Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation

Abstract

Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100+ cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Extensive lymphoid infiltrates composed predominantly of T cells in a bone marrow with ALPS (case 9). (A) H&E, X 40 and X 500 (insert), (B) CD20, X 40, (C) CD3, X 40, (D) CD45RO, X 40, (E) CD4, X 40, (F) CD8, X 40. Note the markedly decreased expression of CD45RO in the T-cell infiltrates, consistent with the increase in DNT cells. The DNT cell population is less morphologically apparent using CD4 and CD8 staining.

Figure 2.

Nodular lymphoid infiltrates containing mixed T and B cells in a bone marrow with ALPS (case l8). (A) H&E, X 40, (B) CD3, X 40, (C) CD45RO, X 40, (D) CD20, X 200. Note the clusters of medium-sized to large B cells surrounded by numerous small T cells. There is loss of expression of CD45RO.

Figure 3.

Lymphohistiocytic infiltrate with features of Rosai-Dorfman disease in a bone marrow with ALPS (case 23). (A) H&E, X 500, (B) CD20, X 40, (C) CD3, X 40, (D) CD4, X 100, (E) CD8, X 100, (F) Sl00, X 200, (G) and (H) Giemsa, X 500. Note the increased CD4 and CD8 double-negative T cells and histiocytes with emperipolesis.

Figure 4.

Diffuse interstitial lymphoid infiltrates composed predominantly of B cells in a bone marrow with ALPS (case ll). (A) H&E, X l00, (B) CD3, X l00, (C) CD20, X l00.

Figure 5.

Classical Hodgkin lymphoma, EBV-positive, involving a bone marrow with ALPS. (A) H&E, X 100, (B) H&E, X 500, (C) CD30, X 100, (D) EBER ISH, X 100. Note the Reed-Sternberg cells positive for CD30 and EBER.