ABSTRACT
Mantle cell lymphoma (MCL) is a subtype of mature B-cell non-Hodgkin lymphoma (NHL). Most cases exhibit CCDN1/IGH translocation; however, reports indicate that amplification of the fusion gene is extremely rare. A 72-year-old male patient diagnosed with an MCL blastoid variant was referred to us. Amplified CCDN1(11q13)/IGH(14q32.3) fusion genes were observed in 75% of the interphase nuclei of the patient. We present the first case of blastoid variant MCL with multiple IGH/CCND1 fusion signals by interphase fluorescence in situ hybridization. Our patient exhibited an aggressive course and passed away on the second day of treatment.
Keywords: Mantle cell lymphoma, IGH/CCND1, fusion, amplification, fluorescence in situ hybridization
Introduction
Mantle cell lymphoma (MCL) is a subtype of mature B-cell non-Hodgkin lymphoma (NHL), accounting for approximately 7% of adult NHL. Mantle cell lymphoma, which is mostly seen in older men, exhibits clinical and genetic heterogeneity (1). Mantle cell lymphoma tends to disseminate to the bone marrow, blood, lymphoid tissues, and extranodal sites, particularly the gastrointestinal tract (2). Morphologically, there are three types of MCL: classical, pleomorphic, and blastoid variants (1). Most cases carry t(11;14)(q13;q32)/CCND1/IGH, which juxtaposes the IGH locus with the CCND1 gene, resulting in CCND1 overexpression. Deregulation of CCND1 expression increases the G1–S transition in the cell cycle and induces tumor development (3).
More than half of the cases with IGH/CCND1 translocation have additional chromosomal rearrangements, particularly: del(1p), +3, del(6q), del(7q), +7, -8, del(9p), +12, del(13q), del(17p) +18, + mar (4). Moreover, MCL cases have shown abnormalities in the TP53 and ATM genes (5).
We report a case of blastoid variant mantle cell leukemia with multiple IGH/CCND1 fusion signals detected by interphase fluorescence in situ hybridization (FISH). To our knowledge, this is the first case showing amplification of the IGH/CCND1 gene in blastoid variant mantle cell lymphoma.
Case Presentation
A 72-year-old male patient was diagnosed with bladder papillary urothelial carcinoma. A 2×2 cm lymphadenopathy was detected in the left supraclavicular area. The complete blood count showed leukocytosis (White blood cell 21.5×109/L; normal range 4.5-11×109/L) and anemia (Hemoglobin 10.6 g/dL; normal range
12-16 g/dL). A computed tomography scan of the abdomen revealed suggestive lymphoma, thickening of the terminal ileum wall, as well as paraaortic and mesenteric lymphadenopathy. Only weight loss and constitutional type B symptoms were present, with no reports of fever or night sweats. The patient was referred to the hematology clinic. However, he initially refused all the recommended strategies; until a few weeks later, the patient consented to a colonoscopy and a biopsy at the suspicious tumor site. Pathology revealed a blastoid variant of the MCL in a biopsy of the right colon. Immunohistochemical evaluation showed that tumor cells were positive for CD20, CD5,
BCL-2, and cyclin D1 in only 40% of cells. BCL-6 was positive and negative for SOX 11, LEF-1, CD10, CD3, and CD23 staining (Figure 1). The Ki-67 proliferation fraction was determined to be 80%, which is associated with a poor prognosis.
The patient, who was found to have bone marrow involvement on positron emission tomography and was evaluated as stage IV according to the Ann-Arbor staging system, was referred to our department of medical genetics. Fluorescence in situ hybridization analyses were performed using an IGH/CCND1 plus translocation, dual-fusion probe (Cytocell, LPH 072) for CCND1/IGH rearrangements on the bone marrow aspirate sample. CCND1(11q13)/IGH(14q32.3) translocation and amplified fusion genes with three to six yellow signals were observed in 75% of the interphase nuclei (Figure 2A). Additional interphase nuclei FISH analysis was performed using an MYC(8q24) break-apart probe (Cytocell, LPH 010), ATM(11q22.3) (Cytocell, LPH 011), and TP53 (17p13.1) deletion probe (PrimeFISH, LS 17-003) (Figure 2B-D). They revealed a 23% heterozygous deletion in the TP53 gene, a 100% homozygous deletion in the ATM gene, and no amplification or rearrangement in the MYC region. Chromosome analysis, which was performed using the G-banding technique on short-term (24 hours) cultured bone marrow cells, showed 47,XY,+mar [2]/46,XY [5]. The patient was planned to undergo R-CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) chemotherapy but died on the second day of rituximab treatment because of tumor lysis syndrome.
Discussion
Mantle cell lymphoma is caused by the abnormal proliferation of mature B cells. In the clinical course of the disease, the blood, bone marrow, and other systems, especially the gastrointestinal tract, might be involved (2). Both conventional cytogenetics and FISH analyses are commonly performed on patients. Our patient, who had gastrointestinal MCL involvement, underwent these analyses. MYC copy number changes and rearrangements are widely observed in aggressive variants of MCL and are associated with a poor prognosis. However, there was no rearrangement or copy number change in the MYC gene in our patient (6-9). In addition, ATM and/or TP53 gene deletions are expected in these cases. ATM is a tumor suppressor gene, and its deletion is thought to be effective in the onset and progression of the disease. Schaffner et al. (10) demonstrated that ATM gene deletion was found in 58% (7/12) of MCL patients. Similarly, TP53 gene deletions are frequently observed in MCL cases and are associated with aggressive diseases. It was observed in 29 of 176 (16%) MCL patients that were unresponsive to intensive chemoimmunotherapy (9,10). We found a 23% heterozygous deletion in the TP53 gene and a 100% homozygous deletion in the ATM gene in our patient. We believed that these changes in the patient could have contributed to his early death following the diagnosis.
To the best of our knowledge, this is the first report of amplification of the IGH/CCND1 gene in the blastoid variant of mantle cell lymphoma. In the literature, five cases of IGH/CCND1 fusion amplification have been presented. The diagnosis for them was one each of classical type MCL, pleomorphic type MCL, anaplastic multiple myeloma, and two cases of plasma cell leukemia (1,5-7,11).
The first case reported was a 58-year-old female patient with splenomegaly and lymphocytosis. She received an MCL diagnosis after splenectomy, and FISH analysis detected IGH/CCND1 fusion amplification. The patient had a complex karyotype and a heterozygous deletion in the TP53 gene region. The patient began treatment with chlorambucil and prednisolone, but died within 6 months, despite the average life expectancy of MCL cases being 2.5-4.5 years (5).
The second case was a 64-year-old male patient with bone pain, splenomegaly, and enlarged lymph nodes on the left side of his neck. He was diagnosed with plasma cell leukemia on bone marrow examination and had a complex karyotype and amplification of the IGH/CCND1 fusion gene. He died very soon after the initiation of intensive chemotherapy treatment (6).
The third case was a 78-year-old male patient with night sweats, fatigue, dyspnea, and palpable masses in the groin and arm. Doctors diagnosed the patient with MCL, observing intense lymphoid cell infiltration in the bone marrow. The bone marrow cytogenetic examination detected a complex karyotype including t(11;14), and the FISH analysis detected IGH/CCND1 fusion amplification in approximately 90% of the interphase cells. The patient also displayed monosomy 13 and MYC gene amplification. TP53, ATM, and BCL2 gene deletion, rearrangement, and variation analyses were normal. Despite aggressive chemotherapy and radiotherapy, the patient deceased within approximately 15 months (1).
The fourth case was a middle-aged adult with dyspnea, bruising, anemia, and leukopenia. The patient’s bone marrow was hypercellular, and 90% of the cells were composed of plasma cells. Her diagnosis was plasma cell leukemia. Fluorescence in situ hybridization analysis observed CKS1B (1q) amplification, heterozygous deletion of 13q, and IGH/CCND1 fusion amplification, but conventional cytogenetic analysis failed. Although the patient received combination chemotherapy, she died within approximately 1 year (7).
The other case from the literature was a male patient with weight loss and low back and rib cage pain. The tomography revealed lytic lesions, and the bone marrow aspirate revealed 46.4% pleomorphic plasma cells, leading to the diagnosis of multiple myeloma. Conventional cytogenetics resulted in normal. Fluorescence in situ hybridization analysis revealed IGH/CCND1 fusion amplification, CKS1B amplification, 13q deletion, and TP53 gene deletion. This case also had a poor clinical course (11).
Here we report the sixth patient with IGH/CCND1 fusion amplification reported in the literature and the third one with mantle cell lymphoma. To the best of our knowledge, this is the first case of blastoid variant MCL with an amplified IGH/CCND1 fusion gene. It is important to present cases with rare molecular cytogenetic abnormalities to enhance our understanding of their possible effects on prognosis and contribute to the literature.
Ethics
Informed Consent: Informed consent was obtained.
Authorship Contributions
Surgical and Medical Practices: E.G., H.H.E., A.T., Concept: E.G., Design: E.G., Data Collection or Processing: E.G., H.H.E., A.T., Analysis or Interpretation: E.G., S.S., Literature Search: E.G., S.S., Writing: E.G., S.S.
Conflict of Interest: The authors have no conflicts of interest to declare.
Financial Disclosure: The authors declare that this study has received no financial support.
