Histiocytic Disorders Flashcards
Discuss the pathophysiology of HLH
- Multisystem disorder of immune dysregulation
- Characterized by an unchecked and persistent activation of cytotoxic T lymphocytes and natural killer (NK) cells.
- Failure to control the immune response leads to increased secretion of inflammatory cytokines and macrophage activation, causing massive systemic inflammation and potentially life threatening immune mediated injury of multiple organs.
Discuss the pathophysiology of primary HLH
· Disruption of the normal function of perforin and the regulation, storage, transport and release of granzyme via genetic mutations predisposes to the development of primary, or familial, HLH.
· If the above mechanisms are defective, then the antigenic stimulus cannot be effectively cleared by the immune system and persists.
· Proinflammatory molecules continue to be released resulting in high levels of macrophage activation with resultant haemophagocytosis, tissue damage, organ failure, and the other inflammatory manifestations of the syndrome.
List the characteristic lab findings in HLH
o Cytopenias (usually of two or three cell lines: Hb <90g/L, Plts <100x10^9, Neuts <1x10^9)
o Hypertriglyceridemia (>3g/L)
o Hypofibrinogenemia (<1.5g/L)
o Hyperferritinemia (>500ug/L)
- Ferritin levels >10 000 ug/L 90% sensitive and 98% specific in children
- Neither sensitive or specific for HLH in adults
o Elevated sIL2rα levels (CD25, ≥ 2400U/mL)
- Standard sandwich ELISA.
o Reduced NK cell function
- Measured via a radiolabeled chromium release assay:
release of cytotoxic granules containing the radionuclide 51Cr from NK cells is measured and may be reduced in patients with HLH.
- Can also be measured using flow: measure CD107a on CD3 stimulated CD8 positive T cells.
o Abnormal liver function testing.
o Hemophagocytosis
o Elevated inflammatory markers
What are the HLH 2004 diagnostic criteria?
· Must have 5 of the 8 following features:
1) Fever
2) Splenomegaly
3) Cytopenias affecting ≥2 lineages
- Hb <90, plts <100×109/L, ANC <1×109/L
4) Hypertriglyceridemia and/or hypofibrinogenemia
- Triglycerides ≥3 g/L, fibrinogen ≤1.5g/L
5) Haemophagocytosis in bone marrow, spleen, or lymph nodes
6) Low or absent NK cell activity
7) Ferritin≥500 μg/L
8) sCD25 (sIL2Rα) ≥2,400 U/ml
What is the HS score in HLH?
Similar to HLH 2004 criteria.
Uses 9 criteria including presence of immunosuppression and LFT derangement.
More predictive of HLH in children whereas the HLA 2004 criteria are more predictive in adults unless the HS score is utilised very early in the disease process
What is Langerhans cell histiocytosis?
· Grooved, folded nuclei with fine chromatin, inconspicuous nucleoli and moderately abundant cytoplasm.
· Bone marrow aspirates occasionally show cells with typical Langerhans cell features, but evidence of involvement is more easily seen in trephine biopsies.
· Langerhans cells distinguished on electron microscopy by the presence of Birbeck granules and by immunohistologic positivity for CD1a, S‐100, and CD207 (langerin).
· Tumour cell proliferation driven by ERK activation of the MAP kinase pathway, which in about 50% of cases is triggered by BRAF V600E mutation.
· Neoplastic cells, sometimes associated with eosinophils, lymphocytes, neutrophils, and macrophages, infiltrate a wide variety of organs, especially the skin, bone, lymph nodes, liver, spleen, and bone marrow.
· Multisystem disease usually affects children initially in the first 3 years of life, with hepatomegaly, splenomegaly, lymphadenopathy, and eczematoid skin eruptions.
· Localized lesions occur frequently in the skull, ribs, and long bones.
What is Erdheim-Chester Disease?
· Clonal systemic proliferation of histiocytes, commonly having a foamy component containing Touton giant cells
· Rare adult form with bone and lung involvement
· BRAF mutations present
· Diagnosis relies on strict correlation between clinical features, imaging, and histology.
What is Rosai-Dorfman Disease?
· Sinus histiocytosis with massive lymphadenopathy.
· Rare, seen most frequently in young black people.
· It is characterized by lymphadenopathy, fever, leukocytosis, and hypergammaglobulinemia.
· Has been considered a reactive process (possibly sustained by a viral infection)
· Recent demonstration of somatic mutation in some cases challenged this hypothesis.
· Rosai–Dorfman disease can occur in individuals with germline mutations of the SLC29A3 gene and in autoimmune lymphoproliferative syndrome type 1a.
· Nodes show marked sinusoidal dilatation by macrophages with foamy cytoplasm and plasma cells. There is often evidence of engulfment of lymphocytes by hyperplastic histiocytes.
· Immunohistologic staining demonstrates strong positivity for S‐100.
· Although the disease can follow a protracted course, recovery is usually spontaneous and total.
