| Abstract|| |
Aggressive natural killer-cell leukaemia is a rare aggressive form of natural killer-cell neoplasm. We report a case of a 40-year-old male who presented with jaundice, raised blood counts,generalised lymphadenopathy and hepatosplenomegaly. The diagnosis was established by flow cytometric analysis of bone marrow aspirate. The patient, however, succumbed to his illness within 2 weeks of starting chemotherapy. To the best of our knowledge, this is the third reported case from India.
Keywords: Aggressive natural killer, hepatosplenomegaly, natural killer
|How to cite this article:|
Jacob PM, Nair RA, Nair AA. Aggressive natural killer-cell leukemia: Classical presentation of a rare disease. Indian J Pathol Microbiol 2014;57:483-5
|How to cite this URL:|
Jacob PM, Nair RA, Nair AA. Aggressive natural killer-cell leukemia: Classical presentation of a rare disease. Indian J Pathol Microbiol [serial online] 2014 [cited 2020 Jun 6];57:483-5. Available from: http://www.ijpmonline.org/text.asp?2014/57/3/483/138787
| Introduction|| |
Aggressive natural killer-cell leukemia (ANKL) is a highly aggressive disease, which has been recognized as a distinct clinical entity only in the last 20 years.  It is a rare malignancy accounting for <1% of all non-Hodgkin lymphoma in Europe and North America, being more prevalent in Asia and Latin America.  ANKL often affects young patients and is characterized by relative resistance to standard chemotherapy, association with Epstein-Barr virus (EBV) infection,  and a dismal prognosis with a median survival of <2 months.  Patients with the disease generally have hepatomegaly, splenomegaly, lymphadenopathy and bone marrow involvement by large granular lymphocytes. Owing to the rarity and often rapid fatal course of this disease, no randomized prospective clinical trials have been performed, and the therapeutic principles are based on case reports and small retrospective cohorts of patients. 
| Case report|| |
This is a case of a 40-year-old gentleman, autorickshaw driver by profession and a chronic alcoholic. He gave a history of generalized weakness, yellowish discoloration of eyes and abdominal distension of 1-month duration. On examination, he had icterus. He had (1 cm size) cervical, axillary and inguinal lymph node enlargement. No skin lesions were seen. Per abdomen, ascites was present with hepatosplenomegaly. His blood counts were as follows: Hemoglobin = 10.8 g%, total leukocyte count = 63,000 cells/mm 3 , and platelet count = 51 × 10 9 /L. His blood picture showed 80% atypical cells with moderate cytoplasm, some showing fine granules, indented to irregular nuclei and some showing nucleoli [Figure 1]a and b. The cytoplasmic granules were negative with myeloperoxidase stain [Figure 1]c. Among the other investigations, his erythrocyte sedimentation rate was 63 mm/h (normal range = 0-20 mm/h), total bilirubin = 3.98 mg/dL (normal range = 0-1.0 mg/dL), direct bilirubin = 1.5 (normal range = 0-0.3 mg/dL), indirect bilirubin = 2.48 (normal range = 0.2-0.8 mg/dL). Total protein = 8.5 g/dL (normal range = 6.4-8.2 g/dL). His serum lactate dehydrogenase was 585 U/L (normal range = 313-618 U/L). His HBsAg, anti-HIV and anti-HCV tests were negative. An ultrasound abdomen revealed gross ascites, liver enlarged to 16.5 cm with minimum coarse echotexture and spleen enlarged to 18.5 cm. His bone marrow was sample was sent for flow cytometry. For flow cytometric immunophenotyping, the cells were stained within 24 h of collection using a whole blood lyse wash technique. Panel of directly conjugated monoclonal antibodies comprised of CD20, CD5, CD2, CD3, CD5, CD7, CD4, CD8, CD25, CD34, CD10, CD19, CD33, CD45, CD56, CD11b and CD38. Six parameter, four color immunophenotyping was performed using a FACS Calibur (Becton Dickinson, San Jose, CA, USA). Minimum 10,000 events were acquired using leukocyte common antigen gating. Data was analyzed with CellQuest Pro software (Becton Dickinson,San Jose, USA). The R1 (in red) gated population (50%) expressed CD56, CD7, CD2, CyCD3 and CD38 (dim). They were negative for CD20, CD19, CD10 and CD33. Among the T-cell markers, they were negative for CD5, CD3 (surface), CD4, CD8 and CD25. A small subset of tumor cells, the R2 (in green) gated population (15%) co-expressed CD8 in addition to the above mentioned antibodies [Figure 1]d. Based on the morphological features, acute clinical presentation and immunophenotype a diagnosis of ANKL was made. The patient was started on chemotherapy, but his liver functions rapidly deteriorated and he succumbed to hepatic failure within 2 weeks.
|Figure 1: (a) Giemsa ×200 peripheral smear. (b) Some of the tumor cells show prominent nucleoli (inset). (c) Myeloperoxidase ×1000 bone marrow aspirate showing tumor cells. Cytoplasm shows fine granules, which are myeloperoxidase negative. (d) Flow cytometric dot plots: The R1 (in red) gated populati on (69%) were CD56+, CD2+, CD7+, CyCD3+ and CD38 (dim+). They were CD4–, CD8–, CD5–, CD3–, CD20–. The R2 (in green) gated subpopulati on (7%) coexpressed CD8 in addition|
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| Discussion|| |
About 150 cases have been reported in the literature, and the largest series is 22 cases analyzed by Suzuki et al.  Among those 150 cases, 107 (71%) showed splenic involvement and 109 (72%) had liver involvement. Major clinical manifestations included hepatosplenomegaly, jaundice and liver function disturbances and very rarely, splenic rupture.  From India, there are two individual case reports, one from Gujarat, in a 13-year-old boy by Patel et al.  and one from Delhi by Gogia et al.  Coming to the differential diagnosis, ANKL must be distinguished from T-cell large granular lymphocyte leukemia and indolent NK-cell lympho-proliferative disorder. These three entities are close differential diagnoses on morphology and immunophenotype, but the clinical picture is entirely different as the latter two are indolent in nature. Extranodal NK-/T-cell lymphoma, nasal type (ENKTCL-N) with advanced stage is also a highly aggressive neoplasm with a dismal clinical outcome, yet the relationship and boundary between ENKTCL-N with advanced stage and ANKL remains unclear.  Although, it has been suggested that ANKL may merely represent the leukaemic manifestation of extranodal NK-/T-cell lymphoma, the following features are distinctive for the former: Younger median age by more than a decade; high frequency of hepatosplenic and bone marrow involvement; low frequency of cutaneous involvement; disseminated disease with uniformly fatal outcome; and frequent expression of CD16. , A recent array-based comparative genomic hybridization study indicates that loss of 7p and 17p and gain of 1q are frequent in ANKL, which are different from ENKTCL-N,  but the genetic changes still need to be proven by larger case-control studies. ANKL involving the liver and spleen can mimic the hepatosplenic T-cell lymphoma, which also presents with jaundice and massive hepatosplenomegaly, but the neoplatic cells in hepatosplenic T-cell lymphomas are commonly observed in sinusoids and express T-cell makers, have rearranged TCR genes and have no relation with EBV infection. Systemic EBV positive T-cell lympho-proliferative disease (LPD) and ANKL also have some similarities: The fulminant clinical manifestations, presence of EBV in proliferating cells and systemic hemophagocytosis. However, systemic EBV + T-cell LPD is more common in children and monoclonal for T-cell receptor gene rearrangement. 
| Conclusion|| |
It is often more challenging to identify phenotypically abnormal T- or NK-cells than abnormal mature B-cells by flowcytomery. In cases where we suspect a T-/NK-cell lympho-proliferative disorder on morphology, we first start with a limited panel such as CD20, CD3, and CD56 with CD45 gating, as we did in this case, and then run the remaining antibodies. In addition, the classification of T- and NK-cell neoplasms is less well - established than that of B-cell neoplasms, due to the rarity of these cases and often requires assimilation of information from multiple sources. Flow cytometric features that are most suspicious for a T-/NK-cell leukemia include loss of a T-cell marker such as CD7 or CD5, and rarely CD3 (surface). As per Gujral et al., nodal T-/NK-cell neoplasms constitute approximately 10% of all NHLs, while T-/NK-cell leukemia's constitute 4% of all mature lymphoid neoplasms presenting as leukemia in India.  T-cell receptor gene rearrangement studies help to clinch the diagnosis in difficult cases.
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Rekha A Nair
Department of Pathology, Regional Cancer Centre, Trivandrum - 695 011, Kerala
Source of Support: None, Conflict of Interest: None