Anaplastic lymphoma kinase (ALK)‐negative anaplastic large cell lymphoma with MYC rearrangement

Anaplastic large-cell lymphoma (ALCL) can be further classified into anaplastic lymphoma kinase-positive (ALK+) and ALK-negative types. ALK-negative ALCL is indistinguishable from ALK+ ALCL by morphology, but lacks ALK translocation or protein expression. Patients with ALK+ ALCL have an overall better prognosis than patients with ALK-negative ALCL, in part because they are younger, but also likely due to biological factors because ALK-negative ALCL is a molecularly heterogeneous entity.1, 2 MYC is altered in many malignancies including lymphomas and some solid tumours.3 Although the role of MYC dysregulation has been studied extensively in B-cell lymphomas,4-8 studies of MYC aberrations in T-cell lymphomas are very limited. A few reports suggest that T-cell lymphomas often have increased MYC copy number, but rarely carry MYC rearrangement (MYC-R).9-12 To date, only three cases of T-cell lymphoma harbouring MYC-R have been reported in the literature. All three cases were ALK+ ALCL and these neoplasms arose in children who had an aggressive clinical course.13-15 The presence or importance of MYC-R in ALK-negative ALCL has not been reported. Here, we describe two patients with MYC-R ALK-negative ALCL, one of whom also had concurrent dual specificity phosphatase 22 (DUSP22) rearrangement (DUSP22-R). Patient 1, a 58-year-old woman presented to another hospital with a neck mass and B symptoms (fever, night sweats and weight loss). Full blood count (FBC) data were not available. Computerised tomography (CT) showed multiple large lymph nodes involving the cervical, axillary, mediastinal, iliac, inguinal regions and subcutaneous nodules. Excisional biopsy of a neck lymph node revealed ALK-negative ALCL (Fig 1). Using immunohistochemistry and flow cytometry immunophenotyping, the lymphoma cells were positive for CD2, CD3, CD4, CD7 (subset), CD8 (dim), CD30 (uniform and strong), T-cell receptor (TCR) alpha/beta, MYC (10–20%) and were negative for ALK, CD5, CD25, TCR gamma/delta and epithelial membrane antigen (EMA). Proliferation Index by Ki67 was ~80%. Fluorescence in situ hybridisation (FISH) analysis revealed MYC-R. Flow cytometric analysis of the peripheral blood showed aberrant T cells, supporting involvement by lymphoma. Polymerase chain reaction (PCR) analysis of the peripheral blood showed monoclonal T-cell receptor beta (TRB) and T-cell receptor gamma (TRG) rearrangements. Bone marrow examination was negative for lymphoma. The patient was diagnosed with Stage IV ALK-negative ALCL, in leukaemic phase. She received two cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy with partial response, but her lymphoma soon progressed. The patient was transferred to our hospital for further treatment. Re-staging evaluation showed leucocytosis (white blood cell [WBC] count 12·0 × 109/l), anaemia (haemoglobin 97 g/l), normal platelet count (316 × 109/l) and a markedly increased serum lactate dehydrogenase (LDH) level (1112 iu/l). Serology testing for human T-cell leukaemia virus (HTLV) I/II was negative. Blood and bone marrow were positive for lymphoma by morphology and flow cytometry immunophenotyping. Positron emission tomography (PET)/CT revealed bilateral fluorodeoxyglucose-avid lymphadenopathy in the cervical and inguinal regions. She was treated with etoposide, methylprednisolone, high-dose cytarabine and cisplatin (ESHAP) for three cycles. Although a rapid initial response was achieved, her disease progressed again with widespread disease involving the spine, nasopharynx, mid skull base, calvarium and skin. Cerebrospinal fluid examination showed lymphoma cells by morphology and flow cytometry immunophenotypic analysis (Fig 1). The patient’s condition deteriorated rapidly with marked leucocytosis (WBC count 28·8 × 109/l with 82% lymphoma cells) and a markedly increased serum LDH level (14 313 iu/l). She died from disease at 9 months after initial diagnosis. Patient 2, a 63-year-old man presented to another hospital with persistent right leg pain and an inguinal mass. His FBC was normal: WBC count 5·8 × 109/l, haemoglobin 132 g/l and platelet count 180 × 109/l. He did not have any B symptoms. Excisional biopsy of an inguinal lymph node showed ALK-negative ALCL (Fig 2). By immunohistochemistry and flow cytometry, the lymphoma cells were positive for CD2, CD4 (subset), CD30 (uniform and strong), CD45 and MYC (60%), and were negative for ALK, CD3, CD5, CD7, CD8, CD25 and EMA. The Proliferation index by Ki67 was ~95%. FISH analysis showed increased MYC copy number, MYC-R and DUSP22-R. TCR gene rearrangement was not assessed. Bone marrow examination was negative for lymphoma. He was diagnosed with Stage III ALK-negative ALCL and was treated with CHOP with a partial initial response. However, after six cycles of CHOP, PET/CT showed an increasing standardised uptake value (SUV) in the right external iliac lesion. The patient was transferred to our hospital for further management. Re-staging evaluation showed a normal FBC (WBC count 7·7 × 109/l, haemoglobin 141 g/l and platelets count 189 × 109/l) and mildly increased serum LDH level (656 iu/l). Serology testing for HTLV I/II was not performed. A PET/CT revealed multiple large lymph nodes involving the right external iliac, superficial inguinal and retroperitoneal regions, consistent with disease progression. He was treated with brentuximab vedotin every 3 weeks, and after 11 cycles PET/CT showed no evidence of lymphoma. Subsequently, he underwent autologous stem cell transplant (SCT) in the 12th month after diagnosis and remained in complete remission for 3 years before being lost to follow-up. He died 53 months after initial diagnosis (41 months after SCT). The cause of death is unknown. Studies of MYC aberrations in T-cell lymphomas are very limited. A few reports suggest that T-cell lymphomas often have increased MYC copy number. In a small series of patients with Sezary syndrome, 75% of patients had MYC gains.10 Similarly, gains of the chromosome 8q24 locus are frequent in cases of peripheral T-cell lymphoma not otherwise specified.11 Chromosomal amplification of MYC also has been detected in adult T-cell leukaemia/lymphoma.9 In contrast, MYC-R in T-cell lymphomas is rare. In a study of 108 T- and NK-cell lymphoma cases (including four ALK+ ALCL cases), all neoplasms with MYC expression lacked MYC-R.12 To date, only three T-cell lymphoma cases harbouring MYC-R have been reported in the literature and all of them were children with ALK+ ALCL who had an aggressive clinical course. Monaco et al.15 reported a 13-year-old boy with the small cell variant of ALK+ ALCL whose disease progressed despite multiple regimens of chemotherapy and SCT. The patient developed a terminal leukaemic phase, and died 6 months after initial presentation. Spectral karyotyping showed t(2;5)(p23;q35) and t(3;8)(q26.2;q24) and FISH analysis confirmed MYC-R. Moritake et al.14 reported a 11-year-old girl with ALK+ ALCL (common morphological pattern) bearing t(2;5)(p23;q35) and t(8;17)(q24;q25). She failed various combinations of intensive chemotherapy and died 5 months after diagnosis. Southern blot analysis identified MYC-R in this neoplasm. Lastly, Liang et al.13 reported a 9-year-old boy with ALK+ ALCL (common morphological pattern) whose disease widely relapsed during chemotherapy and required aggressive chemotherapy, total body radiation and SCT. He subsequently remained in complete remission for >1·5 years. Conventional cytogenetic analysis showed t(2;5)(p23;q35) and ins(6;8)(q23;q24q23) and FISH analysis confirmed MYC-R. Whole chromosome painting suggested that a novel rearrangement partner for MYC was located on chromosome 6q. This is the first report of MYC-R in patients with ALK-negative ALCL. Both patients shared some common clinical features. They were elderly, had advanced stage disease at diagnosis and experienced rapid disease progression despite aggressive treatment. However, patient 1 had a more aggressive clinical course: leukaemic phase at diagnosis with B symptoms, widespread disease despite multiple lines of chemotherapy, and death at 9 months after initial diagnosis. Pathologically, both patients showed large anaplastic cells resembling the common pattern of ALK+ ALCL cases. Both neoplasms were positive for CD2 and CD4, and were negative for CD5, CD25 and EMA. Patient 1 differed from patient 2 in being positive for CD3, CD7 (subset) and CD8 (dim). The association between CD8 and CD3 expression in patient 1 is consistent with the results of a recent study in which CD8 expression was associated with higher relapse rate in patients with ALK+ ALCL, but not in patients with ALK-negative ALCL.16 The neoplasms in both patients harboured MYC-R, but a high level of MYC expression was only identified in patient 2. Therefore, as shown by others,12 MYC expression does not seem to correlate with MYC-R in ALK-negative ALCL. As has been shown in patients with diffuse large B-cell lymphoma (DLBCL), the MYC-R partner genes in DLBCL can be either immunoglobulin (IG) or non-IG genes, and the type of partner has prognostic importance.7 It would be of interest to know the partner(s) of MYC in ALCLs. As chromosomal analyses were not performed in the present two patients we report, the chromosomal loci of the MYC partner genes are unknown. In the three children with MYC-R ALK+ ALCL reported in the literature, the partner genes are also unknown, but the involved chromosomal loci were 3q26.2, 17q25 and 6q23.13-15 It seems likely that the gene located on 17q25 is ALK lymphoma oligomerisation partner on chromosome 17 (ALO17), as this gene has been identified in translocations involving MYC in ALK+ ALCL cases. Although both patients we report had aggressive disease, patient 2 had a somewhat better clinical course and longer survival. It is uncertain if the better course of patient 2 is related to the presence of DUSP22-R. DUSP22-R has been shown in up to 30% of ALK-negative ALCL and is absent in ALK+ ALCL.17 The overall survival of patients with DUSP22-R ALK-negative ALCL is reported to be good, similar to that of patients with ALK+ ALCL and superior to that of patients with other types of ALK-negative ALCL. However, some patients with DUSP22-R can present with high-risk clinical features and have an aggressive course, including central nervous system (CNS) relapse.18 In conclusion, we report two patients with ALK-negative ALCL associated with MYC-R. Both patients were elderly and presented with advanced stage. Their disease progressed rapidly during chemotherapy and required aggressive treatment. The authors have disclosed that they have no relationships with, or financial interests in, any commercial companies pertaining to this article. Mahsa Khanlari collected some data and wrote the manuscript; Guilin Tang performed the FISH analysis and edited the manuscript. Suyang Hao and Yun Gong provided some pathology specimens. Roberto N. Miranda and Cameron C. Yin edited the manuscript. Wei Xie collected some data. Shaoying Li, Pei Lin, Swaminathan Iyer and Francisco Vega provided expert opinion. L. Jeffrey Medeiros analysed data, provided expert opinion, and edited the manuscript. Jie Xu analysed the data and wrote the manuscript.