35 month-old boy. Hemophagocytic syndrome.
Extensive heterogeneous bone marrow hypermetabolism involving axial skeleton as well as the proximal and distal appendicular skeleton. The most active lesion is in left calcaneus with SUVmax 10.0. There is no lytic or blastic lesion on the low-dose CT. Moreover, there are multiple focal active lesions in the thymus, lungs, left parotid gland and likely in the right thyroid lobe. The SUVmax of the most active lung lesion is 5.1 (14mm). There are two FDG-avid lesions in the retroperitoneum most likely adenopathies.
Diffuse mild and homogeneous spleen hypermetabolism.
Hemophagocytic lymphohistiocytosis 2nd Lymphoproliferative disease related to chronic EBV
Hemophagocytic lymphohistiocytosis (HLH) is a disorder related to activation of cytotoxic T cells, natural killer (NK) cells and macrophages. This activation results in uncontrolled hypercytokinemia. Henter et al. established diagnostic criteria (see Table 1).
| Table 1
| Diagnosis of HLH can be established if A or B is fullfilled
| A. A molecular diagnosis consistent with HLH
B. Five of the eight following criteria
- Peripheral cytopenia (at least 2 lineages)
- Hypertriglyceridemia (fasting, >3 mmol/L) and/or hypofibrinogenemia (<1.5 g/dL)
- Hemophagocytosis in BM, spleen, LN or liver
- Ferritin > 500 µg/L
- Low or absent NK cell activity
- Increased soluble CD25 concentration (a chain of soluble interleukin-2 receptor) greater than 2400 U/mL
HLH can be primary or secondary. The primary is an autosomal recessive form and includes several genetic disorders. Primary HLH occurs in children and may be triggered by infection.
Secondary HLH is associated with multiples conditions: infections, malignancy and autoimmune diseases.
They are the most common trigger, in particular EBV and CMV. EBV HLH is likely related to clonal proliferation and activation of infected T cells.
Mycobacteria, bacteria and fungus are also described in literature as triggers.
Hematologic malignancies are the most frequent cause of secondary HLH. T-cell or NK cell lymphomas or leukemias, diffuse large B-cell lymphoma and Hodgkin lymphoma are the most common. Solid tumors are rarely described.
Many autoimmune diseases can trigger secondary HLH including SLE, mixed connective tissue, dermatomyositis and systemic sclerosis. Macrophage activation syndrome typically refer to children with juvenile idiopathic arthritis or other rheumatologic conditions.
One key point is likelihood of an underlying malignant disease increases with age. Prevalence of malignancy has been reported in children and adolescents around 8% in comparison to 68% in patients older than 60 years.
In the present case, the main diagnostic hypothesis was leukemia/lymphoma. There was no lytic lesion usually seen in Langerhans histiocytosis. There was no primary tumor to support neuroblastoma. Moreover, the activity of the lesions was greater than expected in neuroblastoma. Infectious disease (TB, viral disease) was kept in the differential diagnosis.
This patient had a bone marrow biopsy showing abundance of macrophages and extensive hemophagocytosis. There was no leukemia or histiocytosis infiltration. Biopsy of a lung nodule was also performed, demonstrating polymorphic lymphoproliferation associated with EBV.
The final diagnosis in this case was a Hemophagocytic lymphohistiocytosis caused by lymphoproliferative disease associated with chronic EBV. The vast majority of similar cases have been reported in Asia.
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Rosado et al.: Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 2013 Jun;139(6):713-27
Janka et al.: Hemophagocytic syndromes--an update. Blood Rev. 2014 Jul;28(4):135-42
Smith et al.: The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. Int J Clin Exp Pathol. 2014 Aug 15;7(9):5738-49
Lehmerg et al.: Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015 Aug;100(8):997-1004
Campo et al.: Hemophagocytic Lymphohistiocytosis in Adults. Hematol Oncol Clin North Am. 2015 Oct;29(5):915-25