Aggressive natural killer cell leukemia mimicking interstitial lung diseases with the activation of the mitogen-activated protein kinase pathway

Aggressive natural killer (NK) cell leukemia (ANKL) is a rare form of leukemia with an aggressive clinical course. It commonly involves the peripheral blood, bone marrow, liver, and spleen but rarely involves the lungs. We report a 36 year-old woman who presented with pulmonary lesions we suspected to be interstitial lung disease on an imaging study. A lung biopsy showed extensive lymphoid infiltrate growing along pre-existing alveolar septa without destroying the alveolar spaces. Further workup revealed hepatomegaly, borderline splenomegaly, and multiple lymphadenopathies. Her laboratory tests showed leukocytosis, anemia, thrombocytopenia, abnormal liver enzymes, and elevated lactate dehydrogenase. A bone marrow (BM) aspirate smear revealed many intermediate to large lymphocytes with dispersed chromatin, basophilic cytoplasm, and some azurophilic granules. A BM biopsy showed hypercellularity with interstitial lymphoid infiltrate in a background of trilineage hematopoiesis and histiocytosis with hemophagocytosis. Immunohistochemical studies performed on both the lung and BM biopsies showed the neoplastic cells to be positive for CD2, CD3, CD7, CD56, granzyme B, phosphor-MAPK (pMAPK), EBER (Epstein-Barr Virus-encoded small RNA) by in situ hybridization; they were negative for CD4, CD5, CD8, CD30, LMP1, and phospho-STAT3 (pSTAT3). A flow cytometry analysis of the BM aspirate identified a population of atypical lymphocytes with the NK cell phenotype. Molecular studies were negative for T-cell receptor gene rearrangements, and the neoplastic cells displayed a complex karyotype. The patient responded initially to chemotherapy but died of multiorgan failure two months after the diagnosis. We present a case of ANKL mimicking interstitial lung disease with the activation of MAPK pathway.