July 2009
Written by Peter M. Banks, M.D., Director of Hematopathology, Carolinas Medical Center, Charlotte, North Carolina.

Submitting Pathologist
Jagmohan Sidhu, M.D., Wilson Memorial Regional Hospital, Johnson City, New York.

Diagnosis
Spleen and splenic hilar lymph node showing changes consistent with autoimmune lymphoproliferative syndrome (ALPS).

Clinical History
This 25 year old male had a long (reportedly 7-year) history of splenomegaly but remained asymptomatic and otherwise well, although in recent weeks a generalized rash had appeared. The spleen was removed, weighing 1,387 grams.

Microscopy
Conventionally stained sections of spleen indicate relatively normal proportionate sinus and lymphoid pulp (see Figure 1).

At higher magnification one can appreciate some subtle thickening of cords but without evidence of hemolysis: no hemosiderin accumulation or hyaline-ferruginous bodies. There is some increase of small lymphocytes in the sinus pulp, but these are dispersed. The lymphoid pulp shows mild hyperplasia, and some Malphighian corpuscles show expansion in the marginal zone distribution, that is, not of the follicular centers or mantle zones (see Figure 2).

Ancillary Studies
Flow cytometry of splenic tissue revealed a minority of T-cells with an abnormal immunophenotype: these were positive for CD3 and other pan-T-cell markers, but negative for both CD4 and CD8, and negative for CD25 as well. Paraffin section immunohistochemistry (IHC) of the spleen reveals this same abnormal population of T-cells in what was expected to be the (B-cell) expansive marginal zone (see Figure 3).

IHC also discloses a high proliferative rate in this peculiar T-cell zone, as judged by the Ki-67 staining (see Figure 4).
A splenic lymph node was also identified in the surgical specimen. Sections of this show striking expansion of the paracortex, the T-cell zone, recognizable in relation to a network of proliferating venules (seen Figure 5).
Further IHC studies showed an absence of the T-cell associated marker CD45RO in the abnormal T-cell population in both the spleen and the nodal paracortex.

Flow cytometry performed on peripheral blood from this patient detected the same minor abnormal T-cell population. PCR molecular probe studies applied to the splenic tissue failed to detect a clonal T-cell population.

Discussion
ALPS is based on a hereditary deficiency of the Fas receptor (CD95) on T-cells, which results in the failure of normal cell death through apoptosis (1). The persistence of mature T-cells leads to autoimmunity, however, penetrance is highly variable. The most common characteristic immunophenotypic abnormality among the accumulated T-cells is lack of expression of both CD4 and CD8, although other markers may be lost in addition, such as CD25 and CD45RO. In this case there has been almost no clinical evidence of autoimmune disease, although the recent development of a rash may be a harbinger of increasing activity. The presentation of disease in milder adult cases usually includes splenomegaly, often with autoimmune anemia or thrombocytopenia. There is a registry for newly diagnosed patients at the National Institutes of Health, helping patients with genetic testing and counseling (2).

Microscopically, the process is a mimic of T-cell lymphoma, particularly in lymph nodes, where the accumulation of the T-cells can resemble lymphoma. Molecular probe methods may prove essential for recognition of the process as non-neoplastic, in particular because lymphomas can arise in the background setting of this disease (3).

References

1. Holzelova E, Vonarbourg C, Stolzenberg MC et al.
   Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med. 2004; 351: 1409-1418. More online »
2. NIAID website for ongoing studies on ALPS. More online »
3. Straus SE, Jaffe ES, Puck JM, Dale JK et al.
   The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001; 98: 194-200. More online »

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