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Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma

Clinical manifestations, pathologic features, and diagnosis of mantle cell lymphoma
Authors:
Arnold S Freedman, MD
Jon C Aster, MD, PhD
Section Editor:
Andrew Lister, MD, FRCP, FRCPath, FRCR
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 04, 2022.

INTRODUCTION — Mantle cell lymphoma (MCL) is a mature B cell non-Hodgkin lymphoma with a variable clinical course that can involve lymph nodes, extranodal sites, and/or blood [1,2]. MCL is usually composed of small- to medium-sized lymphoid cells that typically express BCL2, CD5, and nuclear cyclin D1. Nearly all cases of MCL have the t(11;14) chromosomal translocation, which involves rearrangement of an immunoglobulin heavy chain and CCND1 (the gene that encodes cyclin D1), and overexpression of cyclin D1. Patients generally present with advanced stage disease, but disease progression is highly variable.

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

The pathobiology and treatment of MCL are presented separately. (See "Pathobiology of mantle cell lymphoma" and "Initial treatment of mantle cell lymphoma".)

EPIDEMIOLOGY — MCL comprises about 7 percent of adult non-Hodgkin lymphomas in the United States and Europe with an incidence of approximately 4 to 8 cases per million persons per year [3-8]. Incidence increases with age and appears to be increasing overall in the United States [9]. Approximately three-quarters of patients are male, and White individuals are affected almost twice as frequently as Black individuals. Median age at diagnosis is 68 years.

PATHOGENESIS — MCL is thought to have two distinct cellular origins, each giving rise to different forms of the disease [10]:

Classic MCL typically involves lymph nodes and extranodal sites, such as the gastrointestinal tract. Classic MCL is believed to arise from naïve B cells that "mis-express" SOX11, which is not expressed in normal B cells. SOX11 has been reported to block B cell differentiation, suggesting that it has a direct role in MCL pathogenesis [11].

The "leukemic" variant of MCL mainly involves the peripheral blood, bone marrow, and/or spleen and often spares lymph nodes. This variant develops from antigen-experienced SOX11-negative B cells and is often clinically indolent, but may acquire secondary abnormalities (eg, TP53 mutations) that lead to a very aggressive course.

Both types of MCL are highly associated with a (11;14) translocation that dysregulates the cyclin D1 gene (CCND1). Acquisition of additional genetic abnormalities, such as translocations involving MYC, can lead to progression to more aggressive forms of MCL with blastoid or pleomorphic morphologies.

Additional details regarding the pathobiology of MCL are discussed separately. (See "Pathobiology of mantle cell lymphoma".)

CLINICAL FEATURES — Most patients with MCL have advanced stage disease at diagnosis (70 percent). Approximately 75 percent of patients initially present with lymphadenopathy, with extranodal disease being the primary presentation in the remaining 25 percent [12]. Common sites of involvement include lymph nodes, spleen (45 to 60 percent), Waldeyer's ring, bone marrow (>60 percent), blood (13 to 77 percent), and extranodal sites, such as the gastrointestinal (GI) tract, breast, pleura, and orbit [12-14].

Up to one-third of patients have systemic B symptoms, such as fever, night sweats, and unintentional weight loss, at presentation (table 1). The definition of systemic B symptoms is presented in more detail separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

MCL can involve any region of the GI tract, occasionally presenting as lymphomatous intestinal polyposis (picture 1) [15,16]. A prospective clinicopathologic study of 31 cases of GI tract involvement found the following distribution of disease: stomach (57 percent), duodenum (52 percent), jejunum/ileum (87 percent), colon (90 percent), and rectum (69 percent) [17]. Lymphomatous submucosal nodules producing polypoid lesions were found in both the small bowel and colon in 28 of 31 cases. (See "Epidemiology, clinical features, and types of small bowel neoplasms", section on 'Primary gastrointestinal tract lymphoma'.)

SOX11-negative forms of MCL often spare lymph nodes and instead have leukemic presentations. Splenomegaly in the absence of lymphadenopathy is common in such variants [18]. Central nervous system involvement is rare overall (<5 percent of cases) but is more common in patients with the leukemic variant [19-21].

MORPHOLOGY — The histologic pattern of nodal MCL growth may be diffuse, nodular, mantle zone, or a combination of the three. Most cases are composed exclusively of small to medium-sized lymphoid cells, with slightly irregular or "notched" nuclei and inconspicuous nucleoli (picture 2). However, the morphology can range from small, more irregular lymphocytes (mimicking the centrocytes or small cleaved cells of follicular lymphoma), to lymphoblast-like cells (in the blastoid variant, raising the question of lymphoblastic lymphoma), and even occasionally to mixtures of small and large cells or markedly atypical large cells (in the pleomorphic variant) (picture 3 and picture 4 and picture 5) [4,22-25]. Despite the small size and bland appearance of the cells in most cases, there is often more mitotic activity than in other histologically low-grade lymphomas. When malignant effusions are present, the cytologic features of the tumor cells in the effusion are similar to those seen with peripheral blood involvement. Single epithelioid macrophages are often interspersed among the tumor cells in tissues, but clusters of macrophages and granulomas are not seen. Transformed tumor cells with basophilic cytoplasm (centroblast- or immunoblast-like cells) are rare or absent from typical cases.

IMMUNOPHENOTYPE — MCL cells express high levels of surface IgM and IgD and, for unknown reasons, show marked skewing towards lambda light chain expression, which is seen in up to 80 percent of cases. They also express pan-B cell antigens (eg, CD19, CD20), CD5, and FMC7. Rare cases may be CD5– or CD23+ [26-29]. A prominent, expanded irregular meshwork of follicular dendritic cells (FDCs) is found even in diffuse cases [22,30,31]. SOX11, a member of the SRY-related HMG family of transcription factors, is a useful marker for MCL, particularly in rare cases in which cyclin D1 expression is not detected [32-34]. (See 'Cyclin D1' below.)

When MCL involves the gastrointestinal tract (lymphomatous polyposis), the tumor cells express the adhesion molecule alpha-4/beta-7 integrin (CD49d), which is normally involved in lymphocyte homing to the high endothelial venules in the gut-associated lymphoid tissues [35,36]. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

Cyclin D1 — Nuclear staining for cyclin D1 (BCL1) is present in 95 percent of cases [37-40], including those that are CD5 negative [41]. The product of the cyclin D1 gene can be detected in the nuclei of neoplastic mantle cells in paraffin-embedded tissue sections with the immunoperoxidase technique, and is useful in distinguishing MCL from other relatively indolent B cell lymphomas, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma [37,38,42].

Cyclin D1 may be overproduced even in cases lacking the t(11;14) (see 'Genetic features' below), suggesting that other types of acquired genetic aberrations (eg, point mutations) may also result in increased expression [39,43-45]. Conversely, in rare instances, cyclin D1 staining is absent in MCLs that have the t(11;14) and high levels of CCND1 expression because of concomitant mutations involving the coding sequence of CCND1 that prevent recognition of cyclin D1 by commonly used antibodies [46]. As is typical of molecular lesions identified in cancer, mis-expression of this single gene is insufficient to cause MCL, as transgenic mice that overexpress cyclin D1 alone do not develop lymphoma [47].

The relationship of cyclin D1 positive MCL and cases resembling MCL that are cyclin D1 negative is unclear. In a study of 151 Japanese patients with MCL morphology, tumors that overexpressed cyclin D1 tended to be composed of larger cells with a higher mitotic index [42]. Also, patients with cyclin D1 positive tumors tended to be older, have more involvement of the gastrointestinal tract, less involvement of the orbit, a higher International Prognostic Index (table 2), and a lower five-year survival (30 versus 86 percent).

On the other hand, a separate study from the United States showed that the expression profiles of cyclin D1 positive and negative "MCL" were very similar, and that tumors that failed to express cyclin D1 instead overexpressed either cyclin D2 or D3 [48], which are highly homologous and functionally identical to cyclin D1. In this well characterized group of cyclin D1 negative and positive tumors, no difference in clinical behavior or outcome was observed. (See "Pathobiology of mantle cell lymphoma", section on 'Cell cycle progression'.)

p53 — Mutations of TP53, which encodes the tumor suppressor p53, are more often found in MCL with blastoid morphology, highly proliferative tumors, and relapsed MCL, and are associated with an adverse prognosis [49-51]. While mutated TP53 cannot be identified based on morphology or proliferative rate, missense mutations in p53 often lead to its accumulation in tumor cells; thus, positive immunohistochemical staining for p53 in routine formalin-fixed paraffin-embedded sections is highly correlated with the presence of TP53 mutations [50].

One study that performed both IHC for p53 and sequencing of TP53 reported that IHC was 82 percent sensitive and 100 percent specific in 11 paired samples; TP53 aberrations were found in 21 percent of 255 patients with MCL and this was associated with a three-fold increased risk of death [52].

GENETIC FEATURES — Immunoglobulin (Ig) heavy and light chain genes are rearranged. The Ig V region genes lack somatic mutations in most cases [53,54], indicating a pre-germinal center stage of differentiation, consistent with an origin from immunologically naïve mantle zone B cells [55].

Overexpression of cyclin D1 in MCL is strongly associated with the t(11;14)(q13;q32), a translocation between the CCND1 locus and the immunoglobulin heavy chain (IgH) locus [56-60]. The t(11;14) is not specific for MCL, as it occurs in a subset of multiple myelomas [61] and rarely in other lymphoid malignancies. This translocation leads to the dysregulated expression of CCND1, the gene that encodes cyclin D1, which is involved in the control of the G1 phase of the cell cycle and is not normally expressed in lymphoid cells [37,62,63]. (See 'Cyclin D1' above and "Pathobiology of mantle cell lymphoma", section on 'Cell cycle progression'.)

Karyotyping of metaphase chromosomes reveals the t(11;14) in only 50 to 65 percent of MCLs, but fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) analyses of cases with cyclin D1 overexpression almost always detect CCND1/IgH fusion genes (picture 6) [64-66]. In addition, DNA sequence analysis of MCL has identified frequent mutations involving exon 1 of the CCND1 gene [67]; these are of uncertain functional importance, but translation of the CCND1 mRNA is regulated through its 5' untranslated region, suggesting that some of these mutations may enhance CCND1 expression. (See 'Cyclin D1' above.)

Other genes associated with the cell cycle may also be involved by genomic aberrations, including rearrangements of CCND2 (cyclin D2) in cyclin D1 negative cases, mutations of the cyclin-dependent kinase (CDK) inhibitors, and p16 and p17 (particularly in blastoid variants). Decreased expression of the CDK inhibitor p27 and disturbances of pathways associated with apoptosis [34,68-70] have also been reported.

In one study of 60 cases of the blastoid variant, 80 percent had at least one cytogenetic abnormality in addition to t(11;14) [71]. Other cases have been reported to have a high incidence of tetraploidy and TP53 gene mutations [72-74]. Patients with TP53 mutation or deletion have poor clinical outcomes, including shortened overall survival, following intensive chemotherapy [75].

Acquisition of a translocation involving the oncogene MYC has been associated with shorter survival [76,77]. Alterations in TP53, p16, p18, p21, and p27 may also play a role in the development and evolution of MCL [78]. Additional chromosomal abnormalities have been reported [79,80]. In one study, genomic loss of 8p occurred in 11 and 79 percent of patients with nodal or leukemic disease, respectively [81].

Comparative genomic hybridization studies have uncovered several recurrent copy number changes in MCL [65,82]. In one of these, for example, at least three regions of copy number change were found in each of 30 patients, involving at least two chromosomes [65]. The most common findings were gains in 3q and 6p and losses in 13q. The presence of more than five chromosomal aberrations (relative risk [RR]: 33), gain of Xq (RR: 4.5), and loss of 17p (RR: 4.8) were all significantly associated with a worse prognosis.

Gene expression profiling, comparative genomic hybridization, proteomics, and deep sequencing of MCL genomes may shed additional light on the biology and clinical heterogeneity of MCL [48,67,83-88]. Other studies have identified activating NOTCH1 mutations in a minority of MCL cases, a finding that may predict a worse clinical outcome [67,89]. (See "Pathobiology of mantle cell lymphoma".)

DIAGNOSIS — Patients suspected of having MCL should undergo tissue biopsy. In addition to routine histology and immunohistochemistry, involvement of cyclin D1 should be evaluated by immunohistochemistry. Cytogenetic detection of the t(11;14) by either karyotyping or fluorescence in situ hybridization (FISH) is a useful adjunct test.

On histologic review, tumor cells are usually monomorphous small to medium-sized B lymphocytes with irregular nuclei. The degree of irregularity is usually, but not always, less than that of the centrocytes found in germinal centers and follicular lymphoma. Large cells resembling centroblasts or immunoblasts are absent. Tumor cells are typically CD5+ and CD23–; the vast majority overexpress cyclin D1 [56]. The t(11;14) translocation, which is not specific for MCL, is seen in a little over half of cases by conventional cytogenetics, but in a much higher percentage of cases screened with FISH. SOX11 staining is helpful in rare cases that fail to express cyclin D1.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for MCL includes other non-Hodgkin lymphomas composed of small to medium-sized cells, most notably chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma, marginal zone lymphoma, and lymphoblastic lymphoma.

In situ mantle cell neoplasia — The 2016 revisions of the World Health Organization (WHO) classification incorporated a new diagnostic category, "in situ mantle cell neoplasia" [90], which was previously termed in situ mantle cell lymphoma [91]. In situ mantle cell neoplasia is characterized by the presence of cyclin D1 positive cells, usually located in the inner mantle zones of follicles, in lymph nodes that otherwise lack diagnostic features of MCL. In situ mantle cell neoplasia is often found incidentally, sometimes in association with other B cell lymphomas. Some patients with this finding will prove to have disseminated MCL on further work-up; the "in situ" component in such cases presumably represents early seeding of systemic MCL to a partially involved node. Other patients, however, will not have evidence of MCL on further evaluation [92]. The natural history of this second group of patients is not yet known.

Chronic lymphocytic leukemia — Both MCL and CLL are neoplasms of small to medium-sized lymphoid cells with similar immunophenotypes. While CLL is positive for CD20, CD5, and CD23, MCL is positive for CD20 and CD5 but negative for CD23. Immunohistochemistry for cyclin D1 is very helpful in excluding CLL. Other discriminating markers include SOX11 (typically positive in MCL) and LEF1 (frequently positive in CLL). Additional testing to identify the t(11;14) by fluorescence in situ hybridization (FISH) can also aid in the diagnosis of MCL [93]. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Follicular lymphoma — On histology, MCL can have a predominantly nodular growth pattern that resembles that of follicular lymphoma. Conversely, an unusual diffuse variant of follicular lymphoma that often presents in inguinal lymph nodes can mimic the histologic appearance of MCL [90]. However, in contrast to follicular lymphoma, MCL cells are usually CD10–, CD5+, CD43+, and cyclin D1+. Like MCL, follicular lymphoma can present with gastrointestinal involvement as lymphomatous polyposis; such tumors are also best distinguished from MCL by immunohistochemistry. (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 gastrointestinal tract and are neoplasms of small to medium-sized B lymphocytes. On immunophenotype, MCL expresses 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)".)

Lymphoblastic lymphoma — The blastoid variant of MCL has a high mitotic rate (typically 20 to 30 per 10 high power fields) and is often comprised of intermediate-sized cells with dispersed chromatin, irregular nuclear contours, and scant cytoplasm that mimic the appearance of lymphoblastic lymphoma, which can be of B or T cell origin. These cases are easily distinguished from lymphoblastic lymphoma by immunohistochemistry, as blastoid variant MCL expresses cyclin D1 and mature B cell markers (eg, surface immunoglobulin), whereas B lymphoblastic lymphomas lack surface immunoglobulin and express TdT, and T lymphoblastic lymphomas express TdT and additional T cell markers besides CD5.

PROGNOSIS — The course of MCL is moderately aggressive and variable. Median overall survival in modern trials incorporating intensive therapy is 8 to 10 years, with no plateau in the survival curve. Shorter survival times are seen with less intensive therapy.

Multiple studies have tried to determine prognostic factors to predict which patients will have a more aggressive course [94-103]. While most patients with MCL who do not begin therapy will die of their disease within a few years, a small proportion, increasingly better defined, may remain stable for years. These occasional patients with low stage (table 3), low-risk (table 2) disease may have an indolent course, managed by observation, splenectomy, or treatment with alkylating agents analogous to the treatment of patients with small lymphocytic lymphoma or follicular lymphoma. (See "Initial treatment of mantle cell lymphoma", section on 'Indications for treatment'.)

Several prognostic indices have been applied to patients with MCL. These include:

The International Prognostic Index (IPI) (table 2)

The Follicular Lymphoma International Prognostic Index (FLIPI) (table 4) [95]

The Mantle Cell Lymphoma International Prognostic Index (MIPI) (calculator 1) (table 5) [94,104]

All of these indices incorporate information about the patient's age, lactated dehydrogenase (LDH), and stage. They vary in how they incorporate information about nodal involvement, performance status, and blood counts.

The MIPI was originally described using data from 455 patients with advanced stage MCL enrolled on one of three clinical trials between 1996 and 2004 [94]. Using information regarding age, performance status, LDH, and leukocyte count, patients could be stratified into three risk groups (low, intermediate, and high) with significantly different estimated median overall survival (not reached, 58 months, and 37 months) and survival at five years (60, 35, and 20 percent) (table 5). The prognostic value of the MIPI was later confirmed in a separate cohort of 958 patients with MCL treated on prospective trials between 2004 and 2010 [105]. This latter study confirmed that the MIPI was able to identify three risk groups with significantly different estimated survival at five years (83, 63, and 34 percent). The differences in survival rates seen in this second study likely reflect differences in patient populations, available treatments, and adjunctive care. This also illustrates the importance of healthy scepticism when applying prognostic indices to the care of individual patients.

The blastoid variant of MCL is reported in some studies to be more aggressive [5,27,96-99], whereas patients presenting without anemia or splenomegaly [27,100], those with a normal serum free light chain ratio [106], or whose tumor cells do not overexpress cyclin D1, may have longer survival (see 'Cyclin D1' above) [42].

In one series of 52 patients with MCL, blastoid transformation occurred in 18 (35 percent), with a median survival time following transformation of four months [101]. Sixteen of the 18 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 an increased risk of this complication. In separate studies, age >60 and an increased mitotic index [102] or increased Ki-67 staining [107-109] were associated with significantly worse overall survival.

Patients whose MCL has mutant TP53 have inferior outcomes, including reduced overall survival (OS), shorter progression-free survival (PFS), and a higher rate of relapse [75]. In a cohort of 365 patients with MCL, high p53 expression by immunohistochemistry was a strong predictor of inferior overall survival (OS) and earlier treatment failure (TTF) [49]. Importantly, patients with high p53 expression (>50 percent positive lymphoma cells) had inferior OS and shorter TTF; this association was independent of MIPI score and Ki-67 index in multivariate analysis.

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

Mantle cell lymphoma (MCL) – MCL is one of the mature B cell non-Hodgkin lymphomas (NHL). Its behavior is most often that of an aggressive disease. (See 'Introduction' above.)

Epidemiology – MCL accounts for 7 percent of NHL in adults in the United States and Europe. Presentation is usually in the sixth decade and there is a male predominance. (See 'Epidemiology' above.)

Clinical presentation – Most patients present with advanced stage disease. Most have lymphadenopathy (75 percent), while approximately 25 percent will present with symptoms from extranodal disease, such as involvement of the gastrointestinal tract. (See 'Clinical features' above.)

Morphology – The histologic pattern of MCL may be diffuse, nodular, or mantle zone, or a combination of the three. Most cases are composed exclusively of small to medium-sized lymphoid cells, with slightly irregular or "notched" nuclei (picture 7). (See 'Morphology' above.)

Immunophenotype – Mantle cell tumor cells express high levels of surface membrane immunoglobulin M and immunoglobulin D (sIgM±IgD), which is more often of lambda light chain type. They also express pan-B cell antigens (eg, CD19, CD20), CD5, and FMC7. Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases, including those that are CD5 negative. (See 'Immunophenotype' above.)

Genetic features – Most cases will demonstrate t(11;14) by conventional cytogenetics or fluorescence in situ hybridization (FISH), although this rearrangement is not specific for MCL. (See 'Genetic features' above.)

Diagnosis – Tissue biopsy is required for diagnosis. Microscopically, this usually reveals a monomorphous pattern of small to medium-sized B lymphocytes with irregular nuclei, nuclear staining for cyclin D1 (BCL1), and t(11;14)(q13;q32) translocation between the CCND1 and immunoglobulin heavy chain (IgH). (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis includes other NHLs composed of small to medium-sized cells, including chronic lymphocytic leukemia, follicular lymphoma, and marginal zone lymphoma. (See 'Differential diagnosis' above.)

Prognosis – The course of MCL is moderately aggressive and variable. The most commonly used prognostic scoring systems are the International Prognostic Index (IPI) (table 2), the Follicular Lymphoma International Prognostic Index (FLIPI) (table 4), and the Mantle cell lymphoma International Prognostic Index (calculator 1) (table 5). (See 'Prognosis' above.)

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Topic 4702 Version 32.0

References