Hemophagocytic Syndromes

Clinical Definition and Features

The genetic forms include familial disease and hemophagocytosis related to immune deficiencies, such as X-linked lymphoproliferative syndrome Opens in new window and Chediak-Higashi syndrome Opens in new window.

The acquired forms of hemophagocytic syndrome include infection-associated hemophagocytic syndrome, historically known as histiocytic medullary reticulosis Opens in new window or virus-associated hemophagocytic syndrome Opens in new window, which is a benign, potentially reversible but often fatal disorder that occurs primarily in immunocompromised patients.

The acquired forms also include the syndrome as described in transplant recipients and in patients with acute lymphoblastic leukemia and T-cell lymphomas. The clinical features, many of which cases are associated with EBV, include:

• high fever,

• constitutional symptoms,
• anemia,
• lymphadenopathy,
• hepatosplenomegaly,
• abnormal liver function test results, and
• coagulopathy.

Lymph nodes from these patients have dilated sinuses filed with bland-appearing histiocytes that contain phagocytosed red blood cells.

The histiocyte cytoplasm may also contain neutrophils, lymphocytes, and platelets, all of which are typically not as prominent as are red blood cells.

The normal nodal architecture is usually intact, but the lymph node may also have evidence of vascular proliferation and a generalized depletion of lymphocytes. In some cases, the entire nodal architecture may be completely effaced.

The differential diagnoses of the hemophagocytic syndromes are usually distinguished on clinical grounds.

Most patients with familial hemophagocytic lymphohistiocytosis Opens in new window are less than 1 year old and have impaired cellular and humoral immunity. These patients often have involvement of the lymph nodes and bone marrow. Spleen, liver, and central nervous system are also affected.

The differential diagnosis of hemophagocytic syndromes also includes malignant histiocytosis and malignant lymphomas associated with benign hemophagocytosis, metastatic carcinoma, and metastatic melanoma.

Most previously reported cases of malignant histiocytosis were probably examples of infection-associated hemophagocytic syndromes.

Cases of malignant histiocytosis in which the cells had malignant cytologic features were most likely examples of anaplastic large cell lymphomas, which often have a sinusoidal localization in lymph nodes.

In these lymphoms, erythrophagocytosis is not prominent, but when it is present, it is almost exclusively present in benign histiocytes and not in cytologically malignant cells.

Furthermore, the sinusoidal cells of anaplastic large cell lymphoma stain immunohistochemically for CD30, unlike the benign phagocytosing histiocytes of infection-associated hemophagocytic syndrome.

Carcinoma and malignant melanoma preferentially metastasize to the lymph node sinuses; when this feature is prominent, it may be confused with hemaphagocytic syndrome.

Cytokeratin immunohistochemical analysis highlights metastatic carcinoma cells, with the caveat that normal lymph node dendritic cells show a spider-like keratin staining pattern that is unlike the exclusively membrane, pericellular staining of carcinoma cells.

S-100 protein shows a similar dendritic pattern of staining in the normal lymph node, but it causes nuclear staining in the malignant cells of metastatic melanoma.

Far less likely, monocytoids B-cell proliferations and hairy cell leukemia in lymph nodes may mimic infection-associated hemophagocytic syndrome.

However, monocytoid B-cell lymphomas, reactive monocytoid B-cell proliferations, and hairy cell leukemia are not associated with hemophagocytosis and resemble the syndrome only in their sinusoidal and parafollicular pattern of nodal involvement.