Prognostic factors for relapse and survival among patients with ocular adnexal lymphoma: validation of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM classification.

BACKGROUND/AIMS: To validate the prognostic performance of the American Joint Committee on Cancer (AJCC) eighth edition classification for ocular adnexal lymphoma (OAL). METHODS: We performed a retrospective review of 140 consecutive patients treated for primary OAL between March 2010 and September 2017. Associations between T/N/M categories at presentation and disease-related outcomes, including relapse, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Seventy-nine women and 61 men (median age, 52 (range 20-84) years; median follow-up, 57 (range 7-131) months) were included. Histological subtypes included mucosa-associated lymphoid tissue lymphoma (92.1%, n=129), diffuse large B-cell lymphoma (5.0%, n=7), follicular lymphoma (1.4%, n=2) and mantle cell lymphoma (1.4%, n=2). Patients with ≥T2 disease had significantly higher risks of overall relapse (unadjusted HR)=4.32, p=0.016), decreased PFS (uHR=5.19, p=0.004) and decreased OS (uHR=9.21, p=0.047). Patients with ≥N1 disease had significantly higher risks of overall relapse (uHR=9.17, p<0.001) and decreased PFS (uHR=9.24, p<0.001). M1 disease was significantly associated with higher risks of overall relapse (uHR=3.62, p=0.036), decreased PFS (uHR=5.13, p=0.001) and decreased OS (uHR=9.24, p=0.013). On considering TNM categories as continuous data, the uHRs for per level increase in T, N and M categories were 1.77, 1.83 and 2.30 for overall relapse and 1.72, 1.87 and 2.78 for decreased PFS, respectively (p<0.05 for each comparison). CONCLUSION: The T, N and M categories of the AJCC eighth edition classification have prognostic value for relapse and survival among patients with primary OAL. Particularly, nodal/metastatic involvement at presentation indicated less favourable outcome.

Cutaneous manifestations of mantle cell lymphoma: an extensive literature review.

Mantle cell lymphomas account for about 2 to 10% of non-Hodgkin B-cell lymphomas. Despite the cellular maturity of B-cell lymphomas, the disease is aggressive in the majority of cases and its course is unpredictable. The clinical presentation is variable, and multiple nodal and extranodal manifestations have been described. Cutaneous infiltration is an uncommon (2-6%) location of the disease. An extensive review of the literature was performed, and 24 case reports and five case series were found describing cutaneous locations. These data were thoroughly studied in order to present their clinical and laboratory characteristics in this review.

Advances in Classification and Treatment of Non-Hodgkin Lymphoma: Mantle Cell.

Mantle cell lymphoma is a rare, aggressive, and largely incurable form of non-Hodgkin lymphoma. There are a number of well-characterized prognostic features but nothing that can help guide therapy. Treatment with chemotherapy is generally effective in the short term, but relapse is inevitable and subsequent treatment is challenging. The use of Bruton tyrosine kinase inhibitors, however, has transformed practice. These agents are highly active in relapsed disease and are very well-tolerated drugs. Chemotherapy-free combinations using Bruton tyrosine kinase inhibitors look very exciting and will likely evolve to be part of frontline care in the future.

Molecular Pathogenesis of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with heterogeneous clinical behavior molecularly characterized by the constitutive overexpression of cyclin D1 and deregulation of different signaling pathways. SOX11 expression determines an aggressive phenotype associated with accumulation of many chromosomal alterations and somatic gene mutations. A subset of patients with the SOX11-negative leukemic non-nodal MCL subtype follows an initial indolent clinical evolution and may not require treatment at diagnosis, although eventually may progress to an aggressive disease. We discuss the genetic and molecular alterations with impact on the cancer hallmarks that characterize the lymphomagenesis of the 2 MCL subtypes.

Blastoid Mantle Cell Lymphoma.

Blastoid and pleomorphic mantle cell lymphoma (MCL) are among the worst prognostic, aggressive histology, high-risk variants of MCL, and, in this article, they are presented as blastoid MCL. Blastoid MCL have not been systematically studied, probably due to their rarity. De novo blastoid MCLs have superior outcomes compared with transformed MCL. Compared with classic MCL, extranodal involvement (mainly skin, central nervous system), frequent relapses, and inferior responses to conventional chemoimmunotherapy, BTK inhibitors and venetoclax are frequent in blastoid MCL. KTE-X19 induces excellent response in blastoid MCL. Combinations with novel agents are actively investigated. This article presents a comprehensive review on blastoid MCL in 2020.

Classification of aggressive and classic mantle cell lymphomas using synchrotron Fourier Transform Infrared microspectroscopy.

Mantle cell lymphoma (MCL) is regarded as an incurable neoplasm, even to the novel drug strategies. It is known MCL has two morphological variants- classic and aggressive. Aggressive MCL is characterized by a higher mitotic index and proliferation rate, and poor overall survival in comparison to classic subtype. The insight into the detailed biochemical composition of MCL is crucial in the further development of diagnostic and treatment guidelines for MCL patients; therefore Synchrotron radiation Fourier Transform Infrared (S-FTIR) microspectroscopy combined with Principal Component Analysis (PCA) was used. The major spectral differences were observed in proteins and nucleic acids content, revealing a classification scheme of classic and aggressive MCLs. The results obtained suggest that FTIR microspectroscopy has reflected the histopathological discrimination of both MCL subtypes.

A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.

La revisión de 2016 de la clasificación de la OMS de las neoplasias linfoides: la visión del clínico / The 2016 revision of the WHO classification of lymphoid neoplasms: The clinician's view

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Smoldering mantle cell lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomatic and can be in observation for a long time without any treatment. The process of "wait and watch" leaves these patients with the potential risk of evolution to classic, aggressive MCL. On the other hand, early treatment for these patients may not impact overall survival but rather affects the quality of life. Therefore, it is essential to clearly identify this type of indolent MCL at the time of diagnosis. RESULTS: Reported findings of indolent presentation of MCL include: lack of B symptoms, normal serum lactic dehydrogenase (LDH) and ß2-microglobulin levels (ß2M), low MCL-International Prognostic Index (MIPI) score, maximum tumor diameter less than 3 cm, spleen size < 20 cm, positron emission tomography/computerized tomography with the Standard Uptake Value max <6, Ki-67 less than 30%, with some particular immunophenotype, such as CD5 and CD38 negative, markedly increased CD23 positive lymphocytes proportions, high expression of CD200, kappa light chain restriction, without C-myc, TP53 and NOTCH1/2 mutations, non-blastoid/pleomorphic histology, and no tumor growth on reevaluation every 2~3 months (followed for at least 6 months). Imaging evaluation may only be performed in the presence of disease-related symptoms or organ involvement. Meanwhile, if novel nodal or extranodal lesion is found, biopsy is mandatory to exclude lymphoma. Common clinopathological forms of indolent presentations include monoclonal B lymphocytosis with t (11; 14); "indolent leukemic" presentation of MCL with involvement of peripheral blood, bone marrow involvement, splenomegaly, and minimal lymphadenopathies and in situ lymphoma (often found in lymph nodes removed for other reasons, and in gastrointestinal biopsies). CONCLUSIONS: Considering these distinct indolent clinical presentations with particular features in cytology and gene mutational status, we propose to include these MCL clinical presentations under the umbrella of "Smoldering Mantle Cell Lymphoma".

[Lymphomas]. / Lymphome.

Although malignant lymphoma is split in over 60 distinct entities, four of them, diffuse large B cell lymphoma, follicular-, Hodgkin's- and mantle cell lymphoma constitute more than half of all new cases. A recent major revision of the Ann Arbor staging system restricts the suffix "A" and "B" just to Hodgkin's lymphoma. Bone marrow exams are abandonned in Hodgkin's and restricted in DLBCL. PET exams at different time points are crucial. PET guided therapy will lead to a reduction of the use of chemo- and radiation therapy. Many new targeted drugs have been introduced. Their therapeutic index is impressive as is their price tag. The radiation and chemotherapy free treatment of malignant lymphoma is within reach.

Ki-67 Labeling Indices in 'Classic' versus 'Blastoid' Mantle Cell Lymphomas--Proposed Cutoff Values for Routine Diagnostic Workup.

BACKGROUND: Mantle-cell lymphoma (MCL) is a unique entity of peripheral B-cell lymphoma that has a discrete morphologic, immunologic, and genetic phenotype, with more common 'classic' and less frequent 'blastoid' and 'pleomorphic' variants, associated with an aggressive clinical course. The aim of this study was to analyze proliferation (Ki-67) indices of 'classic' (c-MCL) and 'blastoid' (b-MCL) variants of a cohort of MCL and to suggest cut off values for the Ki-67 proliferation index in these two subsets. MATERIALS AND METHODS: MCL cases diagnosed over 4 1/2 years at Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi were retrieved and reviewed. Ki-67 labelling was scored and analysed. RESULTS: A total of 90 of cases of MCL were scrutinized. Mean age±SD was 60.2±12.5 years and the male to female ratio was 4:1, with 67 (75%) cases of c-MCL and 23 (25%) cases of b-MCL. Most samples were lymph node biopsies (n=68), whereas the remainder were from various extranodal sites The mean Ki-67 proliferation index was 29.5%±14.4% in classic variants and 64.4±15.2% for the blastoid variant, the difference being statistically significant (p=0.029). CONCLUSIONS: It was concluded that differential cut-off values of Ki-67 labeling may be used in more objective way to reliably classify MCL into classic or blastoid variants by diagnostic pathologists. We propose a <40 proliferative index to be suggestive of c-MCL and one of >50 for the blastoid variant.

CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics. AIMS AND METHODS: A series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry. RESULTS: GEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data. CONCLUSIONS: This study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.

The role of SOX11 immunostaining in confirming the diagnosis of mantle cell lymphoma on fine-needle aspiration samples.

BACKGROUND: Mantle cell lymphoma (MCL) demonstrates cytologic features that overlap with those of other types of B-cell non-Hodgkin lymphomas (B-cell NHLs) containing small to medium-sized cells. The accurate diagnosis of MCL is important because MCL has relatively more aggressive biologic behavior and thus requires specific treatment regimens. Fine-needle aspiration (FNA) is used for diagnosing or staging lymphoma, often with the help of immunophenotyping by flow cytometry. However, the cellularity of an FNA sample may not be high enough for flow cytometry, leading to diagnostic difficulty. SOX11 immunostaining is helpful in the diagnosis of MCL in histologic sections. However, to the authors' knowledge, its diagnostic value for FNA samples has not been studied to date. METHODS: Immunostains for SOX11 were performed on 69 FNA cases with final diagnoses of MCL (13 cases, including 10 classic type and 3 blastoid variant), marginal zone lymphoma (8 cases), follicular lymphoma (10 cases), small lymphocytic lymphoma (12 cases), Burkitt lymphoma (9 cases), plasma cell myeloma (7 cases), and benign lymph nodes (10 cases). Preparation types included cytospin slides (65 cases), direct smears (2 cases), and cell block sections (2 cases). The percentage of positive cells (defined as nuclear staining) and staining intensity were recorded. RESULTS: All 13 cases of MCL were positive for SOX11 staining, with 12 cases demonstrating diffuse positivity. All other types of B-cell NHL cases, plasma cell myelomas, and benign lymph nodes were found to have negative results. Weak staining was found in 1 MCL case of blastoid variant. CONCLUSIONS: SOX11 immunostaining on FNA samples is highly sensitive and specific for MCL and can be used as a reliable adjunct to confirm MCL, especially in a recurrent setting.

B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma.

B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell malignancy that may be hard to distinguish from mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). B-PLL cases with a t(11;14) were redefined as MCL in the World Health Organization 2008 classification. We evaluated 13 B-PLL patients [7 being t(11;14)-positive (B-PLL+) and 6 negative (B-PLL-)] and compared them with MCL and CLL patients. EuroFlow-based immunophenotyping showed significant overlap between B-PLL+ and B-PLL-, as well as between B-PLL and MCL, whereas CLL clustered separately. Immunogenotyping showed specific IGHV gene usage partly resembling MCL. Gene expression profiling showed no separation between B-PLL+ and B-PLL- but identified 3 subgroups. One B-PLL subgroup clustered close to CLL and another subgroup clustered with leukemic MCL; both were associated with prolonged survival. A third subgroup clustered close to nodal MCL and was associated with short survival. Gene expression profiles of both B-PLL+ and B-PLL- showed best resemblance with normal immunoglobulin M-only B-cells. Our data confirm that B-PLL+ is highly comparable to MCL, indicate that B-PLL- also may be considered as a specific subgroup of MCL, and suggest that B-PLL is part of a spectrum, ranging from CLL-like B-PLL, to leukemic MCL-like B-PLL, to nodal MCL-like B-PLL.

Mantle cell lymphoma: 2013 Update on diagnosis, risk-stratification, and clinical management.

DISEASE OVERVIEW: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with a short remission duration to standard therapies and a median overall survival of 4-5 years. DIAGNOSIS: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t(11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION: The Mantle Cell Lymphoma International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median overall survival (OS) for the low risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. RISK-ADAPTED THERAPY: For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytarabine containing regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor) or lenalidamide (anti-angiogenesis) are approved agents. Clinical trials with Ibruitinib (Bruton's Tyrosine Kinase inhibitor) or Idelalisib (PI3K inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients.

Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis.

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1-positive MCL (n = 30) and cyclin D1-negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.

Scoring systems in mantle cell lymphoma: a critical point of view.

A proposal for a scoring system in the diagnosis of chronic lymphoproliferative diseases other than CLL has been recently published in Cytometry Part B. The authors apply this score for deciding whether or not FISH evaluation for the detection of IGH/CCND1 rearrangements must be performed to exclude Mantle Cell Lymphoma (MCL). In their validation series, no MCL scored <3. We have applied their system to our cases of MCL and also to a small series of Marginal Zone lymphomas. In our hands, the scoring system as has been published does not discriminate adequately between both entities. We propose using the negativity of a marker, CD11c, instead of the platelet count to improve the results. However, we believe that given the clinical and prognostic implications of the diagnosis of MCL, scoring systems should be greatly ameliorated prior to their generalized use.

Outcome prediction of advanced mantle cell lymphoma by international prognostic index versus different mantle cell lymphoma indexes: one institution study.

The aim of this study was to evaluate the prognostic significance of international prognostic index (IPI), mantle cell lymphoma IPI (MIPI), simplified MIPI (sMIPI), and MIPI biological (MIPIb), as well as their correlation with immunophenotype, clinical characteristics, and overall survival (OS), in a selected group of 54 patients with advanced-stage mantle cell lymphoma (MCL), treated uniformly with CHOP. Seventeen patients had IV clinical stage (CS), while other 37 had leukemic phase at presentation. Diffuse type of marrow infiltration was verified in 68.5% and nodular in remainder patients. Extranodal localization (25.9%) included bowel (20.4%), pleural effusion, sinus, and palpebral infiltration. All of analyzed patients expressed typical MCL immunophenotypic profile: CD19(+)CD20(+)CD22(+)CD5(+)Cyclin-D1(+)FMC7(+)CD79b(+)smIg(+)CD38(+/-)CD23(-)CD10(-). Median OS of the whole group was 23 months, without significant differences between IV CS and leukemic phase patients. Thirty-two patients (59.3%) responded to initial treatment, 9 (16.7%) with complete and 23 (42.6%) with partial remission. Negative prognostic influence on OS had high IPI (P < 0.01), high sMIPI (P < 0.001), MIPI (P < 0.01), MIPIb (P < 0.01), extranodal localization (P < 0.01), and diffuse marrow infiltration (P < 0.01). Testing between randomly selected groups showed that patients with lower proportion of CD5(+) cells (<80%) correlated with cytological blastoid variant and had shorter survival comparing with the group with higher proportion of CD5(+) cells (>80%) (P < 0.01). Using univariate Cox regression, we proved that IPI, sMIPI, MIPI, and MIPIb had an independent predictive importance (P < 0.01) for OS in uniformly treated advanced MCL patients, although sMIPI prognostic significance was the highest (P < 0.001).