Cytogenetics of Mantle Cell Lymphoma

Mantle Cell Lymphoma (MCL) Overview

• MCL is a chronic B-lineage lymphoproliferative disorder
• Characterized by variable cytological and histological features, but a distinctive cytogenetic and molecular genetic defect
• Histologically low-grade, but prognosis is intermediate between low-grade B-cell lymphomas and high-grade lymphomas
• Median survival is only 3-4 years
• Generally considered incurable
• Increased incidence with a family history of MCL or other non-Hodgkin lymphomas

MCL Characteristics

• Characterized by the t(11;14) translocation, leading to cyclin D1 overexpression
• Exhibits significant clinical and biological heterogeneity, varying from indolent non-nodal leukemic variants to highly aggressive blastoid variants
• Risk stratification at diagnosis is essential for optimal treatment

Clinical Presentation

• Primarily affects middle-aged and older individuals (median age 60) with a marked male predominance
• Presentation is usually with advanced stage disease, often exhibiting lymphadenopathy and splenomegaly
• Extranodal involvement is common (Waldeyer's ring, lung, pleura, gastrointestinal tract)
• Peripheral blood involvement is associated with worse prognosis; leukemic non-nodal MCL, usually involving the spleen, is often clinically indolent
• Central nervous system disease may be more likely in patients with peripheral blood involvement

Diagnosis

• Cytopenias due to marrow infiltration and circulating lymphoma cells are possible
• Mantle cell lymphoma cells exhibit significant pleomorphism – typically medium-sized with irregular nuclei
• Some cells show inconspicuous nucleoli or pronounced nuclear indentations/clefts
• Cytoplasmic vacuoles and granules may be present; chromatin pattern can vary (some cells showing a diffuse pattern)
• Blastoid variant (10-20% of cases): cells predominantly have a diffuse chromatin pattern, and may resemble acute lymphoblastic leukemia (ALL) cells, or show some more mature features
• Bone marrow infiltration is common (up to 80% of patients), usually interstitial or focal with nodules or irregularly shaped infiltrates. Paratrabecular infiltration is uncommon
• In trephine biopsy sections, lymphoma cells may have regular round nuclei or irregular/cleaved nuclei with relatively dense chromatin and inconspicuous nucleoli; blastoid variant may show a "starry sky" appearance
• Lymph node histology can display mantle zone, nodular, or diffuse patterns of infiltration; mantle zone pattern potentially represents the earliest stage of involvement
• Peripheral blood film examination shows marked pleomorphism in conventional MCL and blastoid variant showing medium-sized cells with high ratio of nucleocytoplasm, diffused chromatin pattern and some chromatin condensation; small or medium sized nucleoli. Further, PB film in blastoid variant shows a range of cells from mature lymphocytes to blast-like cells with cleft nuclei and some with cytoplasmic vacuoles

Immunophenotype

• Characterized by expression of B-cell-associated antigens (CD19, CD20, CD22, CD24, CD79a, CD5, CD79b, FMC7, BCL2)
• CD10, CD11c, CD103, and BCL6 are typically not expressed. CD20 expression is often stronger than CD19
• CD5 is usually expressed, but 10-15% of patients may lack CD5 expression
• CD23 expression is variable (generally weak when present)
• Immunophenotype crucial for distinguishing MCL from other B-cell malignancies
• Positive markers: CD19, CD20, CD22, CD24, CD79a, CD5, CD79b, FMC7, BCL2
• Negative markers: CD10, CD11c, CD103, BCL6
• Variable markers: CD23 (weak when present), CD38, CD43
• Diagnostic markers: Cyclin D1, SOX11

Cytogenetic Abnormalities

• Hallmark abnormality is t(11;14) (q13.3;q32), leading to dysregulation of the CCND1 gene encoding cyclin D1 and its translocation into proximity with the IGH locus, resulting in cyclin D1 overexpression
• This is not specific to MCL but is considered diagnostic in appropriate clinical/histological context
• Additional cytogenetic abnormalities are common, including deletions 1p, 6q, 9p, 11q, 13q, and gains 3, 12

Molecular Genetic Features

• MCL cells typically show unmutated IGHV genes, indicating a pre-germinal center origin
• A significant minority exhibit IGHV somatic hypermutation and predominantly non-nodal disease, and may be associated with indolent disease
• Secondary genetic abnormalities are common; gains of MYC, CDK2, CDKN1B, and MDM2; losses of RB1, CDKN2A, ATM, and TP53
• Mutations in TP53, CDKN2A, and CDKN2C are associated with the blastoid variant and worse prognosis
• ATM function loss can occur via point mutation or deletion, frequently affecting both alleles in cases with del(11)(q23)

Pitfalls in Diagnosis

• MCL can be challenging to distinguish from CLL/SLL due to shared CD5 positivity.
• Some MCL cases have small-sized cells resembling CLL/SLL, making distinction challenging
• Immunophenotyping and genetic analysis crucial for accurate diagnosis

CD23-Positive MCL

• CD23 positivity typically associated with CLL/SLL; but a subset of MCL cases can express CD23
• Approximately 13% of MCL cases are weakly positive, and these cases often present with increased leukocyte count, bone marrow involvement, and leukemic presentation
• Importantly, CD23-positive MCL is more frequently associated with CD200 positivity and weak SOX11 expression
• Patients with CD23-positive MCL tend to have a better prognosis than those with CD23-negative MCL

CD200 Expression

• CD200 is typically a marker for CLL/SLL but a subset of MCL expressing CD200 complicates differential diagnosis
• About 4% of MCL cases are CD200-positive (most also positive for CD23)
• Distinct characteristics include 24% express SOX11, 39% exhibit round nuclear contours similar to CLL, and 44% present as a non-nodal leukemic variant of MCL
• Cases are often associated with IGHV-mutated status

Mantle Cell Lymphoma International Prognostic Index (MIPI)

• MIPI is a key prognostic tool for MCL incorporating age, ECOG performance status, lactate dehydrogenase level, and white cell count
• Simplified MIPI (s-MIPI) created for routine clinical use and MIPI (MIPI-b) adds Ki67 proliferation index
• 5-year overall survival (OS) rates for low, intermediate, and high-risk MIPI groups are 83%, 63%, and 34%
• Combined MIPI (MIPI-c) integrating the Ki67 index with the standard MIPI score
• Improved stratification compared to MIPI alone (5-year OS rates for low, low-intermediate, high-intermediate, and high-risk are 85%, 72%, 43%, and 17%, respectively)

TP53 Aberrations

• TP53 aberrations (deletions, mutations) are factors influencing prognosis in MCL
• High TP53 expression by immunohistochemistry is associated with inferior time to treatment failure and overall survival
• Patients with TP53 mutations are often enriched for high Ki67 index, blastoid morphology, and high-risk MIPI, with very short median OS

Early Disease Progression

• Disease progression within 24 months is a strong negative prognostic factor for OS in both younger patients treated with high-dose cytarabine-based induction and in older patients unable to receive standard immunochemotherapy
• Time to relapse after intensive induction and autologous stem cell transplantation is a critical factor in prognosis

Prognostic Factors in Relapsed/Refractory MCL

• Several factors (high-risk s-MIPI score, blastoid morphology, and TP53 mutations) are associated with poor outcomes in relapsed/refractory MCL treated with BTK inhibitors
• Patients with these features tend to have lower overall response rates and shorter progression-free survival

Novel Treatment Strategies

• Chemoimmunotherapy regimens are standard first-line options for MCL
• BTK inhibitors (ibrutinib, etc.) incorporated into frontline MCL treatment without chemotherapy show high response rates, particularly in older patients
• Beyond BTK inhibition, new therapies like CAR T-cell therapy, bispecific antibodies, antibody-drug conjugates, and next-generation small molecule inhibitors are being explored for overcoming resistance to current treatments.

Test your knowledge on the cytogenetic abnormalities associated with mantle cell lymphoma. This quiz covers critical concepts such as the hallmark genetic features, diagnostic methods, and prognostic factors in this condition. Dive into the specifics of genetic events and their implications for patient outcomes.