Answer: Hemaphagocytic syndrome

Histology: The marrow is cellular with trilineage hematopoiesis. There is a maturation arrest of the granulocytic series at the promyelocytic stage with absence of mature granulocytes. There is an erythroid hyperplasia, but blasts are not increased. Most notable is the presence of histiocytes involving the marrow sinuses showing hemophagocytosis.

Discussion: Hemophagocytic syndrome (hemophagocytic lymphohistiocytosis, HLH) is a hyperinflammatory disorder characterized clinically by high fever, hepatosplenomegaly, and often neurologic dysfunction. Patients commonly show pancytopenia, liver function abnormalities (high triglycerides, elevated ferritin, transaminasemia, elevated bilirubin, etc.) and coagulation abnormalities. Lymphadenopathy, skin rash, and pulmonary infiltrates are often present. These abnormalities are caused by uncontrolled proliferation and activation of T cells and macrophages, with subsequent infiltration of multiple organs (bone marrow, liver, spleen, lymph nodes, CNS, lungs). These activated cells produce large amounts of cytokines (IFN-ã, TNF-á, IL-1, IL-6) causing hemophagocytosis by overactivated macrophages.

The most prominent feature in involved tissues is diffuse infiltration by benign histiocytes showing erythrophagocytosis. Phagocytosis of platelets is often present, and ingestion of lymphocytes and cellular debris is present in varying degrees. Bone marrow biopsies often show a decrease in erythropoiesis and myelopoiesis. Importantly, a negative biopsy does not rule out the diagnosis, and repeat marrow biopsies or biopsies of other organs may be considered if the diagnosis is strongly suspected. In the liver, portal tracts and sinusoids are typically involved, and lymphoid hyperplasia is often seen. The infiltrate involves the red pulp of the spleen with accompanying lymphoid depletion. Involved lymph nodes also show lymphoid depletion, and the histiocytic infiltrates are found in the sinuses and paracortical region.

HLH can be inherited or acquired. Acquired HLH is often related to infection (infection-associated hemophagocytic syndrome). Viral infection is commonly implicated, though bacteria, parasites and fungi may induce HLH. Affected patients may have underlying immune deficiencies, often acquired (e.g., immunosuppression following organ transplantation), but many do not. Epstein-Barr virus (EBV) infection is a commonly identified triggering infection, and mortality in this setting is high. Malignancies, particularly lymphomas, may also cause HLH, and EBV may play a role in this process. Some autoimmune and systemic inflammatory diseases are also associated with HLH, including systemic lupus erythematosus, multicentric Castleman’s disease, adult-onset Still’s disease, juvenile idiopathic arthritis, and rarely others. It may occur during disease flares or as a complication of infection in these settings.

Familial HLH is clinically and pathologically indistinguishable from acquired HLH, though the familial form is often fatal within the first few years of life. Recently, mutations in the perforin gene (PRF1) on chromosome 10 were found in some cases. Perforin is a protein expressed in cytoplasmic granules of cytotoxic T cells and NK cells. Following release, it is thought to form a pore-like structure in the target cell membrane, resulting in induction of cell death. Mutations in different genes have been found in other cases, including the UNC13D gene, which encodes Munc13-4, and STX11 which encodes syntaxin 11. These defects all affect steps in the granule-dependent cytotoxic activities of lymphocytes, effectively explaining the HLH manifestations. Specific syndromes of immune deficiency also manifest HLH, namely Chediak-Higashi syndrome, Griscelli syndrome, and X-linked lymphoproliferative syndrome. The genetic defects in these syndromes affect different steps in the above cytotoxic pathway, as well.

Immunohistochemical stains will clarify the nature of the infiltrate when necessary. Specifically, the histiocytes in HLH are CD68 positive, and are negative for S100 (positive in Rosai-Dorfman disease) and CD1a (positive in LCH). Carcinoma would be positive for cytokeratins, and acute leukemia would have increased blasts highlighted by CD117 and/or CD34.

Reference(s):
– Janka G, Stadt UZ. Familial and acquired hemophagocytic lymphohistiocytosis. Hematology (American Society of Hematology Education Program Book) 2005;82-88.
– Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmunity Reviews 2004:3;69-75.
– Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev 2005:203;165-179.
– Weiss LM. Histiocytic and Dendritic Cell Proliferations. In: Knowles DM, ed. Neoplastic Hematopathology. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:1823-1827.