The often aggressive nature of the tumor may be one of the factors why almost 70% of patients present in late stage of the disease, which is characterized by fatigue, systemic symptoms and the appearance of generalized lymphadenopathy and splenomegaly [2] [9]. Splenomegaly is often massive [2], while aberrant WBC count may be seen, either as markedly high leukocytosis or pancytopenia [10]. An indolent type of MCL is seen in approximately 10-15% of cases, with minimal lymphadenopathy and splenomegaly [4].

Initial laboratory studies should encompass a complete blood count (CBC), levels of LDH and basic biochemical parameters (renal function tests, alkaline phosphatase, hepatic enzymes, serum electrolyte levels and serum protein electrophoresis) [3], while imaging studies such as computed tomography (CT) of the chest, pelvis and abdomen are equally important in the diagnostic workup [2]. If possible, fluorodeoxyglucose positron emission tomography (FDG/PET) should be performed [2]. To make the diagnosis, biopsy of the tissue that is suspected to be infiltrated with malignant cells (most commonly the lymph node, but also bone marrow or peripheral blood) is necessary [2]. Immunophenotyping is used to determine presence of CD5+ and CD20+ and absence of CD10 and Bcl6 [2]. Moreover, to confirm the characteristic t(11;14) translocation that causes overexpression of cyclin D1 seen in virtually all mantle cell lymphomas, fluorescent in situ hybridization (FISH) is the recommended diagnostic procedure [4]. The increased expression of the transcription factor SOX11 is also mentioned as a diagnostic marker for MCL, but also as a distinguishing feature from diffuse large B-cell lymphoma, in which SOX11 expression is normal [10], whereas high Ki-67 proliferation index, mutations of p53 and p16 deletions are important markers of more aggressive forms of the disease [2].

Some studies suggest that asymptomatic elderly patients should not receive immediate therapy [10] but treatment should be initiated as soon as the diagnosis is confirmed. Various strategies exist depending on the overall condition of the patient, presence of comorbidities and age [4]. The standard therapeutic approach consists of the R-CHOP regimen (rituximab + cyclophosphamide, doxorubicin, vincristine and prednisone), which is effective in 80% of patients, but approximately 25% of patients relapse within a few years [4]. In patients who are able to tolerate an aggressive approach, R-CHOP together with cytarabine is recommended. A progression-free survival (PFS) was shown to be > 5 years under such circumstances [4]. If patients respond to therapy, evaluation for possible ASCT (allogenic stem cell transplant) is performed [11]. In fact, nonmyeloablative allogeneic HCT has been shown to be of significant benefit, especially in those who experience relapses or those who are refractory to therapy [6]. Additionally, various second-line and third-line agents have been recommended for use [4]. Bortezomib, temsirolimus, lenalidomide, ibrutinib, and bendamustine are all potential agents that are currently in various phases of clinical trials, but their long-term effects and efficacy compared to standard regimens is yet to be confirmed [10] [12].

In the past decades, median overall survival rarely exceeded more than 2.5 years, but the introduction of novel therapeutic strategies has somewhat improved patient outcomes, increasing the overall survival to > 5 years [4]. Other studies report that median survival of MCL patients ranges between 1 year in those with aggressive disease to > 10 years in those who develop an indolent form of the disease [8]. In recent years, the mantle cell lymphoma international prognostic index (MIPI) has been developed and consists of four factors: age, Eastern Cooperative Oncology Group (ECOG) performance status, levels of LDH and white blood cell (WBC) count [1]. On the basis of this prognostic index, patients can be classified into low, intermediate and high-risk groups [1], which is now being used to determine the therapeutic approach. Unfortunately, many patients are diagnosed in advanced stages of the disease, leading to a significantly reduced overall survival [2].

Mantle cell lymphoma originates from antigen-naive B cells in the mantle zone around germinal centers of the lymph nodes [7]. On the basis of its morphologic (diffuse, nodular, mantle zone) and cytologic (pleomorphic, blastoid or small cells) features, the tumor may be subsequently divided into various forms [4]. The cause of malignant transformation stems from a translocation t(11;14) that subsequently leads to overexpression of cyclin D1 protein, which is involved in regulation of the cell cycle [8]. So far, genetic studies have established mutations of various genes, including p53, BIRC3,WHSC1, ATM and NOTCH1 [4], as well as various defects in the cell cycle and DNA signaling pathways [5].

Although exact incidence and prevalence rates of MCL are not known, it comprises approximately 3-6% of all non-Hodgkin lymphomas [1]. This tumor is most frequently diagnosed in the sixth and seventh decade of life and a significant predilection toward males has been observed (3:1 male-to-female ratio) [4]. Apart from typical nodal location of the tumor, various extranodal sites have been described in literature, including the stomach, liver, colon, the skin, lacrimal glands and the central nervous system [2].

The pathogenesis starts with overexpression of cyclin D1, one of the most important regulatory proteins in the cell cycle, specifically during the G1/S phase transition. This genetic aberration occurs as a result of t(11;14)(q13;q32) translocation, which is the hallmark of MCL, while various secondary mutations have been detected, including those involved in cell survival signals, cell cycle defects (specifically BMI1, ARF, CDK4, RB1 and several other) and pathways that involve DNA damage (p53, p16) [5]. These mutations create favorable conditions for malignant proliferation and differentiation, but the exact model of disease is yet to be established. A small subset of patients were diagnosed with cyclin D1-negative MCL that expressed cyclins D2 and D3, showing that other mechanisms are potentially used by malignant cells to continue proliferating [8].

At this moment, preventive strategies against MCL do not exist, despite the fact that the underlying genetic mechanism of disease is established.

Mantle cell lymphoma (MCL) is a rare but insidious and aggressive tumor that belongs to the group of non-Hodgkin lymphomas (NHLs) and constitutes approximately 3-6% of all tumors in this group [1]. MCL stems from naive B cells in the mantle zone, around the germinal centers of the lymph nodes, but various extranodal sites have been described, including the gastrointestinal tract, the central nervous system, skin and lacrimal glands [2]. The main oncogenic event in MCL is translocation t(11;14)(q13;q32) that fuses cyclin D1 gene and IgH locus [3], leading to overexpression of cyclin D1, a protein involved in regulation of the cell cycle during the G1/S phase transition. In addition, several other genetic mutations have been discovered, involving p53, p16, RB1, ARF, CDK4, NOTCH and several other [4] [5]. This tumor is most commonly diagnosed in patients during their sixth and seventh decade of life and a marked predilection toward male gender, with a 3:1 male-to-female ratio, was determined across numerous reports [4]. The clinical presentation involves generalized lymphadenopathy, splenomegaly that is often massive and systemic symptoms, primarily because the vast majority of patients are diagnosed in advanced stages of the disease [2] [3]. In a small subset of patients, an indolent form that is characterized by minimal or absent lymphadenopathy and a milder clinical course may be seen [4]. Laboratory workup must include evaluation of all blood lineages, and either pancytopenia or marked leukocytosis may be observed. Levels of lactate dehydrogenase (LDH), and also hepatic and kidney parameters should be assessed. In addition, imaging studies such as computed tomography and plain radiography of the chest, pelvis and abdomen are recommended, so that the status of the internal organs and lymphoid tissue may be determined [2] [4]. To confirm MCL, however, a biopsy with subsequent immunophenotyping is vital in order to distinguish between various types of lymphomas and to determine optimal therapy [2]. Treatment principles rest on aggressive chemotherapy in younger patients who are able to tolerate the effects of chemotherapeutic drugs. Rituximab, cyclophosphamide, vincristine, prednisone, and doxorubicin, (known as the R-CHOP regimen) together with cytarabine are recommended for MCL treatment [4], whereas autologous stem cell transplantation (ASCT) is recommended as an adjunctive therapeutic measure [6]. Although several drugs are currently being tested in patients, the prognosis is still very poor. Recently, the mantle cell lymphoma international prognostic index (MIPI) was designed to assess patients based on their clinical and laboratory findings and median overall survival rates of little over 5 years have been determined [4]. For this reason, early recognition of the disease is essential in achieving better patient outcomes, but this may not be easy due to the nature of the tumor and its silent clinical progression.

Mantle cell lymphoma (MCL) is a rare but very dangerous tumor of white blood cells and belongs to a large group of non-Hodgkin lymphomas (NHLs), comprising approximately 3-6% of all tumors in this group. Various genetic mutations have been identified, but it is thought that overexpression of one of the proteins involved in regulation of the normal cell cycle occurs due to a specific chromosomal aberration, thus leading to an increased susceptibility for malignant transformation of cells. In most cases, MCL develops in lymph nodes (it was named Mantle cell due to the fact that it develops in mantle zones of the lymph nodes), but other sites have also been reported, such as the gastrointestinal tract, the central nervous system and the skin. This tumor is most frequently diagnosed in elderly individuals in their 60s, with a strong predilection toward male gender for unknown reasons. Many patients present when the disease is already in advanced stages. Extreme fatigue, an enlarged spleen and diffuse swelling of lymph nodes (known as generalized lymphadenopathy) are typical findings. In a small number of cases, however, an indolent form of MCL may be recognized that is distinguished by the absence of lymph node enlargement, which may present a diagnostic challenge for the physician. Nevertheless, a complete laboratory panel should be obtained that will include a complete blood count, liver and kidney function tests, as well as serum electrolytes. Additionally, imaging procedures such as computed tomography (CT scan) of the abdomen, pelvis and chest are equally important in assessing the general status of the patient, but also to determine the stage of the disease. To confirm MCL, a biopsy of the tissue in which the tumor grows (lymph node, bone marrow, gastrointestinal tract) and subsequent microscopic examination is necessary. Treatment is initiated as soon as the diagnosis is confirmed, except in asymptomatic patients and consists of an aggressive chemotherapy regimen known as R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine and prednisone), while cytarabine is added in younger patients and those who do not have additional comorbidities. In addition to chemotherapy, stem cell transplantation is performed as a follow-up measure whenever possible. Despite the fact that many drugs are currently tested to improve patient outcomes in the case of MCL, the prognosis is still very poor, as overall survival rates rarely exceed > 5 years. For this reason, it is imperative to find strategies that will recognize this condition early on.

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