Variant Of Mantle Cell Lymphoma Research Articles

Cyclin D1 + large B-cell lymphoma with altered CCND1 and BCL-6 rearrangements: a diagnostic challenge

BackgroundA subset of diffuse large B-cell lymphoma may show aberrant cyclin D1 expression, which may be confused with blastoid mantle cell lymphoma. These cases usually lack of CCND1 gene rearrangement. Duplication of CCND1 gene was attributed to some of the cases with cyclin D1 expression. The mechanism of overexpression of CCND1 in other cases was not well documented.Case presentationWe report a case of diffuse large B-cell lymphoma with cyclin D1 expression. The underlying mechanism for cyclin D1 expression was due to an abnormal gene rearrangement involving BCL-6 and CCND1, which was different from most reported cases. Rare cases with similar genetic profile were reported and were classified as diffuse large B-cell lymphoma.ConclusionThe phenotype and genetic abnormalities of DLBCL with cyclin D1 overexpression can be complex and may be difficult to differentiate from blastoid and pleomorphic variants of mantle cell lymphoma.

High-grade B-cell lymphomas with TdT expression: a diagnostic and classification dilemma

Mature B-cell neoplasms and immature or precursor B-cell neoplasms need to be distinguished because these patients usually require different therapeutic approaches. B-cell neoplasms that express TdT without unequivocal other features of immaturity may therefore present a diagnostic challenge. We describe 13 patients with TdT-positive aggressive B-cell lymphoma. The clinicopathologic features of these patients were highly heterogeneous, but for the purpose of this study we grouped these cases as follows: (1) de novo high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) with TdT expression. In this group we included two cases of de novo composite lymphoma in which there were components of diffuse large B-cell lymphoma and TdT-positive blastic B-cell lymphoma; (2) TdT-positive aggressive B-cell lymphoma arising in patients who previously had follicular lymphoma; (3) initial relapse of TdT-negative aggressive B-cell lymphoma in patients who previously had follicular lymphoma, followed by relapses in which the neoplasm acquired TdT expression; and (4) mature B-cell lymphomas that acquired TdT expression at relapse. This group included one case of EBV-positive diffuse large B-cell lymphoma and one case of pleomorphic variant mantle cell lymphoma. All patients in this study had an aggressive clinical course and a dismal outcome despite appropriate therapy. Rather than “squeezing” these cases into current World Health Organization classification categories, we suggest the use of a descriptive term such as high-grade B-cell lymphoma with TdT expression. In these tumors, the cytogenetic findings and poor prognosis of this patient subgroup suggest that these neoplasms need to be distinguished from B-lymphoblastic leukemia/lymphoma. Segregation of these neoplasms also may foster additional research on these neoplasms.

Accuracy of diagnosing mantle cell lymphoma and identifying its variants on fine-needle aspiration biopsy.

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma portending an aggressive clinical course; the blastoid and pleomorphic morphological variants have an even worse prognosis. In addition, patients with classic morphology and a high proliferation index (HPI), also have reduced survival. Although variants have been defined, to the authors' knowledge the ability to detect these subtypes by fine-needle aspiration biopsy (FNAB) has not been described. MCL cases diagnosed by lymph node FNAB with concurrent core needle biopsy were reviewed from 146 patients, accounting for 172 specimen pairs. FNAB and core needle biopsy diagnoses were compared to determine concordance rates. Flow cytometric immunophenotype and Ki-67 rates were evaluated. The classic subtype was diagnosed in 58% of cases (99 of 172 pairs) and variant morphology was diagnosed in 42% of cases (73 of 172 pairs) by histology. Twenty-nine patients presented with variant morphology whereas 28 underwent transformation. A nontraditional immunophenotype including loss of CD5 or FMC-7 and expression of CD23 and CD10 was found in 44% of variants (29 of 66 variants) and 19% of classic subtypes (18 of 94 classic subtypes) (P = .0008). Ki-67 rates averaged from 56% to 76% for blastoid and pleomorphic cases, 53% to 55% for MCL-HPI cases, and 17% to 19% for classic cases. The sensitivity and specificity to detect MCL variants by FNAB were 74% and 93%, respectively. The accuracy of diagnosing MCL is high when adequate samples for cytomorphology and flow cytometry are obtained. Subtyping variants by cytomorphology alone has challenges, but overall demonstrates high sensitivity and specificity. The performance of Ki-67 on cytology specimens is useful for detecting MCL with HPI.

Outcome of young patients with blastoid variant mantle cell lymphoma: An analysis of 138 patients.

e19548Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with heterogeneous outcomes. Small studies have shown that the blastoid variant has a particularly poor prognosis. We p...

CD200 expression in mantle cell lymphoma identifies a unique subgroup of patients with frequent IGHV mutations, absence of SOX11 expression, and an indolent clinical course

CD200, a marker currently utilized in the diagnosis of B-cell lymphoma, is uniformly positive in chronic lymphocytic leukemia/chronic lymphocytic leukemia, and is usually absent in mantle cell lymphoma. Over a 6 year-period, of 668 mantle cell lymphoma assessed by flow cytometry, CD200 expression was detected in 25 patients (~4%). All 25 patients had bone marrow involvement; however, 11 (44%) patients had no nodal or extranodal disease and belonged to non-nodal leukemic variant mantle cell lymphoma. Morphologically, bone marrow showed an unusual interstitial infiltrative pattern in 14/25 (56%) and small round cells resembling chronic lymphocytic leukemia in 9/25 (36%). CD23 was positive in 19/25 (76%) patients; and SOX11 was only positive in 5/21(24%). All 4 patients tested showed IGHV mutations. With a median follow-up of 23 months, 12/24 (50%) patients were not treated. These clinicopathological features were significantly different from 154 randomly chosen CD200-negative mantle cell lymphoma patients, in SOX11 positivity (24% versus 74%, P<0.0001), CD23 expression (76% versus 8%, P<0.0001), a non-nodal leukemic presentation (44% versus 2%, P<0.001), and therapy requirement (50% versus 92%, P<0.0001). This is the first study to show that CD200 expression in mantle cell lymphoma, though uncommon, identifies a subgroup of mantle cell lymphoma patients with characteristic pathological features, frequent non-nodal leukemic variant, and an indolent clinical course.

A unique case of blastoid variant of mantle cell lymphoma with an aberrant CD5-/CD10+/Bcl-6+/CD56+ immunophenotype: a case report.

The neural adhesion molecule CD56 is normally expressed on natural killer cells and subsets of T cells and is commonly found in hematolymphoid neoplasms. Expression of CD56 is very rare in B-cell lymphoma and most reported CD56-positive cases were diffuse large B-cell lymphomas. Cases of CD56-positive mantle cell lymphoma (MCL) have not previously been described in the literature. We present a case of CD56-positive MCL. To the best of our knowledge, this is the first case report of MCL expressing CD56.

A possible new morphological variant of mantle cell lymphoma with plasma-cell type Castleman disease-like features

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by overexpression of cyclin D1 resulting from t(11;14)(q13;q32) translocation. Herein, we report 3 cases of MCL with features of plasma cell-type Castleman disease (CD). The 3 patients were all men, ranging from 51 to 74 years in age, and they all presented with systemic lymphadenopathy with anemia, hypoalbuminemia, elevated serum levels of C-reactive protein, and polyclonal hypergammaglobulinemia. Lymph node biopsy specimens of the 3 cases showed histological features of plasma cell-type CD, including atrophic germinal centers and interfollicular plasmacytosis, with no light chain restriction. However, flow cytometric analysis demonstrated an abnormal B-cell population with CD5 expression, and further analysis using cyclin D1 immunostaining highlighted a neoplastic component that was restricted to the mantle zone. These neoplastic cells were immunohistochemically positive for CD20, CD5, and SOX11, and negative for CD3, CD10, and HHV8. The Ki67 index was low. All patients were finally diagnosed with MCL. This rare type of MCL can be misdiagnosed clinically and histologically as CD. Therefore, it is important to recognize this rare type of MCL, and careful examination is required using both histological and flow cytometric analyses.

Use of Ibrutinib Via Nasogastric (NG) Tube & Percutaneous Endoscopic Gastrostomy (PEG) Tube

We describe the successful administration of ibrutinib via nasogastic (NG) tube & percutaneous endoscopic gastrostomy (PEG)tube. It was not previously known by the manufacturer if this route of administration was possible.Our patient was a 71 year old man diagnosed with a leukaemic variant mantle cell lymphoma. He was commenced on R-CHOP (rituximab, cyclophospahmide, doxorubicin, vincristine, prednisolone) chemotherapy however after 3 cycles of chemotherapy there was no reduction in his lymphadenopathy or splenomegaly despite a reduction in the peripheral blood lymphocytosis.During the R-CHOP chemotherapy, the patient suffered left-sided facial shingles causing Ramsay Hunt syndrome. He was left with a residual neurological swallowing deficit requiring nasogastric feeding. Due to the lack of response to R-CHOP chemotherapy, we felt that ibrutinib could be a useful second line treatment, however we were not sure if the capsule could be opened to allow administration via his nasogastric tube. We contacted the manufacturer who said that there was no data about this method of administration and therefore it was not recommended. Our own research identified one ongoing clinical trial comparing suspension and sprinkle formulations of ibrutinib to the capsule formulation (NCT02390609). This trial was unreported however we felt encouraged that this method of administration did seem feasible.It was felt that ibrutinib represented the best chance of a useful disease response so full dose treatment was commenced via the nasogastric tube. This was later changed to a percutaneous endoscopic gastrostomy (PEG) tube. The patient opened the capsule and flushed the contents down the tube with water.A follow up blood count 2 weeks later showed a marked lymphocytosis (baseline lymphocyte count 0.4 x109/L, risen to 40.8 x 109/L), as would be expected with ibrutinib therapy. This reduced to near normal values over the following 3 months, accompanied by an improvement in the haemoglobin and platelet counts. Imaging at 3 months confirmed compete resolution of all pre-existing lymphadenopathy and the previous 25.6 cm splenomegaly.Our patients' dramatic response suggests that capsule formulation ibrutinib can be successfully administered by NG or PEG tubes. DisclosuresMaddox:Janssen: Other: Funding to attend ASH 2016 (travel, accommodation, registration); Boehringer-Ingelheim: Other: Funding to attend ASH 2014 (travel, accommodation, registration).

Clinical Efficacy of the Rivbd Combination for Refractory/Relapsed (R/R) Mantle Cell Lymphoma (MCL) Patients: A Retrospective Study of the French Lysa Group

BackgroundThere is no standard treatment for R/R MCL that fail first line treatment. Non cross resistant regimens are usually used, which provided sometimes good overall response rate (until 93%) but with a minor disease control (PFS<2years). [1] The main objective of these salvage regimens is to bypass disease resistance, to obtain more profound ( deep or durable) response and to ensure, in younger patients, the option of performing autologous or allogenic stem cell transplantation. For older patients prolonging disease free survival is the aim. The new combination RiVBD (Rituximab-Bendamustine-Bortezomib-Dexametasone) has recently shown to be an effective regimen in frontline for eldery patients with a good tolerability profile (NCT 01457144). [2] Many French centers have also used this association for the R/R patients.AimTo explore the efficacy of the RiBVD regimen in the salvage therapy setting following failure of one, two or more prior treatments.MethodsWe proposed to all French LYSA partner centers a survey to retrospectively evaluate the efficacy of the RiBVD regimen in R/R MCL patients, regardless of prior treatments used. The RiBVD regimen comprises : Rituximab 375mg/sqm D1, Bendamustine 90mg/sqm D1 and D2, bortezomib 1,3mg/sqm D1, D4, D8, D11 and dexamethasone 40 mg D2. Analysis was performed in June 2016.ResultsFrom January 2012 to December 2015, 49 patients from 17 French hematological centers were recruited to the study. The median age was 72 years (50-91y) with 14 young (<65y) and 35 older patients (> 65y). Thirty eight cases presented with classic MCL variant and 11 had a blastoid variant. All patients but one were CD20+, CD5+, CD10- and were positive CYCLIN D1 expression and/or the t(11;14)(q13;q32). Eighteen patients presented a t(11;14) (q13;q32).The CYCLIN D1 negative patient had a t(11;14).Treatment history: Twenty seven patients received RiBVD in second line, 12 in third line and 10 patients after the third lines. Twenty two patients were refractory to their previous line and 27 were in relapse. Before RiBVD 44/49 patients (90%) had received high dose cytarabine, 3 Ibrutinib and 14 patients were intensified (11 at diagnosis, 3 in relapse).Efficacy: The global overall response rate (ORR) was 75% (37/49, 23 CR and 14 PR). For patients treated in 2nd line, the ORR was 85% (23/27, 16 CR and 7 PR), in 3nd line 58% (7/12, 4 CR and 3 PR), and 70% (7/10) for the others (3 CR and 4 PR). Young patients had an ORR of 64% (9/14, 8 CR, 2 RP) and elderly pts 77% (27/35, 15 CR, 12 PR). For relapsed and refractory pts the ORR was respectively 85% (23/27, 15 CR and 8 PR) and 63% (14/22 with 8 CR and 6 PR). For Classic and blastoid variants the ORR was 81.5% (31/38, 20 CR and 11 PR) and 54% (6/11, 3 CR and 3 PR) respectively. Note that 2/3 pts receiving RiBVD regimen post Ibrutinib failure, reached PR (n=2) and showed stable disease (n=1).Major toxicities were seen in 31 pts (63%) with grade 3/4 hematological toxicity in 22 pts, grade 3 neurotoxicity in 3 pts, grade 3/4 cardiotoxicity in 3 pts, grade 3/4 infectious complications in 8 pts, grade 4 fatigue in 3 pts and grade 3 digestive-tract or cutaneous toxicity in one pt each.At the update point, 17 pts had died, 15 for lymphoma progression, 2 for TRM while experiencing a CR (infectious and leukemia). The follow-up of the 32 surviving pts was 14.5 month. The median PFS was 9 months for the 49 pts. The PFS was statistically affected by the pathologic type (classic vs Blastoid, p=0.03), the number of prior treatment (one vs >one, p=0.04) and response to RiBVD (CR vs PR vs no response, p<0.0001 with a median PFS not reached for CR pts, 6 months for PR and 2 months for no response. The age (<65 vs >65) or the state (relapse or refractory) at the time of RiBVD had no impact on PFS.ConclusionThe RiBVD regimen which shows remarkable efficacy in frontline treatment of elderly MCL pts, shows potential as a salvage therapy for refractory or relapsed MCL following cytarabine based treatment. This is particularly true for the 47% of patients achieving CR for which 2 years PFS was 71% regardless of their age.1. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol 2016; 34: 1256-1269.2. Gressin R, Callanan M, Daguindau N et al. Frontline therapy with the RiBVD regimen elicits high Clinical and Molecular Response Rates and long PFS in elderly patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II trial by the LYSA group. Blood 2014. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

47 - Bi-allelic Amplification of ATM Gene in Blastoid Variant of Mantle Cell Lymphoma: A Novel Mechanism of Inactivation Due to Chromothripsis?

Mantle cell lymphoma (MCL) is a lymphoid tumor derived from naïve CD5+ cells with the cytogenetic hallmark t(11;14) resulting in over-expression of the CCND1 gene. The presence of multiple chromosome abnormalities in addition to t(11;14) is known to be associated with blastoid variants (BMCL) and poor prognosis in MCL. High proportion of these tumors also show deletion of chromosome 11q22-23 or loss of heterozygosity; a region where the ATM gene located. The principal function of the ATM protein is integration of cellular responses to DNA double-strand breaks and this function is vital in preventing propagation of DNA damage and transmission of DNA errors resulting in tumorigenesis. MCL tumors with bi-allelic ATM inactivation show significantly higher chromosome imbalances compared to MCLs with wild type ATM alleles suggesting that loss of ATM alleles increases chromosomal instability of the tumor cells. We report a unique case of BMCL where conventional cytogenetic analysis showed multiple chromosome abnormalities including t(11;14) and, contrary to published reports, bi-allelic amplification of ATM by FISH and SNP microarray. Apart from several characteristic gains, losses and regions of LOH, SNP microarray also showed high complexity abnormalities suggestive of chromothripsis involving chromosomes 7 and 11, especially involving the ATM gene region. Although Bi-allelic ATM mutations are common, gene amplification has never been reported in MCL. Focal chromothripsis as a mechanism of inactivating tumor suppressor genes was postulated in Retinoblastoma and we propose that chromothripsis inactivated both ATM alleles in our patient leading to multiple chromosome abnormalities and development of BMCL.

Nasal Blastoid Variant of Mantle Cell Lymphoma with Rearrangement of CCND1 and c-myc Genes with One Case Report

Nasal Blastoid Variant of Mantle Cell Lymphoma with Rearrangement of CCND1 and c-myc Genes with One Case Report

Clinicopathologic features, management and outcomes of blastoid variant of mantle cell lymphoma: a Nebraska Lymphoma Study Group Experience

The objective of this retrospective study (N = 169) was to compare the overall survival (OS) of different subtypes of mantle cell lymphoma (MCL) treated by the Nebraska Lymphoma Study Group between 1984 and 2012. The overall response rate to various therapies including stem cell transplant (SCT) was similar (p = 0.44) between blastoid, diffuse and nodular subtypes. At 5 years, blastoid and diffuse subtypes had worse OS (overall p = 0.005) compared to nodular subtype. In multivariate analysis, the blastoid and diffuse subtypes had similar risk of death (p = 0.14) whereas the nodular subtype had a lower risk compared to blastoid (HR 0.48, 95% CI 0.27–0.87, p = 0.01). The use of SCT was associated with lower risk of death. In univariate analysis, blastoid subtype had better OS with intensive upfront therapy. In conclusion, the OS of blastoid subtype is worse than nodular MCL but may improve with the use of SCT and probably intensive induction therapy.

Combined systemic and ocular chemotherapy for anterior segment metastasis of systemic mantle cell lymphoma.

BackgroundMantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma that rarely metastasizes to the iris and the anterior segment. Blastic/pleomorphic morphology is thought to have an adverse effect on prognosis in MCL. MCL is resistant to conventional chemotherapeutic regimens with a tendency for multiple relapses. Management of anterior segment metastasis of systemic MCL has not been described in literature.FindingsA 58-year-old male presented with an aggressive, relapsing, metastatic, systemic blastic variant of MCL with ocular involvement. At the time of initial presentation, large tumor cells were visible in the anterior chamber (AC) along with hypopyon and fibrin. The AC cells stained positively for CD20. The iris was thickened and coated with lymphoma cells. Iris neovascularization was present. Given extensive systemic and ocular involvement, the patient was given combination chemotherapy with systemic ibrutinib and intravitreal injections of methotrexate and rituximab. The disease response was monitored using multimodal imaging, including anterior segment optical coherence tomography and ultrasound biomicroscopy. Following combination of systemic and intraocular chemotherapy, there was a marked decrease in the ocular tumor load and the systemic disease.ConclusionsCombination therapy with intravitreal injections of chemotherapeutic agents targeting monoclonal B-cell population and novel systemic agents may help to achieve remission in anterior segment metastasis of aggressive subtypes of NHL such as blastic variant of MCL. Multimodal imaging may assist in the management of these cases.

Mantle Cell Lymphoma-Lymphomatous Intestinal Polyposis

Mantle Cell Lymphoma (MCL) is a rare and aggressive form of the mature B cell non-Hodgkin lymphomas (NHL) that commonly affects older individuals and has one of the worst outcomes of all the lymphomas. It comprises of about 7% of adult NHLs in the U.S. and Europe with an incidence of 4 to 8 cases per million persons per year. Most present with lymphadenopathy, extranodal disease is infrequent with GI tract involvement referred to as lymphomatous intestinal polyposis. Patients may have systemic B symptoms, such as fever, night sweats, and weight loss. Diagnosis often requires a combination of tissue biopsy, immunohistochemistry, karyotyping or fluorescence in situ hybridization (FISH). Prognosis is dismal especially with blastoid variant. It was first described and also reviewed by Cornes in 1961. Treatment may alter progression that consists of combination chemotherapy plus immunotherapy with or without autologous hematopoietic cell transplantation (HCT). Surgery and radiation is usually of no benefit except in cases of bowel obstruction or palliation. 76 y/o M with PMHx of Barrett's esophagus, GERD, Anemia, and colon polyp presents for surveillance of his colon polyp and Barrett's esophagus. He denies any dysphagia, abdominal pain, n/v/d, decrease appetite, GI bleed, fever, night sweats, or weight loss. Physical examination was normal. Labs were unremarkable except mild anemia. A scheduled surveillance EGD and colonoscopy showed negative Barrett's but revealed numerous polypoid lesions throughout left and right colon all pathologically confirming MCL. Immunochemistries were positive for CD5, Bcl-2, CD20, and PAX-5 with strong expression of Cyclin D-1. CD-3 was also positive. CD23 stain and PCR for t(11;14) were pending. Oncology referral was made for treatments of MCL. Mantle cell lymphoma with GI involvement i.e. lymphomatous intestinal polyposis is a rare phenomenon worth sharing for future research. The difficulty lies in differentiating disease burden because those with GI involvement are likely to have worse outcome. We conclude that we need a better predictor for highrisk population with diagnosis of MCL. We propose a retrospective study of all MCL cases to find a possible common factor for early recognition. Early treatment may improve survival, prevent recurrences, and potentially decrease resistance to treatment, especially in the blastoid variant of MCL.

MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma.

We aimed to investigate MYC expression and chromosomal aberration in mantle cell lymphoma (MCL), and the clinical significance of these factors. Sixty-five patients with MCL, including 54 classic, nine blastoid and two pleomorphic variants, were enrolled. Expression of MYC, Ki67 and p53 was assessed by immunohistochemistry. MYC amplification or translocation was examined by fluorescence in-situ hybridization. MYC expression was higher in blastoid/pleomorphic MCL variants (mean, 19.0%) than in classic MCL (mean, 1.9%; P < 0.001). Expression of p53 and Ki67 was also significantly higher in these variants. MYC amplification was found in two of 53 cases tested, both of which were blastoid variants with high MYC expression (29.7% and 20.4%). MYC translocation was found in two of 52 cases tested, both of which were pleomorphic variants with remarkably high MYC expression (68.5% and 71.0%). High MYC or p53 expression was significantly associated with shortened overall survival and progression-free survival in univariable and multivariable analyses (all P < 0.05). MYC overexpression is a negative predictor of MCL patient outcomes. MYC gene amplification or translocation might be related to the pathogenesis of MCL, particularly in blastoid/pleomorphic variants.

Mantle cell lymphoma with skin involvement.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Kalińska-Bienias A, Ziarkiewicz-Wróblewska B, Kowalewski C, Woźniak K. Letter to the EditorMantle cell lymphoma with skin involvement. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2015;32(3):229-234. doi:10.5114/pdia.2014.44028. APA Kalińska-Bienias, A., Ziarkiewicz-Wróblewska, B., Kowalewski, C., & Woźniak, K. (2015). Letter to the EditorMantle cell lymphoma with skin involvement. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 32(3), 229-234. https://doi.org/10.5114/pdia.2014.44028 Chicago Kalińska-Bienias, Agnieszka, Bogna Ziarkiewicz-Wróblewska, Cezary Kowalewski, and Katarzyna Woźniak. 2015. "Letter to the EditorMantle cell lymphoma with skin involvement". Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii 32 (3): 229-234. doi:10.5114/pdia.2014.44028. Harvard Kalińska-Bienias, A., Ziarkiewicz-Wróblewska, B., Kowalewski, C., and Woźniak, K. (2015). Letter to the EditorMantle cell lymphoma with skin involvement. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 32(3), pp.229-234. https://doi.org/10.5114/pdia.2014.44028 MLA Kalińska-Bienias, Agnieszka et al. "Letter to the EditorMantle cell lymphoma with skin involvement." Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, vol. 32, no. 3, 2015, pp. 229-234. doi:10.5114/pdia.2014.44028. Vancouver Kalińska-Bienias A, Ziarkiewicz-Wróblewska B, Kowalewski C, Woźniak K. Letter to the EditorMantle cell lymphoma with skin involvement. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2015;32(3):229-234. doi:10.5114/pdia.2014.44028.

De Novo CD5 Negative Blastic Mantle Cell Lymphoma Presented with Massive Bone Marrow Necrosis without Adenopathy or Organomegaly.

The recent World Health Organization (WHO) classification defines mantle cell lymphoma (MCL) as a distinct entity characterized by a unique immunophenotype and a molecular hallmark of chromosomal translocation t(11;14)(q13;q32). We report an unusual case of an advanced stage of CD5 negative MCL with a blastoid variant with a massive bone marrow (BM) necrosis as an initial presenting feature, with no adenopathy or hepatosplenomegaly. The pathologic features showed blastoid variant of MCL and flow cytometry showed that the tumor cells were CD5−, CD19+, CD20+, FMC-7+, CD23−, and lambda light chain restricted. Chromosomal analysis, using karyotype and fluorescent in situ hybridization (FISH), demonstrated karyotypic abnormalities in addition to the t(11;14). Our case study may be reported as a unique case of CD5− blastic MCL with unusual presentation and findings which made the diagnosis of MCL difficult.

Clinicopathologic Features, Management and Outcomes of Blastoid Variant (BV) of Mantle Cell Lymphoma (MCL): A Nebraska Lymphoma Study Group (NLSG) Experience

Background: Prior studies have demonstrated unique clinicopathologic features of the BV of MCL including an inferior response to chemotherapy and poor long-term outcomes as compared to other MCL variants in the pre-rituximab era. A paucity of data precludes whether the use of rituximab or intensified therapy can overcome the inferior outcome associated with the BV.Methods MCL patients (n=169) treated by NLSG between 1983 and 2010 were included. Morphologic variants were classified based on published WHO criteria. We compared disease characteristics, therapy and outcomes according to MCL subtypes using the Kruskal Wallis or Chi-square tests. Univariate probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression to evaluate differences in outcomes of MCL subtypes while adjusting for prognostic covariates.Results The study population included 19% BV, 37% diffuse and 44% nodular subtypes. BV, diffuse and nodular subtypes differed in the median age (61 vs. 68 vs. 59, p=.002) and stage III/IV disease (81% vs. 79% vs. 93%, p=.05) at diagnosis, but did not differ in the distribution of sex, Karnofsky performance status (KPS), MCL international prognostic index (MIPI), lactate dehydrogenase (LDH) level, B-symptoms, or extranodal involvement. Patients received the following therapies: intensified therapy such as Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) +/- Rituximab (R) (30%), Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-R-like (24%), CHOP-like (35%) or others (11%). Approximately one-third received autologous (25%) or allogeneic (8%) SCT. There was a significant difference in the type of chemotherapy given in each group (p=.002) but not in the use of radiation therapy or proportion in each group receiving autologous/allogeneic stem cell transplant (SCT). Median follow-up across MCL subtypes was similar. Overall response rate was similar for BV, diffuse and nodular subtypes (68% vs. 65% vs. 80%, p=.44). The 5-year progression-free survival for BV vs. diffuse vs. nodular was 16% vs. 22% vs. 31%; p=.06, (Figure 1) and 5-year OS was 24% vs. 32% vs. 56% respectively; p=.005, (Figure 2). In multivariate analysis, compared to BV, diffuse subtype had similar risk of disease progression or death (hazard ratio, HR of 0.78, 95% confidence interval (CI) of 0.48-1.26) whereas nodular subtype had lower risk (HR 0.62, 95% CI 0.39-0.99). Additionally, low or intermediate MIPI, good KPS, absence of B-symptoms and undergoing SCT were associated with lower risk of progression or death. A subset univariate analysis of BV demonstrated no survivors beyond 5 years after conventional chemotherapy, whereas 33% remained alive at 10 years after intensified therapy.Conclusions BV and nodular MCL presented at a somewhat younger median age compared to diffuse MCL, and BV and diffuse MCL was more likely to present as stage I/II disease, compared to nodular MCL. The PFS and OS of BV MCL are similar to diffuse MCL but OS is worse than nodular MCL. The use of SCT may improve survival in MCL including BV variant. [Display omitted] [Display omitted] DisclosuresArmitage:Ziopharm Oncology: Consultancy; GlaxoSmithKline: Consultancy; Spectrum Pharmaceuticals: Consultancy; Roche: Consultancy; Tesaro bio Inc: Membership on an entity’s Board of Directors or advisory committees.

Observational Study Alternating R-CHOP21 and R-Cytarabine (3+3 Cycles) for Patients with Newly Diagnosed Mantle Cell Lymphoma Not Eligible for High-Dose Therapy: A Czech Lymphoma Study Group Trial Preliminary Results

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma characterized by frequent relapses and adverse prognosis. Implementation of high-dose cytarabine (HDAC) and incorporation of anti-CD20 antibody rituximab (R) into induction and maintenance, and consolidation with high-dose therapy and autologous stem cell transplantation (HDT-ASCT) significantly improved pt´s outcome. Therapy of the elderly or comorbid (not eligible for HDT-ASCT) is largely based on R-CHOP or R-bendamustin induction with or without R maintenance. Minimal residual disease (MRD) assessment by quantitative PCR (qPCR) from peripheral blood or bone marrow (BM) has emerged as a powerful molecular marker of outcome. Based on the results of the younger pts some centers adopted the use of HDAC in elderly as well, but no data has been presented yet. Aim: We initiated the observational study as a non-intervention, multi-center trial with the primary objectives to prospectively evaluate efficacy of alternating R-CHOP21 and R-HDAC (1 or 2 g / m2, 2 doses a 24 hours) in newly diagnosed MCL pts not eligible for HDT-ASCT. Methods: Primary endpoints were overall response rate (ORR) by PET-CT, and MRD assessment by qPCR after completion of induction. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The choice between 1 and 2 g / m2 cytarabine was left at investigator´s discretion, as well as the rituximab maintenance. Patients with known cardiac co-morbidity could be treated with R-COEP (etoposid 50 mg / m2, D1-D3) instead of R-CHOP. Exclusion criteria included eligibility to HDT-ASCT, ECOG≥ 4, and CNS involvement. Results: Altogether 61 pts (38 men and 23 women, ratio 1.7:1) were enrolled into the study between 16-JUN-2011 and 18-MAR-2014. Median age was 70 years both for men and women. 91.5%, and 80% pts presented with stage 3/4 disease, and infiltration of BM, resp. According to the MIPI, 55.7%, 39.4%, and 4.9% pts had high, intermediate and low risk disease, resp. B-symptoms were recorded in 33.3% of pts. 76.8% and 24.2% pts were diagnosed from the lymph node, and trephine biopsy, resp. 62.8%, 27.9%, and 9.3% pts presented with classical, pleomorphic and blastoid variant MCL, resp. Ki67/MIB1 ≥ 30% was observed in 38% of pts. Bulky disease &gt;5cm, and &gt;10cm, was noticed in 31% and 13% pts. Spleen involvement was observed in 53% pts. Extra-nodal involvement other than BM was histologically confirmed in 11.5% pts. R-CHOP was used in 88% pts (12% pts received R-COEP), 86% pts received 2g / m2 cytarabine (14% pts 1g / m2). 86.3% pts with response were treated with R maintenace. Only one patient was excluded from the study due to unacceptable toxicity. 57.7% pts developed grade 3/4 hematologic toxicity (neutropenia, anemia or thrombocytopenia). Grade 3/4 non-hematologic toxicity occurred in 27.3% pts. All pts had PET-CT restaging after completion of induction. Overall response rate (CR+PR) reached 91.7%. CR and PR rate by PET was 76.7%, and 15%, resp. SD, and progression on therapy was noticed in 3.3%, and 5.0%, resp. Samples for MRD assessment were collected from 41 out of 54 pts, who completed induction and achieved response (CR or PR). At the time of abstract submission 21, 7, and 7 (out of 36 so far evaluated pts) were MRD negative, MRD positive-not quantifiable, and MRD positive-quantifiable, resp. With the median follow-up 19.1 month, there were 7 progressions and 6 deaths. 2-year PFS and OS probability were 83.9% and 88.1%. Conclusion: Alternation of R-CHOP and R-HDAC in newly diagnosed elderly or co-morbid MCL pts represents a promising, very effective and well-tolerated treatment approach that induces high ORR, and MRD negativity. Grant Support: IGA-MZ NT/13072-4, PRVOUK-27/LF1/1 Disclosures No relevant conflicts of interest to declare.

Four Genetic Lymphoma-Specific Events (MYC, BCL2, BCL6 and CCND1) in High Grade B-Cell Lymphoma: Aggressive Mantle Cell Lymphoma or Cyclin D1-Positive DLBCL?

The term « double » or « triple hit lymphoma » is commonly used to describe mature B cell neoplasms with either BCL2 and/or MYC and/or BCL6 gene rearrangements. These rare and aggressive lymphomas with high Ki67 expression are categorized as « B-cell lymphomas unclassified, with features intermediate between diffuse B-cell lymphoma and Burkitt lymphoma » category in the WHO 2008 classification. To our knowledge, only 2 cases of lymphoma have been described with four specific genetic events (quadruple hit) involving MYC, BCL2, BCL6 and CCND1 genes (Bacher U. et al., Genes Chromosomes Cancer 2011). We describe here the third observation.A patient, a 79 years old man, suffering from paraesthesias for 4 months, was admitted for polyneuritis in a context of poor general condition. Clinical examination showed the presence of numerous axillary, supraclavicular, mediastinal and inguinal lymphadenopathy, neuro-meningeal invasion and skin infiltration. The biopsy of a skin nodule of left arm revealed an infiltration consisting in large proliferating cells (Ki67 80%) stained by anti-CD20, BCL2 and BCL6 antibodies, but not with CD10 nor CD23, consistent with a diffuse large B-cell lymphoma (DLBCL), NOS diagnosis. Blood cell count showed 8.1 G/L leukocytes, 13.2 g/dL hemoglobin, 166 G/L platelets. LDH and β-2 microglobulin were elevated (989 U/I, and 9.14 mg/L respectively). Blood cell film examination showed the presence of 28% of pathological basophil lymphocytes (medium sized, with slightly clumped chromatin and frequent prominent nucleoli). Flow cytometry revealed that these cells expressed a monotypic lambda immunoglobulin light chain and were CD19, CD20, FMC7, CD22 positive, with a dim CD5 positivity and no CD10 staining. The negativity of CD23 associated to strong CD148 staining (Miguet et al, J Proteome Res2009) were in favour of the diagnosis of variant pleomorphic mantle cell lymphoma (MCL).Cytogenetic study performed in the WBC found a complex hyperdiploid karyotype (47 chromosomes) with a t(3;22) translocation involving BCL6 and IGL genes, structural abnormality of a chromosome 8 resulting in juxtaposition of 5’MYC and BCL2 in FISH (with break of the MYC probe in FISH), a derivative chromosome 18 from a t(14;18) translocation with fusion of 5’IGH and BCL2, and a t(11;14) complex translocation involving IGH and CCND1 (54% of the nuclei). Overexpression of cyclin D1 was detected in the WBC by RQ-PCR, as well as in the skin lesion using immunochemistry. Others numeral (trisomy 12) and structural abnormalities (involving the 1, 7, 14 and 21 chromosomes) were also detected.The patient was treated with a chemotherapy combining rituximab, ifosfamide, cytosine arabinoside and intrathecal methotrexate. He is still alive 5 months after the diagnosis.This third case of quadruple hit lymphoma confirms the complexity of the classification of such aggressive malignancies. Initial rearrangement of the CCND1 gene characterizes MCL that may harbour in very rare cases additional rearrangements of MYC or BCL6. Conversely, cyclin D1 overexpression is considered a rare feature in DLBCL. Recently, Ok CY et al. (Cancer 2014) proposed to reclassify DLBCL with expression of cyclin D1 and CCND1 chromosomal rearrangement and CD5 positivity as aggressive pleomorphic MCL variant. But no case with rearrangement of 2 (or more) genes (BCL2 and/or MYC and/or BCL6) was described in this study.Juskevicius D et al. (Am J Surg Pathol 2014) suggest the existence of a “gray zone” in which morphologic, clinical and genetic features are insufficient to segregate CD5- and SOX11-negative lymphomas with overexpression of cyclin D1/ translocation involving CCND1between blastoid MCL from cyclin D1-positive DLBCL.In our case, immunophenotyping of circulating cells (CD5+, CD148++) as well as genetic and molecular features (translocation involving CCND1 and IGH, and overexpression of cyclin D1) allow us to diagnose a probable genetically unstable aggressive pleomorphic MCL variant with rearrangement of several extra genetic hits. DisclosuresNo relevant conflicts of interest to declare.