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Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis

Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis
Literature review current through: Jan 2024.
This topic last updated: Jan 05, 2024.

INTRODUCTION — Mantle cell lymphoma (MCL) is a mature B cell non-Hodgkin lymphoma with a variable clinical course. MCL can involve lymph nodes and extranodal sites, such as the gastrointestinal tract or blood and bone marrow. It is usually composed of small to intermediate size lymphoid cells that express BCL2, CD5, and nuclear cyclin D1, and lack CD23 expression. Nearly all cases have the t(11;14) chromosomal translocation, which fuses CCND1 (which encodes cyclin D1) and the immunoglobulin heavy chain gene, resulting in overexpression of cyclin D1. Most patients with MCL present with advanced stage disease.

The pathobiology, epidemiology, clinical presentation, evaluation, diagnosis, and prognosis of MCL are discussed in this topic.

Management of MCL is discussed separately. (See "Mantle cell lymphoma: Initial management".)

EPIDEMIOLOGY — Mantle cell lymphoma (MCL) accounts for 3 to 7 percent of non-Hodgkin lymphomas in the United States and Europe, with an incidence estimated to be 4 to 8 cases per million persons per year [1-4]. The incidence increases with age and appears to be rising in the US [5]. Median age at diagnosis is 68 years. Approximately three-quarters of patients with MCL are male, and White individuals are affected almost twice as frequently as Black individuals.

PATHOBIOLOGY — MCL is associated with increased cellular proliferation, a blunted response to deoxyribonucleic acid (DNA) damage, and enhanced cell survival caused by impaired apoptosis (figure 1). Nearly all cases of MCL overexpress cyclin D1 due to the t(11;14), a chromosomal translocation that juxtaposes CCND1 (the gene that encodes cyclin D1 at 11q13) with the immunoglobulin heavy chain gene joining region at 14q32 [6,7]. Overexpression of cyclin D1 fosters proliferation by overcoming cell cycle suppressive effects of RB and p27, thereby promoting the transition from G1 to S phase of the cell cycle [8,9].

Two distinct variants of MCL are recognized, the classic subtype and the non-nodal subtype, both of which are associated with the t(11;14). Classic MCL resembles immunologically-naïve mantle zone B cells, based on the presence of productive clonal rearrangements of the immunoglobulin heavy and light chain genes, expression of IgM and IgD, and lack of somatic hypermutation of immunoglobulin genes. By contrast, the non-nodal MCL subtype shows somatic hypermutation and has distinctive clinical and pathologic features [10-14].

Cell cycle abnormalities – MCL cells exhibit increased cell division and replication. In nearly all cases, proliferation is driven by cyclin D1 overexpression, but rare cases are related to deregulation of cyclin D2 or cyclin D3.

Cyclin D1, which is a regulatory subunit for cyclin dependent kinases (CDKs) 4 and 6, is not expressed by normal B lymphocytes [15]. Activated cyclin D-CDK complexes phosphorylate and inactivate retinoblastoma protein (Rb), an inhibitor of the G1 to S phase progression. This complex also binds cyclin dependent kinase inhibitor 1B (CDKI1B; also called Kip1 and p27) [8]. Binding of cyclin D1/CDK4 to CDKI1B stabilizes the complex and enhances proliferation.

Up to half of patients with MCL demonstrate activation of the WNT signaling pathway, which stabilizes beta-catenin, allowing it to translocate into the nucleus and form a transcription complex that upregulates the expression of multiple target genes, including CCND1 [16].

Increased NOTCH signaling may also contribute to MCL cell proliferation by increasing MYC-controlled transcription through B cell-specific enhancers [17]. Increased MYC activity may also be related to stabilization of MYC protein through signals that require MALT1, a component of the CARD11-BCL10-MALT1 complex, which links B cell receptor (BCR) signaling to NF-kB [18].

Enhanced cell survival – MCL cases display disturbances in pathways and factors that regulate apoptosis (programmed cell death) [19,20]. MCL cells avoid apoptosis through expression of BCL2, upregulation of the PI3 kinase (PI3K)/AKT pro-survival signaling pathway, activation of nuclear factor-kB (NF-kB), and loss-of-function TP53 mutations.

BCL2 – BCL2, which enhances cell survival by blocking apoptosis, is overexpressed in more than half of cases of MCL [21]. Effects of BCL2 overexpression are discussed separately. (See "Pathobiology of follicular lymphoma", section on 'Aberrant BCL-2 expression'.)

PI3K/AKT signaling – The PI3K/AKT signaling pathway promotes cell growth, survival, and tumorigenesis by inactivating CDKI1B/p27, BAD (a BCL2-related protein), and FOXO1 (a transcription factor that regulates the expression of pro-apoptotic genes) [22,23]. The PI3K/AKT pathway also increases NF-kB and mTOR (mammalian target of rapamycin), which reduces functional p53 and enhances cell survival. Abnormal PI3K/AKT signaling is often seen in MCL with blastoid morphology [24].

NF-kB – NF-kB comprises a family of transcription factors with important roles in regulating immune function. NF-kB is constitutively activated in a subset of MCL and in vitro treatment with an NF-kB inhibitor caused cell cycle arrest and apoptosis [25]. Recurrent mutations in NF-kB pathway components, TRAF2 or BIRC3, were found in 15 percent of 165 primary MCL tumors [26].

BTK – Bruton tyrosine kinase (BTK) functions downstream of membrane-bound BCR and links constitutive BCR signaling to PI3K/AKT activation and NF-kB activation. BTK inhibitors, such as ibrutinib, have single-agent activity in MCL [27].

p53 – p53 is a tumor suppressor, encoded by TP53, that can induce apoptotic cell death. TP53 mutations or deletions are associated with poor response to chemoimmunotherapy and adverse outcomes in MCL [28].

Impaired DNA damage response – Some MCL cells have an impaired response to DNA damage that increases chromosome instability. This blunted response is largely due to defects in TP53 and ATM, but some cases have decreased expression of the cell cycle checkpoint kinases 1 and 2.

RNA-binding proteins – Abnormal expression of RNA-binding proteins (eg, HNRNPH1) and associated perturbations of mRNA processing may also contribute to the pathobiology of MCL [29].

Mutations found in MCL are discussed below. (See 'Genetic features' below.)

CLINICAL FEATURES — The clinical presentation differs among the two major subtypes of MCL: nodal MCL and leukemic, non-nodal MCL [30,31].

Nodal MCL — Nodal MCL accounts for at least three-quarters of cases of MCL. Most patients present with lymphadenopathy, but nodal MCL may also manifest splenomegaly and/or involve extranodal sites. Nodal MCL can display classic pathologic features or blastoid/pleomorphic morphology. (See 'Morphology' below.)

Lymphadenopathy may be relatively asymptomatic (eg, with smoldering MCL), or it can be more generalized and progressive. Involvement that is limited to a single lymph node region (ie, stage I) is rare.

Extranodal disease – Extranodal sites are often involved by MCL, but isolated or predominant extranodal presentation is uncommon [32]. Examples of extranodal involvement by MCL include:

Gastrointestinal (GI) tract – GI tract involvement is very common, and it can involve any region of the GI tract. Patients may present with prominent GI symptoms, but others are asymptomatic [32-34]. In some instances, GI tract involvement takes the form of symptomatic intestinal polyps (so-called multiple lymphomatous polyposis) (picture 1) [32,33,35,36].

A study of 31 cases of MCL with GI tract involvement reported the following distribution of disease: stomach (57 percent), duodenum (52 percent), jejunum/ileum (87 percent), colon (90 percent), and rectum (69 percent) [35]. Lymphomatous submucosal nodules producing polypoid lesions were found in both the small bowel and colon in 28 of the 31 cases.

Other extranodal sites – MCL can involve any organ system, including the kidneys and, rarely, the central nervous system [37,38]. Extranodal involvement may cause significant symptoms.

Smoldering MCL – Patients with smoldering MCL are asymptomatic or have modest symptoms and have favorable prognosis, even without treatment [39]. These patients generally have lymph nodes <3 cm and spleen <20 cm, normal lactate dehydrogenase (LDH), leukocyte count <30 x 109/L, and Ki-67 index <30 percent. They do not have blastoid/pleomorphic features or mutations of TP53 or NOTCH 1/2.

Leukemic, non-nodal MCL — This is a generally indolent form of MCL with a favorable prognosis. It commonly presents with lymphocytosis and splenomegaly.

Some cases of leukemic, non-nodal MCL exhibit marked lymphocytosis that can mimic prolymphocytic leukemia, acute leukemia, or chronic lymphocytic leukemia. In some cases, acquisition of TP53 mutation can be associated with more aggressive behavior. (See 'Differential diagnosis' below.)

EVALUATION — Evaluation includes history and physical examination, laboratory studies, imaging, and biopsy.

Clinical — History and physical examination should evaluate the patient for lymphadenopathy, splenomegaly, gastrointestinal (GI) findings, and constitutional symptoms (unexplained fever, sweats, weight loss). The size of the liver and spleen should be documented, and examination should include Waldeyer's ring.

Laboratory studies — Laboratory tests include:

Hematology – Complete blood count (CBC) with differential count

Serum chemistries – Comprehensive metabolic panel, including lactate dehydrogenase (LDH) and uric acid

Infectious diseases – Hepatitis B and HIV testing

Imaging — Positron emission tomography (PET)/computed tomography (CT) should be performed. If not, contrast-enhanced CT of neck, chest, abdomen, and pelvis should be obtained.

PET activity can vary in MCL and may be modest in cases with a low Ki-67 index.

Clinical testing — The following tests should be performed in selected patients.

GI – Upper endoscopy and colonoscopy should be performed for patients with GI symptoms. Some experts obtain these studies in all patients with apparent early-stage MCL (ie, non-bulky stage I or stage II) to identify more extensive disease that might affect management.

Bone marrow – Bone marrow aspirate and biopsy should be obtained for patients with unexplained cytopenias. Bone marrow specimens can be useful to establish the diagnosis of MCL in cases that are not straightforward.

Some experts perform bone marrow examination in all patients with early-stage MCL, when PET does not suggest bone marrow involvement; note that PET is not a sensitive method for detecting marrow involvement, especially in cases with a low Ki-67 index.

Central nervous system (CNS) – Patients with unexplained neurologic abnormalities should have a lumbar puncture (LP; including cytology and molecular studies) and CNS imaging.

We consider performing an LP for patients with blastoid or pleomorphic features, who have greater risk of CNS involvement.

PATHOLOGY — Morphology, immunophenotyping, and genetic characterization are used to diagnose MCL.

Morphology — MCL ordinarily displays a monomorphic pattern of small and intermediate size lymphoid cells with a diffuse or vaguely nodular pattern of growth. However, cellular features and growth patterns may vary from this typical appearance.

Cellular features – There is a spectrum of morphologic variants of MCL, which includes classic MCL and blastoid or pleomorphic subtypes [40]. Recognition of patients with the blastoid/pleomorphic subtype of MCL has implications for management. (See "Mantle cell lymphoma: Initial management", section on 'MCL with adverse features'.)

Classic MCL – Classic MCL (picture 2) is typically manifest as an infiltrate of small to medium size lymphocytes with scant cytoplasm, irregular or "notched" nuclear contours, dispersed or clumped chromatin, and inconspicuous nucleoli. The malignant cells can resemble centrocytes or small cleaved cells of follicular lymphoma; despite their small size and bland appearance, mitotic activity varies widely. Transformed tumor cells with basophilic cytoplasm (centroblast- or immunoblast-like cells) are rare or absent in classic MCL. Classic MCL often includes single interspersed epithelioid macrophages, which may be skewed towards an immunosuppressive "M2" state through cross-talk with MCL cells [41].

Blastoid/pleomorphic MCL – These MCL variants include larger cells or cells of variable size. In the blastoid variant (picture 3), the large cells have dispersed chromatin and a high mitotic rate that can resemble lymphoblastic lymphoma. In pleomorphic MCL, tumors are mixtures of small and large cells or atypical large cells with pale cytoplasm, oval irregular nuclei, prominent nucleoli, and a high mitotic rate (eg, 20 to 30 per 10 high power fields).

Non-nodal MCL – This subtype is characterized by the presence of small sized tumor cells in blood and the absence of nodal disease. Nuclear irregularity is less marked than in classic MCL, sometimes leading to confusion with chronic lymphocytic leukemia.

Immunophenotype and genetic findings of MCL cells are described below.

Growth patterns – Growth patterns of MCL in lymph nodes are usually diffuse or vaguely nodular (picture 4 and picture 5), or a combination of the two patterns. Some cases present with predominant involvement of mantle zones surrounding reactive B cell follicles.

With in situ mantle cell neoplasm, characteristic MCL cells (with nuclear cyclin D1) are scattered in the mantle zones of otherwise normal-appearing lymph nodes. In situ mantle cell neoplasm is usually an incidental finding, but care must be taken to exclude minimal involvement by systemic MCL.

Immunophenotype — MCL cells are uniformly BCL2-positive and usually positive for CD5, negative (or weakly positive) for CD23, and negative for CD10 or BCL6 [40]. Nuclear cyclin D1 is expressed by >95 percent of cases and SOX11 is expressed by >90 percent of cases. Occasional cases are CD5–negative or CD23-positive.

Nuclear cyclin D1 – Nuclear staining for cyclin D1 is present in 95 percent of MCL cases, including those that are CD5-negative [40]. Cyclin D1 can be detected by immunohistochemical (IHC) staining in paraffin-embedded tissue sections, which distinguishes MCL from most other lymphomas. (See 'Differential diagnosis' below.)

Cases that lack the t(11;14) may overexpress cyclin D1 by other mechanisms, such as CCND1 point mutations that increase its expression [42]. Conversely, in rare instances, cyclin D1 staining is absent in MCL that have the t(11;14) and high levels of CCND1 expression, due to mutations of the CCND1 coding sequence that prevent recognition by commonly used anti-cyclin D1 antibodies [43].

Cyclin D2 or cyclin D3 are overexpressed in rare cases of MCL that are cyclin D1-negative and lack t(11;14) [44-47]. Morphology, immunophenotype, gene expression profiles, and clinical characteristics of cyclin D1-negative MCL are similar to those of cyclin D1-positive MCL [45,46,48,49]. Cyclins D1, D2, and D3 are highly homologous and functionally interchangeable. However, IHC for cyclin D2 or cyclin D3 is not helpful for diagnosing cyclin D1-negative MCL, as these proteins are also expressed in other B cell malignancies. Recognition that cyclin D1-negative MCL usually expresses SOX11 (which is only rarely expressed by other lymphoid neoplasms) provides a generally reliable means to recognize these rare variants [50].

SOX11 – SOX11, a member of the SRY-related HMG family of transcription factors, is expressed in >90 percent of cases, including cyclin D1-negative cases and blastoid variants [51-53]. SOX11 is a useful marker for MCL, particularly in rare cyclin D1-negative cases.

Lymphoid antigens – MCL cells are typically positive for CD5, pan-B cell antigens (eg, CD19, CD20, FMC7), and CD43 (leukosialin), and generally do not express CD23 [40]. MCL cells express high levels of surface IgM and IgD. For unknown reasons, there is marked skewing (up to 80 percent of cases) towards lambda immunoglobulin light chain expression. Rare cases of MCL are CD5–negative or CD23-positive.

In lymphomatous polyposis (GI tract involvement), tumor cells express alpha-4/beta-7 integrin (CD49d), which is normally involved in lymphocyte homing to high endothelial venules in gut-associated lymphoid tissues [54,55].

p53 – Accumulation of the tumor suppressor p53 (encoded by TP53) in tumor cells is a surrogate for the presence of TP53 mutations and is more often found in the blastoid variant and in highly proliferative tumors. Accordingly, IHC detection of p53 in tumor cells is associated with an adverse prognosis [56-58].

IHC staining for p53 in formalin-fixed paraffin-embedded sections generally correlates well with TP53 mutations, as these mutations stabilize the p53 protein, which accumulates in tumor cells. Some experts favor the use of DNA sequencing to detect cases with mutated TP53 that may not exhibit p53 by IHC staining [59].

In one study, IHC was 82 percent sensitive and 100 percent specific for TP53 mutations [57]. In another study, TP53 abnormalities were found in 21 percent of 255 patients with MCL and were associated with a threefold increased risk of death [60]; in this study, IHC failed to detect approximately 5 percent of cases with mutated TP53 [60].

Genetic features — The t(11;14)(q13;q32), which rearranges the CCND1 locus (encoding cyclin D1) and immunoglobulin heavy chain (IgH) locus (picture 6), is present in >95 percent of cases of MCL. Cyclin D1 is considered the primary genetic driver of MCL.

The t(11;14) deregulates expression of CCND1 mRNA and cyclin D1 protein [40]. The translocation appears to be mediated by recombinase-activating genes (RAG) and activation-induced cytidine deaminase (AID) [61]. The t(11;14) rearrangement is not specific for MCL, as it occurs in some cases of multiple myeloma and, rarely, in other lymphoid malignancies [62].

Chromosomal changes – In addition to the t(11;14), MCL cells often have non-random secondary chromosomal abnormalities, including [15,63,64]:

Gains – Gain of 3q26 (31 to 50 percent of cases), 7p21 (16 to 34 percent), and 8q24 (including MYC; 16 to 36 percent)

Losses – Loss of 1p13 (29 to 52 percent), 6p23-27 (23 to 38 percent), 9p21 (CDKN2A, which encodes p16INK4a and p14ARF; 18 to 31 percent), 11q22-23 (ATM; 21 to 59 percent), 13q11-13 (22 to 55 percent), 13q14-34 (43 to 51 percent), and 17p13 (TP53; 21 to 45 percent)

In 60 cases of the blastoid variant of MCL, 80 percent had at least one cytogenetic abnormality in addition to t(11;14) [65].

Molecular changes – Most mutations in MCL affect cell cycle regulators, DNA damage response pathways, cell survival pathways, and other mechanisms [26,66-70], as described above. (See 'Pathobiology' above.)

Cyclins – In addition to the t(11;14), CCND1 mutations are seen in one-third of cases [67,68]. Point mutations and deletions that affect the 3' untranslated region of CCND1 can generate a truncated mRNA, which increases mRNA levels and is associated with poor clinical outcomes [42,66,71,72]. Occasionally, the immunoglobulin light chain loci, IGK or IGL, serve as the CCND1 translocation partner; in some cases that strongly express cyclin D1 without CCND1 rearrangement by fluorescence in situ hybridization (FISH), cryptic rearrangements of IGK or IGL enhancers with CCND1 are found [73-75].

In rare cases of MCL with cyclin D2 or cyclin D3 overexpression, CCND2, CCND3, or CCNE rearrangements have been identified [44,48].

Other mutations – Other mutated genes in MCL include:

-SOX11 – Expressed in >90 percent of cases of MCL [76-78].

-TP53 – Patients with TP53 mutation or deletion generally have poor clinical outcomes, including shortened survival and poor response to chemoimmunotherapy [28].

-Others – Other aberrant genes include gain-of-function mutations of NOTCH1 or NOTCH2, DNA damage response genes (ATM, TP53), apoptosis regulators (BIRC3, TLR2), and chromatin modifiers (WHSC1, MLL2, MEF2B) [66,67,79]. A study of 134 cases of MCL also reported mutations of LRP1B, PCLO, RYR2, PCDH10, OBSCN, TACC2, FAT3, LRP2, SVEP1, ZFHX4, MPDZ, DCDC1, IKBKB, and ARID1A [80].

DIAGNOSIS AND CLASSIFICATION — MCL and other lymphomas may be suspected in individuals with lymphadenopathy, splenomegaly, circulating aberrant lymphoid cells, and/or unexplained gastrointestinal (GI) symptoms.

The International Consensus Classification (ICC) [30] and the World Health Organization 5th edition (WHO5) [31] use similar criteria to diagnose and classify MCL. Further description of the ICC and WHO5 systems is presented separately. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

Diagnosis — Diagnosis of MCL requires a tissue specimen, including:

Morphology and immunophenotype – Microscopy and immunophenotyping indicate a B cell lymphoma consistent with MCL:

Microscopy – Tissues involved by classic MCL are generally effaced by a monomorphous infiltrate of small to intermediate size lymphocytes with irregular nuclei and a diffuse or vaguely nodular pattern of growth. The blastoid/pleomorphic subtype may have larger or more variable cell size and other features, described above. (See 'Morphology' above.)

Non-nodal MCL usually presents with peripheral blood lymphocytosis and bone marrow involvement. Nuclear irregularity is often less prominent than in classic MCL, which may lead to confusion with chronic lymphocytic leukemia.

In rare cases of in situ mantle cell neoplasm, characteristic cyclin D1-positive tumor cells are scattered in mantle zones of otherwise normal-appearing lymph nodes.

Immunophenotype – In classic MCL, involved nodal and extranodal tissues reveal tumor cells that express nuclear cyclin D1 by immunohistochemistry and are typically CD5-positive and CD23–negative. SOX11 staining is helpful in the cases of classic MCL that are negative for t(11;14) and fail to express cyclin D1.

Non-nodal MCL is usually characterized by flow cytometry (rather than immunohistochemistry) of blood or marrow, while CCND1 rearrangement is more often recognized directly by karyotyping or fluorescence in situ hybridization (FISH; rather than by immunostaining for cyclin D1). SOX11 is often weakly expressed or negative and this variant is also more likely to be CD5-negative and CD23-positive. The Ki-67 proliferation index is usually less than 10 percent.

Other immunophenotypic features of MCL cells are discussed above. (See 'Immunophenotype' above.)

Genetics – The t(11;14) rearrangement is detected by karyotype (chromosomal banding) or FISH in nearly all cases of MCL.

Rare cases of cyclin D1-positive MCL without detectable t(11;14), and cyclin D1-negative cases that express cyclin D2 or cyclin D3 are described above. (See 'Genetic features' above.)

Classification — Both ICC and WHO5 classify cases of MCL as follows [30,31]:

Classic MCL – Conventional cyclin D1-positive MCL is associated with the IGH::CCND1 fusion and t(11;14) in ≥95 percent of cases [81,82]. Rare cases with alternative genetic findings are described above. (See 'Genetic features' above.)

We evaluate cases of classic MCL for high-risk features that are associated with adverse prognosis, including cytomorphology (pleomorphic or blastoid appearance), high Ki-67 proliferative index, and p53 expression/TP53 mutation [28,56,83-85]. (See 'Morphology' above.)

Non-nodal MCL – Recognition of this more favorable prognosis subtype relies on a combination of clinical and pathological characteristics. Non-nodal MCL is generally asymptomatic and typically involves blood, bone marrow, and spleen, with little or no lymphadenopathy. GI involvement may occasionally be seen. Non-nodal MCL typically shows little (<10 percent of cells) or no SOX11 expression, and low Ki-67 index. It is more likely than classic MCL to express CD23 and CD200 and to lack CD5 expression [13,86-93].

In situ mantle cell neoplasm – In situ mantle cell neoplasm is a rare and often incidental finding manifest as colonization by cyclin D1-positive B cells of the inner mantle zones of follicles in otherwise normal-appearing lymph nodes [94]. Some patients with suspected in situ mantle cell neoplasm will prove to have disseminated MCL on further work-up [95]. In situ mantle cell neoplasm is sometimes seen in association with other B cell lymphomas.

DIFFERENTIAL DIAGNOSIS — MCL is typically characterized by an infiltrate of small to intermediate size B lymphocytes with irregular nuclei and a diffuse or vaguely nodular pattern of growth; the t(11;14) and nuclear cyclin D1 is seen in most cases. MCL is distinguished from other lymphomas in the differential diagnosis by morphology, immunophenotype, and genomic features.

Chronic lymphocytic leukemia — Both MCL and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are neoplasms of small to medium-sized lymphoid cells that can present with lymphadenopathy, splenomegaly, and constitutional symptoms. They have similar immunophenotypes, but while CLL is positive for CD20 (usually dimly), CD5, CD23, and CD200, MCL is positive for CD20 (usually brightly) and CD5 and negative for CD23 and CD200. Non-nodal MCL may more closely resemble CLL phenotypically but can be reliably distinguished by detection of the t(11;14) and overexpression of cyclin D1.

Immunohistochemistry for cyclin D1 is helpful for excluding CLL. Other discriminating markers include SOX11 (positive in most MCL) and LEF1 (frequently positive in CLL). Demonstration of the t(11;14) by fluorescence in situ hybridization (FISH) also distinguishes MCL from CLL/SLL [96]; instead, CLL cells may have del(11q), trisomy 12, del(13q), or del(17p). (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Follicular lymphoma — Some cases of MCL have a predominantly nodular growth pattern that resembles follicular lymphoma; conversely, an unusual variant of follicular lymphoma with a predominantly diffuse growth pattern that usually presents in inguinal lymph nodes can mimic the histologic appearance of MCL [97]. Both MCL and follicular lymphoma can present with gastrointestinal (GI) symptoms from lymphomatous polyposis. In contrast to follicular lymphoma, MCL cells are usually positive for CD5, CD43, and cyclin D1 and lack the characteristic genetic finding in follicular lymphoma, the t(14;18). (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Marginal zone lymphoma (nodal or extranodal) — Both extranodal marginal zone lymphoma (MZL) and MCL can involve the GI tract and are neoplasms of small to medium-sized B lymphocytes. MCL cells generally express CD5 and cyclin D1, while extranodal MZL does not. In addition, MZL often contains monocytoid B cells and shows plasmacytic differentiation, which are not features of MCL. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Large B cell lymphoma — Malignant cells of large B cell lymphoma are generally larger than the tumor cells of MCL, but blastoid/pleomorphic MCL may include larger cells. MCL is distinguished from large B cell lymphoma by the characteristic immunophenotype of MCL and the t(11;14) or IGH::CCND1 rearrangement. However, CCND1 rearrangement has been found in some large B cell lymphomas, sometimes in association with MYC, and BCL2 or BCL6 translocations. In ambiguous cases, a diagnosis of large B cell lymphoma is favored by lack of CD5 and SOX11 expression and/or detection of mutations that are uncommon in MCL [98]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Lymphoblastic lymphoma — The blastoid variant of MCL, with intermediate size cells with dispersed chromatin and high mitotic rate, can resemble lymphoblastic lymphoma, which can be of B or T cell origin.

Blastoid MCL is readily distinguished from lymphoblastic lymphoma by immunohistochemistry. Blastoid MCL expresses cyclin D1 and mature B cell markers, whereas B lymphoblastic lymphomas lack surface immunoglobulin and express TdT, while T lymphoblastic lymphomas express TdT, lack B cell markers, and express additional T cell markers besides CD5. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Plasma cell neoplasm with CCND1 rearrangement — Plasma cell neoplasms (eg, multiple myeloma) can also have the t(11;14) with IGH::CCND1 rearrangement; notably, these tumors are often composed of small plasma cells that express B cell markers such as CD20, leading to possible confusion with MCL. The distinction is typically made by recognizing plasmacytoid differentiation; the failure to express MCL markers (eg, CD5 and SOX11); and the presence of typical clinical features of plasma cell neoplasms, such as monoclonal gammopathy, hypercalcemia, and renal dysfunction.

PROGNOSTIC FEATURES — Prognosis of MCL is affected by the clinical presentation, disease stage, and pathologic features. Prognosis of patients with MCL is variable, but it can be estimated using a clinical prognostic model.

Pathologic features — Histologic and genetic features of MCL tumor that are associated with adverse outcomes include:

Blastoid/pleomorphic histology – The blastoid/pleomorphic variant of MCL is associated with adverse outcomes and poor response to chemoimmunotherapy [99-104]. Pathologic features of blastoid/pleomorphic MCL are described above. (See 'Diagnosis and classification' above.)

In one series of 52 patients with MCL, blastoid transformation occurred in one-third of cases, with a median survival time following transformation of four months [105]. Nearly all (16 or 18 patients) had systemic involvement with circulating blastoid cells at the time of transformation. Leukocytosis, elevated serum LDH level, and high proliferative activity (as assessed by Ki-67 staining) were associated with increased risk of transformation. In separate studies, age >60 and an increased mitotic index [106] or increased Ki-67 staining [83,107,108] were associated with significantly worse overall survival.

Genetics – Patients whose MCL has mutant TP53 or high p53 expression have reduced survival and a higher rate of relapse [28]. In a cohort of 365 patients with MCL, high p53 expression by immunohistochemistry was a strong predictor of inferior overall survival (OS) and earlier time to treatment failure (TTF); this association was independent of MIPI score and Ki-67 index in multivariable analysis [56].

Other genetic findings are associated with inferior outcomes, including unmutated IGHV; mutated CDKN2A, NOTCH1, or NOTCH2; MYC overexpression; and genomic complexity [20,87-89].

Mantle cell lymphoma international prognostic index (MIPI) — The mantle cell lymphoma international prognostic index (MIPI) (calculator 1) (table 1) can be used to estimate prognosis in patients with MCL [109,110].

The MIPI and a simplified MIPI (performance status, age, increased serum lactate dehydrogenase [LDH], and leukocyte count) were created using data from 455 patients with advanced-stage MCL who enrolled in clinical trials between 1996 and 2004 [109]. Patients were stratified into three risk groups (low, intermediate, and high) with distinct outcomes (median OS not reached, 58 months, and 37 months, respectively) and five-year OS (60, 35, and 20 percent) (table 1). The prognostic value of the MIPI was confirmed in a separate cohort of 958 patients with MCL treated on prospective trials (2004 to 2010); in this analysis, estimated five-year OS were 83, 63, and 34 percent in the low, intermediate, and high groups, respectively [111].

Modifications of a simplified MIPI score have incorporated Ki-67 expression (MIPI-B) and miR-18b expression (MIPI-B-miR). These modified MIPI scores were effective for estimating prognosis in trials with long-term follow-up [111-113].

In a study of 158 patients with MCL who received intensive induction chemoimmunotherapy followed by autologous hematopoietic cell transplantation, MIPI was superior to the International Prognostic Index (IPI) for predicting survival [110].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Management of mantle cell lymphoma".)

SUMMARY

Description – Mantle cell lymphoma (MCL) is a mature B cell non-Hodgkin lymphoma (NHL) with a variable natural history that can involve lymph nodes or extranodal sites, including blood, bone marrow, or gastrointestinal (GI) tract. Among lymphomas, MCL is distinguished by nuclear expression of cyclin D1 and t(11;14).

Epidemiology – MCL accounts for approximately 7 percent of NHL, with a strong male predominance and median 68 years at presentation. (See 'Epidemiology' above.)

Pathobiology – Increased proliferation, blunted DNA damage response, and impaired apoptosis are seen (figure 1). Nearly all cases express cyclin D1, due to the t(11;14), which juxtaposes CCND1 and IGH (immunoglobulin heavy chain gene) and acts as the genetic driver of most cases. (See 'Pathobiology' above.)

Clinical presentation – Most patients have lymphadenopathy and splenomegaly; some have constitutional symptoms and/or GI or other extranodal symptoms. The two major subtypes, classic MCL and non-nodal MCL, present differently. Most patients have advanced-stage disease at diagnosis. (See 'Clinical features' above.)

Pathology – Characteristic features include:

Morphology – Small to intermediate size lymphoid cells with irregular, notched nuclei in a diffuse or vaguely nodular pattern (picture 2). However, morphology may vary, and the blastoid/pleomorphic subtype has larger, more proliferative cells. (See 'Morphology' above.)

Immunophenotype – Nuclear cyclin D1 is nearly universal. Most cells are positive for CD5, BCL2, and SOX11, and negative for CD23. However, occasional cases (particularly non-nodal MCL) are CD5–negative or CD23-positive. (See 'Immunophenotype' above.)

Genetic features – Nearly all cases demonstrate the t(11;14), which rearranges CCND1 and immunoglobulin regulatory elements. Some cases overexpress cyclin D1 due to CCND1 mutation or variant rearrangements, while rare variants express cyclins D2 or D3. (See 'Genetic features' above.)

Diagnosis – Requires a tissue biopsy that demonstrates (see 'Diagnosis' above):

Morphology – Consistent with MCL, described above.

Immunophenotype – Typically positive for nuclear cyclin D1 and CD5, BCL2, and SOX11, and negative for CD23.

Genetics – The t(11;14)(q13;q32) and/or CCND1::IGH rearrangement; rare cases have variant molecular events.

Classification – We classify MCL as (see 'Classification' above):

Classic MCL – Cyclin D1-positive MCL with t(11;14) and/or IGH::CCND1. This includes cases with high-risk features/adverse prognosis (eg, blastoid/pleomorphic morphology, high Ki-67 index, p53 expression/mutated TP53).

Non-nodal – A more favorable prognostic group recognized by clinical and pathological characteristics, including asymptomatic presentation with splenomegaly and little/no lymphadenopathy, low/negative SOX11 expression, low Ki-67 index, CD23 and CD200 expression, and often lacks CD5 expression.

In situ mantle cell lymphoma – Rare and typically incidental finding of colonization by cyclin D1-positive cells in mantle zones of otherwise normal-appearing lymph node follicles.

Differential diagnosis – Other lymphomas with small or intermediate size tumor cells, including chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, large B cell lymphoma, or lymphoblastic lymphoma, which are distinguished from MCL by the characteristic immunophenotype and/or genetic findings of MCL. (See 'Differential diagnosis' above.)

Prognostic features – Prognosis is associated with:

Pathology – Blastoid/pleomorphic morphology and TP53 mutations are associated with adverse outcomes.

Prognostic index – Mantle cell lymphoma International Prognostic Index (MIPI) (calculator 1) (table 1). (See 'Prognostic features' above.)

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Topic 4702 Version 37.0

References

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