[CANCER RESEARCH (SUPPL.) 52, 5447s-5452s. October I. 1992|

An Overview of the Classification of Non-Hodgkin's Lymphomas: An Integration

of Morphological and Phenotypical Concepts1

Elaine S. Jaffe,2 Mark Raffeid, L. Jeffrey Medeiros, and Maryalice Stetler-Stevenson

Hematopathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20982

Abstract

An analysis of trends in the incidence of non-Hodgkin's lymphoma

requires an understanding of individual disease entities within thisbroad group. The non-Hodgkin's lymphomas represent a diverse group

of malignancies that have in common an origin from lymphoid cells.Nevertheless, these disorders are heterogeneous in their clinical behavior, morphological appearance, cellular origin, etiology, and pathogen-esis. A modern classification of non-Hodgkin's lymphomas must include

an integration of morphological, immunophenotypical, and molecularconcepts in order to delineate individual diseases within this broadgroup. Existing classification schemes such as the working formulation,while they may be useful in providing a guide to clinical management,cannot provide this information in the absence of other data.

This point is most readily made with the low-grade B-cell lymphomaswhich include follicular lymphomas, mantle cell lymphomas, small lym-

phocytic lymphomas, immunosecretory disorders, and lymphomas ofmucosa-associated lymphoid tissues. Each of these malignancies has a

distinct phenotype and genotype, and indubitably each has a differentetiology. The postthymic T-cell tumors are equally diverse. Analysis of

epidemiológica! data from cancer registries must include a recognitionthat our ability to recognize individual diseases from historical data islimited. Studies of trends in the non-Hodgkin's lymphomas should at

tempt to delineate biological markers that may be of relevance to patho-

genesis in both historical and prospectively accrued cases.

IntroductionThe non-Hodgkin's lymphomas are not a single disease

but represent a diverse group of clinicopathological and biological entities. The modern approach to lymphoma diagnosisshould include both morphological and phenotypic techniques.The Rappaport classification is not in current use; however,when this classification scheme was proposed in the 1960s, itimmediately became popular among clinicians and is the terminology that has been most widely utilized in the SurveillanceEpidemiology and End Results program (SEER) data base (Table 1)(1).

The classification of non-Hodgkin's lymphomas, as proposed

by Rappaport (1), first divided lymphomas according to theirarchitectural pattern, nodular or diffuse, and then according tothe cytological cell type. If the cells were small, they weretermed "lymphocytic," or if large, "histiocytic." However, dur

ing the 1970s when the field of immunology was undergoing arapid expansion, the scientific basis for this scheme came intoquestion. It became apparent that the large cell tumors thatRappaport termed histiocytic were, in fact, composed of transformed lymphoid cells. Furthermore, the Rappaport schemedid not take into consideration the phenotypic heterogeneity ofthe immune system as it related to the classification of lymphomas (2).

1 Presented at the National Cancer Institute Workshop, "The Emerging Epidemic of Non-Hodgkin's Lymphoma: Current Knowledge Regarding EtiologicalFactors," October 22-23, 1991, Bethesda. MD.

2 To whom requests for reprints should be addressed, at Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20982.

As a result of this dissatisfaction, a variety of classificationschemes were proposed. Two of them, the Lukes and CollinsClassification (3) and the Kiel Scheme (4), as proposed by Len-

nert and colleagues, are shown in Table 1. The complexity ofthis terminology is obvious. All of these terms have been inInternational Classification of Diseases for Oncology, andprobably all are reflected in the SEER data at one point oranother. Moreover, if one tries to discern individual diseaseentities from these data, it is virtually impossible.

The National Cancer Institute responded to this problem byfunding a study to test the six major classification schemesproposed at this time. They examined 1175 cases of lymphomathat had been prospectively staged and treated in a uniformmanner at one of four major treatment centers (5). Not surprisingly, all six classification schemes could identify tumors oflow- or high-grade clinical behavior, and no one scheme seemedto work significantly better than any other.

Consequently, the investigators involved in that study proposed a working formulation for non-Hodgkin's lymphoma di

agnosis, and they divided the tumors into morphological groupsranked according to their clinical behavior in these 1175 cases(Table 2). At the time that the working formulation was published, the authors (5) of it stated that it was "not proposed as

a new classification, but as a means of translation among thevarious systems." Unfortunately, this subtle distinction has not

always been appreciated.The working formulation categories do not identify individ

ual disease entities. The terms that it uses are microscopicdescriptors. They describe the cellular population that the pathologist sees in the histológica! section, but one cannot inferthat each category is an individual disease. In fact, we have verygood evidence today that most of these categories do not represent individual diseases. If one wishes to understand the epidemiology of lymphomas and to understand time trends, onemust step away from this approach and look at individual diseases rather than morphological categories.

Essential to this process is the use of immunological approaches. The malignant lymphomas are tumors of the immunesystem, and the malignant cells retain both the phenotypic andfunctional properties of their precursors. Using the tools ofimmunology, we can begin to dissect out individual diseasesamong the malignant lymphomas.

The development of monoclonal antibodies has been invaluable in providing us with a battery of reagents that can beconsistently used among different laboratories. Most of thesereagents have to be applied to freshly isolated cells, either in cellsuspension or in frozen sections, but increasingly, monoclonalantibodies are available that can be used on routinely processedparaffin-embedded sections (6). These reagents provide an im

portant step in permitting the use of these techniques on aroutine basis for most lymphomas.

The vast majority of non-Hodgkin's lymphomas diagnosed in

the United States and in Europe are of B-cell origin and fall into

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CLASSIFICATION OF NON-HODGKIN'S LYMPHOMAS

Table 1 Comparison of commonly used classifications for non-Hodgkin's lymphomas

Modified Rappaportclassification

Workingformulation"

Lukes and Collinsclassification

Workingformulation Kiel classification

Workingformulation

NodularLymphocytic, well differentiated ALymphocytic, poorly B

differentiated CMixed, lymphocytic and histiocytic DHistiocytic

DiffuseLymphocytic, well differentiated A

without plasmacytoid featuresLymphocytic, well differentiated A

with plasmacytoid features ELymphocytic, poorly I

differentiated ILymphoblastic, convoluted FLymphoblastic, nonconvoluted GMixed, lymphocytic and histioytic GHistiocytic without sclerosis JHistiocytic with sclerosis JBurkitt's tumor

UndifferentiatedMalignant lymphoma, unclassifiedComposite lymphoma

Undefined cell typeT-cell type, small lymphocyticT-cell type, Sézary-mycosisfungoides

(cerebriform)T-cell type, convoluted lymphocyticT-cell type, immunoblastic sarcoma(T-cell)B-cell type, small lymphocyticB-cell type, plasmacytoid lymphocyticFollicular center cell, small cleavedFollicular center cell, large cleavedFollicular center cell, small

noncleavedFollicular center cell, large

noncleavedImmunoblastic sarcoma (B-cell)Subtypes of follicular center cell

lymphomas1. Follicular2. Follicular and diffuse3. Diffuse4. Sclerotic with follicles5. Sclerotic without follicles

HistiocyticMalignant lymphoma, unclassified

Low-grade malignancyA Lymphocytic, chronic lymphocytic/

leukemia ALymphocytic, other A

I Lymphoplasmacytoid ACentrocytic E

H Centroblastic-centrocytic, follicularA without sclerosis B, CA Centroblastic-centrocytic, follicular D

B-E with sclerosisD-G Centroblastic-centrocytic, follicular

J and diffuse, without sclerosisD-G Centroblastic-centrocytic, follicular

and diffuse, with sclerosisCentroblastic-centrocytic, diffuse

H Low-grade malignant lymphoma, Funclassified

High-grade malignancyCentroblasticLymphoblastic, Burkitt's type G

Lymphoblastic, convoluted cell type JLymphoblastic, other (classified) IImmunoblastic

High-grade malignant lymphoma, Hunclassified

Malignant lymphoma, unclassified(unable to specify "high grade"or "low grade")

Composite lymphoma

" Letters indicate equivalent or related category in the working formulation as shown in Table 2.

Table 2 National Cancer Institute working formulation of non-Hodgkin's

lymphomas for clinical usage (Ref. 5)

Low gradeA. Small lymphocyticB. Follicular, predominantly small cleaved cellC. Follicular, mixed small cleaved and large cell

Intermediate gradeD. Follicular, predominantly large cellE. Diffuse, small cleaved cellF. Diffuse, mixed small cleaved and large cellG. Diffuse, large cell

High gradeH. Large cell, immunoblasticI. LymphoblasticJ. Small noncleaved cell

MiscellaneousCompositeMycosis fungoidesHistiocyticExtramedullary plasmacytomaUnclassifiable, other

the midstage of B-cell differentiation (6). At this stage of differentiation, cells express monoclonal surface immunoglobulin,most often IgM, with or without IgD, and usually express thepan-B-cell antigens, CD 19, CD20, and CD22.

Low-Grade B-Cell Lymphomas

Within the working formulation, virtually all low-grade lymphomas are of B-cell origin, but one can begin to recognizedifferent disease entities among the low-grade B-cell lymphomas that are not readily apparent in the pure working formulation approach. First and foremost among these is follicularlymphoma, which is well recognized in the working formulationbut spans three separate clinical groups, in both the low-gradeand intermediate-grade categories. Other disease entities areless readily identified in the working formulation (Table 3). Forexample, mantle zone lymphoma, or mantle cell lymphoma,falls within several different working formulation groups. Conversely, the small lymphocytic lymphoma group (A) includesseveral different disease entities.

Follicular lymphoma is the prototype of the low-grade B-celllymphomas and is the single largest group of non-Hodgkin's

lymphomas, accounting for approximately 45% of all cases (5).It is a disease of adult life and occurs equally in males andfemales. The neoplastic cells form follicular aggregates, whichtend to mimic normal lymphoid follicles. Cytologically, the celltypes that we see within follicular lymphomas resemble the cellswithin the normal germinal center, as described by Lukes andCollins (3) and Gerard-Marchant et al. (4). Follicular lymphomas are subclassified according to the proportion of these various cytological cell types (7). In the working formulation, thesmall cleaved and mixed small cleaved and large cell categoriesare in the low-grade group, whereas the follicular large cell typeis in the intermediate-grade group, based on its more aggressiveclinical behavior. However, all of these cells exist in all follicular lymphomas, and the Kiel classification takes the approachof considering all tumors centrocytic/centroblastic, without theidentification of cytological subgroups.

The follicular lymphomas are monoclonal B-cell neoplasms;the cells express monoclonal surface immunoglobulin and arefrequently confined to the neoplastic nodules (8, 9). In fact, inearly lymph node involvement, one can show that the neoplasticcells selectively home to or colonize the germinal centers,focally involving these structures within the lymph node (10,11).

The cells seem to be held together within these follicles bydendritic reticulum cells, which are a normal structural andfunctional component of the germinal center. These cells are aninvariant component of follicular lymphomas but are not considered neoplastic. When the dendritic reticulum cells are lost,the process tends to become diffuse, although these events maynot be causally related. Follicular lymphomas usually presentwith generalized lymphadenopathy and frequent involvementof the bone marrow with paratrabecular lymphoid aggregates(5, 12, 13). In approximately 10% of patients, neoplastic cellsare identified morphologically in the peripheral blood.

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Table 3 A disease-oriented approach to lymphoma classification

Low-grade B-cell lymphomas Working formulation

Follicular lymphomaMantle cell lymphoma

IDL"/centrocytic/mantle zoneSmall lymphocytic lymphoma/CLLImmunosecretory disorders

Waldenström's macroglobulinemia

MALTMonocytoid B-cell lymphoma

B.C. DA, B, E

AA, F

A, E

' IDL, lymphocytic lymphoma of intermediate grade of differentiation.

When more sensitive molecular techniques are used, even ahigher proportion of patients can be shown to have peripheralblood involvement. Follicular lymphomas are characterized bya consistent cytogenetic abnormality; the t(14;18) is found in90% of cases of follicular lymphoma (14). This translocationinvolves the immunoglobulin heavy chain locus on chromosome 14 and the bcl-2 gene on chromosome 18. Probes to thebcl-2 gene can be used to detect this translocation at the molecular level, using either Southern blot hybridization or thepolymerase chain reaction technique (15).

Mantle cell lymphoma is a distinct clinicopathological entity,equivalent morphologically to lymphocytic lymphoma, intermediate grade of differentiation (IDL) of the modified Rappa-port scheme (16); centrocytic lymphoma of the Kiel classification; and mantle zone lymphoma, a term popularized byWeisenburger et al. (17). This form of lymphoma was originallycalled intermediate because it was believed to be intermediate inits cytological characteristics between the well-differentiatedand poorly differentiated lymphocytic lymphomas of the Rap-paport scheme (18). The cells are slightly cleaved and angulatedwith an atypical appearance.

In contrast to follicular lymphoma, in which selective involvement of germinal centers is seen, in mantle cell lymphoma,residual normal germinal centers are often uninvolved by theneoplastic process (16). This mantle zone growth pattern can beseen in the small intestine, bone marrow, and other extranodalsites and provides evidence for a mantle zone derivation of themalignant cells.

In fact, this tumor can have a vaguely nodular growth pattern,which derives from its propensity to grow as an expanded mantle around residual germinal centers. As such, (mis)diagnosis asfollicular small cleaved in the working formulation may occur.Such an error may be avoided if careful cytological criteria areutilized. For example, follicular lymphomas always have a mixture of cell types, so-called "centrocytes" and "centroblasts,"

whereas mantle cell lymphomas are much more homogeneouscytologically. In addition, in contrast to follicular lymphomas,in which one finds a tight meshwork of dendritic reticulumcells, in mantle cell lymphomas, the dendritic reticulum cellsare often disorganized, correlating with the vaguely folliculargrowth pattern (19). Another distinguishing feature of this lymphoma and one that is useful from a diagnostic standpoint isthat this tumor, like chronic lymphocytic leukemia, is almostalways CDS positive (20, 21). CDS is an antigen expressed onnormal T-cells but also expressed on a subset of B-cells. Truefollicular lymphomas are always CDS negative.

Mantle cell lymphomas are unique in that a greater proportion of these cases express monoclonal X-light chain than monoclonal K.For most of the non-Hodgkin's lymphomas, there is

a predominance of Kbecause there is a predominance of normalK-bearing cells in the peripheral blood. But centrocytic lymphomas or mantle cell lymphomas are more often Xpositive than K

positive (20, 21). Like normal mantle zone cells, the tumor cellsalso often coexpress IgM and IgD.

In the working formulation, mantle cell lymphomas fall intothe diffuse small cleaved category, which is in the intermediate-grade group. However, unlike all other intermediate-grade lymphomas, the survival curve does not show a plateau or evidenceof a cured population (20). In this regard, they resemble low-

grade lymphomas. However, the median survival is only 5years, somewhat less than other low-grade lymphomas (20).

Recent studies have shed light on the pathogenesis of mantlecell lymphomas. They are often associated with the t(ll;14)involving the bcl-l breakpoint region (22, 23). Recently, anoncogene, PRAD\, located near this breakpoint has been shownto be overexpressed in centrocytic or mantle cell lymphomas(24).

A third category of low-grade B-cell lymphoma is the smalllymphocytic malignancies, which include chronic lymphocyticleukemia (25, 26). These tumors are composed of cells that arerelatively uniform in their appearance, resembling normal lymphocytes, and thus in the Rappaport classification they werecalled well-differentiated lymphocytic lymphomas. Small lymphocytic malignancies can present either as chronic lymphocytic leukemia or, less commonly, with primarily lymph nodedisease, as a lymphoma. In the latter case, there is usuallygeneralized lymphadenopathy and only focal bone marrow involvement. However, whether the presentation is leukemic orlymphomatous, the process is identical phenotypically andmorphologically and represents different clinical presentationsof the same neoplastic population. Like mantle cell lymphomas, this B-cell neoplasm also expresses CDS in most cases.Small lymphocytic malignancies may represent a block in theterminal maturation of a B-cell toward a plasma cell. Thesepatients often have hypogammaglobulinemia and humoral immunodeficiency (10).

Waldenström's macroglobulinemia represents one step fur

ther in the maturation of a B-lymphocyte (27). In this disease,

the cells express surface and cytoplasmic IgM and secrete immunoglobulin resulting in a monoclonal paraproteinemia.Morphologically, the cells also appear more plasmacytoid.Waldenström's macroglobulinemia usually presents as lym

phoma with generalized lymphadenopathy, although in about10% of patients it may present as chronic lymphocytic leukemiawith a lymphocytosis (27). In tumors with plasmacytic differentiation, there is often a change in the antigenic phenotype(28). The cells may lose many of the pan-B-cell antigens at thislate stage of B-cell differentiation. In addition, there is eventually a loss of surface immunoglobulin and a predominance ofcytoplasmic immunoglobulin in these secretory B-Iymphocytes.

The last category of low-grade B-cell lymphomas, which hasbeen recently proposed by Isaacson and Spencer (29, 30), islymphomas of MALT3. MALT lymphomas usually occur in

extranodal sites, such as the stomach and the lung. Many ofthese tumors were called pseudolymphomas prior to the development of the MALT lymphoma concept because they frequently contain hyperplastic germinal centers. However, inuminophenotypic studies have revealed a monoclonal pattern oflight chain expression in the small lymphocytic component.The reclassification of these lesions because of a change indiagnostic criteria might provide a partial explanation for therecently observed increase in the incidence of lymphoma.

' The abbreviation used is: MALT, mucosa! associated lymphoid tissue.

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Clinically, the MALT lymphomas have a unique and oftenindolent behavior. They tend to recur in extranodal sites butusually do not disseminate widely to bone marrow or to lymphnodes (31 ). In the working formulation, most would fall into thesmall lymphocytic group, but their often heterogeneous cellularcomposition might place them in other categories as well (Table3). In contrast to the other small lymphocytic lymphomas, theyare CDS negative rather than CDS positive (31). MonocytoidB-cell lymphomas, originally described in lymph nodes, appear

to be the nodal counterpart of MALT lymphomas and show ahigh frequency of extranodal disease (32-34).

Aggressive B-Cell Lymphomas

Recognition of distinct disease entities within the aggressivelymphomas is more difficult. The more high-grade lymphomascan occur de novo, or they can occur as a consequence of his-tological transformation of a low-grade lymphoma (35-37).The diffuse aggressive B-cell lymphomas fall into four categories in the working formulation: diffuse mixed small and largecell, diffuse large cell, large cell immunoblastic, and small non-cleaved cell. In the working formulation, diffuse large cell andsmall noncleaved cell lymphomas are almost always of B-cellorigin. By contrast, diffuse mixed, or diffuse large cell immunoblastic lymphomas are phenotypically heterogeneous and canbe derived from either B- or T-lymphocytes (38).

The diffuse aggressive lymphomas differ from the low-gradelymphomas in their biological and clinical manifestations (Table 4) (11). Rather than demonstrating homing to microscopiccompartments of the lymphoid system, these tumors more often spread as large masses. In addition, these tumors have agreater propensity to involve privileged sites, such as the testesand in particular the central nervous system. Virtually all central nervous system lymphomas are of aggressive histológica!grade.

Cytologically, many diffuse aggressive lymphomas resemblethe large follicular center cells encountered in follicularlymphomas—large cleaved, large noncleaved, and immunoblastic. Moreover, if one looks for evidence of the bcl-2 trans-location characteristic of follicular lymphoma, one can findbcl-2 translocations in approximately 35% of patients with diffuse aggressive B-cell lymphomas presenting de novo (39, 40).Either these tumors arose as follicular lymphomas and transformed prior to clinical presentation or they represent anothermanifestation of the bcl-2 translocation.

The aggressive B-cell lymphomas also can represent transformations of other low-grade disorders. For example, smalllymphocytic lymphomas or chronic lymphocytic leukemias cantransform into large cell lymphomas, so-called Richter's syn

drome. While such cases may not be recognizable on purelymorphological grounds, the neoplastic cells may retain the CDSantigen characteristic of small lymphocytic malignancies (41).

Table 4 Clinical, pathological, and experimental characteristics oflow-and high-grade malignant lymphomas

Low grade High grade

Indolent clinical courseRelatively long survivalNot curable with chemotherapy

Nondestructive growth patternAbsence of cellular atypiaRespect privileged sitesRespond to regulatory influencesFail to grow in cultureNontransplantable

Aggressive clinical courseShort survival without therapyPotential for long remission (cure)

with modern chemotherapyDestructive growth patternPresence of cellular atypia/anaplasiaInvade privileged sitesAutonomousImmortalized in cultureTransplantable in immunodeficient host

Table 5 Classification ofpostthymic T-cell malignancies

T-cell "chronic" lymphocytic leukemia

CD4 positive (prolymphocytic)CDS positive/large granular lymphocytesMycosis fungoides-Sezary syndromeLymph node-based peripheral T-cell lymphomasIBL-like" T-cell lymphomaLarge cell anaplastic lymphoma (KÕ-1+)Adult T-cell leukemia/lymphomaSubcutaneous panniculitic T-cell lymphomaAngiocentric immunoproliferative disease

IBL, immunoblastic lymphadenopathy.

The small noncleaved cell lymphomas fall into two groups.Small noncleaved cell lymphoma of the Burkitt's type is a dis

tinct clinicopathological entity, both in its endemic form inAfrica and in its sporadic form in the United States and elsewhere (42, 43). In the working formulation, Burkitt's lym

phoma is called small noncleaved because the nuclei of thetumor cells approximate in nuclear diameter the nuclei of theadmixed starry histiocytes. This tumor is very uniform in itscytological composition and has a very high-growth fraction(44).

Burkitt's lymphoma usually presents in extranodal sites. In

the United States, the most common presentation is as an abdominal mass involving the ileocecal region. In women, it maypresent with ovarian or even breast involvement. Burkitt's lym

phoma is primarily a disease of young children with, of course,sporadic cases occurring in older age groups. Burkitt's lym

phoma is also commonly seen in association with human immunodeficiency virus infection (45).

By contrast, small noncleaved (or undifferentiated) lymphomas of the non-Burkitt's type are much more heterogeneous

and do not represent a disease entity. They exhibit a wide agedistribution, ranging from children to adults (5, 44). Morphologically, these tumors are heterogeneous. While some cellsclosely resemble those of Burkitt's lymphoma, others are more

pleomorphic in terms of nuclear size and shape.The non-Burkitt's cell lymphomas also differ from classic

Burkitt's at the molecular level. Whereas Burkitt's lymphomas

are frequently associated with c-myc translocations, this trans-location is uncommonly seen in the non-Burkitt's lymphomas

(46). In fact, some of these tumors contain bcl-2 translocations,suggesting that they may be more closely related to the diffusefollicular center cell neoplasms.

Postthymic T-Cell Lymphomas

The postthymic T-cell malignancies represent a heterogeneous group of disease entities that can present as leukemia orlymphoma (Table 5). They also range in their clinical behaviorfrom low to high grade. Some clinicopathological entities, suchas mycosis fungoides-Sézarysyndrome, are considered separately from the other non-Hodgkin's lymphomas and are listedin the "miscellaneous" group (Table 2).

Lymphomas with a mature T-cell phenotype are relativelyuncommon and account for only 10-15% of all non-Hodgkin's

lymphomas. The neoplastic cells express one or more of thepan-T-cell antigens, as well as one of the major subset antigens,CD4 or CDS, in most cases (47). Virtually all of the postthymicT-cell lymphomas are clinically aggressive and fall into intermediate- and high-grade categories in the working formulation.Peripheral T-cell lymphomas have a high incidence of involvement of skin and/or mucosal sites, in addition to frequent generalized adenopathy. Clinically, they have an aggressive natural

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history but will respond to multiagent chemotherapy, withlong-term remission in some cases.

Unfortunately, the working formulation is not helpful in delineating the different categories of T-cell malignancy or inidentifying distinct clinicopathological entities. For example,adult T-cell leukemia-lymphoma, a distinct disease associatedwith human T-cell leukemia virus, type 1, is not separatelyidentified in the working formulation (48). Morphologically, itmight fall into the diffuse mixed small and large cell or largecell immunoblastic groups. In fact, most peripheral or postthy-mic T-cell lymphomas are classified in these two categories inthe working formulation. However, even these working formulation groups are not phenotypically homogeneous and includeboth B- and T-cell lymphomas.

Recent studies have shed light on the spectrum of diseasesincluded in the broad group of T-cell lymphomas, and newlyemerging entities have been identified (Table 5). It is also apparent that these diseases vary in their pathogenesis, a fact thatis of great importance in understanding lymphoma trends. Forexample, the angiocentric lymphomas appear to be associatedwith Epstein-Barr virus, whereas the large cell anaplastic lymphomas are frequently found to contain the t(2;5)(p23;q35)translocation (49-53). The recognition of distinct disease entities in the T-cell lymphoma group requires a multidisciplinar)approach using clinical, pathological, immunophenotypic, molecular, and virological data.

Lymphoblastic Malignancies

The last category to be considered in the non-Hodgkin's lym

phomas are the lymphoblastic malignancies; these include lym-

phoblastic lymphomas and acute lymphoblastic leukemias. Themorphological criteria that distinguish lymphoblastic lymphoma from other lymphomas have been clearly delineated,and lymphoblastic lymphoma is a morphological entity (54,55). The nuclei of the neoplastic cells have finely distributedchromatin and resemble the lymphoblasts of acute lymphoblastic leukemia.

Most lymphoblastic lymphomas have an immature T-cellphenotype; they are usually terminal transferase positive andCD7 positive and express one or more of the pan-T-cell antigens. Less commonly, these tumors have a precursor B-cellphenotype comparable to what one would see in common acutelymphocytic leukemia or precursor B-cell leukemia. The precursor B-cell type differs from the precursor T-cell type clinically in that it often presents in skin and/or bone, with anabsence of a mediastinal mass (56-58). Morphological criteriaare not helpful in identifying the immunophenotypic subtypesof lymphoblastic malignancies; consequently, immunologicalmethodologies must be used.

Conclusion

The working formulation is a useful scheme for the clinicianin providing guidance for the clinical management of non-Hodgkin's lymphomas. It also permits the pathologist to inter

pret the material in the absence of immunophenotypic studies.However, the working formulation is an imperfect scheme foridentifying individual disease entities. The identification of individual disease entities is crucial for epidemiological analysisof disease incidence and trends. Other approaches includingimmunophenotypic and molecular studies should be attemptedwhenever possible.

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