Epstein-Barr virus-positive diffuse large B cell lymphoma, not otherwise specified, carrying a t(19;22)(q13;q11) translocation

Kyosuke Yamaguchi1  Yasushi Kubota1,2 Chiyuki Kishimori3  Hitoshi Ohno3,4  Keisuke Kidoguchi1
Haruna Kizuka-Sano 1  Atsujiro Nishioka 1  Hiroo Katsuya1  Toshihiko Ando1  Shinya Kimura 1

Received: 7 November 2019 / Accepted: 10 December 2019
Springer-Verlag GmbH Germany, part of Springer Nature 2019

Dear Editor,
Translocation t(19;22)(q13;q11) is rare in hematological malignancies, and the significance of this chromosomal ab- normality is unknown. Here, we report the first case of Epstein-Barr virus (EBV)–positive diffuse large B cell lym- phoma (DLBCL), not otherwise specified (NOS), with t(19;22)(q13;q11).
A 74-year-old man, attending a dermatology out-patient clinic for intermittently occurring itchy erythematous papular lesions, was admitted to our hospital because of sore throat, tongue ulcers, and lymph node (LN) swelling. Physical exam- ination showed LN swelling of the cervical, axillary, and in- guinal LNs without “B” symptoms. Laboratory examination revealed elevated levels of LDH (350 IU/L) and sIL-2R (1584 U/mL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed hypermetabolic lesions in the oropharynx and multiple LNs, as well as several skin lesions. Histopathological examination of a biopsy spec- imen from the right axillary LN showed diffuse proliferation of lymphoma cells with large nuclei and centroblastic features (Fig. 1a). Immunohistochemistry revealed that the neoplastic cells were positive for CD20, CD79a, CD30, and MUM1, and negative for CD10 and BCL6, suggesting a non-germinal cen- ter B cell origin. Both EBV-encoded small RNA in situ hy- bridization and EBV latent membrane protein were positive,
* Yasushi Kubota [email protected]

1 Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
2 Department of Transfusion Medicine, Saga University Hospital, Saga, Japan
3 Tenri Institute of Medical Research, Tenri, Japan
4 Department of Hematology, Tenri Hospital, Tenri, Japan

and Ki-67 index was approximately 80% (Fig. 1b–h). Based on these findings, the patient was diagnosed with EBV- positive DLBCL, NOS.
Chromosomal analysis revealed the karyotype, 46,XY,t(19;22)(q13.1;q11.2), in 20/20 of metaphases exam- ined (Fig. 1i). Fluorescence in situ hybridization (FISH) anal- ysis was performed using break-apart probes for the BCL3 and IgL genes, as described previously [4]. Both probes showed split signals; however, BCL3/IgL fusion was considered neg- ative (Fig. 1j–k). Bone marrow analysis revealed hypocellular marrow with no lymphoma cells, while G-banding showed a 46,XY karyotype in all analyzed cells, suggesting that the translocation was not constitutional. The patient was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and achieved partial response after two cycles; however, an ulcerative lesion was noted in the hard palate and progressed. The lesion penetrated the nasal cavity and enlarged further after five cycles of R-CHOP (Fig. 1l–m). Biopsy of the ulcer revealed EBV-positive DLBCL. Salvage therapy (rituximab, etoposide, methylpred- nisolone, high-dose cytarabine, cisplatin: R-ESHAP) was started in place of R-CHOP.
There are no known disease-specific chromosomal or ge- netic abnormalities associated with EBV-positive DLBCL, NOS [1]. Unlike EBV-negative DLBCL, genetic aberrations involving BCL2, BCL6, MYC, MDM2, MDM4, and TP53 are infrequent (5–11%), and it is thought that oncogenic effects of EBV may replace the role of chromosomal abnormalities in lymphomagenesis [3]. The present case was CD30-positive and carried a s ingle chromosomal abnormality, t(19;22)(q13;q11), which are both factors potentially contrib- uting to treatment resistance. CD30 is observed in approxi- mately 40% of EBV-positive DLBCL and associated with poor prognosis [5]. A previous study reported that t(19;22)(q13;q11) is a variant of t(14;19)(q32;q13), and is associated with the BCL3/IgL fusion [2]. In the present case, no BCL3/IgL fusion was detected by FISH analyses; however,

Ann Hematol

G-banding FITC/Rhodamine/DAPI FITC Rhodamine
Fig. 1 a Hematoxylin and eosin staining of a section showing diffuse infiltration of abnormal lymphocytes with a high nuclear/cytoplasmic ratio (original magnification × 400). b–g Immunohistochemical analyses demonstrated that the lymphoma cells were positive for CD20 (b), CD30 (c), MUM1 (d), and EBER (e), and negative for CD10 (f) and BCL6 (g); original magnification, × 400. h Anti–Ki-67 immunostaining. i G-band karyotype showing 46,XY,t(19;22)(q13;q11) [20/20]; arrows indicate ab- normal chromosomes. j–k FISH analysis using break-apart probes

(MetaSystems) for the BCL3 and IgL genes, showing that the transloca- tion breakpoint is distal from the BCL3 and IGL genes. Both the BCL3 and IgL probes generated split signals; however, the BCL3 break-apart probe (j) generated a weakly positive green signal on the der(19) chro- mosome, and the IGL break-apart probe (k) generated a weakly positive green signal on the der(22) chromosome. (l–m) Hard palate ulcer after five cycles of R-CHOP therapy (l) and three cycles of R-ESHAP therapy (m)the translocation t(19;22)(q13.1;q11.2) may have contributed to lymphomagenesis in our case, as it was detected in all lymphoma cells examined. Identification of the fusion gene and elucidation of its function is warranted.

Compliance with ethical standards

Informed consent was obtained from the patient.

Conflict of interest The authors declare that they have no conflict of interest.

References

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