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Background
This is a malignant Non-Hodgkin's lymphoma (NHL) of the B-cell type. These tumors must be separated from other small lymphocytic neoplasms such as small lymphocytic lymphoma because of the aggressive clinical course. In addition to the usual lymph node involvement, there is a higher incidence of organs such as the spleen, Waldeyer's ring, and the gastrointestinal tract. The peripheral blood may also show an absolute lymphocytosis. These tumors usually occur in elderly subjects with a male predominance. Tumors usually present with a high stage of disease with lymphadenopathy and splenomegaly common.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Intermediate lymphocytic lymphoma
Centrocytic/diffuse small cleaved cell lymphomaINCIDENCE 12% of NHL
PATHOGENESIS CHARACTERIZATION CELL LINES
Characterization of 4 mantle cell lymphoma cell lines.Amin HM, McDonnell TJ, Medeiros LJ, Rassidakis GZ, Leventaki V, O'Connor SL, Keating MJ, Lai R.
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Arch Pathol Lab Med 2003 Apr;127(4):424-31 Abstract quote CONTEXT: Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkin lymphoma characterized by t(11;14)(q13;q32) and cyclin D1 overexpression. The pathogenesis of MCL has not been comprehensively studied, which can be attributed in part to the paucity of well-characterized MCL cell lines.
OBJECTIVES: We collected 4 previously developed MCL cell lines and performed extensive characterization, including the susceptibly of these cell lines to transduction by adenovirus vectors. Our aim was to facilitate the establishment of an in vitro model that can be reliably used to study the pathogenesis of MCL.
METHODS: Standard techniques were used to compare the morphologic, immunophenotypic, and cytogenetic features of the 4 cell lines. In addition, Western blotting was used to investigate the presence of several cell cycle- and apoptosis-related proteins. TP53 DNA sequencing was also performed on the cell lines. The adenoviral transduction efficiency was assessed using an adenoviral vector carrying the gene encoding for the green fluorescence protein (Ad-GFP).
RESULTS: All cell lines demonstrated evidence of t(11;14)(q13;q32) and overexpression of cyclin D1. Cyclin D2 was not detectable in all cell lines, whereas cyclin D3 was weakly expressed in JeKo-1 and SP-53. Other abnormalities of the cell cycle G1 phase regulatory pathway were detected, including loss of expression of p53 (JeKo-1) and p16(INK4a) (SP-53 and Granta 519), as well as TP53 mutation (Mino). All cell lines express high levels of cyclin E, c-Myc, Bcl-2, Bax, Bcl-x(L), and Mcl-1. Retinoblastoma protein is hyperphosphorylated in all cell lines. With the exception of Mino, MCL cell lines are highly transducible with adenoviral vectors.
CONCLUSION: These cell lines are representative of MCL and can be used as an in vitro model to further explore the pathogenesis of this disease. The susceptibility of these cell lines to gene transfer provides opportunities to evaluate the importance of various oncogenes and tumor suppressor genes that may have an impact on developing effective therapeutic regimens for MCL.
CHROMOSOMAL ABNORMALITIES t(11;14)(q13;q32), overexpression of BCL-1/PRAD-1 gene products
Ig gene rearrangement
- Mantle cell lymphomas with clonal immunoglobulin V(H)3-21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V(H) genes.
Flordal Thelander E, Walsh SH, Thorselius M, Laurell A, Landgren O, Larsson C, Rosenquist R, Lagercrantz S.
1Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Mod Pathol. 2005 Mar;18(3):331-9. Abstract quote
A preferential use of one particular immunoglobulin variable heavy chain gene, V(H)3-21, has recently been reported in mantle cell lymphoma, where almost all of these V(H)3-21(+) mantle cell lymphomas showed usage of the same light chain V(lambda) gene (V(lambda)3-19) and also had a tendency towards improved prognosis. These findings suggested that V(H)3-21(+) mantle cell lymphomas constitute a distinct subgroup, possibly with antigen stimulation involved in disease pathogenesis.
In this study, we applied the comparative genomic hybridization (CGH) method on 37 mantle cell lymphoma tumors in order to investigate if the V(H)3-21(+) tumors are different at the genomic level. Interestingly, V(H)3-21(+) mantle cell lymphomas (n=14) showed significantly fewer genomic aberrations (mean 2.4) compared to non-V(H)3-21 mantle cell lymphomas (n=23) (mean 4.9). The chromosomal aberrations identified in our study were generally in accordance with previous CGH studies of mantle cell lymphoma; the most frequent aberration was complete or partial loss of chromosome 13, followed by recurrent losses within 6q, 9p, 9q and 11q and frequent gains in 3q, 7p, 8q and 15q. Deletions within 8p and 9p as well as gains in 7p and 15q were found exclusively in the non-V(H)3-21-utilizing tumors.
In summary, V(H)3-21(+) mantle cell lymphomas demonstrated both a lower number and a different spectrum of genomic aberrations than mantle cell lymphoma in general, thus supporting the hypothesis that V(H)3-21(+) mantle cell lymphomas constitute a new subgroup. The findings presented in this report may explain the tendency for a better clinical outcome for patients whose tumors utilize V(H)3-21.
Cytogenetic findings in blastoid mantle cell lymphoma.
Khoury JD, sEn F, Abruzzo LV, Hayes K, Glassman A, Medeiros LJ.
Hum Pathol. 2003 Oct;34(10):1022-9 Abstract quote.
A subset of mantle cell lymphoma (MCL) tumors has blastoid morphology, and a number of morphologic variants of blastoid MCL have been described in the literature. In this report, we document the cytogenetic findings in 27 cases of blastoid MCL. Conventional cytogenetic analyses were performed on bone marrow aspirates involved by MCL from 27 patients. There were 14 men and 13 women with a median age of 63 years (range, 40-79 years).
Diagnostic tissue biopsy and bone marrow specimens were reviewed, and cases were divided into 2 morphologic groups: classic (12 cases) and pleomorphic (15 cases), as defined in the World Health Organization classification. All tumors had an immunophenotype compatible with MCL, were positive for cyclin D1, and carried the t(11;14). Twenty-four cases had complex karyotypes with 3 or more chromosomal abnormalities in addition to the t(11;14). In classic blastoid MCL, abnormalities of chromosomes 13, 18, and 8 were most common. In pleomorphic blastoid MCL, abnormalities of chromosomes 13, 17, and 3 were most frequent. Chromosome 22 abnormalities were detected exclusively in the pleomorphic group. Tumors in which the neoplastic cells showed prominent nucleoli had a significantly higher frequency of chromosome 17 abnormalities (P = 0.03).
We conclude that blastoid MCL tumors often show complex cytogenetic aberrations. Some abnormalities correlate with morphologic features, suggesting that morphologic variants of blastoid MCL may arise via different molecular pathways.8q24 Abnormalities Mantle Cell Lymphoma with 8q24 Chromosomal Abnormalities: a Report of 5 Cases with Blastoid Features
Suyang Hao, M.D., Warren Sanger, Ph.D., Mihaela Onciu, M.D., Raymond Lai, M.D., Ph.D, Ellen J. Schlette, M.D. and L. Jeffrey Medeiros, M.D.
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center (SH, MO, RL, EJS, LJM), Houston, Texas; and The Human Genetics Laboratory, University of Nebraska Medical Center (WS), Omaha, NebraskaModern Pathology 2002;15:1266-1272 Abstract quote The t(11;14)(q13;q32) resulting in cyclin D1 overexpression is consistently present in mantle cell lymphoma. However secondary chromosomal aberrations are also extremely common. Of these, 8q24 abnormalities associated with the t(11;14) are rare. Over the course of 10 years at M.D. Anderson Cancer Center, we identified five cases of mantle cell lymphoma in which conventional cytogenetic analysis revealed complex karyotypes, including the t(11;14) and 8q24 abnormalities: one with t(8;14)(q24;q32), one with t(2;8)(q13;q24), and three with add(8)(q24).
We performed fluorescence in situ hybridization (FISH) studies on all cases. In the case with the t(8;14), IgH/myc fusion signals were identified, and in the case with the t(2;8), split c-myc signals were detected. In the three cases with add(8)(q24), one case had split c-myc signals and two cases had three copies of c-myc.
Thus, the c-myc gene was involved in all cases. All five neoplasms had blastoid morphologic features, and four cases, including the cases with the t(8;14) and t(2;8), had leukemic involvement.
We conclude that 8q24 abnormalities involving the c-myc gene are uncommon secondary abnormalities that occur in a subset of mantle cell lymphomas. C-myc gene abnormalities are associated with blastoid cytologic features and also may be associated with leukemic involvement.
JAK/STAT3
- Activation status of the JAK/STAT3 pathway in mantle cell lymphoma.
Yared MA, Khoury JD, Medeiros J, Rassidakis GZ, Lai R.
Department of Hematopathology, The University of Texas, M. D. Anderson Cancer Center, Houston, USA.
Arch Pathol Lab Med. 2005 Aug;129(8):990-6. Abstract quote
CONTEXT: Signal transducer and activator of transcription 3 (STAT3) is oncogenic, and we previously found evidence of constitutive STAT3 activation in a relatively small number of frozen mantle cell lymphoma (MCL) cell tumors.
OBJECTIVES: To comprehensively survey the activation and phosphorylation status of STAT3 in MCL and to assess if STAT3 activation in these tumors is due to cytokine stimulation by examining the phosphorylation and activation status of Janus kinase (JAK), the physiologic activator of STAT3.
DESIGN: We evaluated 43 formalin-fixed, paraffin-embedded MCL tumors using immunohistochemistry and phospho-specific antibodies against STAT3 and JAK.
RESULTS: There were 37 small cell and 6 blastoid cases. There was heterogeneous expression of phospho-STAT3 (pSTAT3), with 23 negative cases (53%), 12 weakly positive cases (28%), and 8 strongly positive cases (19%). JAK3 was the only member detectable in 3 MCL cell lines, and immunoprecipitation data showed a relatively low level of tyrosine phosphorylation of JAK3 in these cells. Using immunohistochemistry, phospho-JAK3 (pJAK3) was detectable in 18 (44%) of 41 MCL tumors examined, and pJAK3 expression correlated with that of pSTAT3 (P = .008). A notable exception to this correlation was seen in the blastoid variant, since 4 (67%) of 6 blastoid cases were pSTAT3 positive but pJAK3 negative.
CONCLUSIONS: We have confirmed our previous finding that STAT3 is constitutively activated in MCL tumors, with an overall frequency of 47% in this series. STAT3 activation in the small cell but not the blastoid variant of MCL is likely mediated by JAK3.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION BONE MARROW Varies but up to 50% CEREBROSPINAL FLUID
Cerebrospinal fluid involvement in mantle cell lymphoma.Valdez R, Kroft SH, Ross CW, Schnitzer B, Singleton TP, Peterson LC, Finn WG.
Department of Pathology, University of Michigan (RV, CWR, BS, TPS, WGF), Ann Arbor, Michigan.
Mod Pathol 2002 Oct;15(10):1073-9 Abstract quote Mantle cell lymphoma (MCL) is an aggressive neoplasm that is incurable by standard therapy. Patients often present with high-stage disease (Stages III-IV) and frequently have involvement at multiple extranodal sites. Although the gastrointestinal tract, spleen, lung, pleura, bone marrow, and peripheral blood are among the most commonly involved tissues, MCL may also disseminate to so-called sanctuary sites including the central nervous system. Despite this, current clinical evaluations do not routinely include assessment of the cerebrospinal fluid (CSF) for lymphomatous infiltrates at presentation, and moreover, only few authors have specifically examined CSF involvement in MCL.
In this study, we reviewed the medical records of 108 patients with MCL seen at three centers over a 5-year period to determine the rate of CSF sampling and the frequency of CSF involvement by MCL. The clinical and cytologic characteristics associated with CSF involvement were also studied. Central nervous system (CNS) signs and/or symptoms prompted CSF sampling in 25/108 patients (23%). Specific radiographic abnormalities were present in 9/25 patients (36%). CSF involvement by MCL was identified in 10 of the 25 CSF-sampled patients (40%) by morphology (3 patients), flow cytometry alone (1 patients), or both (6 patients). The CSF-positive cases included two blastoid variants. The CSF cytology of the nine morphologically positive cases was pleomorphic, and prominent cytoplasmic granules were observed in two cases.
The overall rate of CSF involvement by MCL among the cohort was 9%, which is comparable to that reported in other selected studies examining this issue.
GASTROINTESTINAL TRACT Multiple lymphomatous polyposis in the gastrointestinal tract Mantle cell lymphoma
- Salar A,
- Juanpere N,
- Bellosillo B,
- Domingo-Domenech E,
- Espinet B,
- Seoane A,
- Romagosa V,
- Gonzalez-Barca E,
- Panades A,
- Pedro C,
- Nieto M,
- Abella E,
- Sole F,
- Ariza A,
- Fernandez-Sevilla A,
- Besses C,
- Serrano S.
Departments of *Clinical Hematology daggerPathology section signEndoscopy, Hospital del Mar, Barcelona double daggerInstitut Catala d'Oncologia, Hospitalet de Llobregat parallelHospital Germans Trias i Pujol, Badalona, Spain
The frequency of gastrointestinal (GI) tract involvement in mantle cell lymphoma (MCL) at diagnosis is reported to be below 30%.
To investigate the actual frequency of GI involvement by MCL, upper and lower endoscopy was prospectively performed on 13 untreated MCL patients at diagnosis. Multiple biopsies from endoscopically normal and abnormal gastric and colonic mucosa were studied with immunohistochemistry (IHC) for CD20, CD5, and cyclin D1, as well as fluorescence in situ hybridization (FISH) for t(11;14) and polymerase chain reaction (PCR) for immunoglobulin heavy chain gene. Abnormal mucosa was identified in 38% of cases by upper endoscopy (mainly mild nonspecific gastritis) and in 54% of cases by lower endoscopy (mostly micropolyps). Histologically, infiltration by MCL was demonstrated in the stomach in 77% of cases and in the colon in 77% of cases. As a whole, 92% of patients showed upper or lower GI tract infiltration by MCL.
Histologic evidence of MCL involvement was present in all cases with endoscopically abnormal mucosa, but it was also observed in two-thirds of cases with endoscopically unremarkable mucosa. Positive cyclin D1 IHC was seen in all instances displaying CD20 and CD5-positive lymphoid infiltrates, whereas t(11;14) was demonstrated by FISH in 63.5% and PCR was clonal in 64% of those instances.
In conclusion, the great majority of MCL patients showed GI tract involvement at the time of diagnosis, not uncommonly in the form of minute lymphoid infiltrates. IHC for cyclin D1 was significantly more sensitive than FISH t(11;14) or PCR for immunoglobulin heavy chain gene to confirm MCL in this setting.PERIPHERAL BLOOD SKIN
- Insect Bite-Like Reaction Associated With Mantle Cell Lymphoma: Clinicopathological, Immunopathological, and Molecular Studies.
Khamaysi Z, Dodiuk-Gad RP, Weltfriend S, Ben-Arieh Y, Dann EJ, Sahar D, Bergman R.
From the *Department of Dermatology, daggerDepartment of Pathology, double daggerDepartment of Hematology, and section signMolecular Hematology Laboratory, Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Haifa, Israel.
Am J Dermatopathol. 2005 Aug;27(4):290-295. Abstract quote
A cutaneous eruption simulating insect bites has been repeatedly described in association with chronic lymphocytic leukemia (CLL). It was only rarely described with mantle cell lymphoma (MCL).
Our study was performed to elucidate the clinical, histologic, immunopathological, and molecular characteristics of insect bite like reaction (IBLR) associated with MCL. The clinical presentation and histologic findings in 3 IBLR cases associated with MCL were found to be similar to 3 IBLR cases associated with CLL. The eruptions consisted of itchy erythematous papules, nodules, plaques, and vesicles. Non-vesicular lesions were characterized histologically by normal or mildly spongiotic epidermis. Vesicular lesions were characterized by marked spongiosis and intraepidermal spongiotic vesicles containing eosinophils, or marked subepidermal edema occasionally leading to a dermoepidermal separation. Most of the lesions were characterized by superficial and mid dermal to deep perivascular and interstitial, and occasionally periadnexal, inflammatory-cell infiltrate consisting of mononuclear cells and eosinophils. The densities of the infiltrates varied and the inflammatory-cell infiltrate extended often into the fat lobules.
Neutrophils and nuclear dust were found more frequently and abundantly in the IBLR lesions associated with MCL. Immunophenotyping, direct immunofluorescence (DIF) tests, and IgH gene rearrangement studies were performed in the lesions associated with MCL only. The majority of the infiltrating lymphocytes were CD3+, CD5+ and CD43+, more CD4+ than CD8+, and only a small minority was CD20+. The cells did not stain for bcl-1 protein and CD30, and with no evidence of clonality. The DIF test result was negative.
The IBLR eruption associated with MCL resembles clinically and histologically IBLR associated with CLL. The eruption seems to be reactive rather than neoplastic, because there is no evidence of MCL involvement in the skin lesions.Cyclin D1 as an Aid in the Diagnosis of Mantle Cell Lymphoma in Skin Biopsies: A Case Report
Brent R. Moody, M.D.; Nancy L. Bartlett, M.D.; David W. George, M.D.; Caroline R. Price, M.D.; Wayne A. Breer, M.D.; Yadira Rothschild, M.D.; Madeleine D. Kraus, M.D.
From the Divisions of Dermatology (B.R.M., Y.R.), Medical Oncology (N.L.B.), and Hematopathology (M.D.K.), Washington University School of Medicine, and Departments of Dermatology and Dermatopathology (C.R.P., W.A.B.), St. Louis University School of Medicine, St. Louis, Missouri; and Division of Medical Oncology (D.W.G.), Indiana University School of Medicine, Indianapolis, Indiana.
Am J Dermatopathol 2001;23:470-476 Abstract quote
Mantle cell lymphoma (MCL), an uncommon and aggressive form of non-Hodgkin lymphoma, typically involves lymph nodes. It usually only secondarily involves extranodal sites.
We describe an unusual case of a MCL that presented and relapsed in the earlobes. Light microscopic findings were initially regarded as suggestive of small lymphocytic lymphoma, although subsequent analysis of fresh tissue by flow cytometry led to the diagnosis of MCL. Retrospective application of a broad panel of recently developed markers suitable for analysis of routinely processed tissue yielded results that also permitted a diagnosis of MCL. If these results had been available at the time of initial presentation, they would have obviated the need for rebiopsy.
Greater awareness not only of the phenotypic criteria by which lymphomas are classified but of the lymphoma markers available for evaluation of routinely processed tissue should facilitate the accurate diagnosis of diseases like MCL and minimize the risk of misdiagnosis as an indolent disorder.
Mantle cell lymphoma involving skin: cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cytologic features.Sen F, Medeiros LJ, Lu D, Jones D, Lai R, Katz R, Abruzzo LV.
Am J Surg Pathol 2002 Oct;26(10):1312-8 Abstract quote We describe five cases of mantle cell lymphoma involving skin. Three patients initially presented with skin lesions but had evidence of widespread disease at time of diagnosis or with relatively short follow-up.
One patient was known to have disseminated disease before he developed skin lesions. One patient presented with a solitary skin nodule on the thigh and has developed multiple smaller nodules on the same leg, but no other sites of disease over 30 months of clinical follow-up. This case fulfills the criteria for primary cutaneous lymphoma as proposed by the European Organization for Research and Treatment of Cancer. Biopsy of the skin lesions in all cases showed predominantly dermal and focally subcutaneous lymphoid infiltrates, preferentially perivascular and periadnexal in four cases, and nodular in one case. The tumors were composed of small- to medium-sized lymphocytes with irregular nuclear contours. Four cases had blastoid and one case had typical cytologic features. Immunophenotypic studies showed that all cases were positive for CD20 and cyclin D1, and four of five were positive for CD5. Four cases, including the CD5-negative case, had evidence of the t(11;14) shown by either fluorescence in situ hybridization methods performed on skin tumors or conventional cytogenetic analysis performed on involved bone marrow.
We conclude that mantle cell lymphoma can involve skin, usually as a manifestation of disseminated disease, and is often associated with blastoid cytologic features. Rare cases of mantle cell lymphoma may arise in skin.
Value of Interphase FISH for the Diagnosis of t(11;14)(q13;q32) on Skin Lesions of Mantle Cell Lymphoma
Pierre Dubus, MD, PhD
Paul Young, MD
Marie Beylot-Barry, MD, PhD, etal.Am J Clin Pathol 2002;118:832-841 Abstract quote
The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at the onset of the disease. We observed 2 patients with papules of the trunk and 1 with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules. Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3–, CD5+ (2/3), CD20+, CD23–, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected, and the t(11;14)(q13;q32) breakpoint was amplified from both lymph node and skin DNA.Competitive reverse transcriptase–polymerase chain reaction was not contributive for skin specimens. In all 3 cases, interphase fluorescence in situ hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin sections or on fresh frozen touch preparations of skin biopsies.
The recognition of skin lesions of MCL from other B-cell infiltrates can be established by interphase FISH.
HISTOLOGICAL TYPES CHARACTERIZATION LYMPH NODES Follicular and diffuse pattern
Small to medium-sized lymphoid cells with scanty cytoplasm, round or irregular nuclei, clumped chromatin, and inconspicuous nucleoli
KEY:
No proliferation centers
No or few large transformed cells with distinct nucleoli
Absence of pseudofollicular structuresLack of prolymphocytes and paraimmunoblasts
Often no significant T cells mixed with B cells Naked germinal centers (no mantle zone) may be identified in diffuse forms
Scattered macrophages are present but usually do not contain tangible bodies but have abundant eosinophilic staining cytoplasm
Frequent presence of aggregates of dendritic follicular cells with pale naked nucleiVARIANTS BLASTIC VARIANT Mimic lymphoblastic lymphoma, but retain their immunophenotypic characteristics and are usually Ki-67 positive Blastic mantle cell leukemia: an unusual presentation of blastic mantle cell lymphoma.
Viswanatha DS, Foucar K, Berry BR, Gascoyne RD, Evans HL, Leith CP.
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, USA.
Mod Pathol 2000 Jul;13(7):825-33 Abstract quote
Six patients had blood and bone marrow manifestations characterized by the presence of morphologically immature or blastic B-lineage lymphoid cells expressing CD5 antigen.
The median patient age was 70 years, and the male-to-female ratio was 5:1. The presence or degree of lymphadenopathy and splenomegaly was variable among this group at staging evaluation, although two patients did not have these features. One patient had an antecedent diagnosis of classical nodal mantle cell lymphoma, without prior morphologic blood or bone marrow involvement. Other patients lacked a history of underlying lymphoproliferative disorders. The median white blood cell count was 120 x 10(9)/L. Most patients had thrombocytopenia, whereas only one patient had neutropenia at presentation. Leukemic peripheral blood cells in these six cases were small to medium in size with fine or granular nuclear chromatin and small or inconspicuous nucleoli. The pattern of marrow involvement was interstitial or diffuse, with cells showing immature nuclear features resembling acute leukemia or blastic lymphoma. All tumors demonstrated a consistent immunophenotype of B-cell lineage, surface immunoglobulin positivity, and CD5 antigen expression. The progenitor cell-associated markers CD34 and TdT were not expressed, and CD23 antigen was either negative (three of four cases) or only weakly present (one of four cases). The presence of a karyotypic t(11;14)(q13;q32) was documented in one tumor, whereas two other cases had BCL-1 gene rearrangements by either polymerase chain reaction or Southern blot analysis. Cyclin D1 mRNA overexpression was noted in three of four cases tested. This patient group was characterized by very poor overall survival (median, 3 months; range, 0.5 to 6 months).
The aggregate clinical, pathologic, and genetic data in these unusual cases are consistent with de novo or predominant leukemic presentations of blastic mantle cell lymphoma. Accurate diagnosis in such cases is greatly facilitated by cytogenetic studies or the demonstration of BCL-1/cyclin D1 abnormalities.
Blastic variant of mantle cell lymphoma following interfollicular hodgkin's lymphoma.
Grosso LE, Collins BT, Visconti J.
Department of Pathology; Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
Leuk Lymphoma 2001 May;41(5-6):675-81 Abstract quote
Infrequently, patients are diagnosed with Hodgkin's lymphoma and a morphologically distinct lymphoma. While specific subtypes of lymphomas (including Hodgkin's lymphoma) may present diagnostic difficulties, fine needle aspiration biopsy (FNAB) is sometimes useful in the evaluation and classification of these lymphoproliferative processes.
We report a case of the blastic variant of mantle cell lymphoma following Hodgkin's lymphoma, interfollicular variant. A 66-year-old woman with a history of Hodgkin's lymphoma presented with increasing contralateral cervical adenopathy three years after receiving chemotherapy. FNAB with ancillary immunophenotypic characterization identified mantle cell lymphoma, blastic variant. Subsequent excisional biopsy confirmed this diagnosis and also aided in the exclusion of recurrent Hodgkin's lymphoma.
In addition to identifying the previously unreported combination of blastic variant of mantle cell lymphoma and Hodgkin's lymphoma, this case emphasizes the utility of FNAB in evaluation of new masses in patient's with a previous diagnosis of Hodgkin's lymphoma.
CLEAR CELL VARIANT Hyperplasia of Mantle/Marginal Zone B Cells With Clear Cytoplasm in Peripheral Lymph Nodes A Clinicopathologic Study of 35 Cases
John P. Hunt, MD
Joel A. Chan, MD
Michael Samoszuk, MD
Russell K. Brynes, MD
Antonio M. Hernandez, MD
Randall Bass, MD
Dennis D. Weisenburger, MD
Konrad Müller-Hermelink, MD
and Bharat N. Nathwani, MDAm J Clin Pathol 2001;116:550-559 Abstract quote
We describe 35 peripheral lymph nodes classified as mantle cell/marginal zone B-cell hyperplasia with clear cells using morphologic and immunologic findings.
For the purpose of this study, we obtained clinical follow-up information and performed immunoglobulin gene rearrangement studies on paraffin sections by polymerase chain reaction. Architecturally, the nodes were suggestive of a benign process: no pericapsular infiltration, sinuses readily identified, scattered reactive follicles present, and paracortical nodular hyperplasia present. No monocytoid B cells were present. Focally, small lymphoid cells with round nuclei and clear cytoplasm (clear cells) formed monomorphic nodular, inverse follicular, and/or marginal zone patterns. Flow cytometry and immunohistochemical analysis revealed neither light chain restriction nor an aberrant B-cell phenotype. Immunoglobulin gene rearrangement studies showed a clonal band in 1 of 26 cases in which DNA was amplified. To ascertain the clinical relevance of this positive case, follow-up information was obtained 30 months after the initial biopsy; the 83-year-old woman was alive without treatment but had splenomegaly and bone marrow involvement by marginal zone B-cell lymphoma.
The morphologic and immunologic criteria used for diagnosis of mantle cell/marginal zone B-cell hyperplasia with clear cytoplasm are valid; however, to rule out the possibility of occult lymphoma, immunoglobulin gene rearrangement studies and clinical follow-up are necessary.
HODGKIN LYMPHOMA
Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors.
Caleo A, Sanchez-Aguilera A, Rodriguez S, Dotor AM, Beltran L, de Larrinoa AF, Menarguez FJ, Piris MA, Garcia JF.
Department of Anatomic Pathology and Cytopathology, Faculty of Medicine and Surgery, Universita di Napoli Federico II, Naples, Italy.
Am J Surg Pathol. 2003 Dec;27(12):1577-80. Abstract quote
Association of Hodgkin lymphoma and non-Hodgkin lymphoma is rare and, specifically, the combination of Hodgkin lymphoma and mantle cell lymphoma has not been previously described.
Here we describe composite mantle cell lymphoma and Hodgkin lymphoma affecting the spleen in one case and the eyelid and cervical lymph nodes in a second. In both, nodules of classical Hodgkin lymphoma were intermixed with diffuse or nodular areas of typical mantle cell lymphoma. Immunohistochemical and molecular analyses confirmed cyclin D1 overexpression secondary to the translocation t(11;14) in the small mantle cell lymphoma component; with CD30, CD15, and EBV expression in the Hodgkin and Reed-Sternberg cells. Finally, clonal analysis of rearranged immunoglobulin genes performed on microdissected Hodgkin and Reed-Sternberg and mantle cell lymphoma cells provided definite evidence of separate clonal origins of the two tumors in the patients.
These EBV-positive, clonally unrelated tumors seem to represent true composite neoplasms, in contrast to cases showing merely clonal progression.INDOLENT
- Clonal proliferation of cyclin D1-positive mantle lymphocytes in an asymptomatic patient: an early-stage event in the development or an indolent form of a mantle cell lymphoma?
Espinet B, Sole F, Pedro C, Garcia M, Bellosillo B, Salido M, Florensa L, Camacho FI, Baro T, Lloreta J, Serrano S.
Servei de Patologia (Laboratori de Citogenetica i Biologia Molecular, Laboratori de Citologia Hematologica, Laboratori de Patologia), Hospital del Mar, IMAS, URNHE, PRBB, Barcelona 08003, Spain.
Hum Pathol. 2005 Nov;36(11):1232-7. Abstract quote
Mantle cell lymphoma (MCL) is a B-cell neoplasm with a relatively aggressive clinical course. There is a very small subgroup of patients who present with atypical lymphocytes in peripheral blood, with or without lymphocytosis, lymphadenopathy, or splenomegaly, and with an indolent clinical course. They frequently show mutated IgV(H) genes and CD5 negativity.
We report an asymptomatic elderly patient who presented with a single submandibular lymphadenopathy. The biopsy showed immunophenotype and t(11;14)(q13;q32) consistent with MCL. The abnormal lymphoid population was also detected in peripheral blood and bone marrow. The patient has remained asymptomatic for 5 years without receiving any therapy. It is uncertain whether these cases represent an early-stage event in the development or an indolent form of MCL.
The existence of such asymptomatic patients with an indolent clinical course should induce a strict clinical judgment in terms of therapeutic decisions.
Indolent mantle cell lymphoma with nodal involvement and mutated immunoglobulin heavy chain genes.
Nodit L, Bahler DW, Jacobs SA, Locker J, Swerdlow SH.
Hum Pathol. 2003 Oct;34(10):1030-4 Abstract quote.
Mantle cell lymphoma (MCL) is typically considered an aggressive but incurable neoplasm composed of cyclin D1+ monoclonal B-cells with a t(11;14)(q13;q32) and usually unmutated immunoglobulin (Ig) genes. Although it has been suggested that a more indolent leukemic disorder exists with the same phenotype and genotype but with mutated Ig genes, others have considered these cases to be variants of chronic lymphocytic leukemia.
We present a case of an indolent MCL that was documented with cyclin D1 expression in a lymph node biopsy performed more than 12 years ago. The patient has peripheral blood involvement with a lymphocyte count in the reference range, variable thrombocytopenia, and minimal adenopathy but is otherwise well, never having received any antineoplastic therapy. Study of peripheral blood samples from 2002 revealed a CD5-variable B-cell monoclonal proliferation with a t(11;14)(q13;q32) plus other karyotypic abnormalities, positive fluorescence in situ hybridization studies for the CCND1/IgH translocation, and clonal Ig gene rearrangement with mutated Ig genes (95.7% homology to VH 4-31).
The subtle but diagnostic lymph node biopsy in this case helps to further support that an indolent t(11;14) monoclonal lymphocytosis with mutated Ig genes can represent an MCL variant rather than chronic lymphocytic leukemia.LARGE CELL VARIANT Large Cell Variants of CD5+, CD23 B-Cell Lymphoma/Leukemia Morphologic Findings and Bone Marrow Involvement
Cherie H. Dunphy, etal.
Arch Pathol Lab Med 2001;125:513–518. Abstract quote
Mantle cell lymphoma (MCL), and its leukemic phase, constitute a well-studied hematologic malignancy with known overall survival, prognostic indicators, morphologic findings at diagnosis and in bone marrow, and known incidence of the bcl-1 immunoglobulin gene rearrangement. Large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype (CD5+, CD23), including but not limited to blastic MCL, prolymphocytoid MCL, blastic mantle cell leukemia, and prolymphocytic mantle cell leukemia, are not as well characterized. Although blastic MCL is known to be associated with a shorter overall survival than conventional MCL, the large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype have not been described as fully as conventional MCL.
Objective.—The purpose of the present study was to describe the large cell variants of B-cell lymphoma/leukemia with a mantle cell immunophenotype.
Design.—Nineteen cases of large cell variants of CD5+, CD23 B-cell lymphoma/leukemia are reviewed and described in regard to morphology, bone marrow morphological findings, Cyclin D1 immunostaining, and bcl-1 analysis. Clinical data were not available owing to the varied clinical sources of the specimens.
Setting.—Tertiary-care academic institution.
Results.—Lymph node involvement in blastic CD5+, CD23 B-cell lymphoma was diffuse (100%) with a nodular component (33%) or focal mantle zone pattern (10%). Bone marrow involvement in blastic CD5+, CD23 B-cell lymphoma was seen in only 27% of cases and was composed predominantly of small, slightly irregular lymphocytes. Cyclin D1 was demonstrated in 60% of the 15 cases analyzed and more sensitive in B5–fixed tissue. Bcl-1 (performed in 5 cases) was not detected in the 4 cases of blastic CD5+, CD23 B-cell lymphoma analyzed and was detected in the case of the prolymphocytoid MCL. Cyclin D1 was demonstrated in all 4 bcl-1 negative cases and was negative in the bcl-1 positive prolymphocytoid MCL.
Conclusion.—Careful analysis of clinical data, morphology, immunophenotype, Cyclin D1 expression, and molecular analysis are required to differentiate the unusual large cell variants of MCL from other processes.
LEUKEMIC PHASE
William G. Morice, MD, PhD, Janice M. Hodnefield, MS, Paul J. Kurtin, MD, and Curtis A. Hanson, MD
Characteristically, mantle cell lymphoma (MCL) expresses surface immunoglobulin (sIg), CD19, CD20, and CD5 and lacks CD10 and CD23. Rare CD5– MCL variants have been described. This report describes a case of leukemic MCL with morphologically and immunophenotypically distinct classic MCL and blastoid-variant MCL (BV-MCL) components. The classic MCL had typical morphologic features and immunophenotype (k sIg light chain–restricted and CD5+; CD10– and CD23–). The BV-MCL had larger nuclei and open chromatin; these cells also were k sIg light chain–restricted; however, they were CD10+ and CD5–.
Fluorescence in situ hybridization studies demonstrated cyclin D1–immunoglobulin heavy chain gene fusion in both components; the bone marrow biopsy cellularity was replaced by CD10+ and cyclin D1+ and CD5– BV-MCL.
This case illustrates the phenotypic heterogeneity of MCL and underscores the need for histopathologic correlation and, in some instances, ancillary genetic studies to accurately classify B-cell lymphomas.Mantle cell lymphoma in leukemic phase: characterization of its broad cytologic spectrum with emphasis on the importance of distinction from other chronic lymphoproliferative disorders.
Wong KF, Chan JK, So JC, Yu PH.
Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
Cancer 1999 Sep 1;86(5):850-7 Abstract quote
BACKGROUND: Mantle cell lymphoma is a mature, virgin B-cell neoplasm characterized immunologically by a panB+, CD5+, CD23-, cyclin D1+ phenotype and genetically by t(11;14)(q13;q32) with overexpression of the cyclin D1 (bcl-1) gene. It usually presents as advanced stage disease, involving lymph nodes, spleen, bone marrow, and extranodal sites, particularly the gastrointestinal tract. However, frank leukemic presentation with high white cell counts is uncommon and can be difficult to distinguish from other chronic lymphoproliferative disorders. The aim of this study was to characterize the morphologic spectrum of leukemic mantle cell lymphoma.
METHODS: During the period July 1994 through October 1998, 14 patients with mantle cell lymphoma in leukemic phase were diagnosed at the Department of Pathology, Queen Elizabeth Hospital, Hong Kong. The diagnosis of mantle cell lymphoma was based on histologic and immunocytochemical findings and was confirmed by cyclin D1 immunoreactivity in all cases. The clinical records and laboratory results were reviewed. Peripheral blood smears, bone marrow, and other tissue biopsies were examined, with particular attention to the cytologic features of the leukemic mantle cells.
RESULTS: Mantle cell lymphoma in leukemic phase showed a very aggressive clinical course. Eight patients died at a mean of 13 months, and only 1 patient was disease free. Morphologically, the leukemic mantle cells exhibited a broad morphologic spectrum, with several cytologic patterns identified: 1) mixed small and medium-sized cells, 2) predominantly medium-sized cells, 3) predominantly large cells, and 4) giant cells. Despite variations in the size and nuclear shape, the leukemic mantle cells could usually be recognized by the nuclear irregularity and clefting, moderately dense but evenly distributed chromatin, small nucleoli, and scant cytoplasm.
CONCLUSIONS: Recognition of the characteristic cytologic features of leukemic mantle cells can help to distinguish them from other chronic lymphoproliferative disorders. In contrast to the latter, the clinical course is aggressive and response to conventional chemotherapy is poor.
Leukemic Mantle Cell Lymphoma: Clinical and Pathologic Spectrum of Twenty-Three Cases
Ellen Schlette, M.D., Raymond Lai, M.D., Ph.D., Mihaela Onciu, M.D., Dorota Doherty, Ph.D., Carlos Bueso-Ramos, M.D., Ph.D. and L. Jeffrey Medeiros, M.D.
Departments of Hematopathology (ES, RL, MO, CB-R, LJM) and Biostatistics (DD), University of Texas M.D. Anderson Cancer Center, Houston, Texas
Mod Pathol 2001;14:1133-1140 Abstract quote
Twenty-three patients with marked leukemic involvement by mantle cell lymphoma (MCL) are described. Each patient had an absolute lymphocyte count more than 10 x 109/L.
The diagnosis of MCL was supported by compatible immunophenotypic findings and the t(11;14)(q13;q32) in all cases. Morphologically, these cases exhibited a spectrum of findings that we divided into two groups using a cutoff of 20% large or blastoid cells (log rank test, P = .004). Patients with small-cell (<20%) morphologic features survived longer than patients with large/blastoid (20%) morphologic features, (P = .003, log rank test). The most common additional karyotypic abnormality identified in this study involved chromosome 17, in 13 of 23 (56.5%) cases, which correlated with p53 overexpression but not with cytologic features.
We conclude that cytologic features of MCL predict the prognosis of patients with marked leukemic involvement. Chromosome 17 abnormalities are common in leukemic MCL, may be involved in pathogenesis, and are associated with p53 expression.
NUCLEOLATED VARIANT Nucleolated Variant of Mantle Cell Lymphoma With Leukemic Manifestations Mimicking Prolymphocytic Leukemia
Kit-fai Wong, MD, Chi-chiu So, MRCPath, and John K.C. Chan, FRCPath
Am J Clin Pathol 2002;117:246-251 Abstract quote
Chronic lymphoproliferative disorders sometimes can be difficult to classify.
We report 4 cases characterized by large cells with distinct central nucleoli, reminiscent of prolymphocytic leukemia, but shown on further workup to represent mantle cell lymphoma. At initial examination, the patients had generalized lymphadenopathy, splenomegaly, and a leukemic blood picture. The peripheral blood showed many large cells with round to slightly irregular nuclei, single central nucleoli, and a fair amount of pale cytoplasm. The picture was not typical of prolymphocytic leukemia because of the presence of generalized lymphadenopathy and the large size of the circulating abnormal cells. Immunophenotypic study showed that the large lymphoid cells were CD5+ CD23– mature B cells with overexpression of cyclin D1, and cytogenetic study demonstrated the translocation t(11;14)(q13;q32) in 3 patients. Lymph node biopsy confirmed a diagnosis of mantle cell lymphoma, pleomorphic variant, in all 4 patients.
This study documents the existence of an unusual leukemic form of mantle cell lymphoma with prominent nucleoli; the clinicopathologic features that distinguish it from other chronic lymphoproliferative disorders are discussed.
PLASMA CELL DIFFERENTIATION
*Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital and Clinics, University of Wisconsin School of Medicine and Public Health, Madison, WI daggerDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
- The differentiation of B lymphocytes into plasma cells (PCs) is an antigen-mediated process that largely depends on the interaction between B cells and regulatory factors in their microenvironment. Long-lived PCs are derived from activated B cells in the germinal center (GC), whereas PC differentiation from naive B cells occurs in the extrafollicular areas and the PCs are short-lived. Consequently, lymphomas arising from post-GC B cells often exhibit plasmacytic differentiation, whereas lymphomas arising from naive B cells less commonly show plasmacytic differentiation.
Herein, we report 2 cases of mantle cell lymphoma (MCL) with clonal PC differentiation. Both cases presented with the typical cytologic features of MCL and were characterized by a nodular and mantle-zone growth pattern. Clusters of clonal PCs with monotypic kappa light chain expression were identified in the centers of the tumor nodules and within reactive GCs. FICTION (Fluorescence immunophenotyping and Interphase Cytogenetics as a Tool for the Investigation Of Neoplasms) analysis demonstrated the characteristic t(11;14)(q13;q32) in both the MCL cells and clonal PCs, indicating that both cell types were derived from the same B-cell clone.
These findings indicate that the clonal PC differentiation may occur within GCs in some cases of MCL.PLATELET SATELLITISM Platelet Satellitism as Presenting Finding in Mantle Cell Lymphoma A Case Report
Christine Cesca, etal.
Am J Clin Pathol 2001;115:567-570 Abstract quote
Platelet satellitism surrounding polymorphonuclear neutrophils has been observed almost exclusively in EDTA-treated blood at room temperature. The mechanism underlying this phenomenon is not understood fully.
We report a case of platelet rosetting around atypical lymphocytes in peripheral blood smears made from EDTA-treated and untreated blood. Flow cytometry of the peripheral blood sample and immunohistochemical stains of the subsequent bone marrow biopsy specimen revealed a monoclonal B-cell population positive for CD5, CD20, and cyclin D1 and negative for CD3 and CD23; cytogenetic findings revealed a complex karyotype that included t(11;14). These findings were consistent with mantle cell lymphoma.
To our knowledge, the finding of platelet satellitism involving mantle cell lymphoma cells in peripheral blood has not been reported previously.
PLEOMORPHIC VARIANT Variation in tumor cell size and presence of larger tumor cells with irregular nuclei with scanty cytoplasm
Occasional large bizarre cells with occasional nucleoli
p53 mutations commonPROLYMPHOCYTIC ASSOCIATED Mature B-Cell Leukemias With More Than 55% Prolymphocytes A Heterogeneous Group That Includes an Unusual Variant of Mantle Cell Lymphoma
Ellen Schlette, etal.
Am J Clin Pathol 2001;115:571-581 Abstract quote
We studied 20 cases of mature B-cell leukemia with more than 55% prolymphocytes in peripheral blood or bone marrow, fulfilling the French-American-British criteria for B-cell prolymphocytic leukemia (PLL). Cases segregated into 3 groups: de novo PLL, 6; PLL occurring in patients with a previous well-established diagnosis of chronic lymphocytic leukemia (PLL-HxCLL), 10; and t(11;14)(q13;q32)-positive neoplasms, 4. All cases expressed monotypic immunoglobulin light chain, and most were positive for CD5. All t(11;14)-positive neoplasms were CD23– and uniquely positive for cyclin D1. Cytogenetic abnormalities were present in 19; in all 19, the karyotype was complex, indicating clonal evolution and genomic instability. The most frequent cytogenetic abnormality in de novo PLL involved chromosome 7 in 4 cases. Trisomy 12 or add(12p) was present in 4 cases of PLL-HxCLL.
We conclude that mature B-cell leukemias with more than 55% prolymphocytes are a heterogeneous group that includes t(11;14)-positive neoplasms, which we suggest are best classified as mantle cell lymphoma. We also suggest that prolymphocytic morphologic features are a common end-stage of transformation for several B-cell neoplasms.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Positive IgM/D, Ig lambda predominant
Pan B
CD5+
CD20+
Cyclin D1+
bcl-2+CD23-nodular meshworks of follicular dendritic cells
CD10-bcl-6 Aberrant Bcl6 Protein Expression in Mantle Cell Lymphoma.
Camacho FI, Garcia JF, Cigudosa JC, Mollejo M, Algara P, Ruiz-Ballesteros E, Gonzalvo P, Martin P, Perez-Seoane C, Sanchez-Garcia J, Piris MA.
*Molecular Pathology Program and daggerCytogenetics Unit, Centro Nacional de Investigaciones Oncologicas, Madrid; double daggerDepartment of Pathology and Genetics, Complejo Hospitalario de Toledo, Toledo; section signDepartment of Pathology, Hospital de Jarrio. Coana; paragraph signDepartment of Pathology, Hospital Ramon y Cajal, Madrid; and Departments of Pathology and Hematology, Hospital Reina Sofia, Cordoba, Spain.
Am J Surg Pathol. 2004 Aug;28(8):1051-1056. Abstract quote
Mantle cell lymphoma is routinely considered as a Bcl6-negative B-cell lymphoma carrying the translocation t(11;14).
Here we describe a series of five Bcl6-positive mantle cell lymphoma cases, including three classic and two blastoid variants. The proliferative index of these cases, measured with the Ki-67 antibody, was slightly higher than in Bcl6-negative mantle cell lymphoma cases (32.2 vs. 23.7%) Bcl6 expression was associated with translocations involving 3q27 in four of the five cases and an extra copy of the BCL6 gene in the fifth. A mutational study of the major mutational cluster in the BCL6 gene revealed no increased mutation rate, except in one case. One of the three cases displayed a high mutational index in the IgVH gene, suggesting exposure to a germinal center microenvironment.
Chromosomal alterations involving 3q27 seem to be responsible for this increased Bcl6 expression, which needs to be considered when Bcl6 is used in lymphoma diagnosis.CD5 CD5– Mantle Cell Lymphoma
Zach Liu, MD
Henry Y. Dong, MD
Wojciech Gorczyca, MD, etal.
Am J Clin Pathol 2002;118:216-224 Abstract quote
Mantle cell lymphoma (MCL) typically expresses B-cell antigens and CD5 and overexpresses bcl-1 protein. However, unusual cases of bcl-1+ and CD5– MCL have been observed, posing a practical challenge for correct diagnosis and management.We identified 25 cases (48 samples) of bcl-1+ and CD5– lymphoma. CD5 expression was assessed by flow cytometric analysis alone (1 case), immunohistochemical analysis alone (17 cases), or dual flow cytometric/immuno-histochemical methods (7 cases). The morphologic features were consistent with MCL with centrocytic cytomorphology in 20 cases and blastic variant in 5 cases. The t(11;14) was confirmed in 8 of 11 cases by fluorescence in situ hybridization of paraffin-embedded tissue. Cytogenetic analysis revealed the t(11;14) within a complex karyotype in 2 additional cases.
These data show that MCL may lack CD5 expression. Evaluation of bcl-1 expression by immunohistochemical analysis or molecular genetics may be indicated if MCL is suspected clinically or morphologically despite a lack of CD5 expression.
CD23 CD23 Expression in Mantle Cell Lymphoma: Clinicopathologic Features of 18 Cases
Ellen Schlette, MD, Kai Fu, MD, PhD, and L. Jeffrey Medeiros, MDAm J Clin Pathol 2003;120:760-766 Abstract quote
The distinction between small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and mantle cell lymphoma (MCL) has important clinical implications. Typically, SLL/CLL is CD23+, whereas MCL is CD23–. However, CD23 is expressed in a subset of MCLs, and the clinicopathologic features of patients with these neoplasms are not well described.
We report 18 CD23+ MCLs, detected by flow cytometry in all cases (dim intensity, 16; bright intensity, 2), 5 (28%), also positive by immunohistochemical analysis. There were 13 men and 5 women (median age, 56 years), 5 of whom died (median survival, 46 months). Seventeen (94%) had bone marrow involvement. Lymphadenopathy (14 cases [78%]), splenomegaly (11 cases [61%]), and leukemic involvement (10 cases [56%]) were common. Five cases (28%) had blastoid morphologic features. The frequency of CD23 expression by MCL is method-dependent, being typically dim and most commonly detected by flow cytometry.
In this small study group, bone marrow and leukemic involvement were relatively common.CYCLIN D1 DCS-6 from Neomarkers is a good antibody clone
Internal controls that are positive are some histiocytes and endothelial cells
If all these cells are negative, it is possible that the stain is not workingConsistent immunostaining for cyclin D1 can be achieved on a routine basis using a newly available rabbit monoclonal antibody.
Cheuk W, Wong KO, Wong CS, Chan JK.
Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong, SAR China.
Am J Surg Pathol. 2004 Jun;28(6):801-7. Abstract quote
Rabbit monoclonal antibody (MAb), which has become available only recently, theoretically combines the advantage of the high affinity attributable to its rabbit origin and the high specificity due to its monoclonal nature.
Since immunohistochemical demonstration of cyclin D1 is notoriously difficult, this study aims to assess whether a newly available rabbit MAb against cyclin D1 (SP4) can improve the consistency of immunostaining, especially for the diagnosis of mantle cell lymphoma (MCL).
A total of 150 cases of lymphoproliferative lesions, including 30 cases of MCL, histologic mimickers of MCL, and various types of lymphomas and leukemias, were studied. Immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections using a labeled streptavidin-biotin peroxidase system in an automated immunostainer.
All cases of MCL expressed cyclin D1, with a higher median staining score (8 out of a maximum of 12) compared with mouse MAb DCS-6 (score 4). In addition, 2 of 15 cases of B-cell chronic lymphocytic leukemia (B-CLL), 3 of 12 cases of multiple myeloma, and 2 of 5 cases of hairy cell leukemia were also positive. Comparable staining results could also be achieved by an optimized manual staining protocol.
This study thus confirms the superior performance of the rabbit MAb SP4, which should permit consistent immunostaining for cyclin D1 to be readily achieved. The value of cyclin D1 immunohistochemistry in the differential diagnosis of MCL from other low-grade B-cell lymphomas is also affirmed, but with the caveat that rare cases of B-CLL can also be cyclin D1 positive.Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma.
Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, Yamaguchi M, Tamaru J, Uike N, Hashimoto Y, Morishima Y, Suchi T, Seto M, Nakamura S.
Department of Pathology, Laboratory of Chemotherapy, Aichi Cancer Center, Nagoya, Japan.
Blood 2000 Apr 1;95(7):2253-61 Abstract quote
Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin's lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation.
We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry.
128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P =.04), larger cell size (P =.02), higher mitotic index (P =.01), more frequent gastrointestinal involvement (P =.05), higher international prognostic index score (P =.05), and lower p27(KIP1) expression (P <.0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P =.0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL.
We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria.
Immunohistochemical detection of cyclin D1 using optimized conditions is highly specific for mantle cell lymphoma and hairy cell leukemia.
Miranda RN, Briggs RC, Kinney MC, Veno PA, Hammer RD, Cousar JB.
Department of Pathology, Truman Medical Center and University of Missouri-Kansas City, 64108, USA.
Mod Pathol 2000 Dec;13(12):1308-14 Abstract quote
Mantle cell lymphoma (MCL) is more aggressive when compared with other lymphomas composed of small, mature B lymphocytes. Cyclin D1 is overexpressed in MCL as a result of the translocation t(11;14)(q13;q32). Cyclin D1 immunohistochemistry in fixed, paraffin-embedded tissue contributes to the precise and reproducible diagnosis of MCL without the requirement of fresh tissue. However, its use in bone marrow biopsies is not well established. In addition, increased levels of cyclin D1 mRNA have been found in hairy cell leukemia but have not consistently been detected by immunohistochemistry.
We used a polyclonal antibody and heat-induced antigen retrieval conditions to evaluate 73 fixed, paraffin-embedded bone marrow, spleen, and lymph node specimens with small B-cell infiltrates, obtained from 55 patients. Cyclin D1 was overexpressed in 13/13 specimens of MCL (usually strong, diffuse reactivity in most tumor cells) and in 14/14 specimens of hairy cell leukemia (usually weak, in a subpopulation of tumor cells). No reactivity was detected in five cases of B-chronic lymphocytic leukemia; five cases of splenic marginal zone lymphoma; six cases of nodal marginal zone cell lymphoma; two cases of gastric marginal zone cell lymphoma; or ten benign lymphoid infiltrates in bone marrow, spleen, or lymph nodes.
In summary, although the total number of studied cases is small and a larger series of cases may be required to confirm our data, we present optimized immunohistochemical conditions for cyclin D1 in fixed, paraffin-embedded tissue that can be useful in distinguishing MCL and hairy cell leukemia from other small B-cell neoplasms and reactive lymphoid infiltrates.
Negative CD10
CD23
Pan T cell antigens
CD11cAlkaline phosphatase 50% of cases are positive
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES p27Kip1 Immunostaining for the Differential Diagnosis of Small B-Cell Neoplasms in Trephine Bone Marrow Biopsies
Marcus Kremer, M.D., Stephan Dirnhofer, M.D., Anna Nickl, Heinz Hoefler, M.D., Leticia Quintanilla-Martínez, M.D. and Falko Fend, M.D.
Institute of Pathology (MKHH, FF), Technical University Munich, Germany; Institute of Pathology (SD), University of Innsbruck, Austria; Institute of Pathology (MK, AN, HH, LQM), GSF-National Research Center for Environment and Health, Neuherberg, Germany; and Institute of Pathology (SD), University of Basel, Switzerland.
Mod Pathol 2001;14:1022-1029 Abstract quote
The distinction between mantle cell lymphoma (MCL) and other small B-cell non-Hodgkin lymphomas (NHL) is important because MCL has a more aggressive clinical course. In bone marrow (BM) biopsy specimens, this distinction can be particularly difficult. Although cyclin D1 immunostaining and molecular detection of the t(11;14) translocation are highly specific markers for MCL, they fail to detect a proportion of cases.
We have recently described that MCL typically lacks detectable expression of the cyclin-dependent kinase inhibitor p27kip1 protein by immunostaining, which is expressed at high levels in most small B-cell NHL inversely correlated to the proliferation rate. We therefore examined whether p27kip1 immunostaining could be a useful adjunct for the differential diagnosis of small B-cell NHL infiltrates in the BM.
Trephine BM biopsy specimens of 96 patients, including well-characterized MCL (19 cases), B-cell chronic lymphocytic leukemia (27 cases), follicular lymphoma (18 cases), hairy cell leukemia (22 cases), and marginal zone lymphoma (10 cases) as well as 10 reactive BM, including five with benign lymphoid aggregates were investigated. In addition, the presence of a t(11;14) translocation involving the major translocation cluster was studied by PCR in all MCL. All cases of B-cell chronic lymphocytic leukemia, follicular lymphoma, and marginal zone lymphoma revealed a strong p27kip1 nuclear staining in the majority of neoplastic cells. Fourteen (78%) cases of MCL were p27kip1-negative in the tumor cells, whereas four cases revealed a weak nuclear positivity. Seventeen (77%) cases of hairy cell leukemia were also either completely negative for p27kip1 or showed a faint positive staining in a minority of the neoplastic cells. Nine of 19 cases (47%) of MCL showed a bcl1 rearrangement involving the major translocation cluster region.
These findings demonstrate that p27kip1 immunostaining is a valuable additional marker for the differential diagnosis of small B-cell NHL infiltrates in BM biopsies. The reduction or lack of p27kip1 protein expression in MCL, as well as in hairy cell leukemia, might be an important event in the pathogenesis of these disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Diffuse forms and those which show a high mitotic figure (> 20 HPF in diffuse and >10 HPF in follicular) have poor prognosis
Most patients die within 3-5 years
Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants.
Majlis A, Pugh WC, Rodriguez MA, Benedict WF, Cabanillas F.
Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA
J Clin Oncol 1997 Apr;15(4):1664-71 Abstract quote
PURPOSE: Clinical data and histologic material were retrospectively analyzed in 46 cases of previously untreated mantle cell lymphoma (MCL) to more fully characterize the clinical response pattern of these lymphomas and to determine whether growth pattern significantly affected clinical outcome.
MATERIALS AND METHODS: The histologic pattern was classified as diffuse (61%), nodular (13%), and mantle zone (26%) in accordance with stated criteria.
RESULTS: Bone marrow infiltration was detected in 69% of cases; the frequency of involvement correlated with histologic pattern, being most common in diffuse variants and least common in mantle zone variants. Other sites of extranodal involvement were observed in 50% of cases. Cyclin-D1 staining revealed nuclear positivity in 23 of 25 patients (92%) and no difference was observed between the various histologic patterns. Rearrangement at the bcl-1 major translocation cluster (MTC) was detected in seven of 21 cases, without regard for histologic pattern. Complete response rates to doxorubicin-based regimens showed a striking correlation with histologic pattern. Seventy-three percent of patients with a mantle zone pattern attained a complete response compared with only 25% of patients with a nodular pattern and 19% with a diffuse pattern. Three-year survival rates were 100%, 50%, and 55% for patients with mantle zone, nodular, and diffuse histologic patterns, respectively.
CONCLUSION: We conclude that (1) diffuse and nodular MCL are associated with a poor treatment response and a poor overall survival rate; (2) the mantle zone variant exhibits the clinical attributes of a low-grade lymphoma; and (3) the poor survival rates of patients with nodular and diffuse MCL suggest that these variants be classified as intermediate-grade lymphomas. However, the trend of the time to treatment failure curve does not indicate that current regimens can cure MCL.
TREATMENT Autologous hematopoietic stem cell transplantation for mantle cell lymphoma.
Vose JM, Bierman PJ, Weisenburger DD, Lynch JC, Bociek Y, Chan WC, Greiner TC, Armitage JO.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198-7680, USA.
Biol Blood Marrow Transplant 2000;6(6):640-5 Abstract quote
This study evaluated the outcomes of patients who underwent high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (autoHSCT) for mantle cell non-Hodgkin's lymphoma and the effect of clinical and treatment characteristics.
The clinical outcome and prognostic factors in 40 patients who underwent HDC and autoHSCT for mantle cell lymphoma between June 1991 and August 1998 were analyzed. With a median follow-up of 24 months for the surviving patients (range, 4-68 months), the 2-year overall survival was 65% and the 2-year event-free survival (EFS) was 36%. In univariate analysis, characteristics predictive of a poor EFS were blastic morphology (P = .019) and the patient having received 3 or more prior chemotherapy regimens (P = .004). In a multivariate analysis, the only factor associated with a poor EFS was the number of prior chemotherapy regimens. Those patients who received 3 or more prior therapies had a 2-year EFS of 0%, and those who received <3 therapies had a 2-year EFS of 45% (P = .004). Patients with mantle cell lymphoma can obtain prolonged EFS with HDC and autoHSCT; however, this strategy for prolonged EFS appears to work optimally in patients who are less heavily pretreated.
Whether this therapy will increase the overall survival or EFS in patients receiving transplants in first complete remission will need to be tested in prospective randomized clinical trials.
Dexa-BEAM: an effective regimen for cytoreduction prior to high-dose chemotherapy with autologous stem cell support for patients with relapsed/refractory mantle-cell lymphoma.
Josting A, Reiser M, Wickramanayake PD, Rueffer U, Draube A, Sohngen D, Tesch H, Wolf J, Diehl V, Engert A.
First Department of Internal Medicine, University Hospital Cologne, Koln, Germany.
Leuk Lymphoma 2000 Mar;37(1-2):185-7 Abstract quote
Mantle-cell lymphoma (MCL) is not a curable disease using conventional chemotherapy. Patients with MCL have the shortest median time to progression and the shortest median survival of all lymphoma subtypes after first-line treatment.
In the present study we determined the efficacy of maximal cytoreductive therapy with up to four cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell support (ASCT) for patients with advanced relapsed or refractory MCL. Nine consecutive patients with relapsed or refractory MCL were included. Three patients had partial remission (PR), three patients progressive disease (PD) upon first line tretment, and three patients first or subsequent relapse. After 2 to four cycles of Dexa-BEAM eight patients achieved complete remission (CR), resulting in a response rate of 88%. Six of 8 patients responding to Dexa-BEAM received high-dose chemotherapy HDCT (BEAM) and autologous hematopoietic stem cell transplantation (ASCT).
With a median follow up of 24 months six patients are alive. Five of those six patients are still in contiuous CR (range 13-54 months).
Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody.
Maeda T, Yamada Y, Tawara M, Yamasaki R, Yakata Y, Tsutsumi C, Onimaru Y, Kamihira S, Tomonaga M.
Unit of General Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Japan.
Int J Hematol 2001 Jul;74(1):70-5 Abstract quote
Mantle cell lymphoma (MCL) has a poor prognosis without cure; the median overall survival ranges only from 3 to 4 years irrespective of conventional therapeutic regimens. IDEC-C2B8 (rituximab), a chimeric monoclonal antibody against the B-cell-specific antigen CD20, induces an evaluable clinical response in patients with MCL with mild toxicities. However, the single agent rituximab cannot cure MCL. Due to its low immunogenicity, an antibody against IDEC-C2B8 (human antichimeric antibody [HACA]) has rarely been produced in vivo.
We report a patient with relapsed MCL who was successfully treated with IDEC-C2B8 for over a year although she developed HACA 6 months after the initial administration of IDEC-C2B8 in the phase II clinical trial conducted by Zenyaku Kogyo Co. Ltd. We followed the pharmacokinetics of IDEC-C2B8, the serum HACA titer, and the number of B lymphocytes in the peripheral blood in relation to clinical response. The HACA became undetectable soon after subsequent administrations of IDEC-C2B8. When the serum level of IDEC-C2B8 was kept elevated, clinical responses were apparently observed and HACA disappeared during this response period. There were no significant clinical toxicities related to the appearance of HACA.
The present findings suggested that IDEC-C2B8 is effective and safe even in patients who have developed HACA.
Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001
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Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
Last Updated October 4, 2006
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