Hematopathology Diagnoses Too Easy to Miss!
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.
Autoimmune Lymphoproliferative Syndrome (ALPS)
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.
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.  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).  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.
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
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.  Since that time only a few hundred patients have been reported.
Patients with ALPS have mutations in the FAS apoptotic pathway resulting in chronic lymphoproliferation
and a breakdown in immunologic tolerance.
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.  ALPS has rarely been diagnosed in adults
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. 
Autoimmune manifestations occur in approximately 40%-70% of patients and include thrombocytopenia,
hemolytic anemia and less commonly neutropenia or glomerulonephritis.
antibodies and antiplatelet antibodies are seen in 46% and 35% of ALPS patients, respectively, but there
is no correlation with clinical neutropenia or thrombocytopenia.  Other serologic
abnormalities include positive direct Coombs test, alloantibodies, and IgG and/or IgM antibodies to
cardiolipin, and a Factor VIII inhibitor.
Despite the relatively frequent presence of
anti-cardiolipin antibodies, thrombotic or embolic events are rare.  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,  indicating that many cases are likely ALPS.
Note: See Table 1 from Jackson, 1999  and Table 2 from Sneller, 2003
 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;
2. Defective in vitro FAS-mediated
3. > 1% TCR a b+, CD3+, CD4-, CD8- cells in peripheral blood or
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.
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
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.  Peripheral blood absolute lymphocyte counts vary from patient to patient and range
from normal or mildly elevated to up to 12,328.  Lymphocytes undergoing apoptosis can be seen
on peripheral blood smears.  Approximately 16% of ALPS patients have eosinophilia with
increased peripheral blood leukocytes of multiple lineages, increased serum IgE and higher mortality from
infection.  These patients have more severe cytopenias leading to splenectomy.
ALPS results from defects in the FAS/FAS ligand apoptotic
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. 
Figure 1. Normal Fas mediated lymphocyte apoptosis (Corresponds to Figure 1 in
Rieux-Laucat, 2003 )
It was shown in 1992 that ALPS patients shared similarities with two mouse models of autoimmunity,
lpr and gld,
equivalent to genes encoding CD95 (FAS/APO1) and CD95L (FASL) in humans.  Classification of
ALPS is based on the type of mutation (See Table 2).  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.
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 ) and in caspase 8 deficiency (CED); see Figure 1, reference Su,
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 )
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
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.  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.  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).  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.
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).  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.  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.
ALPS patients have normal apoptotic responses to steroids, anti-metabolites, and some infectious
agents suggesting other apoptotic pathways are intact.
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.  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
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.  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. 
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%).
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. 
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.  Although a few recent studies suggest that the CD4-CD8- T-cells are not clonally
related to CD4+ or CD8+ T-cells.  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.  ALPS patients have increased serum IL-10; the double negative T-cells secrete very
large amounts of FASL and IL-10.
The elevated IL-10 may be produced by the expanded
monocyte/macrophage population see in ALPS.  Excess production of IL-10 likely promotes the
proliferation of autoimmune B-cells  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
Treatment, Course and Prognosis:
Longitudinal follow-up of ALPS Ia
patients has shown significant decrease in lymphoproliferation over time, even in the absence of
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
Treatment has included steroids, intravenous immunoglobulin and/or immunosuppressive drugs, and
chemotherapy that only give transient clinical improvement.
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 
but severe hypersensitivity reactions can occur with Fansidar and further information is needed before
this becomes routine treatment.  Bone marrow transplantation has been performed rarely in
patients with homozygous mutations in the FAS gene and severe
disease.  Recent murine studies have demonstrated efficacy of rapamycin
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).
Approximately 3% of ALPS patients develop lymphoma, usually as adults with Straus et al. reporting
an average age at onset of 28 years.  Most ALPS associated lymphomas have developed in
patients with Type Ia ALPS with intracellular death domain mutations.  One patient with ALPS
and a large B-cell lymphoma was found to have a perforin gene mutation in addition to a FAS mutation,
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. 
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.  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
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
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
Drug reactions are a notorious cause of lymphadenopathy that can mimic lymphoma. 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.  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-.  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
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.  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.  The lymphocytes are CD4+
T-cells that may show expression of CD10. 
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
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,
HPS , hemophagocytic syndrome
* Cytolytic granule proteins are more prominent in CD8+ or CD4+ T-cells rather then CD4- CD8- T-cells.
- Lim MS, Straus SE, Dale JK, et al. Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 153: 1541-1550, 1998.
- Maric I, Pittaluga S, Dale JK, et al. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol 29: 903-911, 2005.
- Canale VC, Smith CH. Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr 70: 891-899, 1967.
- Rieux-Laucat F, Fischer A, Deist FL. Cell-death signaling and human disease. Curr Opin Immunol 15: 325-331, 2003.
- Straus SE, Sneller M, Lenardo MJ, et al. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 130: 591-601, 1999.
- Jackson CE, Puck JM. Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr 11: 521-527, 1999.
- Su HC, Lenardo MJ. Genetic defects of apoptosis and primary immunodeficiency. Immunol Allergy Clin North Am 28: 329-351, 2008.
- Le Deist F, Emile JF, Rieux-Laucat F, et al. Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet 348: 719-723, 1996.
- Deutsch M, Tsopanou E, Dourakis SP. The autoimmune lymphoproliferative syndrome (Canale-Smith) in adulthood. Clin Rheumatol 23: 43-44, 2004.
- Auricchio L, Vitiello L, Adriani M, et al. Cutaneous manifestations as presenting sign of autoimmune lymphoproliferative syndrome in childhood. Dermatology 210: 336-340, 2005.
- Siegel RM, Fleisher TA. The role of Fas and related death receptors in autoimmune and other disease states. J Allergy Clin Immunol 103: 729-738, 1999.
- Kanegane H, Vilela MM, Wang Y, et al. Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis. Pediatr Nephrol 18: 454-456, 2003.
- Kwon SW, Procter J, Dale JK, et al. Neutrophil and platelet antibodies in autoimmune lymphoproliferative syndrome. Vox Sang 85: 307-312, 2003.
- Carter LB, Procter JL, Dale JK, et al. Description of serologic features in autoimmune lymphoproliferative syndrome. Transfusion 40: 943-948, 2000.
- Fang BS, Sneller MC, Straus SE, et al. Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome. Am J Hematol 64: 214-217, 2000.
- Sneller MC, Dale JK, Straus SE. Autoimmune lymphoproliferative syndrome. Curr Opin Rheumatol 15: 417-421, 2003.
- Teachey DT, Manno CS, Axsom KM, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood 105: 2443-2448, 2005.
- Chiocchetti A, Indelicato M, Bensi T, et al. High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation. Blood 103: 1376-1382, 2004.
- Dianzani U, Bragardo M, DiFranco D, et al. Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. Blood 89: 2871-2879, 1997.
- Kim YJ, Dale JK, Noel P, et al. Eosinophilia is associated with a higher mortality rate among patients with autoimmune lymphoproliferative syndrome. Am J Hematol 82: 615-624, 2007.
- Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol 133: 124-140, 2006.
- Sneller MC, Straus SE, Jaffe ES, et al. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest 90: 334-341, 1992.
- Puck JM, Straus SE. Somatic mutations--not just for cancer anymore. N Engl J Med 351: 1388-1390, 2004.
- Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314-317, 1992.
- Roesler J, Izquierdo JM, Ryser M, et al. Haploinsufficiency, rather than the effect of an excessive production of soluble CD95 (CD95 [Delta]TM), is the basis for ALPS Ia in a family with duplicated 3' splice site AG in CD95 intron 5 on one allele. Blood 106: 1652-1659, 2005.
- Bleesing JJ, Brown MR, Straus SE, et al. Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood 98: 2466-2473, 2001.
- Bi LL, Pan G, Atkinson TP, et al. Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med Genet 8: 41, 2007.
- Chun HJ, Zheng L, Ahmad M, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419: 395-399, 2002.
- Bidere N, Su HC, Lenardo MJ. Genetic disorders of programmed cell death in the immune system. Annu Rev Immunol 24: 321-352, 2006.
- Holzelova E, Vonarbourg C, Stolzenberg MC, et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med 351: 1409-1418, 2004.
- Oliveira JB, Bidere N, Niemela JE, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A 104: 8953-8958, 2007.
- Mateo V, Menager M, de Saint-Basile G, et al. Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes. Blood 110: 4285-4292, 2007.
- Ramsay AD. Reactive lymph nodes in pediatric practice. Am J Clin Pathol 122 Suppl: S87-97, 2004.
- van den Berg A, Tamminga R, de Jong D, et al. FAS gene mutation in a case of autoimmune lymphoproliferative syndrome type IA with accumulation of gammadelta+ T cells. Am J Surg Pathol 27: 546-553, 2003.
- Bristeau-Leprince A, Mateo V, Lim A, et al. Human TCR alpha/beta+ CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells. J Immunol 181: 440-448, 2008.
- Marlies A, Udo G, Juergen B, et al. The expanded double negative T cell populations of a patient with ALPS are not clonally related to CD4+ or to CD8+ T cells. Autoimmunity 40: 299-301, 2007.
- Fuss IJ, Strober W, Dale JK, et al. Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. J Immunol 158: 1912-1918, 1997.
- Lopatin U, Yao X, Williams RK, et al. Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression. Blood 97: 3161-3170, 2001.
- Watanabe N, Ikuta K, Nisitani S, et al. Activation and differentiation of autoreactive B-1 cells by interleukin 10 induce autoimmune hemolytic anemia in Fas-deficient antierythrocyte immunoglobulin transgenic mice. J Exp Med 196: 141-146, 2002.
- Rieux-Laucat F, Blachere S, Danielan S, et al. Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations. Blood 94: 2575-2582, 1999.
- Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology 11: 15-23, 2006.
- Bleesing JJ, Straus SE, Fleisher TA. Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival. Pediatr Clin North Am 47: 1291-1310, 2000.
- van der Werff Ten Bosch J, Schotte P, Ferster A, et al. Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations. Br J Haematol 117: 176-188, 2002.
- Teachey DT, Obzut DA, Axsom K, et al. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood 108: 1965-1971, 2006.
- Teachey DT, Seif AE, Brown VI, et al. Targeting Notch signaling in autoimmune and lymphoproliferative disease. Blood 111: 705-714, 2008.
- Gronbaek K, Straten PT, Ralfkiaer E, et al. Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. Blood 92: 3018-3024, 1998.
- Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98: 194-200, 2001.
- Boulanger E, Rieux-Laucat F, Picard C, et al. Diffuse large B-cell non-Hodgkin's lymphoma in a patient with autoimmune lymphoproliferative syndrome. Br J Haematol 113: 432-434, 2001.
- Schattner EJ, Friedman SM, Casali P. Inhibition of Fas-mediated apoptosis by antigen: implications for lymphomagenesis. Autoimmunity 35: 283-289, 2002.
- van den Berg A, Maggio E, Diepstra A, et al. Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma. Blood 99: 1492-1494, 2002.
- Poppema S, Maggio E, van den Berg A. Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. Leuk Lymphoma 45: 423-431, 2004.
- Clementi R, Dagna L, Dianzani U, et al. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. N Engl J Med 351: 1419-1424, 2004.
- Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med 352: 306-307; author reply 306-307, 2005.
- Strobel P, Nanan R, Gattenlohner S, et al. Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome with functional FAS (CD95/APO-1) deficiency. Am J Surg Pathol 23: 829-837, 1999.
- Shin MS, Kim HS, Kang CS, et al. Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas. Blood 99: 4094-4099, 2002.
- Gaulard P, Zafrani ES, Mavier P, et al. Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. Hepatology 6: 864-868, 1986.
- Farcet JP, Gaulard P, Marolleau JP, et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood 75: 2213-2219, 1990.
- Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia 14: 991-997, 2000.
- Belhadj K, Reyes F, Farcet JP, et al. Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 102: 4261-4269, 2003.
- Ioachim HL, Ratech H, Ioachim's lymph node pathology. 3rd ed. 2002, Philadelphia: Lippincott, Williams & Wilkins. xiv, 624 p.
- Kinney MC, Collins RD, Greer JP, et al. A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 17: 859-868, 1993.
- Onciu M, Behm FG, Raimondi SC, et al. ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature. Am J Clin Pathol 120: 617-625, 2003.
- Dogan A, Attygalle AD, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol 121: 681-691, 2003.
- Ree HJ, Kadin ME, Kikuchi M, et al. Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. Am J Surg Pathol 22: 643-655, 1998.
- Attygalle A, Al-Jehani R, Diss TC, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 99: 627-633, 2002.
- Ishii E, Ohga S, Imashuku S, et al. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences. Crit Rev Oncol Hematol 53: 209-223, 2005.
- Ishii E, Ueda I, Shirakawa R, et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 105: 3442-3448, 2005.