RAB29-NUCKS1 유전자재배열을 동반한 공격성NK세포백혈병: 증례보고
Aggressive NK Cell Leukemia with RAB29-NUCKS1 Gene Rearrangement: A Case Report
연세대학교 의과대학 세브란스병원 진단검사의학과1, 연세대학교 의과대학 용인세브란스병원 병리과2, 명지병원 진단검사의학과3, 연세대학교 의과대학 용인세브란스병원 진단검사의학과4
Department of Laboratory Medicine1, Yonsei University College of Medicine, Severance Hospital, Seoul; Department of Pathology2, Yonsei University College of Medicine, Yongin Severance Hospital, Yongin; Department of Laboratory Medicine3, Myongji Hospital, Goyang; Department of Laboratory Medicine4, Yonsei University College of Medicine, Yongin Severance Hospital, Yongin, KoreaCorrespondence to:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lab Med Online 2023; 13(1): 22-26
Published January 1, 2023
Copyright © The Korean Society for Laboratory Medicine.
Aggressive natural killer (NK) cell leukemia (ANKL) is a rare type of leukemia that occurs due to systemic neoplastic proliferation of NK cells and mainly involves peripheral blood, bone marrow (BM), the liver, and the spleen. It is rare but more prevalent in Asians than in other ethnic populations . Epstein-Barr virus (EBV) is commonly found in leukemic cells in patients with ANKL, suggesting an association between EBV and the pathogenesis of ANKL . In patients with ANKL, various chromosomal abnormalities such as del(6)(q21q25) or del(11q) can be detected . Here, we report a case of a patient with ANKL and a novel
A 62-year-old man with a history of asthma was scheduled to undergo excision for a mass on his back. He visited the outpatient clinic in the plastic surgery department at Yongin Severance Hospital in November 2021 for a preoperative evaluation. His complete blood counts were as follows: white blood cell count, 206.94×109/L (abnormal cells: 84%, segmented neutrophils: 5%, lymphocytes: 9%, monocytes: 2%, nucleated RBC: 1/100 white blood cells); hemoglobin level, 126 g/L; and platelet count, 68×109/L (Fig. 1A). Based on his results, he was referred to the hematology department and hospitalized for a BM biopsy and further evaluations. He complained of a weight loss of 5 kg over the last 6 months; however, there were no signs of coagulopathy, hemophagocytic syndrome, and multi-organ failure. His serum lactate dehydrogenase level had increased to 381 IU/L; nevertheless, the findings of other blood test results were not remarkable. EBV polymerase chain reaction (PCR) of whole blood was negative. Computed tomography of the abdomen and pelvis revealed splenomegaly (length: 24 cm). Computed tomography scans did not show any abnormal lymph node enlargement or neoplasms in the chest and neck. A BM aspiration smear showed 56.0% abnormal cells with atypical nuclei, distinct nucleoli, clumped chromatin, and basophilic cytoplasm containing azurophilic granules (Fig. 1B). BM biopsy showed approximately 50% interstitially scattered CD56+ and granzyme B focal+ atypical NK cell proliferation (Fig. 1C, D). Flow cytometry (Beckman Coulter, Miami, FL, USA) using a BM specimen showed an abnormal population (85.3% of total nucleated cells) with the following phenotype: CD3-, diminished cytoplasmic CD3 expression (cytoplasmic CD3 dim+), CD5-, CD7+, CD8+, CD16+, CD38+, and CD56+ (Fig. 2).
Figure 1. Peripheral blood smear and bone marrow findings and genetic test results of the patient. (A) Abnormal cells resembling large granular lymphocytes (Wright-Giemsa stain, ×1,000). (B) Abnormal cells with irregular nuclear folding, clumped chromatin, distinct nucleoli, and lightly basophilic cytoplasm containing azurophilic granules in the bone marrow aspiration smear (Wright-Giemsa stain, ×1,000). Proliferation of neoplastic cells showing positive staining for (C) CD56 (×200) and (D) granzyme B (×200) in the bone marrow biopsy section. (E) G-banded karyogram showing 46,XY,t(5;7)(p15.3;q11.2). (F)
RAB29-NUCKS1gene rearrangement detected in the RNA fusion panel test. (G) Identification of the gene fusion breakpoint between exon 5 of the RAB29gene (reference transcript: NM_003929.2) and exon 2 of the NUCKS1gene (NM_022731.4) by using Sanger sequencing.
Figure 2. Flow cytometry findings of the patient. Abnormal lymphoid cells highlighted in red exhibited the CD3-, cCD3 dim+, CD5-, CD7+, CD8+, CD16+, and CD56+ phenotypes at diagnosis.
Abbreviations: cCD3, cytoplasmic CD3; SSC, side scatter.
Next-generation sequencing and karyotype analysis were performed using the BM aspirate. A custom next-generation sequencing panel targeting 497 genes associated with hematologic neoplasms was performed using the NextSeq 550Dx platform (Illumina, San Diego, CA, USA), and a matched skin biopsy sample from the patient was used to differentiate somatic and germline variants. A somatic variant of
There were three possible diagnoses associated with NK cells: ANKL, extranodal NK/T-cell lymphoma, nasal type, and chronic lymphoproliferative disorder of NK cells. The neoplastic cells of ANKL typically show the following phenotype: CD2(+), surface CD3(-), CD3-epsilon(+), CD5(-), and CD56(+) and positivity for cytotoxic molecules. CD16 is frequently positive (75%) in ANKL but usually negative in extranodal NK/T-cell lymphoma . In our patient, flow cytometry of the BM specimen showed CD3(-), CD5(-), CD16(+), and CD56(+). There was no definite involvement of the upper aerodigestive tract (the nasal cavity, nasopharynx, paranasal sinuses, and palate). Furthermore, given the clinical presentation and laboratory findings, chronic lymphoproliferative disorder of NK cells, which is clinically indolent and usually associated with diminished CD56 expression, could be ruled out. Therefore, he was diagnosed with ANKL and transferred to another hospital for a second opinion. Then, he began receiving chemotherapy consisting of vincristine, cyclophosphamide, and prednisolone.
Compared with classical cytogenetics, a target RNA panel allows accurate and more comprehensive identification of rare gene fusions . However, it is important to exclude analytical errors and the possibility of chimeric RNAs in normal tissues to interpret the RNA fusion panel results . We confirmed
There are no recurrent cytogenetic abnormalities including leukemic fusion in ANKL.
In conclusion, to our knowledge, this is the first report of a case of ANKL with a
Conflicts of Interest
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