Mantle cell lymphoma, previously known as diffuse small cleaved cell lymphoma and centrocytic lymphoma , is a low-grade non-Hodgkin lymphoma. It is a mature B cell neoplasm, consisting of mature B cells which have exited the bone marrow. Traditionally, MCL is known to be a very aggressive NHL despite its low-grade nature, and is considered to be incurable with current therapies. It typically afflicts the older population, with the median age of presentation of patients ranging from 60-68 . MCL has shown a clear male predisposition as well, with the male-to-female ratio of 3:1 . It is a rare lymphoma, which accounts for 8% of all NHL . Racially, it has a higher incidence in Caucasians than African Americans and Asians .
The initiating oncogenic mutation for MCL would be t(11,14)(q13;32), which concerns the oncogene bcl-1 on 11q13 and the immunoglobulin heavy chain gene on 14q32. Bcl-1 encodes for cyclin D1, a cell cycle protein regulating the progression of the cell from G1 phase to S phase . The translocation juxtaposes the bcl-1 gene next to the immunoglobulin heavy chain gene, which is highly active in mature B cells. This results in the overexpression of cyclin D1 in MCL cells, leading to disrupted cell cycle entry. It should be noted that t(11,14)(q13;32) itself alone does not have full oncogenic potential; oncogenicity is acquired through the gaining of additional genetic lesions and increased genomic instability. The WHO 2016 Classification has delineated 2 subtypes of MCL based on the clinical presentation and the cell of origin of the malignant clone, which in turn is differentiated by the expression status of the transcription factor Sex Determining Region Y-Box 11 (SOX11) . In classical MCL (cMCL), a more aggressive clinical course with general lymphadenopathy is common. De novo SOX11 expression is noted, which prevents virginal B cells from entering the germinal centre and participating in GC reactions. cMCL cells therefore have minimal IGHV mutation and are naïve-like as they have not experienced GC events. In contrast, the non-nodal subtype of MCL (nnMCL) has a more indolent course, and their presentation is leukaemic rather than with strong lymph node involvements. Splenomegaly is also common. SOX11 negativity allows the nnMCL cells to experience germinal centre reactions, with the resultant cells having a higher number of IGHV mutations resembling memory B cells. nnMCL cells also have a more stable karyotype and further progression into more malignant variants is less likely than cMCL . nnMCL accounts for about 10-20% of all MCL cases .
Histologically, MCL consists of small to medium sized lymphoid cells with irregular nuclei . Chromatin is condensed with inconspicuous nucleoli, hence its low-grade classification. Large cells are uncommon . Cytologically, variants of MCL include classic, small cell, blastoid and pleomorphic. Cytological variations of MCL is associated with disease severity and survival, with blastoid and pleomorphic variants having a worse prognosis . Blastoid MCL has a higher genomic instability with of additional mutations, such as tumour suppressor gene TP53 . It should be noted that blastoid transformation can occur from milder cytological variants through the gaining of additional genetic lesions, or from other haematological malignancies including chronic lymphocytic leukaemia (CLL), though the molecular events leading to such transformation is distinctive process known as MCL-variant Richter transformation. Lymph node involvements in MCL can be classified as distinctive patterns, namely mantle zone, nodular and diffuse by the extent of germinal centre disruption .
Upon staining, the neoplastic cells show positive staining for pan-B antigens, including CD19, CD20, CD22 with surface immunoglobulins IgM and IgD, in line with its B cell nature. Aberrant positivity of CD5, a T cell marker, is noted. Staining with cyclin D1 and cyclin D1/BCL1 is positive. Rare presentations of cyclin D1-negative MCL may yield negative cyclin D1, but positive stain on cyclin D2 or D3 . Negative stains include CD10 and 23, with the latter differentiating MCL from small lymphocytic lymphoma .
Most patients present with late stage MCL, with 70% presenting with stage IV disease. Generalized, extensive lymphadenopathy and splenomegaly are common findings. A high proportion of patients also presents with extranodal involvements, with lymphoma cells spreading to mucosa-associated lymphatic tissues such as Waldeyer’s ring. GI involvement is also common, which mainly manifests in stomach and colon. Occasionally, incidental cases of lymphomatous polyposis are discovered when the patient undergoes colonoscopy . Bone marrow involvement is also extremely common. Leukaemic presentation can also be found in patients with nnMCL, or in late-stage patients with MCL cells spillover to peripheral blood. Pancytopenia may be observed if marrow failure occurs due to extensive bone marrow involvement. B symptoms, the triad of unintentional weight loss, night sweat and fever, may also be reported by the patient.
Treatment for MCL remains diversified, but chemotherapy remains the mainstay of treatment. Considerations for regimens include patient age and risk stratification. The Mantle cell International Prognostic Index (MIPI), devised by the European MCL Network, is commonly used for the formulation of risk-adapted therapy. MIPI identifies patient age, Eastern Oncology Group (ECOG) Performance Status, LDH status and WBC count as independent prognostic factors that impact patient survival, and stratifies the patient pool into 3 categories: MIPI low-risk, MIPI median-risk and MIPI-high risk. The recent incorporation of proliferative index Ki67 takes into account of the proliferative activity of the neoplastic cells in vivo, and further improves the prognostic accuracy of MIPI as biological MIPI (bMIPI) . A higher proliferative index (>20%) is associated with a worse prognosis. For asymptomatic patients with an indolent disease presentation, or in the low-risk group, an observational approach should be adopted to avoid the initial use of aggressive therapy. Clinical interventions should be adopted when the patient progresses. For these patients, a commonly used regimen would be cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone. An anti-CD20 monoclonal antibody, most commonly rituximab, can also be added (RCHOP). RCHOP combination therapy yields a satisfactory overall response rate as high as 96%, with a complete remission (CR) of 48% . For elderly patients, a milder approach should be considered in the view of cardiac toxicities of anthracycline-containing regimens and slower marrow recovery. Rituxumab-bendamustine (RB) is commonly used due to the less severe side effects of bendamustine, such as haematological toxicities and alopecia . Although less agents are used in the RB regimen when compared with RCHOP, it is shown that the efficacy of RB is similar to RCHOP, reaching an ORR of 89% . Other alkylating agents such as chlorambucil, and the purine analogue fludarabine are shown to be effective against MCL as well. For patients with a high tumour burden or patients in a palliative settting, hydroxyurea can be given for cytoreduction. For younger patients, an aggressive therapeutic approach should be considered to establish CR. R-HyperCVAD alternating with high dose cytarabine and methotrexate, or other similar modified regimens including Nordic Protocol, is considered the treatment of choice. However, severe haematological toxicity may lead to marrow suppression, and make marrow recovery difficult. It is shown that stem cell transplantation, including autologous and allogenic HSCT, improves survival outcomes . Younger patients that can tolerate total body irradiation and myeloablative conditioning should considered HSCT for consolidation.
Despite promising statistics is shown for different first line treatments of MCL, a high proportion of patients will stop responding to treatment and progress. A collection of studies has shown that the progression free survival (PFS) is 7-20 months, with the longest study reported 26 months. Relapse after attaining CR is extremely common as well.10-year OS for MCL is reported to be as low as 5-10% . Curative therapies for MCL remains lacking and more research is needed to develop novel agents. However, with respect to the latest researches concerning mantle cell lymphoma, both epidemiological and therapeutic research seems to be heavily biased towards Western Caucasian population. In particular, epidemiological information on Asian patients, especially Chinese, are lacking, with only 1 paper by Chim et al. providing details on the epidemiological features of Chinese MCL patients. Constructing an accurate epidemiological background on Chinese patients is paramount to provide a better picture for further clinical research. Therefore, the clinical and epidemiological data of MCL patients processed at Queen Mary Hospital is organized and presented in this paper.
Due to administrative constraints between different hospital clusters, only QMH. Biopsy records with a diagnosis of MCL established by the Department of Pathology of Queen Mary Hospital during the period of 2003-2018 were recovered. A total of 83 biopsy records were reviewed. Among repeating records, the actual number of diagnoses made in the period is 65. Further selection of included patients was made, since some of these patients were non-Chinese or had limited information on the Clinical Management System (CMS) available. Exclusion criteria includes non-Chinese ethnicity, concurrent diagnosis of any non-haematological malignancy, concurrent diagnosis of any haematological malignancy that is not therapy-related, and incomplete medical records.