A 7-year-old boy developed recurrent fever and hypersensitivity to mosquito bites one year ago. The symptoms persisted for three months and then resolved without any treatment.
During the two months before admission, the patient showed no obvious emergence of recurrent fever, with his highest temperature being 39℃. Physical examination showed that the left cervical lymph node was enlarged having a diameter of 1.2 cm and hepatosplenomegaly was also detected. After admission, the biopsy of the enlarged lymph node was performed. Four months later, the patient presented with fever and hepatosplenomegaly again, and a peripheral blood lymphocyte smear was conducted this time. The child did not possess any immunodeficiency.
The results of laboratory tests conducted after patient admission are listed in Table 1. Blood tests showed a reduction in all three blood cell lines. The NK cell activity was lower than the normal value, whereas the other indexes related to hemophagocytic syndrome, such as the levels of soluble CD25 and CD163 were significantly higher than the normal. The content of serum ferritin was shown to be significantly increased. The EB virus encoded DNA was also detected in the peripheral blood.
Table 1
The results of laboratory tests of peripheral blood.
Items | Value |
White blood cell | 1.2×109/L |
Hemoglobin | 68g/L |
Platelet | 15×109/L |
Absolute count of neutrophils | 0.03×109/L |
NK cell activity | 15.82% |
Soluble CD25 | 44000pg/ml |
CD163 | 2249ng/ml |
Ferritin | 1471.3ng/ml |
EBV-DNA loading | 2.34×104 |
The biopsy of the lymph node showed that the paracortical area of the lymph node was hyperplastic and the marginal and medullary sinuses were open (Fig. 1a). Lymphocytes vary in size and are interspersed with a small number of immunoblasts and plasma cell (Fig. 1b). Furthermore, the hyperplasia of histiocytes could be detected in the opened lymphatic sinuses, and the phenomenon of histiocyte swallowing red blood cells was distinctly observed (Fig. 1c).
Immunohistochemistry showed that CD20 positive cells were predominantly located in the follicular area (Fig. 2a). CD3 and CD5 was positive in the interfollicular and paracortical areas (Fig. 2b, 2c). The ratio of CD4: CD8 T cells was around 2:1 (Fig. 2d, 2e). CD56 was positive in a small number of scattered cells (Fig. 2f). CD30 was positive in transformed large cells (Fig. 2g). The proliferation index of Ki67 in the interfollicular zone was found to be around 10% (Fig. 2h). In situ hybridization showed that the cells in the interfollicular zone were Epstein-Barr virus encoded RNA (EBER) positive (Fig. 2i). The gene rearrangement detection showed that TCRγ and IgH were negative.
Combined with clinical data, the pathological diagnosis of the lymph node was analysed as systemic chronic active EBV infection-T/NK cell phenotype (CAEBV-T/NK) with hemophagocytic lymphohistiocytosis (HLH). After diagnosis, the patient accepted chemotherapy and reached complete remission (CR).
Four months after being discharged from the hospital, the patient developed fever and hepatosplenomegaly again, and underwent a peripheral blood separated lymphocyte smear.
The smears were found to be densely packed with lymphoid cells, and the features of these lymphoid cells were medium in size, uniform in shape, and irregular in nucleus (Fig. 3a). Degeneration was observed in some cells. Immunohistochemistry showed striking positivity in lymphoid cells for CD3ε (Fig. 3b), granzyme B (Fig. 3c) and CD56 (Fig. 3d), and in situ hybridization showed EBER was positive (Fig. 3e).
Combined with the clinical characteristics, the aggressive clinical course, the systemic symptoms and the neoplastic NK cells in the peripheral blood, the pathological diagnosis was aggressive natural killer cell leukemia (ANKL).
In time, the gene mutation detection was performed, and a UNC13D gene heterozygous mutation was detected in the patient as well as his father.
Follow-up: The patient underwent allogeneic hematopoietic stem cell transplantation and had CR currently.