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| OJHAS Vol. 20, Issue 3:
(July-September 2021) |
Case Report
EBV Positive Aggressive NK-Cell Leukemia
Authors:
Ankitha Hebbar, Assistant Professor, Department of Pathology, Melaka Manipal Medical College, MAHE, Manipal, Udupi District- 576104,
Ruchee Khanna, Associate Professor, Department of Pathology, Kasturba Medical College, MAHE, Manipal, Udupi District- 576104,
Sushma Belurkar, Associate Professor, Department of Pathology, Kasturba Medical College, MAHE, Manipal, Udupi District- 576104,
Shubham Varshney, Junior Resident, Department of Pathology, Kasturba Medical College, MAHE, Manipal, Udupi District- 576104,
Aradhana Harrison, Assistant Professor, Department of Pathology, Melaka Manipal Medical College, MAHE, Manipal, Udupi District- 576104,
Sindhura Lakshmi KL, Associate Professor, Department of Pathology, Kasturba Medical College, MAHE, Manipal, Udupi District- 576104.
Address for Correspondence
Dr. Ankitha Hebbar,
Assistant Professor,
Department of Pathology,
Melaka Manipal Medical College,
MAHE, Manipal,
Udupi District- 576104,
Karnataka, India.
E-mail: ankitha.hebbar@manipal.edu.
Citation
Hebbar A, Khanna R, Belurukar S, Varshney S, Harrison A, Lakshmi SKL. EBV Positive Aggressive NK-Cell Leukemia. Online J Health Allied Scs.
2021;20(3):14. Available at URL:
https://www.ojhas.org/issue79/2021-3-14.html
Submitted: Jul 19,
2021; Accepted: Oct 5, 2021; Published: Oct 31, 2021 |
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Abstract: Introduction: Aggressive NK cell leukemia (ANKL) is a rare malignant lymphoproliferative disorder of mature NK cells associated with poor overall survival. Significant variation in the morphology of the neoplastic cells on peripheral smear makes it diagnostically challenging. Case Report: A 54-year old male presented with fever and icterus since 15 days. Peripheral smear showed 64% abnormal cells. Flow cytometry showed positivity of abnormal cells for CD2, CD3, CD7, CD56 and HLA-DR. EBV DNA tested positive by Real-time PCR. A final diagnosis of aggressive NK-cell leukemia was made. Conclusion: The diagnosis of aggressive NK cell leukemia is usually delayed due to the non-specific clinical symptoms and varied morphology. However, early recognition and diagnosis of the disease is important, as the introduction of combined chemotherapy and allogenic hematopoietic stem cell transplantation can help achieve complete response and potential cure.
Key Words: EBV, ANKL, Flow cytometry. |
Introduction:
Aggressive NK cell leukemia (ANKL) is a very rare malignant lymphoproliferative disorder of mature NK cells seen more often in Eastern Asian populations. It is associated with Epstein-Barr viral infection in 90% of the cases. (1) The affected population includes young to middle aged adults with a median age of 42 years. There is no standard treatment described for this malignant neoplasm with a high mortality and rapidly fatal clinical course. (2) Here we describe the case of a middle aged man with ANKL presenting with fever, malaise and yellowish discolouration of sclera.
Case Report:
A 54 years old man who was a known case of diabetes mellitus and recently diagnosed septum secundum ASD came with complaints of fever, malaise, fatigue and yellowish discolouration of sclera since 10 days with two episodes of non-bilious vomiting. On examination, icterus was present and systemic examination revealed hepatosplenomegaly. No skin lesions were observed on physical examination.
Blood cell counts on admission were as follows: Haemoglobin-13.3g/dl, WBC count-3.8x103/µl, Neutrophils-61%, Lymphocytes-33%, Monocytes-06%, and Platelet count-77 x103/µl. Biochemistry reports showed direct bilirubin-4.07 mg/dl, aspartate transaminase- 124 IU/L, alanine transaminase-79 IU/L, alkaline phosphatase-278U/L, mildly elevated C-reactive protein-5.91mg/L with normal renal function test results. Anti-Dengue IgM tested positive by ELISA.
His platelet counts continued to drop and the leucocyte counts started escalating by the 10th day of admission to 33.2x103/µl with a differential count of neutrophils-20%, lymphocytes-12%, monocytes-04% and abnormal lymphoid cells-64% on peripheral smear. The abnormal lymphoid cells were irregular in shape with large nuclei, open chromatin and moderate amount of basophilic cytoplasm, few of them showing azurophilic granules. Flow cytometry and bone marrow studies were advised in view of presence of abnormal lymphoid cells.
CT scan of the brain and chest was done which showed inhomogenous opacities in the left middle zone of lung and no specific lesions in the nose or paranasal sinuses.
8-colour flow cytometric immunophenotyping was performed on peripheral blood using the instrument BD FACS CANTOII and the FACS DIVA V8.0 software. Bright CD45 and low to moderate side scatter events were gated as abnormal lymphoid cells. The abnormal lymphoid cells were seen to exhibit positivity for CD2, cytoplasmic CD3, CD7, CD56 and HLA-DR and negative expression for T-cell markers: surface CD3, CD4, CD8; B-cell markers: CD19, CD79a, CD10; myeloid and stem cell markers: cMPO, CD13, CD33, CD36, CD117, CD34, CD14, CD64 and CD1a.
Real-time PCR for Epstein-Barr virus tested positive. Based on the clinical, immunophenotypic and morphologic features, a diagnosis of aggressive NK-cell leukemia was offered. However, the bone marrow examination was not performed as the patient developed electrolyte imbalance, worsening renal functions and finally he succumbed to a cardiac arrest. Specific treatment for ANKL was not administered.
Discussion:
ANKL is classified under mature NK-cell neoplasms in the WHO 2017 classification of tumours of haematopoietic and lymphoid tissues. Chronic lymphoproliferative disorder of NK cells, EBV-positive T-cell and NK-cell lymphoproliferative diseases of childhood and extranodal NK/T-cell lymphoma (ENKL), nasal type are the other neoplasms listed under the mature NK-cell neoplasms. (3) ANKL is an EBV-associated NK-cell neoplasm which is thought to arise de-novo, like our case, or from pre-existing chronic active EBV infection which may transform to ANKL in younger patients. Less than 300 cases have been reported so far, most commonly from the Eastern Asian regions like China and Japan. (1, 3)
The affected population includes young and middle aged adults with no clear gender predilection. The most common presenting symptoms are fever, jaundice, lymphadenopathy, hepatosplenomegaly and cytopenias. Hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC) as secondary complications are frequently reported. (4) Ishida F et al. in 2010 retrospectively studied 41 cases of ANKL and described 3 types of ANKL cells based on morphology and compared the survival of patients based on various different treatment regimens. (5) The neoplastic cells morphologically may resemble large granular lymphocytes or may be seen as atypical cells with irregular nuclei, basophilic cytoplasm and cytoplasmic azurophilic granules. The immunophenotype of ANKL cells resemble that of normal NK-cells in expressing CD2, CD7, cytoplasmic CD3, CD16, CD56 and being negative for surface CD3 and CD57. (6) A similar morphology was seen in the peripheral smear of our patient which were considered as abnormal lymphoid cells and the flow cytometry findings showed positive expression of NK cell markers and negative expression for T-cell markers which helped in establishing a diagnosis.
There is a significant overlap in the features of ANKL and systemic involvement by ENKL, nasal type. The difference between the two can be established by the sites of involvement, genetic mutations and CD16 immunoexpression. ANKL has a younger median age of onset and usually involves the liver, spleen, peripheral blood and bone marrow while ENKL is known to involve the nasal mucosa and skin and rarely the blood and bone marrow. The expression of CD16 is higher in ANKL (75%) when compared to ENKL which usually shows negative expression. A significant difference was identified between ANKL and ENKL by array based comparative genomic hybridization: loss of 7p, 17p and gain of 1q seen frequently with ANKL, while loss of 6q was more often seen with ENKL. Also, the EBV infected ANKL cells secrete high levels of IFN-γ which prevents apoptosis and improves cell survival. (6, 7) Takahashi et al. in their study, distinguished the cases of ANKL from ENKL by the degree of peripheral blood and bone marrow involvement; tumour cells in excess of 30% in the blood were considered ANKL. (7) The absence of skin and nasal mucosal involvement in our case along with the presence of 64% abnormal cells on peripheral smear favoured a diagnosis of ANKL over ENKL though he belonged to an older age group.
Tang YT et al. in a retrospective study with 113 cases of ANKL identified patients with subacute and classical clinical course and by sequencing, noted frequent mutations in the JAK/STAT pathway in both the types and in TP53 gene in the ones with classical course. (8) Complex cytogenetic abnormalities and absence of clonal T-cell receptor gene rearrangements are frequently seen in most cases of ANKL. (9) ANKL manifests with a rapidly aggressive clinical course with a median survival of less than 2 months irrespective of the treatment. Owing to the rarity of this aggressive neoplasm, no randomized prospective clinical trials have been performed so far and the principles of therapy are largely based on case reports and retrospective analysis. Although no standard chemotherapeutic regimen is described for this leukemia, L-asparaginase containing regimens are found to have better outcome leading to better survival and remission. Allogenic hematopoietic stem cell transplantation (HSCT) after chemotherapy is recommended to achieve complete remission. The disease activity and remission status can be monitored by measuring the EBV DNA levels. (8, 10)
To the best of our knowledge, this rare neoplasm is reported in the Indian subcontinent in only 3 case reports so far by Patel et al. (11), Gogia et al. (12) and Jacob PM et al (13). This is the fourth case reported from India.
Conclusion:
Although the diagnosis of ANKL can be challenging and delayed owing to its rarity, non-specific clinical symptoms and varied morphological features, a careful look at the morphology along with flow cytometry can help reach at an early diagnosis. Accurate early diagnosis is important as the disease has a rapid clinical course and can be fatal as in our case which may be prevented by newer approaches of therapy with L-asparaginase, HSCT along with intense chemotherapy. An insight into the molecular rearrangements and mutations may help in developing specific targeted therapies which may improve the prognosis of this catastrophic disease.
References:
- Ishida F. Aggressive NK-cell leukemia. Front. Pediatr. 2018;6:1-5.
- Jin X et al. Aggressive natural killer cell leukemia or extranodal NK/T cell lymphoma? A case with nasal involvement. Diagn. Pathol. 2017;12:1-5.
- Chan JKC, Jaffe ES, K. Y.-H. WHO classification of tumors of hematopoietic and lymphoid tissues (Revised 4th edition) IARC. In WHO classification of tumors of hematopoietic and lymphoid tissues (Revised 4th edition) IARC (eds. Swerdlow, S. H. et al.) 353-4 (International Agency for Research on Cancer, Lyon, 2017).
- Hu Y and Wang J. Aggressive natural killer cell leukemia: A case report. Int. Med. Case Rep. J. 2017;10:389-391.
- Ishida F, Kim WS, Ko YH et al. Aggressive NK Cell Leukemia (ANKL): Experience with 34 Patients and Therapeutic Potentials of L-Asparaginase and Allogeneic Hematopoietic Cell Transplantation - A Japan-Korea Multicenter Study for ANKL (ANKL07). Blood 2010;116:3091.
- Nazarullah A, Don M, Linhares Y et al. Aggressive NK-cell leukemia: A rare entity with diagnostic and therapeutic challenge. Hum. Pathol. Case Reports 2016;4:32-37.
- Takahashi E et al. Clinicopathological analysis of the age-related differences in patients with Epstein-Barr virus (EBV)-associated extranasal natural killer (NK)/T-cell lymphoma with reference to the relationship with aggressive NK cell leukaemia and chronic active EBV inf. Histopathology 2011;59:660-671.
- Tang YT et al. Aggressive NK-cell leukemia: Clinical subtypes, molecular features, and treatment outcomes. Blood Cancer J. 2017:7
- Li C et al. Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia. Transl. Res. 2014;163:565-77.
- Boysen AK, Jensen P, Johansen P et al. Treatment of Aggressive NK-Cell Leukemia: A Case Report and Review of the Literature. Case Rep. Hematol. 2011;1-3.
- Patel AP, Ghatak SB PJ. Long term survival in aggressive NK cell leukemia. Indian Pediatr 2010;47:807-8.
- Gogia A, Kakar A, Byotra SP, Bhargav M. Aggressive natural killer cell leukaemia: a rare and fatal disorder. J Assoc Physicians India. 2010;58:702-4.
- Jacob PM, Nair RA, Nair AKAR. Aggressive natural killer-cell leukemia: Classical presentation of a rare disease. Indian J. Pathol. Microbiol. 2014;57:483-485.
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