logo logo
Search: Organ site Search: Tumor / Syndrome
or
WHO Classification of Tumours
Introduction: Classification of lymphoid neoplasms


Definition
B cell and T/NK cell neoplasms are clonal tumours of mature and immature B cells, T cells or natural killer (NK) cells at various stages of differentiation. Because NK cells are closely related, and share some immunophenotypic and functional properties with T cells, these two classes of neoplasms are considered together.

B-cell and T-cell neoplasms in many respects appear to recapitulate stages of normal B-cell or T-cell differentiation, so that they can be to some extent classified according to the corresponding normal stage. However, some common B-cell neoplasms, e.g. hairy cell leukaemia, do not clearly correspond to a normal B-cell differentiation stage. Some neoplasms may exhibit lineage heterogeneity, or even more rarely, lineage plasticity

Click to access Pubmed
Jaffe ES, Chan JK, Su IJ, Frizzera G, Mori S, Feller AC, Ho FC (1996)
Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology.
Am J Surg Pathol 20: 103-11




Click to access Pubmed
Macon WR, Levy NB, Kurtin PJ, Salhany KE, Elkhalifa MY, Casey TT, Craig FE, Vnencak-Jones CL, Gulley ML, Park JP, Cousar JB (2001)
Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas.
Am J Surg Pathol 25: 285-96



. Thus, the normal counter­part of the neoplastic cell cannot at this time be the sole basis for the classification.

Pathobiology of lymphoid neoplasms and the normal immune system
There are two major arms of the immune system that differ, both in the nature of the target and the type of the immune response, known as the innate and adaptive immune responses. Cells of the innate ­immune system represent a first line of defense, a primitive response. Cells of the innate immune system include NK cells, CD3+ CD56+ T-cells or NK-like T-cells, and γδ T cells. These cells play a role in barrier defenses involving mucosal and cutaneous immunity. They do not need to encounter antigen in the context of the major histocompatibility complex (MHC), and thus do not require antigen presenting cells to initiate an immune response.

The adaptive immune system is a more sophisticated type of immune response. It is specific for a particular pathogen; two key features of the adaptive immune response are specificity and memory. This contrasts with innate immune responses which are non-specific for the target, and do not require or lead to immunological memory.

B-cell lymphomas: lymphocyte differentiation and function
B-cell neoplasms tend to mimic stages of normal B-cell differentiation, and the resemblance to normal cell stages is a major basis for their classification and nomenclature.

Normal B-cell differentiation begins with precursor B cells known as progenitor B cells/B lymphoblasts (blast cells that are the precursors of the entire B-cell line), which undergo immunoglobulin VDJ gene rearrangement and differentiate into mature surface immunoglobulin (sIg) positive (IgM+ IgD+) naïve B cells via pre-B cells with cytoplasmic µ heavy chains and immature IgM+ B cells. Naïve B cells, that are often CD5+, are small resting lympho­cytes that circulate in the peripheral blood (PB) and also occupy primary lymphoid follicles and follicle mantle zones (so-called recirculating B cells)

Click to access Pubmed
Inghirami G, Foitl DR, Sabichi A, Zhu BY, Knowles DM (1991)
Autoantibody-associated cross-reactive idiotype-bearing human B lymphocytes: distribution and characterization, including Ig VH gene and CD5 antigen expression.
Blood 78: 1503-15




Click to access Pubmed
Kipps TJ (1989)
The CD5 B cell.
Adv Immunol 47: 117-85



. Most cases of mantle cell lymphoma are thought to correspond to CD5 positive naïve B cells
Click to access Pubmed
Hummel M, Tamaru J, Kalvelage B, Stein H (1994)
Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle.
Blood 84: 403-7



.

On encountering antigen that fits their surface Ig receptors, naïve B cells undergo transformation, proliferate, and ultimately mature into antibody-secreting plasma cells and memory B cells. Transformed cells formed from naïve B cells that have encountered antigen may mature directly into plasma cells that produce the early IgM antibody response to antigen. T-cell independent maturation can take place outside of the germinal centre

Click to access Pubmed
Chiorazzi N, Rai KR, Ferrarini M (2005)
Chronic lymphocytic leukemia.
N Engl J Med 352: 804-15



. It is debated whether somatic hypermutation of the IGH@ genes occurs during this extrafollicular maturation. Other antigen-exposed B cells migrate into the centre of a primary follicle, proliferate, and fill the follicular dendritic cell (FDC) meshwork, forming a germinal centre
Click to access Pubmed
Liu YJ, Zhang J, Lane PJ, Chan EY, MacLennan IC (1991)
Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.
Eur J Immunol 21: 2951-62




Click to access Pubmed
MacLennan IC (1994)
Germinal centers.
Annu Rev Immunol 12: 117-39



. Germinal centre centroblasts express low levels of sIg, and also switch off expression of BCL2 protein; thus, they and their progeny are susceptible to death through apoptosis
Click to access Pubmed
Reed JC (2008)
Bcl-2-family proteins and hematologic malignancies: history and future prospects.
Blood 111: 3322-30



. Centroblasts express CD10 and BCL6 protein, a nuclear transcription factor that is expressed by both centroblasts and centrocytes. BCL6 is not expressed in naïve B cells and is switched off in memory B cells and plasma cells
Click to access Pubmed
Luna-Fineman S, Shannon KM, Atwater SK, Davis J, Masterson M, Ortega J, Sanders J, Steinherz P, Weinberg V, Lange BJ (1999)
Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients.
Blood 93: 459-66




Click to access Pubmed
Pittaluga S, Ayoubi TA, Wlodarska I, Stul M, Cassiman JJ, Mecucci C, Van Den Berghe H, Van De Ven WJ, De Wolf-Peeters C (1996)
BCL-6 expression in reactive lymphoid tissue and in B-cell non-Hodgkin's lymphomas.
J Pathol 179: 145-50



.

In the germinal centre, somatic hyper­mutation occurs in the immunoglobulin heavy and light chain variable (IGV) ­region genes; these mutations may result in a non-functional gene, or a gene that produces antibody with lower or higher affinity for antigen than the native IG gene. Also in the germinal centre some cells switch from IgM to IgG or IgA production. Through these mechanisms, the germinal centre reaction gives rise to the higher affinity IgG or IgA antibodies of the late primary or secondary immune response

Click to access Pubmed
MacLennan IC, Liu YJ, Oldfield S, Zhang J, Lane PJ (1990)
The evolution of B-cell clones.
Curr Top Microbiol Immunol 159: 37-63



. The BCL6 gene also undergoes somatic mutation in the germinal centre, however, at a lower frequency than is seen in the IG genes
Click to access Pubmed
Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, Chaganti RS, Klein U, Küppers R, Rajewsky K, Dalla-Favera R (1998)
BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci.
Proc Natl Acad Sci U S A 95: 11816-21



. Ongoing IGV region gene mutation with intra­clonal diversity is a hallmark of germinal centre cells, and both IGV region gene mutation and BCL6 mutation serve as markers of cells that have been through the germinal centre. Most diffuse large B-cell neoplasms (DLBCL) are composed of cells that at least in part resemble centroblasts and that have mutated IGV genes, consistent with a derivation from cells that have been exposed to the germinal centre. Burkitt lymphoma cells are BCL6+ and have mutated IGH genes, and are thus also thought to correspond to a germinal centre blast cell. Both Burkitt and DLBCL correspond to proliferating cells, and are clinically aggressive tumours.

Centroblasts mature to centrocytes, and these cells are seen predominantly in the light zone of the germinal centre. Centrocytes express sIg that has an altered antibody combining site as compared with that of their progenitors, based both on somatic mutations and heavy chain class switching. Centrocytes with mutations that result in increased affinity are rescued from apoptosis and they re-express BCL2 protein

Click to access Pubmed
MacLennan IC (1994)
Germinal centers.
Annu Rev Immunol 12: 117-39



. Through interaction with surface molecules on FDC’s and T-cells, such as CD23 and CD40 ligand, centrocytes switch off BCL6 protein expression
Click to access Pubmed
Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B, Louie DC, Offit K, Chaganti RS, Dalla-Favera R (1995)
BCL-6 protein is expressed in germinal-center B cells.
Blood 86: 45-53




Click to access Pubmed
Pittaluga S, Ayoubi TA, Wlodarska I, Stul M, Cassiman JJ, Mecucci C, Van Den Berghe H, Van De Ven WJ, De Wolf-Peeters C (1996)
BCL-6 expression in reactive lymphoid tissue and in B-cell non-Hodgkin's lymphomas.
J Pathol 179: 145-50



, and differentiate into either memory B-cells or plasma cells
Click to access Pubmed
MacLennan IC (1994)
Germinal centers.
Annu Rev Immunol 12: 117-39



. BCL6 and IRF4/MUM1 are reciprocally expressed, with IRF4/MUM1 being positive in late centrocytes and plasma cells
Click to access Pubmed
Falini B, Fizzotti M, Pucciarini A, Bigerna B, Marafioti T, Gambacorta M, Pacini R, Alunni C, Natali-Tanci L, Ugolini B, Sebastiani C, Cattoretti G, Pileri S, Dalla-Favera R, Stein H (2000)
A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells.
Blood 95: 2084-92




Click to access Pubmed
Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G, Pernis A, Pasqualucci L, Dalla-Favera R (2007)
A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.
Cancer Cell 12: 280-92



. IRF4/MUM1 plays a critical role in down-regulating BCL6 expression
Click to access Pubmed
Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G, Pernis A, Pasqualucci L, Dalla-Favera R (2007)
A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.
Cancer Cell 12: 280-92



. Follicular lymphomas are tumours of germinal centre B-cells (centrocytes and centroblasts) in which the germinal centre cells fail to undergo apoptosis, in most cases due to a chromosomal rearrangement, t(14;18), that prevents the normal switching off of BCL2 protein expression. Centrocytes usually predominate over centroblasts, and these neoplasms tend to be indolent.

Post-germinal centre memory B-cells circulate in the PB and comprise at least some of the cells in the follicular marginal zones of lymph nodes, spleen and mucosa-associated lymphoid tissue (MALT). Marginal zone B-cells of this compartment typically express pan-B antigens, surface IgM with only low level IgD and lack both CD5 and CD10

Click to access Pubmed
Spencer J, Finn T, Pulford KA, Mason DY, Isaacson PG (1985)
The human gut contains a novel population of B lymphocytes which resemble marginal zone cells.
Clin Exp Immunol 62: 607-12




Click to access Pubmed
van den Oord JJ, de Wolf-Peeters C, Desmet VJ (1989)
Marginal zone lymphocytes in the lymph node.
Hum Pathol 20: 1225-7



. Plasma cells produced in the germinal centre enter the PB and home to the bone marrow (BM). They contain predominantly IgG or IgA; they lack sIg and CD20, but express IRF4/MUM1, CD79a, CD38 and CD138. Both memory B-cells and long-lived plasma cells have mutated IGV region genes, but do not continue to undergo mutation. Post-germinal centre B-cells retain the ability to home to tissues in which they have undergone antigen stimulation, probably through surface integrin expression, so that B-cells that arise in MALT tend to return there, while those that arise in lymph nodes will home to nodal sites and BM
Click to access Pubmed
Butcher EC (1990)
Warner-Lambert/Parke-Davis Award lecture. Cellular and molecular mechanisms that direct leukocyte traffic.
Am J Pathol 136: 3-11



. Marginal zone lymphomas of MALT, splenic, and nodal types correspond to post germinal centre, memory B cells of marginal zone type that derive from and proliferate specifically in extranodal, splenic or nodal tissues. Plasma cell myeloma corresponds to a BM homing plasma cell.

T-cell lymphomas: lymphocyte differentiation and function
T lymphocytes arise from a BM precursor that undergoes maturation and acquisition of function in the thymus gland. Antigen specific T cells mature in the thymic cortex. T cells recognizing self-peptides are eliminated via apoptosis, in a process mediated by cortical epithelial cells and thymic nurse cells. Cortical thymocytes have an immature T-cell phenotype, and express terminal deoxynucleotidyl transferase (TDT), CD1a, CD3, CD5, and CD7. CD3 is first expressed in the cytoplasm, prior to complete T-cell receptor gene rearrangement and export to the cell membrane. Cortical thymocytes are initially double-negative for both CD4 and CD8. These antigens are co-expressed in maturing thymocytes, and later more mature T-cells express only CD4 or CD8. These varying stages of T-cell maturation are reflected in T lymphoblastic leukaemia/ lymphoma (T-ALL/LBL).

Medullary thymocytes have a phenotype similar to that of mature T-cells of the peri­pheral lymphoid organs. There are two classes of T-cells: αβ T-cells and γδ T-cells

Click to access Pubmed
Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM (2002)
Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.
Arthritis Rheum 46: 3151-8



. This distinction is based on the structure of the T-cell receptor. The αβ and γδ chains are each composed of a variable (V) and constant (C) portion. They both are associated with the CD3 complex, which contains γ, δ and ε chains. NK-cells do not have a complete T-cell receptor complex, activated NK cells express the ε and ζ chains of CD3 in the cytoplasm. They express CD2, CD7, and sometimes CD8, but not surface CD3. They also typically express CD16, CD56, and variably CD57 and contain cytoplasmic cytotoxic granule proteins. NK-cells kill their targets, through antibody dependent cytotoxicity (ADCC) or a second mechanism involving killer activating receptors and killer inhibitory receptors (KIRs). As NK-cells do not rearrange the T-cell receptor genes, analysis of clonality in NK-cell proliferations can utilise antibodies to the various KIR receptors.

Toll-like receptors play a role in cell-cell interactions and signaling. They play a critical role in the recognition of infectious agents, initiating signaling through NFkB. While they function most prominently in innate immune responses, they also have a role in the adaptive immune system

Click to access Pubmed
Leulier F, Lemaitre B (2008)
Toll-like receptors--taking an evolutionary approach.
Nat Rev Genet 9: 165-78



.

The lymphomas of the innate immune system are predominantly extranodal in presentation, mirroring the distribution of the functional components of this system. It is interesting that many T-cell and NK-cell lymphomas observed commonly in the paediatric and young adult age group are derived from cells of the innate immune system

Click to access Pubmed
Jaffe ES (2006)
Pathobiology of peripheral T-cell lymphomas.
Hematology Am Soc Hematol Educ Program : 317-22



. These include aggressive NK-cell leukaemia, systemic EBV-positive T-cell lymphoproliferative disease (LPD) of childhood, most hepato­splenic T-cell lymphomas, and γδ T-cell lymphomas affecting cutaneous and mucosal sites. Anaplastic large cell lymphoma (ALCL) is the most common paediatric T-cell lymphoma, and also is of cytotoxic origin. However its normal cellular counterpart, if one exists, is unknown.

γδ T-cells express neither CD4 nor CD8, and also usually lack CD5. A subpopulation expresses CD8. They comprise less than 5% of all normal T-cells, and show a restricted distribution, being found mainly in the splenic red pulp, intestinal epithelium, and other epithelial sites. It is notable that these sites are more commonly affected by γδ T-cell lymphomas, which otherwise are relatively rare

Click to access Pubmed
(1982)
National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project.
Cancer 49: 2112-35




Click to access Pubmed
Borenstein J, Pezzella F, Gatter KC (2007)
Plasmablastic lymphomas may occur as post-transplant lymphoproliferative disorders.
Histopathology 51: 774-7




Click to access Pubmed
Lima M, Almeida J, Dos Anjos Teixeira M, Alguero Md Mdel C, Santos AH, Balanzategui A, Queirós ML, Bárcena P, Izarra A, Fonseca S, Bueno C, Justiça B, Gonzalez M, San Miguel JF, Orfao A (2003)
TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder.
Am J Pathol 163: 763-71



. γδ T-cells have a restricted range of antigen recognition, and represent a first line of defense against bacterial peptides, such as heat shock proteins
Click to access Pubmed
Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM (2002)
Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.
Arthritis Rheum 46: 3151-8



. They are often involved in responses to mycobacterial infections, and in mucosal immunity.

More recently, the pattern of cytolytic molecules has been investigated and correlated with both cellular origin and function. For example, to date five granzymes have been demonstrated in human cells

Click to access Pubmed
Sedelies KA, Sayers TJ, Edwards KM, Chen W, Pellicci DG, Godfrey DI, Trapani JA (2004)
Discordant regulation of granzyme H and granzyme B expression in human lymphocytes.
J Biol Chem 279: 26581-7



. These enzymes are similar in structure, but differ in their substrate specificity and chromosomal locations. Granzyme M, a novel member of this family, has unusual enzyme specificity, preferring cleavage after methionine, leucine or norleucine. It has been suggested that this enzyme may play a role in the effector phase of innate immune responses. Its expression is restricted to NK-cells, CD3+ CD56+ T-cells, and γδ T-cells, but it is absent in other cytotoxic T-cell subsets. Granzyme M is expressed in hepatosplenic T-cell lymphomas, cutaneous γδ T-cell lymphomas, and most intestinal T-cell lymphomas tested, linking these neoplasms to the innate immune system
Click to access Pubmed
Krenacs L, Smyth MJ, Bagdi E, Krenacs T, Kopper L, Rudiger T, Zettl A, Muller-Hermelink HK, Jaffe ES, Raffeld M (2003)
The serine protease granzyme M is preferentially expressed in NK-cell, gamma delta T-cell, and intestinal T-cell lymphomas: evidence of origin from lymphocytes involved in innate immunity.
Blood 101: 3590-3



.

T-cells of the adaptive immune system are heterogeneous and functionally complex, and include naïve, effector (regulatory and cytotoxic), and memory T-cells. Interestingly, T-cell lymphomas of the adaptive immune system present primarily in adults, and are mainly nodal in origin, contrasting with the extranodal T-cell lymphomas of the innate immune system

Click to access Pubmed
Jaffe ES (2006)
Pathobiology of peripheral T-cell lymphomas.
Hematology Am Soc Hematol Educ Program : 317-22



. CD4-positive T-cells are primarily regulatory, acting via cytokine production. CD4-positive cells are divided into two major types, based on their cytokine secretion profiles, known as Th1, and Th2. Th1 cells secrete interleukin (IL)-2 and interferon γ, but not IL-4, 5, or 6. In contrast, Th2 cells secrete IL-4, 5, 6, and 10
Click to access Pubmed
Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM (2002)
Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.
Arthritis Rheum 46: 3151-8



. Th1 cells provide help mainly to other T-cells and macrophages, whereas Th2 cells provide help mainly to B-cells, in the production of antibodies
Click to access Pubmed
Brugières L, Deley MC, Pacquement H, Meguerian-Bedoyan Z, Terrier-Lacombe MJ, Robert A, Pondarré C, Leverger G, Devalck C, Rodary C, Delsol G, Hartmann O (1998)
CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology.
Blood 92: 3591-8



. CD4-positive T-cells can act to both help and suppress immune responses, and consist of multiple subpopulations only recently recognized.

Recently much has been learned about a unique CD4+ T-cell subset found in the normal germinal centre. These cells, termed follicular T-helper cells (TFH), provide help to B-cells in the context of the germinal centre reaction

Click to access Pubmed
Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B, Baglin AC, Haioun C, Delfau-Larue MH, Gaulard P (2006)
Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells.
Am J Surg Pathol 30: 490-4




Click to access Pubmed
Grogg KL, Attygalle AD, Attygale AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A (2006)
Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified.
Mod Pathol 19: 1101-7




Click to access Pubmed
Ortonne N, Dupuis J, Plonquet A, Martin N, Copie-Bergman C, Bagot M, Delfau-Larue MH, Gaulier A, Haioun C, Wechsler J, Gaulard P (2007)
Characterization of CXCL13+ neoplastic t cells in cutaneous lesions of angioimmunoblastic T-cell lymphoma (AITL).
Am J Surg Pathol 31: 1068-76



. They have a unique phenotype, expressing the germinal centre-associated markers BCL6 and CD10, normally found on B-cells. TFH express CD4, CD57, PD-1, and produce the chemokine CXCL13 and its receptor CXCR5. CXCL13 causes induction and proliferation of FDC; CXCL13 also facilitates the migration of B and T cells expressing CXCR5 into the germinal centre. Recent studies have identified increased expression of CXCL13 in angioimmunoblastic T-cell lymphoma (AITL), a finding that helps to link together many of its clinical and pathological features
Click to access Pubmed
Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B, Baglin AC, Haioun C, Delfau-Larue MH, Gaulard P (2006)
Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells.
Am J Surg Pathol 30: 490-4




Click to access Pubmed
Grogg KL, Attygalle AD, Attygale AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A (2006)
Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified.
Mod Pathol 19: 1101-7




Click to access Pubmed
Ortonne N, Dupuis J, Plonquet A, Martin N, Copie-Bergman C, Bagot M, Delfau-Larue MH, Gaulier A, Haioun C, Wechsler J, Gaulard P (2007)
Characterization of CXCL13+ neoplastic t cells in cutaneous lesions of angioimmunoblastic T-cell lymphoma (AITL).
Am J Surg Pathol 31: 1068-76



. Notably AITL is associated with polyclonal hypergammaglobulinaemia and expansion and proliferation of both B-cells and CD21+ FDC’s within the lymph node.

A CD4+ T cell with very different properties is the regulatory T cell (Treg), which functions to shut off and suppress immune responses

Click to access Pubmed
Sojka DK, Huang YH, Fowell DJ (2008)
Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target.
Immunology 124: 13-22



. This cell is thought to play an important role in preventing autoimmunity. Tregs express high density CD25, and the transcription factor FOXP3, in combination with CD4. Adult T-cell leukaemia/lymphoma (ATLL), has been linked to Treg cells based on expression of both CD25 and FoxP3, and this finding helps to explain the marked immunosuppression associated with ATLL
Click to access Pubmed
Roncador G, Garcia JF, Garcia JF, Maestre L, Lucas E, Menarguez J, Ohshima K, Nakamura S, Banham AH, Piris MA (2005)
FOXP3, a selective marker for a subset of adult T-cell leukaemia/lymphoma.
Leukemia 19: 2247-53



.

Recent studies have tried to relate the pathological or clinical manifestations of T-cell lymphomas to cytokine or chemo­kine expression by the neoplastic cells, or accompanying accessory cells within the lymph node. For example, the hyper­calcemia associated with ATLL has been linked to secretion of factors with osteoclast-activating activity

Click to access Pubmed
Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT, Diverio D, Nicoletti I, Pacini R, Tabarrini A, Galletti BV, Mannucci R, Roti G, Rosati R, Specchia G, Liso A, Tiacci E, Alcalay M, Luzi L, Volorio S, Bernard L, Guarini A, Amadori S, Mandelli F, Pane F, Lo-Coco F, Saglio G, Pelicci PG, Martelli MF, Mecucci C (2006)
Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia.
Blood 108: 1999-2005




Click to access Pubmed
Macon WR, Williams ME, Greer JP, Cousar JB (1995)
Paracortical nodular T-cell lymphoma. Identification of an unusual variant of peripheral T-cell lymphoma.
Am J Surg Pathol 19: 297-303



. The haemophagocytic syndrome seen in some T-cell and NK-cell malignancies has been associated with secretion of both cyto­kines and chemokines, in the setting defective cytolytic function
Click to access Pubmed
Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K (2004)
CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations.
J Clin Oncol 22: 624-33




Click to access Pubmed
Lennert K, Stein H, Kaiserling E (1975)
Cytological and functional criteria for the classification of malignant lymphomata.
Br J Cancer Suppl 2: 29-43



.

Genetics
Several mature B-cell neoplasms have characteristic genetic abnormalities that are important in determining their biologic features and can be useful in differential diagnosis. These include the t(11;14) in mantle cell lymphoma, t(14;18) in follicular lymphoma, t(8;14) and variants in Burkitt lymphoma, and t(11;18) in MALT lymphoma

Click to access Pubmed
de Boer CJ, van Krieken JH, Kluin-Nelemans HC, Kluin PM, Schuuring E (1995)
Cyclin D1 messenger RNA overexpression as a marker for mantle cell lymphoma.
Oncogene 10: 1833-40




Click to access Pubmed
Kanungo A, Medeiros LJ, Abruzzo LV, Lin P (2006)
Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis.
Mod Pathol 19: 25-33




Click to access Pubmed
Levine EG, Arthur DC, Machnicki J, Frizzera G, Hurd D, Peterson B, Gajl-Peczalska KJ, Bloomfield CD (1989)
Four new recurring translocations in non-Hodgkin lymphoma.
Blood 74: 1796-800



. The t(11;14) is seen in both mantle cell lymphoma and a fraction of cases of plasma cell myeloma, but minor differences in the translocation exist, involving different portions of the immunoglobulin heavy chain gene (IGH@)
Click to access Pubmed
Bergsagel PL, Kuehl WM (2001)
Chromosome translocations in multiple myeloma.
Oncogene 20: 5611-22



. The most common paradigm for translocations involving the IGH@ on 14q, is that a cellular proto-oncogene comes under the influence of the IGH@ promoter. For example, in follicular lymphoma, the overexpression of BCL2 blocks apoptosis in germinal centre B-cells. The t(11;18), common in MALT lymphoma, results in a fusion gene, API2/MALT1
Click to access Pubmed
Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (1999)
The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas.
Blood 93: 3601-9




Click to access Pubmed
Remstein ED, James CD, Kurtin PJ (2000)
Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas.
Am J Pathol 156: 1183-8




Click to access Pubmed
Streubel B, Huber D, Wöhrer S, Chott A, Raderer M (2004)
Frequency of chromosomal aberrations involving MALT1 in mucosa-associated lymphoid tissue lymphoma in patients with Sjögren's syndrome.
Clin Cancer Res 10: 476-80



. The expression of API2 inhibits the activity of several caspases. The partner gene, MALT1, activates the NFkB pathway, as do other translocations found in MALT lymphoma, such as t(1;14) and t(14;18).

Only a few T-cell neoplasms have thus far been associated with specific genetic abnormalities. Anaplastic large cell lymphoma, ALK+, is defined by translocations involving the ALK (anaplastic lymphoma kinase) gene on chromosome 5, (t(2;5) and variants

Click to access Pubmed
Dimopoulos MA, Moulopoulos LA, Maniatis A, Alexanian R (2000)
Solitary plasmacytoma of bone and asymptomatic multiple myeloma.
Blood 96: 2037-44




Click to access Pubmed
Kyle RA, Rajkumar SV (2006)
Monoclonal gammopathy of undetermined significance.
Br J Haematol 134: 573-89



). Hepatosplenic T-cell lymphoma is associated with isochromosome 7q. However, the molecular pathogenesis of most other T-cell and NK-cell neoplasms remains to be defined.

Multiple other genetic tools have been brought to bear on the study of mature lymphoid neoplasms. These include comparative genomic hybridisation (CGH), and the newer and more sensitive technique of array CGH, both of which can identify areas of deletion or amplification within the genome . Gene expression microarrays can interrogate the expression of thousands of genes at the RNA level, helping to elucidate pathways of activation and transformation

Click to access Pubmed
Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Müller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM, (2006)
Molecular diagnosis of Burkitt's lymphoma.
N Engl J Med 354: 2431-42




Click to access Pubmed
Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, Miller TP, LeBlanc M, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, Montserrat E, Wilson WH, Jaffe ES, Simon R, Yang L, Powell J, Zhao H, Goldschmidt N, Chiorazzi M, Staudt LM (2004)
Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.
N Engl J Med 351: 2159-69




Click to access Pubmed
Davies AJ, Rosenwald A, Wright G, Lee A, Last KW, Weisenburger DD, Chan WC, Delabie J, Braziel RM, Campo E, Gascoyne RD, Jaffe ES, Muller-Hermelink K, Ott G, Calaminici M, Norton AJ, Goff LK, Fitzgibbon J, Staudt LM, Andrew Lister T (2007)
Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms.
Br J Haematol 136: 286-93




Click to access Pubmed
Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G, Kurtin P, Pinkus GS, de Leval L, Harris NL, Savage KJ, Neuberg D, Habermann TM, Dalla-Favera R, Golub TR, Aster JC, Shipp MA (2005)
NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes.
Blood 106: 1392-9




Click to access Pubmed
Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA (2005)
Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.
Blood 105: 1851-61




Click to access Pubmed
Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM (2001)
Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.
J Exp Med 194: 1639-47




Click to access Pubmed
Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, Kurtin P, Dal Cin P, Ladd C, Feuerhake F, Aguiar RC, Li S, Salles G, Berger F, Jing W, Pinkus GS, Habermann T, Dalla-Favera R, Harris NL, Aster JC, Golub TR, Shipp MA (2003)
The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.
Blood 102: 3871-9



. Most recently, studies have begun to explore changes at the epigenetic level that control the expression of multiple genes
Click to access Pubmed
Lindström MS, Wiman KG (2002)
Role of genetic and epigenetic changes in Burkitt lymphoma.
Semin Cancer Biol 12: 381-7



.

Principles of classification
The classification of lymphoid neoplasms is based on utilisation of all available information to define disease entities

Click to access Pubmed
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (1994)
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
Blood 84: 1361-92



. Morphology and immunophenotype are sufficient for the diagnosis of most lymphoid neoplasms. However, no one antigenic marker is specific for any neoplasm, and a combination of morphologic features and a panel of antigenic markers are necessary for correct diagnosis. Most B-cell lymphomas have characteristic immunophenotypic profiles that are very helpful in diagnosis. However, immune profiling is somewhat less helpful in the subclassification of T-cell lymphomas.

In addition, while certain antigens are commonly associated with specific disease entities, these associations are not entirely disease-specific. For example, CD30 is a universal feature of ALCL, but can be expressed in other T-cell and B-cell lymphomas and classical Hodgkin lymphoma (CHL). Similarly, while CD56 is a characteristic feature of nasal NK/T-cell lymphoma, it can be seen in other T-cell lymphomas, and in plasma cell neoplasms

Click to access Pubmed
Berti E, Gianotti R, Alessi E (1988)
Unusual cutaneous histiocytosis expressing an intermediate immunophenotype between Langerhans' cells and dermal macrophages.
Arch Dermatol 124: 1250-3




Click to access Pubmed
Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G, Kurtin P, Pinkus GS, de Leval L, Harris NL, Savage KJ, Neuberg D, Habermann TM, Dalla-Favera R, Golub TR, Aster JC, Shipp MA (2005)
NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes.
Blood 106: 1392-9




Click to access Pubmed
Liu YJ (2005)
IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.
Annu Rev Immunol 23: 275-306



. Within a given disease entity, variation in immunophenotypic features can be seen. For example, most hepatosplenic T-cell lymphomas are of γδ T-cell phenotype, but some cases are of αβ derivation. Likewise, some follicular lymphomas are CD10-negative. Additionally, the presence of an aberrant immuno­phenotype may suggest or help to confirm a diagnosis of malignancy
Click to access Pubmed
Jaffe ES (2001)
Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology.
Mod Pathol 14: 219-28



.

While lineage is a defining feature of most lymphoid malignancies, in recent years there has been a greater appreciation of lineage plasticity within the haematopoietic system. Lineage switch, or demonstration of multiple lineages is most often encountered in immature haematolymphoid neoplasms, but also can be seen rarely in mature lymphomas

Click to access Pubmed
Cobaleda C, Busslinger M (2008)
Developmental plasticity of lymphocytes.
Curr Opin Immunol 20: 139-48




Click to access Pubmed
Feldman AL, Arber DA, Pittaluga S, Martinez A, Burke JS, Raffeld M, Camos M, Warnke R, Jaffe ES (2008)
Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone.
Blood 111: 5433-9




Click to access Pubmed
Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M, Creyghton MP, Steine EJ, Cassady JP, Foreman R, Lengner CJ, Dausman JA, Jaenisch R (2008)
Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency.
Cell 133: 250-64



.

Genetic features are playing an increasingly important role in the classification of lymphoid malignancies, and for many of the small B-cell lymphomas and leukaemias, recurrent genetic alterations have been identified. However, the molecular pathogenesis of most T-cell and NK-cell lymphomas remains unknown. Genetic studies, in particular PCR studies of IGH@ and T-cell receptor (TCR) gene rearrangements and fluorescence in situ hybridization (FISH), are valuable diagnostic tools, both for determination of clonality in B-cell and T-cell proliferations (aiding in the differential diagnosis with reactive hyperplasia), and in identifying translocations associated with some disease entities.

The WHO classification emphasizes the importance of knowledge of clinical features, both for accurate diagnosis, as well as for the definition of some diseases, such as marginal zone lymphoma of MALT type versus nodal or splenic marginal zone lymphoma, mediastinal large B-cell lymphoma versus DLBCL, and most mature T-cell and NK-cell neoplasms. Diagnosis of lymphoid neoplasms should not take place in a vacuum, but in the context of a complete clinical history.

Lymphoid malignancies range in their clinical behaviour from low grade to high grade. However, within any one entity a range in clinical behaviour can be seen. Moreover, histological or clinical progression is often encountered during a patient’s clinical course. For these reasons, the WHO classification does not attempt to stratify lymphoid malignancies in terms of grade. Both morphology and immuno­phenotype often change over time, as the lymphoid neoplasm undergoes clonal evolution with the acquistion of additional genetic changes. In addition, evolution over time does not necessarily lead to the development of a more aggressive lymphoma. For example, patients with DLBCL can relapse with a more indolent clonally related follicular lymphoma. Some of these clonal evolutions can be unexpected and not obviously connected, such as the development of a plasmacytoma in a patient with CHL

Click to access Pubmed
Jaffe ES, Zarate-Osorno A, Kingma DW, Raffeld M, Medeiros LJ (1994)
The interrelationship between Hodgkin's disease and non-Hodgkin's lymphomas.
Ann Oncol 5 Suppl 1: 7-11



.

Traditionally, classical Hodgkin lymphomas (CHL) have been considered separately from so-called "non-Hodgkin lymphomas." However, with the recognition that CHL is of B-cell lineage, greater overlap has been appreciated between CHL and many forms of B-cell malignancy. The 4th edition of the WHO classification recognizes these grey zones, and provides for the recognition of cases that bridge the gap between these various forms of lymphoma

Click to access Pubmed
Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES (2005)
Mediastinal gray zone lymphoma: the missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma.
Am J Surg Pathol 29: 1411-21



.

Epidemiology
Precursor lymphoid neoplasms including B lymphoblastic leukaemia/lymphoma (B-ALL/LBL) and T lymphoblastic leukaemia/ lymphoma (T-ALL/LBL) are primarily diseases of children. 75% of cases occur in children under six years of age. Approximately 85% of cases presenting as ALL are of precursor B-cell type, whereas lymphoblastic malignancies of precursor T-cell type more often present as lymphoma, with mediastinal masses. A male predominance is seen in lymphoblastic malignancies of both B-cell and T-cell lineages.

Mature B-cell neoplasms comprise over 90% of lymphoid neoplasms worldwide

Click to access Pubmed
(1997)
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.
Blood 89: 3909-18




Click to access Pubmed
Armitage JO, Weisenburger DD (1998)
New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project.
J Clin Oncol 16: 2780-95



. They represent approximately 4% of new cancers each year. They are more common in developed countries, particularly the United States, Australia, New Zealand and Western Europe. The most recent survey from the Surveillance, Epidemiology and End Results (SEER) program in the United States indicated an incidence rate per 100 000 persons per year of 33.65 for all lymphoid neoplasms, 26.13 for B-cell neoplasms, 1.79 for all T-cell neoplasms, and 2.67 for Hodgkin lymphoma
Click to access Pubmed
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS (2006)
Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.
Blood 107: 265-76



. The most common types are follicular lymphoma and DLBCL, which together make up more than 60% of all lymphomas exclusive of Hodgkin lymphoma and plasma cell myeloma
Click to access Pubmed
Anderson JR, Armitage JO, Weisenburger DD (1998)
Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project.
Ann Oncol 9: 717-20




Click to access Pubmed
(1997)
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.
Blood 89: 3909-18



. The incidence of lymphomas, in particular B-cell lymphomas, is increasing worldwide, with more than 280 000 cases occurring annually each year
Click for details
Stewart BW, Kleihues P (Eds.)
World Cancer Report
IARC Press: Lyon 2003



. The individual B-cell neoplasms vary in their relative frequency in different parts of the world. Follicular lymphoma is more common in the United States (35% of non-Hodgkin lymphomas) and Western Europe, and is uncommon in South America, Eastern Europe, Africa and Asia. Burkitt lymphoma is endemic in equatorial Africa, where it is the most common childhood malignancy, but it comprises only 1-2% of lymphomas in the United States and Western Europe. The median age for all types of mature B-cell neoplasms is in the 6th and 7th decades, but mediastinal large B-cell lymphoma has a median age of ~35 years. Of the mature B-cell lymphomas, only Burkitt lymphoma and DLBCL occur with any significant frequency in children. Most types have a male predominance (52-55%), but mantle cell lymphoma has a striking male predominance (74%), while females predominate in follicular lymphoma (58%) and most particularly in primary mediastinal large B-cell lymphoma (66%). Primary mediastinal large B-cell lymphoma and classical Hodgkin lymphoma of the nodular sclerosis subtype have similar clinical profiles at presentation, most commonly affecting adolescent and young adult females. These common clinical features first prompted consideration that these lymphomas might be related
Click to access Pubmed
Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, Chan WC, Zhao T, Haioun C, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Campo E, Montserrat E, Lopez-Guillermo A, Ott G, Muller-Hermelink HK, Connors JM, Braziel R, Grogan TM, Fisher RI, Miller TP, LeBlanc M, Chiorazzi M, Zhao H, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Staudt LM (2003)
Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.
J Exp Med 198: 851-62




Click to access Pubmed
Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, Kurtin P, Dal Cin P, Ladd C, Feuerhake F, Aguiar RC, Li S, Salles G, Berger F, Jing W, Pinkus GS, Habermann T, Dalla-Favera R, Harris NL, Aster JC, Golub TR, Shipp MA (2003)
The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma.
Blood 102: 3871-9




Click to access Pubmed
Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES (2005)
Mediastinal gray zone lymphoma: the missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma.
Am J Surg Pathol 29: 1411-21





One major known risk factor for mature B-cell neoplasia appears to be an abnormality of the immune system, either immuno­deficiency or autoimmune disease. Although evidence of immune system abnormalities are lacking in most patients with mature B-cell neoplasms, immunodeficient patients have a markedly increased incidence of B-cell neoplasia, particularly DLBCL and Burkitt lymphoma

Click to access Pubmed
Beral V, Peterman T, Berkelman R, Jaffe H (1991)
AIDS-associated non-Hodgkin lymphoma.
Lancet 337: 805-9




Click to access Pubmed
Canioni D, Jabado N, MacIntyre E, Patey N, Emile JF, Brousse N (2001)
Lymphoproliferative disorders in children with primary immunodeficiencies: immunological status may be more predictive of the outcome than other criteria.
Histopathology 38: 146-59




Click to access Pubmed
Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J (1988)
The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression.
Am J Pathol 133: 173-92



. Major forms of immuno­deficiency currently include infection with the human immunodeficiency virus (HIV), iatrogenic immunosuppression to prevent allograft rejection or graft versus host disease (GVHD) and primary immune deficiencies. Some autoimmune diseases are also associated with an increased risk of lymphoma, particularly B-cell lymphomas in patients with lymphoepithelial siala­denitis or Hashimoto thyroiditis
Click to access Pubmed
Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR, Costa J, Decker JL, Chused TM (1978)
Increased risk of lymphoma in sicca syndrome.
Ann Intern Med 89: 888-92




Click to access Pubmed
Kato I, Tajima K, Suchi T, Aozasa K, Matsuzuka F, Kuma K, Tominaga S (1985)
Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid gland.
Jpn J Cancer Res 76: 1085-90



.

Mutations in genes controlling lymphocyte apoptosis have been linked to a risk for both autoimmune disease and lymphoma (mainly B-cell types). Patients with the autoimmune lymphoproliferative syndrome, which usually is caused by germline mutations in FAS, have an increased risk for B-cell lymphomas and Hodgkin lymphomas

Click to access Pubmed
Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rösen-Wolff A, Peters AM, Sneller MC, Hallahan CW, Wang J, Fischer RE, Jackson CM, Lin AY, Bäumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ (2001)
The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.
Blood 98: 194-200



. Somatically acquired FAS gene mutations also have been reported in some sporadic B-cell lymphomas, most commonly marginal zone lymphomas
Click to access Pubmed
Grønbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen MK, Hansen NE, Zeuthen J, Hou-Jensen K, Guldberg P (1998)
Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.
Blood 92: 3018-24



. Recent studies employing molecular epidemiology have identified polymorphisms in a number of immunoregulatory genes that appear to impact both risk of lymphoma and prognosis within a patient cohort
Click to access Pubmed
Cerhan JR, Wang S, Maurer MJ, Ansell SM, Geyer SM, Cozen W, Morton LM, Davis S, Severson RK, Rothman N, Lynch CF, Wacholder S, Chanock SJ, Habermann TM, Hartge P (2007)
Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival.
Blood 109: 5439-46




Click to access Pubmed
Lan Q, Zheng T, Chanock S, Zhang Y, Shen M, Wang SS, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Hosgood D, Boyle P, Rothman N (2007)
Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma.
Carcinogenesis 28: 823-7




Click to access Pubmed
Wang SS, Cozen W, Cerhan JR, Colt JS, Morton LM, Engels EA, Davis S, Severson RK, Rothman N, Chanock SJ, Hartge P (2007)
Immune mechanisms in non-Hodgkin lymphoma: joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors.
Cancer Res 67: 5042-54



. Molecular epidemiology is a relatively recent area of investigation and more data will be accumulated in the coming years. For example, a recent study found increased risk associated with polymorphisms in certain drug metabolizing enzymes
Click to access Pubmed
Al-Dayel F, Al-Rasheed M, Ibrahim M, Bu R, Bavi P, Abubaker J, Al-Jomah N, Mohamed GH, Moorji A, Uddin S, Siraj AK, Al-Kuraya K (2008)
Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population.
Leuk Lymphoma 49: 122-9



.

Mature T-cell and NK-cell neoplasms are relatively uncommon. In a large international study that evaluated lymphoma cases from the United States, Europe, Asia and South Africa, T-cell and NK-cell neoplasms accounted for only 12% of all non-Hodgkin lymphomas

Click to access Pubmed
(1997)
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.
Blood 89: 3909-18



. The most common subtypes of mature T-cell lymphomas are peripheral T-cell lymphoma, not otherwise specified (NOS) (25.9%) and angioimmunoblastic T-cell lymphoma (AITL) (18.5%), respectively
Click to access Pubmed
Vose J, Armitage J, Weisenburger D, (2008)
International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
J Clin Oncol 26: 4124-30



.

T-cell and NK-cell lymphomas show significant variations in incidence in different geographical regions and racial populations. In general, T-cell lymphomas are more common in Asia

Click to access Pubmed
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001)
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med 344: 1031-7



. These differences result from both a true increased incidence, as well as a relative decrease in the frequency of many B-cell lymphomas, such as follicular lymphoma. One of the main risk factors for T-cell lymphoma in Japan is the virus, human T-cell leukaemia virus type I (HTLV-I). In endemic regions of southwestern Japan, the seroprevalence of HTLV-I is 8-10%. The cumulative life-time risk for the development of adult T-cell leukaemia/lymphoma (ATLL) is 6.9% for a seropositive male and 2.9% for a seropositive female
Click to access Pubmed
Fenaux P, Jouet JP, Zandecki M, Lai JL, Simon M, Pollet JP, Bauters F (1987)
Chronic and subacute myelomonocytic leukaemia in the adult: a report of 60 cases with special reference to prognostic factors.
Br J Haematol 65: 101-6



. Other regions with a relatively high seroprevalence for HTLV-I include the Caribbean basin, where Blacks are primarily affected over other racial groups
Click to access Pubmed
Gascoyne RD, Aoun P, Wu D, Chhanabhai M, Skinnider BF, Greiner TC, Morris SW, Connors JM, Vose JM, Viswanatha DS, Coldman A, Weisenburger DD (1999)
Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma.
Blood 93: 3913-21



. Differences in viral strain also may affect the incidence of the disease
Click to access Pubmed
de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, Lamant L, Leroy K, Brière J, Molina T, Berger F, Gisselbrecht C, Xerri L, Gaulard P (2007)
The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells.
Blood 109: 4952-63




Click to access Pubmed
Lukes RJ, Craver L, Hall T, Rappaport H, Ruben P (1966)
Report of the nomenclature committee.
Cancer Res 26: 1311.



.

Another major factor influencing the incidence of T-cell and NK-cell lymphomas is racial predisposition. EBV-associated NK and T-cell neoplasms, including extranodal NK/T-cell lymphoma, nasal type, aggressive NK leukaemia, and paediatric EBV+ T-cell and NK-cell lymphomas are much more common in Asians than they are in other races

Click to access Pubmed
Alonsozana EL, Stamberg J, Kumar D, Jaffe ES, Medeiros LJ, Frantz C, Schiffer CA, O'Connell BA, Kerman S, Stass SA, Abruzzo LV (1997)
Isochromosome 7q: the primary cytogenetic abnormality in hepatosplenic gammadelta T cell lymphoma.
Leukemia 11: 1367-72



. In Hong Kong, nasal NK/T-cell lymphoma is one of the more common subtypes, accounting for 8% of cases. By contrast, in Europe and North America, it accounts for less than 1% of all lymphomas. Other populations at increased risk for this disease are individuals of Native American descent in Central and South America, and Mexico
Click to access Pubmed
Anderson T, Bender RA, Fisher RI, DeVita VT, Chabner BA, Berard CW, Norton L, Young RC (1977)
Combination chemotherapy in non-Hodgkin's lymphoma: results of long-term followup.
Cancer Treat Rep 61: 1057-66




Click to access Pubmed
Carroll A, Civin C, Schneider N, Dahl G, Pappo A, Bowman P, Emami A, Gross S, Alvarado C, Phillips C (1991)
The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study.
Blood 78: 748-52



, who are genetically related to Asians
Click to access Pubmed
Harif M, Barsaoui S, Benchekroun S, Boccon-Gibod L, Bouhas R, Doumbé P, El Haffaf Z, Khattab M, Ladjadj Y, Mallon B, Moreira C, Msefer-Alaoui F, Patte C, Rakotonirina G, Raphael M, Raquin MA, Tournade MF, Lemerle J (2005)
[Treatment of childhood cancer in Africa. Preliminary results of the French-African paediatric oncology group].
Arch Pediatr 12: 851-3



. Finally, enteropathy-associated T-cell lymphoma is most common in individuals of Welsh and Irish descent, who share HLA haplotypes that confer an increased risk of gliadin allergy and susceptibility to gluten-sensitive enteropathy
Click to access Pubmed
Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, Ge Y, Gascoyne RD, Chott A, Müller-Hermelink HK, Lam WL (2007)
Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes.
Gastroenterology 132: 1902-11



.

γδ PTCL occur with increased frequency in the setting of immune suppression, especially following organ transplantation, a finding that is not well understood

Click to access Pubmed
Gardner RV, Velez MC, Ode DL, Lee JW, Correa H (2004)
Gamma/delta T-cell lymphoma as a recurrent complication after transplantation.
Leuk Lymphoma 45: 2355-9




Click to access Pubmed
Navarro JT, Ribera JM, Mate JL, Granada I, Juncà J, Batlle M, Millá F, Feliu E (2003)
Hepatosplenic T-gammadelta lymphoma in a patient with Crohn's disease treated with azathioprine.
Leuk Lymphoma 44: 531-3



. The combination of two factors, both immunosuppression and chronic antigenic stimulation, appear to increase risk. Hepatosplenic T-cell lymphomas are most common, but primary cutaneous and mucosa-associated T-cell lymphomas have been reported as well
Click to access Pubmed
Canioni D, Jabado N, MacIntyre E, Patey N, Emile JF, Brousse N (2001)
Lymphoproliferative disorders in children with primary immunodeficiencies: immunological status may be more predictive of the outcome than other criteria.
Histopathology 38: 146-59



. Recent data from the SEER program indicate a modest increase in the incidence of T-cell neoplasms in the United States to 2.6 cases per 100 000 persons per year, with the greatest increase occuring in the category of cutaneous T-cell lymphoma
Click to access Pubmed
Criscione VD, Weinstock MA (2007)
Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002.
Arch Dermatol 143: 854-9




Click to access Pubmed
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS (2006)
Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.
Blood 107: 265-76



.

Etiology
Infectious agents have been shown to contribute to the development of several types of mature B-cell, T-cell and NK-cell lymphomas. Epstein-Barr virus (EBV) is present in nearly 100% of endemic Burkitt lymphoma and in 15-35% of sporadic and HIV-associated cases

Click to access Pubmed
Hamilton-Dutoit SJ, Raphael M, Audouin J, Diebold J, Lisse I, Pedersen C, Oksenhendler E, Marelle L, Pallesen G (1993)
In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site.
Blood 82: 619-24




Click to access Pubmed
Prevot S, Hamilton-Dutoit S, Audouin J, Walter P, Pallesen G, Diebold J (1992)
Analysis of African Burkitt's and high-grade B cell non-Burkitt's lymphoma for Epstein-Barr virus genomes using in situ hybridization.
Br J Haematol 80: 27-32



, and it is involved in the pathogenesis of many B-cell lymphomas arising in immuno­suppressed or elderly patients, including many post-transplant lymphoproliferative disorders, plasmablastic lymphoma and EBV+ large B-cell lymphoma of the elderly. EBV is also associated with extra­nodal NK/T-cell lymphoma and two paediatric T-cell lymphomas, systemic EBV+ T-cell LPD of childhood and hydroa-­vacciniforme-like T-cell lymphoma. The exact cause of these EBV+ T-cell lymphomas of childhood is not clear. Risk factors may be either high viral load at presentation, or a defective immune response to the infection
Click to access Pubmed
Quintanilla-Martinez L, Kumar S, Fend F, Reyes E, Teruya-Feldstein J, Kingma DW, Sorbara L, Raffeld M, Straus SE, Jaffe ES (2000)
Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome.
Blood 96: 443-51



. Chronic active EBV infection may precede the development of some EBV+ T-cell lymphomas
Click to access Pubmed
Kanegane H, Bhatia K, Gutierrez M, Kaneda H, Wada T, Yachie A, Seki H, Arai T, Kagimoto S, Okazaki M, Oh-ishi T, Moghaddam A, Wang F, Tosato G (1998)
A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma.
Blood 91: 2085-91




Click to access Pubmed
Quintanilla-Martinez L, Kumar S, Fend F, Reyes E, Teruya-Feldstein J, Kingma DW, Sorbara L, Raffeld M, Straus SE, Jaffe ES (2000)
Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome.
Blood 96: 443-51



. In cases associated with chronic EBV infection, a polyclonal process may be seen early in the course, with progression to monoclonal EBV+ T-cell lymphoma
Click to access Pubmed
Kanegane H, Bhatia K, Gutierrez M, Kaneda H, Wada T, Yachie A, Seki H, Arai T, Kagimoto S, Okazaki M, Oh-ishi T, Moghaddam A, Wang F, Tosato G (1998)
A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma.
Blood 91: 2085-91



.

Human herpesvirus-8 (HHV8) is found in primary effusion lymphoma and the lymphomas associated with multicentric Castleman disease, mainly seen in HIV-infected patients

Click to access Pubmed
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995)
Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.
N Engl J Med 332: 1186-91



. It is of interest that the same virus causes a number of B-cell lymphoproliferative disorders which differ in their clinical manifestations
Click to access Pubmed
Du MQ, Bacon CM, Isaacson PG (2007)
Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and lymphoproliferative disorders.
J Clin Pathol 60: 1350-7



. Human T-cell leukaemia virus type I is the causative agent of adult T-cell lymphoma/ ­leukaemia, and is clonally integrated into the genome of transformed T-cells
Click to access Pubmed
Takatsuki K, Yamaguchi K, Watanabe T, Mochizuki M (1992)
Adult T-cell leukemia and HTLV-1 related disease.
Gann mono Can Res 32: 1–15.



. In this condition as in HHV8-associated disorders, a spectrum of clinical behaviours are seen, although most cases of ATLL are aggressive.

Hepatitis C virus has been implicated in some cases of lymphoplasmacytic lymphoma associated with type II cryoglobulinaemia, splenic marginal zone lymphoma, nodal marginal zone lymphoma and DLBCL

Click to access Pubmed
Agnello V, Chung RT, Kaplan LM (1992)
A role for hepatitis C virus infection in type II cryoglobulinemia.
N Engl J Med 327: 1490-5




Click to access Pubmed
Ascoli V, Lo Coco F, Artini M, Levrero M, Martelli M, Negro F (1998)
Extranodal lymphomas associated with hepatitis C virus infection.
Am J Clin Pathol 109: 600-9




Click to access Pubmed
de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, Spinelli JJ, Zheng T, Zhang Y, Franceschi S, Talamini R, Holly EA, Grulich AE, Cerhan JR, Hartge P, Cozen W, Boffetta P, Brennan P, Maynadié M, Cocco P, Bosch R, Foretova L, Staines A, Becker N, Nieters A (2008)
Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium.
Clin Gastroenterol Hepatol 6: 451-8




Click to access Pubmed
De Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, Crovatto M, Santini G, Dolcetti R, Boiocchi M, Carbone A, Zagonel V (1997)
Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection.
Blood 90: 776-82




Click to access Pubmed
Jorgensen C, Legouffe MC, Perney P, Coste J, Tissot B, Segarra C, Bologna C, Bourrat L, Combe B, Blanc F, Sany J (1996)
Sicca syndrome associated with hepatitis C virus infection.
Arthritis Rheum 39: 1166-71




Click to access Pubmed
Mazzaro C, Franzin F, Tulissi P, Pussini E, Crovatto M, Carniello GS, Efremov DG, Burrone O, Santini G, Pozzato G (1996)
Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy.
Cancer 77: 2604-13




Click to access Pubmed
Pozzato G, Mazzaro C, Crovatto M, Modolo ML, Ceselli S, Mazzi G, Sulfaro S, Franzin F, Tulissi P, Moretti M (1994)
Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia.
Blood 84: 3047-53




Click to access Pubmed
Zuckerman E, Zuckerman T, Levine AM, Douer D, Gutekunst K, Mizokami M, Qian DG, Velankar M, Nathwani BN, Fong TL (1997)
Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma.
Ann Intern Med 127: 423-8



. The role of the virus in tumour initiation is not clear. However, it does not directly infect neoplastic B-cells, and appears to influence lymphoma development through activation of a B-cell immune response.

Bacteria, or at least immune responses to bacterial antigens, have also been implicated in the pathogenesis of MALT lymphoma. These include H. pylori in gastric MALT lymphoma

Click to access Pubmed
Hussell T, Isaacson PG, Crabtree JE, Spencer J (1993)
The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori.
Lancet 342: 571-4




Click to access Pubmed
Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, Wündisch T, Ehninger G, Stolte M, Bayerdörffer E (1997)
Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma.
J Natl Cancer Inst 89: 1350-5




Click to access Pubmed
Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, Isaacson PG (1993)
Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori.
Lancet 342: 575-7




Click to access Pubmed
Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG (1991)
Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma.
Lancet 338: 1175-6



,

B. burgdorferi in cutaneous MALT lymphoma in Europe

Click to access Pubmed
Bentz M, Barth TF, Brüderlein S, Bock D, Schwerer MJ, Baudis M, Joos S, Viardot A, Feller AC, Müller-Hermelink HK, Lichter P, Döhner H, Möller P (2001)
Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line.
Genes Chromosomes Cancer 30: 393-401



, Chlamydia psittaci, C. pneumoniae and C. trachomatis in ocular adnexal MALT lymphomas in some geographic areas
Click to access Pubmed
Chanudet E, Zhou Y, Bacon CM, Wotherspoon AC, Müller-Hermelink HK, Adam P, Dong HY, de Jong D, Li Y, Wei R, Gong X, Wu Q, Ranaldi R, Goteri G, Pileri SA, Ye H, Hamoudi RA, Liu H, Radford J, Du MQ (2006)
Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions.
J Pathol 209: 344-51




Click to access Pubmed
Ruiz A, Reischl U, Swerdlow SH, Hartke M, Streubel B, Procop G, Tubbs RR, Cook JR (2007)
Extranodal marginal zone B-cell lymphomas of the ocular adnexa: multiparameter analysis of 34 cases including interphase molecular cytogenetics and PCR for Chlamydia psittaci.
Am J Surg Pathol 31: 792-802



and Campylobacter jejuni in intestinal MALT lymphoma associated with alpha heavy chain disease
Click to access Pubmed
Price SK (1990)
Immunoproliferative small intestinal disease: a study of 13 cases with alpha heavy-chain disease.
Histopathology 17: 7-17




Click to access Pubmed
RAMOT B, SHAHIN N, BUBIS JJ (1965)
MALABSORPTION SYNDROME IN LYMPHOMA OF SMALL INTESTINE. A STUDY OF 13 CASES.
Isr J Med Sci 1: 221-6





Environmental exposures also have been linked to a risk of developing B-cell lymphoma. Epidemiological studies have implicated herbicide and pesticide use in the development of follicular lymphoma and DLBCL

Click to access Pubmed
Colt JS, Davis S, Severson RK, Lynch CF, Cozen W, Camann D, Engels EA, Blair A, Hartge P (2006)
Residential insecticide use and risk of non-Hodgkin's lymphoma.
Cancer Epidemiol Biomarkers Prev 15: 251-7




Click to access Pubmed
Hartge P, Colt JS, Severson RK, Cerhan JR, Cozen W, Camann D, Zahm SH, Davis S (2005)
Residential herbicide use and risk of non-Hodgkin lymphoma.
Cancer Epidemiol Biomarkers Prev 14: 934-7



. Exposure to hair dyes had been identified as a risk factor in some older studies, but newer dye formations have removed potential carcinogens
Click to access Pubmed
Zhang Y, Sanjose SD, Bracci PM, Morton LM, Wang R, Brennan P, Hartge P, Boffetta P, Becker N, Maynadie M, Foretova L, Cocco P, Staines A, Holford T, Holly EA, Nieters A, Benavente Y, Bernstein L, Zahm SH, Zheng T (2008)
Personal use of hair dye and the risk of certain subtypes of non-Hodgkin lymphoma.
Am J Epidemiol 167: 1321-31



.

Conclusion
The multiparameter approach to classification adopted by the WHO classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory

Click to access Pubmed
(1997)
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.
Blood 89: 3909-18




Click to access Pubmed
Jaffe ES (2001)
Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology.
Mod Pathol 14: 219-28




Click to access Pubmed
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS (2006)
Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.
Blood 107: 265-76



.







Elaine S. Jaffe
Click to contact editor
Elaine S. Jaffe
Laboratory of Pathology
National Cancer Institute, NIH
Bethesda
USA




Nancy Lee Harris
Click to contact editor
Nancy Lee Harris
Pathology-Warren 2
Massachusetts General Hospital
Boston
USA




Harald Stein
Click to contact editor
Harald Stein
Institute for Pathology
Campus Benjamin Franklin
Berlin
Germany




Elias Campo
Click to contact editor
Elias Campo
Department of Pathology
Hospital Clinic, University of Barcelona
Barcelona
Spain




Stefano A. Pileri
Click to contact editor
Stefano A. Pileri
Department of Haematology and Oncological Sciences
St Orsola - Malpighi Hospital, University of Bologna
Bologna
ITALY




Steven H. Swerdlow
Click to contact editor
Steven H. Swerdlow
Department of Pathology, Division of Hematopathology
UPMC Presbyterian
Pittsburgh
USA





Innate and adaptive immune system
Innate and adaptive immune system

B-cell differentiation and relationship to major B-cell neoplasms
B-cell differentiation and relationship to major B-cell neoplasms

Immunophenotypic features of common mature B-cell neoplasms
Immunophenotypic features of common mature B-cell neoplasms

Phenotype of B lymphocytes
Phenotype of B lymphocytes

Diagrammatic representation of T-cell differentiation
Diagrammatic representation of T-cell differentiation

T-cell maturation
T-cell maturation

Immunophenotypic features of common mature T-cell and NK-cell neoplasms
Immunophenotypic features of common mature T-cell and NK-cell neoplasms

Relative frequencies of B-cell lymphoma subtypes in adults
Relative frequencies of B-cell lymphoma subtypes in adults

Relative frequencies of mature T-cell lymphoma subtypes in an adult patient population
Relative frequencies of mature T-cell lymphoma subtypes in an adult patient population