Mantle cell lymphoma (MCL) is an uncommon, distinct clinical subtype of non-Hodgkin lymphoma (NHL) that comprises approximately 8% of all lymphoma diagnoses in the United States and Europe.1,2 Considered incurable, MCL often presents in advanced stages, particularly with involvement of the lymph nodes, spleen, bone marrow, and gastrointestinal tract in the form of lymphomatous polyps. MCL disproportionately affects males, and incidence rises with age, with a median age at diagnosis of 68 years.2 Historically, the prognosis of patients with MCL has been among the poorest among B-cell lymphoma patients, with a median overall survival (OS) of 3 to 5 years, and time to treatment failure (TTF) of 18 to 24 months, although this is improving in the modern era.3 Less frequently, patients with MCL display isolated bone marrow, peripheral blood, and splenic involvement. These cases tend to behave more indolently with longer survival.4,5 Recent advances in therapy have dramatically impacted treatment alternatives and outcomes for MCL. As such, the therapeutic and prognostic landscape of MCL is evolving rapidly.
The histologic diagnosis of MCL by morphology alone is often challenging. Accurate diagnosis relies on immunohistochemical staining for the purposes of immunophenotyping.6 MCL typically expresses B-cell markers CD5 and CD20, and lacks both CD10 and CD23. The genetic hallmark of MCL is the t(11;14) (q13;q32) chromosomal translocation leading to upregulation of the cyclin D1 protein, a critical regulator of the G1 phase of the cell cycle. Specifically, the t(11;14) translocation, present in virtually all cases of MCL, juxtaposes the proto-oncogene CCND1 to the immunoglobulin heavy chain gene.7 Consequently, cyclin D1, normally not expressed in B lymphocytes, becomes constitutively overexpressed. This alteration is thought to facilitate the deregulation of the cell cycle at the G1-S phase transition.8
Gene expression profiling studies have underscored the importance of cell cycle deregulation in MCL, and high proliferation is associated with a worse prognosis.9 More than 50% of the genes associated with poor outcomes were derived from the “proliferation signature” that was more highly expressed in dividing cells. In the seminal Rosenwald study, a gene expression–based outcome model was constructed in which the proliferation signature average represents a linear variable that assigns a discrete probability of survival to an individual patient.9 The proliferative index, or proliferative signature, of MCL can be estimated by the percentage of Ki-67–positive cells present in the tumor through immunohistochemistry. This is often used as a marker of poor outcomes, and as a surrogate for the proliferative signature in MCL that can be incorporated into clinical practice (as opposed to gene expression profiling). Statistically significant differences in OS have emerged between groups of MCL patients with Ki-67–positive cells comprising less than 30% of their tumor sample (favorable) and those with Ki-67–positive cells comprising 30% or greater (unfavorable).10
Recent data has also identified the importance of the transcription factor SOX 11 (SRY-related HMG-box), which regulates multiple cellular transcriptional events, including cell proliferation and differentiation, apoptosis, and angiogenesis.11 MCL expressing SOX 11 behaves more aggressively than MCL variants lacking SOX 11 expression, and tends to accumulate more genetic alterations.12 Moreover, lack of SOX 11 expression characterizes a subset of MCL that does not carry the t(11;14) translocation.
DIAGNOSIS AND STAGING
A 62-year-old man with a history of diabetes mellitus and hypertension presents with cervical lymphadenopathy, fatigue, and early satiety over the past several months. He is otherwise in good health. His Eastern Cooperative Oncology Group (ECOG) performance status is 1. On physical examination, 3-cm lymphadenopathy in the bilateral cervical chain is noted. Bilateral axillary lymph nodes measure 2 to 4 cm. His spleen is enlarged and is palpable at approximately 5 cm below the costal margin. A complete blood count reveals a total white blood cell (WBC) count of 14,000 cells/μL, with 68% lymphocytes and a normal distribution of neutrophils. Hemoglobin is 11 g/dL, and platelet count is 112,000/μL. The lactate dehydrogenase (LDH) level is 322 U/L (upper limit of normal: 225 U/L).
• How is MCL diagnosed?
Diagnosis of MCL requires review by expert hematopathologists.13 Whenever possible, an excisional biopsy should be performed for the adequate characterization of lymph node architecture and evaluation by immunohistochemistry. Aside from the characteristic expression of CD5 and CD20 and absence of CD23, MCL should express cyclin D1, which reflects t(11;14). If cyclin D1 is inconclusive or unavailable, fluorescent in situ hybridization (FISH) for t(11;14) should be performed.8 Patients often have circulating malignant lymphocytes, or leukemic phase MCL. Flow cytometry of the peripheral blood can detect traditional surface markers, and FISH can also be performed on circulating abnormal lymphocytes.