“Triple hit” <i><scp>SOX</scp>11<sup>−</sup></i>, <scp><i>MME</i></scp><sup>+</sup>, <scp><i>TP53</i></scp> mutated high‐grade pleomorphic mantle cell lymphoma
Authors: Preetesh Jain, Guilin Tang, Shaoying Li, Michael Wang
Journal: American Journal of Hematology (2020)

A 61-year-old woman presented with a four-week history of breathing difficulty, fatigue, edema and left breast mass. She had performance status of three, pedal edema, bilateral neck lymphadenopathy (>5 cm), oral thrush, diminished breath sounds on left chest and a large soft tissue swelling involving left breast and left anterior chest wall. Laboratory studies showed hemoglobin 9.2 g/dL, leukopenia (WBC 2.4 K/μL) with left-shifted granulocytes and monocytosis, and platelet count of 157 K/uL. She had elevated LDH (2925 IU/L) and low serum albumin 3.1 g/dL. Chest X-ray showed collapse of left lung, massive pleural effusion. The CT scan showed bulky cervical lymphadenopathy, mediastinal mass (6.1 cm × 4.4 cm) with extension into the anterior chest wall and large left pleural effusion, a 13 cm left chest wall mass, contiguous with bulky mediastinal lymphadenopathy and bulky retroperitoneal, pelvic, mesenteric and inguinal lymphadenopathy. A PET-CT confirmed these findings (Image 1I). Further work up was initiated. Thoracentesis confirmed presence of large monoclonal kappa+ CD5 + MME+ B cells. Bone marrow (BM) aspiration and biopsy with cytogenetic analyses were performed. Bone marrow was extensively involved with pleomorphic mantle cell lymphoma (MCL) cells (Image 1A-C) showing the cytomorphology of aggressive MCL cells, which were CD5 dim, and MME positive. Complex karyotype was detected (Image 1D) and FISH studies were positive for IGH/CCND1 and deletion of TP53. Chest wall mass biopsy showed pleomorphic MCL with similar morphology as seen in BM. Immunohistochemical stains were positive for CD5 (dim), MME, CD20, PAX5, MYC, BCL2, BCL6, CyclinD1 and negative for CD3, SOX11, and MUM1. The Ki-67 proliferative index was 90%. Epstein-Barr virus-encoded small RNA (EBER) was negative. Flow cytometry confirmed monoclonal kappa light chain expressing MCL cells with same immunophenotype as in the BM. Note, FISH analyses revealed IGH/CCND1 (Image 1E), IGK/MYC (Image 1F-G) and BCL6 rearrangement (Image 1H) with an unknown partner gene on 11q13; TP53/CEP17 dual-color probes revealed one copy TP53 deletion and trisomy 17 in 47% of cells, and the BCL2 break apart probe was negative for BCL2 rearrangement. The patient was given one cycle of R-CHOP but she developed multiple complications (severe sepsis, pneumonia, worsening pleural effusion needing bilateral chest tube insertion, respiratory distress requiring intubation and ventilator support. She developed pulmonary emboli and progressive disease within a week after chemotherapy and remained in the intensive care unit for 3 weeks. After discharge, she was bed bound, oxygen dependent, severely deconditioned and malnourished. We discussed regarding starting her on acalabrutinib as a salvage, however considering the patient's worsening clinical picture and very poor prognosis, the patient and family decided to transfer to hospice facility. This patient had an ultra-high risk MCL variant with a constellation of poor risk features (pleomorphic histology,1 complex karyotype including MYC rearrangement and P53 deletion, CD10+,2 Ki-67 90%). The SOX11 negative MCL generally exhibits an indolent clinical course3 but the presence of high-risk features have likely subdued the impact of SOX11 negativity. Triple-hit MYC-BCL6-CCND14 with deleted TP53 is a very rare and high risk category of MCL. These patients are uncommon and demonstrate a poor response to various therapies. If feasible, CAR-T therapy5 might be beneficial in such patients. The authors do not have any disclosures/conflicts of interest related to this manuscript. P.J., G.T., S.L. and M.W. collected and analyzed pathology and wrote the paper. P.J. and M.W. managed the patient. All authors have reviewed and approved the manuscript.