Mantle cell lymphoma

This perspective article by Drs. Pileri and Falini examines the diagnosis and bio-pathology of mantle cell lymphoma in the light of the criteria of the WHO Classification and recent reports. See related articles on pages 1555, 1563 and 1595.In 1982, Weisenburger et al. first introduced the concept of mantle-zone lymphoma.¹ According to the terminology used at that time, this was regarded as a variant of intermediate lymphocytic lymphoma that proliferated as wide mantles around non-neoplastic appearing germinal centers (GC). One year later, Swerdlow et al. found that the pattern described above was part of the spectrum of the centrocytic lymphoma of the Kiel Classification and might correspond to initial lymph node involvement by the tumor.^2,3 In 1985, Pileri et al. reported on 18 cases of small B-cell lymphomas displaying a mantle-fashion growth around reactive GC, which turned out to be quite heterogeneous on closer examination.⁴ In fact, at disease presentation 13 of the 18 cases displayed cytological and immunological findings consistent with centrocytic lymphoma, while the remaining ones corresponded to neoplasms that nowadays would be diagnosed as marginal zone lymphoma. Interestingly, the centrocytic lymphomas were CD5⁺, FMC7⁺ and CD10⁻ and showed progression to a diffuse growth pattern in follow-up biopsies. Two important conclusions were reached: (i) the mantle-fashion growth was produced by different types of B-cell lymphoma and could not be used as a diagnostic criterion, and (ii) conversely to what is reported in the Kiel Classification,³ centrocytic lymphomas are derived from a normal counterpart other than GC, possibly related to mantle cells. In 1992, the International Lymphoma Study Group (ILSG) made its first experiment to overcome the discrepancies in terms of lymphoma classification that had hampered communication across the Atlantic for some decades.⁵ In particular, the American and European ILSG members agreed on the existence of a tumor derived from mantle B cells that was consequently termed mantle-cell lymphoma (MCL). The criteria for its recognition were drafted and included 2 years later in the Revised European-American Lymphoma Classification that led the way to the latest edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues.^6,7 The present article will focus on the diagnosis and bio-pathology of MCL in the light of the criteria of the WHO Classification⁷ and recent reports in the literature including those of Quintinilla-Martinez et al., Mozos et al. and Dictor et al. in this issue of the journal.^8–10 It will not include the still ongoing debate on the multiple options proposed for the treatment of MCL patients, which often have limited efficacy (comprehensively reviewed by Ghielmini et al.).¹¹     

Mantle cell lymphoma

PURPOSE OF REVIEW: Mantle cell lymphoma is the B-cell lymphoma with the worst prognosis. Until now, no standard treatment has resulted in cure. Improvements in understanding of the disease are needed to advance therapeutic efforts. RECENT FINDINGS: Pathology and immunohistochemistry can identify the subset of patients with the worse prognosis. New data suggest that at least a subset of mantle cell lymphoma cases have undergone some form of antigene selection, and particular types of Ig gene rearrangement seem to give a better prognosis. The cell cycle, the ATM, gene and the nuclear factor kappaB pathways are the main targets of the genetic abnormalities occurring in mantle cell lymphoma: new genomic and expression data have been recently published. Unfortunately, this progress has not yet brought any major improvements in therapeutic approaches, which still remain highly unsatisfactory. Autologous and allogenic bone marrow transplantations appear to be the only current treatments that might improve the outcome of patients with PMCL. New additional treatment modalities are currently under investigation. SUMMARY: This review summarizes all the most recent data published on the biology and treatment of mantle cell lymphoma.     

Mantle cell lymphoma

MCL is a well-characterized clinically aggressive lymphoma with a poor prognosis. Recent research findings have slightly improved the outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it does not improve overall survival with respect to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidated by ASCT ameliorates response rate and prolongs progression-free survival, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better dissection of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy in most patients and spare the toxicity of intense therapy in a minority of MCL patients characterized by a relatively indolent disease. Patients not eligible for intensive regimens, such as hyperC-VAD, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy for relapsed disease, although there are currently no data to recommend this approach as the first-line strategy. As the optimal approach to the management of MCL is still evolving, it is critical that these patients be enrolled in clinical trials to identify better treatment options.     

Changing epidemiology and risk factors for gastrointestinal non-Hodgkin's lymphoma in a North American population: population-based study

OBJECTIVES: To assess the incidence, risk factors, and endoscopic presentation of gastrointestinal non-Hodgkin's lymphoma (GI NHL) in a large predominantly urban adult population sample.
METHODS: A comprehensive database review of all diagnoses of GI NHL in the Calgary Health Region over a 5-yr period (1999–2003) was undertaken. Longer-term data from a population-based HIV database (1985–2004) were also reviewed. A regional pathology database was used to corroborate case identification. All patients 18 yr of age or older were included. Age- and gender-adjusted incidence rates were calculated. Within the HIV-positive population, incidence rates were compared over time. Endoscopic appearances were assessed and compared.
RESULTS: Fifty-six GI NHL cases occurred during the study period. The age- and gender-adjusted annual incidence of GI NHL was 1.73 per 100,000 in the study population. The majority were diffuse large B-cell histology (54%), followed by lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (29%). Increasing age, history of kidney transplant, and H. pylori positivity in MALT lymphoma were identified as risk factors. Within the HIV-positive population, a highly significant drop in GI NHL was seen over time, with an incidence of 3.86 per 1,000 patient-years in 1985–1989 compared to zero cases in 2000–2004, despite a greater prevalence of HIV disease ( P < 0.0001 for trend). MALT lymphoma was less likely to manifest as a mass on endoscopy versus other presentations ( P < 0.05).
CONCLUSIONS: Population-based GI NHL incidence rates in Calgary are higher than those described elsewhere in North America or in Britain. The incidence of GI NHL within the HIV population has virtually disappeared, presumably due to the advent of highly active retroviral therapy.     

The epidemiology of inflammatory bowel disease in Canada: a population-based study

BACKGROUND: Previously, we have demonstrated a high incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in the Canadian province of Manitoba. However, the epidemiology of inflammatory bowel disease (IBD) in other regions of Canada has not been defined. The aim of this study was to estimate the incidence and prevalence of CD and UC in diverse regions of Canada and the overall burden of IBD in Canada. METHODS: We applied a common case identification algorithm, previously validated in Manitoba to the provincial health databases in British Columbia (BC), Alberta (AB), Saskatchewan (SK), Manitoba (MB), and Nova Scotia (NS) to determine the age-adjusted incidence rates per 100,000 person-years for 1998-2000 and prevalence per 100,000 for mid 2000 and to estimate the IBD burden in Canada. Poisson regression was used to assess differences in incidence rates and prevalence by gender, age, and province. RESULTS: The incidence rate for CD ranged from 8.8 (BC) to 20.2 (NS), and for UC ranged from 9.9 (BC) to 19.5 (NS). The prevalence of CD was approximately 15- to 20-fold higher than the incidence rate, ranging from 161 (BC) to 319 (NS). This was similar for the prevalence of UC, which ranged from 162 (BC) to 249 (MB). Adjusting for age and province, the female:male ratio for incidence ratio was 1.31 (p < 0.0001) for CD and 1.02 (n.s.) for UC and was mostly stable across the five provinces. CONCLUSIONS: Approximately 0.5% of the Canadian population has IBD. Canada has the highest incidence and prevalence of CD yet reported.     

Survival analysis in treated plasmablastic lymphoma patients: a population-based study

Herein we analyzed survival outcomes in chemotherapy-treated patients with plasmablastic lymphoma (PBL) diagnosed between 2010 to 2016 (n = 248). Data was acquired from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database (April 2019 release based on November 2018 submission). The majority of patients were male (81.9%) and younger than 60 years (71.0%). Oral and gastrointestinal (GI) sites were the most frequent primary extranodal locations (23% and 19.4%, respectively). Oral primary location was inversely associated with presence of B symptoms and advanced Ann-Arbor stage. The 3-year and 5-year overall survival (OS) rates of treated PBL patients were 54% (95% CI: 46.5%-60.8%) and 52.8% (95% CI: 45.2%-59.8%). Three-year conditional survival for 2-year and 3-year survivors were 90.3% and 97.8%, overlapping the survival of a general population matched by age, sex and calendar year. In a multivariable analysis, oral primary location was associated with not only better OS (HR 0.43; 95% CI: 0.21-0.88, P = .021) but also better lymphoma-specific survival (LSS) (SHR 0.36; 95% CI: 0.15-0.86, P = .022); age ≥60 years was associated with shorter LSS (SHR 1.73; 95% CI: 1.02-2.96, P = .043). Seven registries granted access to HIV status (n = 93) where HIV infection was detected in 52.7% of cases. The HIV status did not affect survival outcomes in unadjusted and adjusted analyses. We identified clinical characteristics associated with survival and showed that treated PBL patients may achieve long-term survival.     

Mantle cell lymphoma mimicking chronic lymphocytic leukemia

A 62-year-old male was admitted to our hospital complaining of dyspnea in March, 2002. He had remarkable bone marrow invasion with a significant number of leukemic cells, anemia and thrombocytopenia. In addition he had generalized lymphadenopathy including a bulky mass in the left cervix. Surface marker analysis of abnormal cells showed CD 5+, 10-, 19+, 20+, 23+, and kappa+, and immunohistochemistry revealed cyclin D1-positive cells. Chromosome analysis showed del(11q). The patient was diagnosed as having mantle cell lymphoma, stage IVB, and received combination chemotherapy. He could not obtain complete remission and died after 29 months. We found it very difficult in this case to make a differential diagnosis between mantle cell lymphoma and chronic lymphocytic leukemia. We report on this case and summarize the problem of the differential diagnosis.     

Mantle cell lymphoma: established therapeutic options and future directions

During the last few years, new insights into the biology of mantle cell lymphoma have been obtained. However, with a median survival of only 3 years, mantle cell lymphoma remains the lymphoma subtype with the poorest prognosis. At initial diagnosis most patients present with advanced Ann Arbor stage III or IV and conventional chemotherapy hardly alters the continuously declining survival curve. Recently, two prospective randomized studies of the German Low Grade Lymphoma Study Group (GLSG) clearly confirmed the superiority of a combined immunochemotherapy. In a randomized study of the European mantle cell lymphoma Network, consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation improved the progression-free survival in patients younger than 65 years. However, relapses are still observed at a high frequency. Thus, new therapeutic strategies such as radioactively labeled antibodies or molecular targeting agents (e.g. Bortezomib or flavopiridol) are urgently warranted to further improve the clinical outcome of mantle cell lymphoma.     

Mantle cell lymphoma: the promise of new treatment options

Though the expected overall survival (OS) for mantle cell lymphoma (MCL) has doubled in the last 30 years it is still in the range of only 4–5 years. Despite high response rates with current first-line treatments, most patients eventually relapse and become typically chemoresistant, leading to very poor outcome in the relapsed setting. Here, we summarize the clinical characteristics of MCL and frontline strategies used in MCL, and review a number of novel options that are currently being investigated in an effort to extend survival outcomes for this difficult-to-treat patient population. Among these novel options figure cytotoxics (bendamustine, cladribine), new biologicals/small molecules such as proteasome inhibitors (bortezomib 1st drug approved in the USA for MCL), mTOR inhibitors with temsirolimus (1st drug approved in EU for MCL), CDK inhibitors (flavopiridol); IMiDs (thalidomide, lenalidomide); HDAC inhibitors, Bcl-2 inhibitors and second or third generation monoclonal antibodies or immunotoxins. The panel of novel drugs approved or being tested offers new opportunities in the management of MCL from combination in the frontline setting (e.g. bortezomib-R-chemo) to post-induction strategies such as consolidation (e.g. radioimmunotherapy, bortezomib) or maintenance therapy (e.g. rituximab, lenalidomide).