Pathological findings in human autoimmune lymphoproliferative syndrome

Abstract

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).

Figure 1.

Histopathology of lymph nodes. A: The paracortex is markedly expanded by lymphocytes with pale pink cytoplasm. Primary and secondary follicles are numerous. Some follicles show regressive changes (upper right ). H&E; original magnification, ×100. B: Progressive transformation of germinal centers was a focal but relatively frequent finding. H&E; original magnification, ×200. C: The paracortex is populated by lymphocytes, plasma cells, and immunoblasts. Note frequent mitotic figures. H&E; original magnification, ×600.

Figure 2.

Lymph node demonstrates paracortical expansion by CD3⁺ DN T cells. Immunoperoxidase stains (ABC immunoperoxidase technique, hematoxylin counterstain; original magnification, ×200) performed in paraffin sections demonstrates expansion of interfollicular regions by CD3⁺ T cells (A) that are largely CD4⁻ (B) and CD8⁻ (C). Most CD4⁺ cells are within germinal centers. The paracortex contains numerous lymphocytes positive for CD57 (D) and TIA-1 (E) with weaker and patchy staining for perforin (F).

Figure 3.

Spleen. A: The spleen shows follicular hyperplasia of white pulp, with an expanded marginal zone. The red pulp is greatly expanded. H&E; original magnification, ×200. B: The cytological composition of the red pulp resembles that of the lymph node paracortex and contains numerous lymphocytes, plasma cells, and immunoblasts. H&E; original magnification, ×400.