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May 1999

Pathological Case of the Month

Arch Pediatr Adolesc Med. 1999;153(5):547. doi:

Diagnosis and Discussion: Neuropathology of Familial Hemophagocytic Lymphohistiocytosis

Figure 1. Coronal slice of the brain showing mild dilation of the ventricles and periventricular sclerosis. Focal softening with degeneration is also seen.

Figure 2. Microphotograph showing heavy lymphohistiocytic infiltrate in the meninges (hematoxylin-eosin, original magnification ×140).

Figure 3. Microphotograph of the brain showing a heavy perivascular lymphohistiocytic infiltrate (hematoxylin-eosin, original magnification ×280).

Figure 4. Microphotograph of the brain showing a lymphohistiocytic infiltrate diffusely infiltrating the parenchyma and intermingling with the proliferating astrocytes (hematoxylin-eosin, original magnification ×280).

Figure 5. Gross photograph of a slice of the enlarged liver and spleen.

Figure 6. Microphotograph of the liver with sinusoids packed with histiocytes showing prominent erythrophagocytosis (Masson trichrome, original magnification ×280).

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder that is indistinguishable from viral-associated hemophagocytic syndrome (VAHS). Both disorders are included in the broad category of hemophagocytic lymphohistiocytosis (class 2 histiocytosis).1 Familial hemophagocytic lymphohistiocytosis is a disease seen in infants and young children and the age of onset ranges from 1 day2 to 7 years,3 with more than 80% of cases presenting before age 2 years. It is usually fatal, with extensive brain involvement. Viral-associated hemophagocytic syndrome can occur in any age group, but is rare and patients usually recover. Diagnostic guidelines1 for hemophagocytic lymphohistiocytosis are fever (>7 days, >38.5°C), splenomegaly (>3 cm), cytopenia (>2 or 3 lineages in the peripheral blood and unassociated with a hypocellular or dysplastic marrow), hypertriglyceridemia [>2 mmol/L], and hypofibrinogenemia [<1.5 g/L]). Pathologically, hemophagocytic lymphohistiocytosis is in bone marrow, spleen, or lymph nodes with no evidence of malignancy. Histiocytes have morphologic immunophenotypic and ultrastructural features of normal sinus histiocytes4 and show prominent erythrophagocytosis. Clinically, patients with FHL present with fever, hepatosplenomegaly, pancytopenia, abnormal liver function test results, coagulopathies, and hypertriglyceridemia. Thirty percent of cases have shown neurologic abnormalities such as alteration of the level of conciousness, nuchal rigidity, seizures, and hemiparesis.5-7 Major changes were meningeal, perivascular, and intraparenchymal lymphohistiocytic infiltrates.8 Erythophagocytosis was a variable finding.

The pathogenesis of FHL remains uncertain. Multiple immune defects have been reported in FHL.9-11 These are impaired natural killer cell activity, decreased T-lymphocyte response to mitogens, impaired monocyte-mediated, antibody-dependent cellular cytotoxicity, impaired interleukin 1 and interferon production, and an abnormal interleukin 2–interleukin 2 receptor system. A defect in immunomodulation results in an unrestricted release of inflammatory cytokines.

Differential diagnosis of FHL includes VAHS that was first associated with viral infection, but may also occur with bacterial, fungal, and parasitic infections or with an immunodeficiency. The accelerated phase of Chédiak-Steinbrinck-Higashi syndrome may also mimic FHL and VAHS. This suggests that these 3 disorders associated with immunodeficiency may all share the common pathway of an abnormal immune response to a stimulus, resulting in marked unregulated histiocytic activation.

Familial hemophagocytic lymphohistiocytosis is a rapidly fatal disorder. All temporary treatment protocols for FHL that are successful have employed epipodophyllotoxin with additional intrathecal methotrexate and cranial irradiation therapy.12 This does not cure the disease and despite remissions lasting up to 57 months, relapses have eventually occurred in most patients.13 Bone marrow transplantation may be a potential treatment for this disorder, as it could possibly correct the underlying immune defect.10,14

Accepted for publication October 1, 1998.

Corresponding author: R. K. Vasishta, MD, MRCPath, Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.

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