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. MYC is altered in many malignancies including lymphomas and some solid tumours. Although the role of MYC dysregulation has been studied extensively in B-cell lymphomas, 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 (MYCR). 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. 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. Restaging evaluation showed leucocytosis (white blood cell [WBC] count 12 0 9 10/l), anaemia (haemoglobin 97 g/l), normal platelet count (316 9 10/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 9 10/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 9 10/l, haemoglobin 132 g/l and platelet count 180 9 10/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 Correspondence