA-DR is typically absent.

Hepatosplenic lymphoma occurs predominantly in young adult males and with little or no lymphadenopathy. [56, 57, 58, 59] Bone marrow involvement is present in virtually all of the cases. The tumor cells are homogeneous small to medium-sized lymphocytes with partially dispersed chromatin that infiltrate the liver and spleen and bone marrow in a sinus pattern. The cells are CD4-CD8-/+ γδ T-cells (rare cases have an αβ T-cell receptor) that express TIA-1 (and lack granzyme B and perforin) and are often CD56+ (60%-83%). Isochromosome (7q) is the characteristic cytogenetic abnormality. Hepatosplenic lymphoma is aggressive with a median survival of 16 months. This tumor may be seen in the post-transplant setting or in other settings of immunosuppression/chronic antigen stimulation.

Drug reactions are a notorious cause of lymphadenopathy that can mimic lymphoma. [60]The triad of fever, rash, and lymphadenopathy clinically should bring up the differential of a drug reaction and is a well-known feature of the anticonvulsant hypersensitivity syndrome. Lymph nodes can show marked follicular hyperplasia, paracortical expansion, and immunoblastic proliferation similar to a viral infection, or features of angioimmunoblastic lymphadenopathy. The cellular infiltrates are composed of variable numbers of large lymphocytes (transformed cells, immunoblasts) with small lymphocytes, plasma cells and eosinophils. Reed-Sternberg-like atypical large cells may be seen. The lymphocytes are predominantly T-cells with a variable number of B-cells. B-cell lymphomas can also develop after long-term anticonvulsant therapy. Scattered large CD30+ lymphocytes are typically present, but they do not form large masses or have marked cytologic atypia. Sulfa drugs, penicillin, allopurinol, aspirin, and erythromycin can cause similar changes.

The small cell variant of anaplastic large cell lymphoma is readily misdiagnosed as a reactive process. [61] The patients are typically children or young adults with fever and symptoms suggesting a viral illness. Nodal architecture in most cases is only partially effaced by a paracortical infiltrate composed predominantly of small to medium-sized lymphocytes with irregular, folded nuclei with clear to indistinct cytoplasm. A small population of large lymphocytes is present and has a preferential distribution around blood vessels, an important diagnostic feature. The large lymphocytes and a variable number of the small lymphocytes are CD30+. Most cases are CD4+ although rare cases are CD4-, CD8-. [61] ALK-1 is expressed in 80%-100% of cases and EMA and TIA-1 are typically present. Extranodal disease (liver, skin, CSF, and marrow) is often present and may be the first site of biopsy, making the diagnosis even more difficult. Peripheral blood involvement [61, 62] portends a poor prognosis. On Wright stained preparations the large cells have basophilic, finely vacuolated cytoplasm, and may represent less than 1% of white blood cells present. Despite ALK expression, these tumors often have an aggressive course.

Patients with angioimmunoblastic T-cell lymphoma (AILT) have systemic symptoms, hypergammaglobulinemia, peripheral adenopathy, and frequently skin rash and pruritus. [63] There is a paracortical to diffuse infiltration of lymph nodes by a mixed population of small, medium and large T-cells and large B-cells (immunoblasts and large transformed cells), plasma cells and a variable number of eosinophils and histiocytes. The T-cells vary from small to large and often have clear cytoplasm. Numerous arborizing vessels with prominent endothelial cells are present. Burned out germinal centers with expanded follicular dendritic cell meshworks (highlighted by immunostaining for CD21) are present except in rare cases with expanded hyperplastic germinal centers. [64] The lymphocytes are CD4+ T-cells that may show expression of CD10. [65] EBV+ large lymphocytes (predominantly B-cells) are present in approximately 80%-90% of cases. In approximately 10% of cases, the B-cells are clonal. The most frequent cytogenetic abnormalities include trisomy 3, trisomy 5, and an additional X chromosome.

Hemophagocytic lymphohistiocytosis is a rare cause of fever, hepatosplenomegaly, and a systemic hemophagocytic syndrome (hypertriglyceridemia, hypofibrinogenemia) in infants and young children that can mimic lymphoma. [66, 67] The disease is due to uncontrolled T-cell activation associated with defects in NK-cell and cytotoxic T-cell function. There is excessive production of inflammatory cytokines and abnormal macrophage activation. Genetic defects in the perforin gene (PRF1) and MUNC13-4 genes have been described. Clonal T-cell proliferations are rarely reported.

Table 3. Clinical and Pathologic Features of ALPS and Reactive and Neoplastic T-cell Lymphoproliferations in the Differential Diagnosis

Diagnosis Distribution Cell Morphology Predominant Cell Differential Antigen Expression Other Differential Features
ALPS Lymph node, spleen, bone marrow, liver Mixed small, medium, large cells CD4-CD8- αβ T-cell TIA-1+, GrB+*, perforin+*, HLA-DR+, CD57+ FAS-FASL mutations
T-ALL Bone marrow, lymph node, spleen Blasts Variable expression of CD4 and CD8 TdT+, CD10+/-, CD34+/-; CD4-CD8- (stage 1 of thymocyte differentiation lacks CD3 and αβ TCR, HLA-DR-) Cytogenetic abnormalities
SCV ALCL Lymph node, liver, bone marrow, skin, CSF Small, irregular lymphocytes, small population of large cells CD4+ T-cells CD30+, TIA-1+, ALK1+, EMA+ t(2;5)(p23;q35)
HSL Liver, spleen, bone marrow (60%-70% with sinus pattern) Homogeneous medium-sized cells CD4- CD8- γθ > CD4- CD8+ T-cell; rarely an αβ T-cell TIA-1+; granzyme - perforin-; CD56+ in 60%-70% Isochromosome 7q; +8
AILT Lymph node, liver, spleen, skin Small, medium, large cells, some with clear cytoplasm CD4+ T-cells CD10+, BCL-6+, CXCL13+, expanded FDC meshworks, EBV+ B-cells Trisomy 3, 5, +X
HLH Liver, spleen Mixed small, medium and some large cells; hemophagocytosis CD4+ T-cells Reduced cytotoxic T-cell and NK-cell activity PRF1, MUNC13-4 gene mutations; Systemic HPS with hypertriglyceridemia, hypofibrinogenemia
Drug Reactions Lymph nodes, skin Mixture of small and large lymphocytes, eosinophils, variable follicular hyperplasia Mixture of B-cells and T-cells; predominantly CD4+ T-cells Fever, rash, eosinophilia

ALPS , autoimmune lymphoproliferative syndrome SCV ALCL, small cell variant of anaplastic large cell lymphoma

HSL , hepatosplenic lymphoma ALL, acute lymphocytic leukemia HLH, hemophagocytic lymphohistiocytosis

HPS , hemophagocytic syndrome

* Cytolytic granule proteins are more prominent in CD8+ or CD4+ T-cells rather then CD4- CD8- T-cells.

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