NON-HODGKIN LYMPHOMA ________________________________________________________________________________
`
`The 2008 WHO classification of lymphomas:
`implications for clinical practice and translational
`research
`
`Elaine S. Jaffe1
`
`1Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer
`Institute, National Institutes of Health, Bethesda, MD
`
`The 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published
`in 2008 builds upon the success of the 2001 3rd edition; new entities are defined, and solutions for
`problematic categories are sought. Recent studies have drawn attention to the biological overlap be-
`tween classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphomas (DLBCL). Similarly, there is
`a greater appreciation of the borderlands between Burkitt lymphoma and DLBCL. Strategies for the
`management of these borderline lesions are proposed. Additionally, age-specific and site-specific factors
`play an important role in the definition of several new entities, which also have biological underpinnings.
`Among the peripheral T-cell lymphomas (PTCL), more precise definitions were introduced for several
`entities, including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-
`associated T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Several new variants of
`primary cutaneous T-cell lymphomas are proposed. Finally, the subclassification and categorization of the
`most common lymphoma subtypes, follicular lymphoma (FL) and DLBCL, were altered to enhance diag-
`nostic accuracy and aid in clinical management. The 2008 WHO classification also draws attention to early
`events in lymphomagenesis. These lesions help delineate the earliest steps in neoplastic transformation
`and generally mandate a conservative therapeutic approach. The 2001 classification was rapidly adopted
`for clinical trials and successfully served as a common language for scientists comparing genetic and
`functional data. The modifications made in the 2008 classification are the result of this successful part-
`nership among pathologists, clinicians, and biologists, but are only a stepping stone to the future.
`
`I n 2008 the International Agency for Research on
`
`Cancer (IARC) published the 4th Edition of the WHO
`Classification of Tumours of Haematopoietic and
`Lymphoid Tissues,1 an effort that involved 138 authors and
`two clinical advisory committees comprising 62 clinical
`specialists with expertise in lymphoid and myeloid
`disorders. As in the 3rd edition, the effort was coordinated
`by the European Association for Haematopatholgy and the
`Society for Hematopatholgy, led by the eight editors, who
`served as a steering committee.
`
`This review will focus on changes in the classification of
`lymphomas, which resulted from new insights derived from
`clinical and laboratory research to better define heteroge-
`neous or ambiguous categories of disease. The areas of
`modification relate to several discrete topics: (1) a greater
`appreciation of early or in situ lesions that challenge us to
`define the earliest steps in neoplastic transformation; (2) the
`recognition of age as a defining feature of some diseases,
`both in young and the elderly; (3) further appreciation and
`
`recognition of site-specific impact on disease definitions;
`and (4) a recognition of borderline categories, in which
`current morphological, immunophenotypic, and genetic
`criteria do not permit sharp delineations into existing
`disease categories. Finally, the 4th edition incorporates some
`provisional entities for which sufficient data are lacking,
`either clinically or biologically, leading to uncertainty in
`definitional criteria.
`
`Continued challenges remain in the stratification and
`subclassification of major disease groups including
`follicular lymphoma (FL) and diffuse large B-cell lym-
`phoma (DLBCL). Genomic and genetic studies have led to
`significant new insights with the identification of biologi-
`cal and clinical subgroups. Nevertheless, the authors
`concluded that application of this research to clinical
`practice on a daily basis was premature, as many of the
`relevant techniques are not yet available in the clinical
`laboratory. The thematic approach to peripheral T-cell
`lymphomas (PTCL) is unchanged. Some diseases are
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`defined based on clinical, pathological, immunopheno-
`typic, or genetic parameters, while the others are provision-
`ally lumped in PTCL, not otherwise specified (NOS).
`
`The 2008 classification has incorporated minor changes in
`terminology, reflecting our better understanding of disease
`entities and their relationship to the immune system. For
`example, the authors concluded that the modifier “B-cell”
`was no longer required for nodal, extranodal or splenic
`marginal zone lymphomas (MZL), as there are no T-cell
`marginal zone neoplasms (Table 1). The modifier “B-cell”
`previously had been eliminated from chronic lymphocytic
`leukemia (CLL). The names for the precursor lymphoid
`neoplasms also were simplified to eliminate redundancy;
`thus, the modifier “precursor” is no longer required for
`either B- or T-lymphoblastic leukemia/lymphoma, as the
`term lymphoblastic itself carries this meaning.
`
`Early Events in Lymphoid Neoplasia—
`Borderlands of Malignancy
`The multi-step pathway of tumorigenesis has parallels in
`most organ systems, best documented in the evolution of
`colonic adenocarcinoma.2 Histological progression is a
`well-recognized feature of many lymphoid neoplasms, but
`the earliest events in lymphoid neoplasia are difficult to
`recognize. In fact, the lymphoid system historically has had
`no recognized “benign neoplasms,” a fact that may be
`related to the propensity of lymphoid cells to circulate or
`home, and not remain confined to a single anatomic site.3
`The 2008 WHO classification addresses the problem of
`clonal expansions of B cells, or less often T cells, that
`appear to have limited potential for histological or clinical
`progression.
`
`The use of flow cytometry on a routine basis led to the
`recognition that populations of monoclonal CD5+ B-cells
`could be identified in the healthy, unaffected first-degree
`relatives of patients with CLL, and in 3% of healthy adults
`over the age of 40.4,5 Many of these clones have genetic
`abnormalities associated with CLL including 13q14
`deletion and trisomy 12, similar to sporadic CLL.6 Never-
`theless, only a small percentage of these patients progress to
`clinically significant CLL, at a rate of less than 2% per year.
`This condition has been termed monoclonal B-cell lympho-
`cytosis (MBL) and should be distinguished from CLL. The
`minimal diagnostic criteria for a diagnosis of CLL have
`been modified to require ≥ 5 × 109/L of monoclonal B cells
`in the peripheral blood or evidence of extramedullary tissue
`involvement. A level below this threshold is considered
`MBL. The data suggest that most patients ultimately
`diagnosed as CLL go through a prolonged prodromal
`phase, with evidence of the circulating clone found many
`years prior to diagnosis.7 Thus, the distinction of MBL from
`
`Table 1. WHO 2008: the mature B-cell neoplasms.
`
`Chronic lymphocytic leukemia/small lymphocytic lymphoma
`B-cell prolymphocytic leukemia
`Splenic marginal zone lymphoma
`Hairy cell leukemia
`Splenic lymphoma/leukemia, unclassifiable
`Splenic diffuse red pulp small B-cell lymphoma*
`Hairy cell leukemia-variant*
`Lymphoplasmacytic lymphoma
`Waldenström macroglobulinemia
`Heavy chain diseases
`Alpha heavy chain disease
`Gamma heavy chain disease
`Mu heavy chain disease
`Plasma cell myeloma
`Solitary plasmacytoma of bone
`Extraosseous plasmacytoma
`Extranodal marginal zone B-cell lymphoma of mucosa-associated
`lymphoid tissue (MALT lymphoma)
`Nodal marginal zone B-cell lymphoma (MZL)
`Pediatric type nodal MZL
`Follicular lymphoma
`Pediatric type follicular lymphoma
`Primary cutaneous follicle center lymphoma
`Mantle cell lymphoma
`Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
`T cell/histiocyte rich large B-cell lymphoma
`DLBCL associated with chronic inflammation
`Epstein-Barr virus (EBV)+ DLBCL of the elderly
`Lymphomatoid granulomatosis
`Primary mediastinal (thymic) large B-cell lymphoma
`Intravascular large B-cell lymphoma
`Primary cutaneous DLBCL, leg type
`ALK+ large B-cell lymphoma
`Plasmablastic lymphoma
`Primary effusion lymphoma
`Large B-cell lymphoma arising in HHV8-associated multicentric
`Castleman disease
`Burkitt lymphoma
`B-cell lymphoma, unclassifiable, with features intermediate
`between diffuse large B-cell lymphoma and Burkitt lymphoma
`B-cell lymphoma, unclassifiable, with features intermediate between
`diffuse large B-cell lymphoma and classical Hodgkin lymphoma
`
`
`
`
`Hodgkin LHodgkin Lymphomaymphoma
`ymphomaHodgkin LHodgkin LHodgkin Lymphomaymphoma
`
`
`
`
`Nodular lymphocyte-predominant Hodgkin lymphoma
`Classical Hodgkin lymphoma
`Nodular sclerosis classical Hodgkin lymphoma
`Lymphocyte-rich classical Hodgkin lymphoma
`Mixed cellularity classical Hodgkin lymphoma
`Lymphocyte-depleted classical Hodgkin lymphoma
`
`*These represent provisional entities or provisional subtypes of other
`neoplasms.
`Diseases shown in italics are newly included in the 2008 WHO
`classification.
`
`CLL is largely one of practice guidelines, as we lack any
`proven biological parameters that can distinguish MBL
`from CLL or identify which patients will progress to
`clinically significant disease more rapidly. A recent
`report suggested that the cut-point between MBL and
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`CLL should be modified and increased to a B-cell count
`of 11 × 109 L.8
`
`Another area that challenges us to define “lymphoma” is
`early events in follicular lymphoma. Up to 70% of normal
`healthy adults have circulating clonal memory B cells with
`the t(14;18)(q32;q21); however, these cells presumably lack
`other genetic alterations necessary for development of
`malignant behavior.9,10 The tissue equivalent of this process
`is thought to be in situ FL, also termed “intrafollicular
`neoplasia” in the WHO classification.11 These lesions are
`often discovered incidentally, and comprise isolated
`scattered follicles colonized by monoclonal t(14;18) B-
`cells over-expressing both BCL2 and CD10 within an
`otherwise uninvolved lymph node. Rarely the in situ FL
`lesion may be discovered in lymph nodes involved by a
`clonally unrelated process.12 Further evaluation reveals
`evidence of FL at another site in about half of the patients,
`but in approximately 50% progression to FL does not occur,
`at least with current follow-up. The challenge is to distin-
`guish the true in situ FL case from lymph nodes with partial
`involvement by FL due to the naturally occurring dissemi-
`nation of the disease. In instances of partial involvement by
`FL many or most of the follicles are involved, but definitive
`criteria for this distinction are lacking.
`
`A related condition is localized FL presenting as small
`polyps in the duodenum; these duodenal FLs rarely, if ever,
`progress to nodal or systemic disease.13,14 Duodenal FL cells
`express intestinal homing receptors that may retain the
`clonal B cells within the intestinal mucosa.15 A similar in
`situ form of mantle cell lymphoma has been described in a
`few isolated cases, although little is known about the
`clinical outcome of this lesion.16,17 There are other instances
`in which one encounters clonal proliferations with limited
`potential for clinical aggressiveness. This phenomenon is
`exemplified by Epstein-Barr virus (EBV)–driven B-cell
`proliferations arising in the setting of altered immunity, but
`also pertains to early gastric extranodal marginal zone
`(MALT) lymphomas lacking secondary genetic alterations.
`These lymphomas appear dependent upon continued
`antigen activation from Helicobacter pylori and may
`regress with antibiotic therapy alone.18 In the T-cell system
`lymphomatoid papulosis (LYP), part of the spectrum of
`primary cutaneous CD30+ T-cell lymphoproliferative
`disorders, is a clonal T-cell proliferation that also has
`limited malignant potential.19-21
`
`The 3rd edition of the WHO classification included a
`category of B-cell or T-cell proliferations of uncertain
`malignant potential. This category encompassed conditions
`such as LYP or lymphomatoid granulomatosis, in which
`spontaneous regression may be seen. However, the decision
`
`was made to eliminate this designation, as a broader view of
`lymphoid malignancies indicates that within many well-
`recognized disease entities one encounters “proliferations
`of uncertain malignant potential.” This is especially true
`among some pediatric lymphomas, as will be discussed
`below. It is incumbent upon the pathologist and clinician to
`be aware of the spectrum of disease and to manage each
`case appropriately, taking into consideration biological and
`clinical factors. These early events of lymphomagenesis
`also can provide instructive models of lymphocyte homing
`and migration.
`
`Age as a Key Feature in Disease Definition
`The 2008 WHO classification utilizes patient age as a
`defining feature in a number of newly incorporated disease
`entities. For example, within the categories of FL and nodal
`MZLs there are distinctive variants that present almost
`exclusively in the pediatric age group, and differ from their
`adult counterparts clinically and biologically. The pediatric
`variant of FL usually presents with localized disease and is
`of high histological grade. These lymphomas lack BCL2/
`IGH@ translocations and do not express BCL2 protein.
`They may present at nodal or extranodal sites (testis;
`gastrointestinal tract; Waldeyer’s ring).22 Pediatric FL have a
`good prognosis, with the optimal management not yet
`determined.22-24 A challenging area of diagnosis is rare cases
`of florid reactive follicular hyperplasia in children that have
`been reported to contain clonal populations of CD10+
`germinal center B cells and yet do not progress to overt
`lymphoma.25
`
`Nodal MZL in children, while monoclonal at the
`immunophenotypic and genetic level, also appear to have a
`low risk of progression.26 Most patients present with stage I
`disease and have a low risk of recurrence following conser-
`vative therapy. Pediatric nodal MZL are often associated
`with marked follicular hyperplasia and changes resembling
`progressive transformation of germinal centers, with the
`distinction from pediatric FL sometimes being problematic.
`As there is no molecular hallmark for adult nodal MZL,
`knowledge of the biological underpinnings of this diagno-
`sis are lacking. Interestingly, pediatric MZL are relatively
`more common in males, in contrast to female predominance
`in adult MZL.
`
`The 2008 classification also recognizes two rare EBV-
`associated T-cell diseases that occur almost entirely in
`children, primarily affecting children of Asian origin but
`also seen in ethnic populations from Mexico and Central/
`South America. (Table 2) These are systemic EBV+ T-cell
`lymphoproliferative disease of childhood and hydroa
`vacciniforme–like lymphoma. Both types lesions have been
`included under the broad heading of chronic active EBV
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`Table 2. WHO 2008: the mature T-cell and NK-cell
`neoplasms.
`
`T-cell prolymphocytic leukemia
`T-cell large granular lymphocytic leukemia
`Chronic lymphoproliferative disorder of NK-cells*
`Aggressive NK cell leukemia
`Systemic EBV+ T-cell lymphoproliferative disease of childhood
`(associated with chronic active EBV infection)
`Hydroa vacciniforme-like lymphoma
`Adult T-cell leukemia/ lymphoma
`Extranodal NK/T cell lymphoma, nasal type
`Enteropathy-associated T-cell lymphoma
`Hepatosplenic T-cell lymphoma
`Subcutaneous panniculitis-like T-cell lymphoma
`Mycosis fungoides
`Sézary syndrome
`Primary cutaneous CD30+ T-cell lymphoproliferative disorder
` Lymphomatoid papulosis
` Primary cutaneous anaplastic large-cell lymphoma
`Primary cutaneous aggressive epidermotropic CD8+ cytotoxic
`T-cell lymphoma*
`Primary cutaneous gamma-delta T-cell lymphoma
`Primary cutaneous small/medium CD4+ T-cell lymphoma*
`Peripheral T-cell lymphoma, not otherwise specified
`Angioimmunoblastic T-cell lymphoma
`Anaplastic large cell lymphoma (ALCL), ALK+
`Anaplastic large cell lymphoma (ALCL), ALK–*
`
`*These represent provisional entities or provisional subtypes of other
`neoplasms.
`Diseases shown in italics are newly included in the 2008 WHO
`classification.
`
`infection in the Japanese literature,27 and are derived from
`EBV+ clonal T cells.28 Hydroa vacciniforme-like lymphoma
`has a chronic and protracted clinical course, with remissions
`often during winter months. It may resolve spontaneously
`in adult life or progress to more systemic and aggressive
`disease. Systemic EBV+ T-cell lymphoproliferative disease
`is highly aggressive, with survival measured in weeks to
`months, and is usually associated with a hemophagocytic
`syndrome.29
`
`By contrast, some diseases appear to occur most often at
`advanced age, such as EBV+ DLBCL of the elderly, which
`likely arises because of decreased immune surveillance.30
`These lymphomas are clinically aggressive and occur more
`often in extranodal rather than nodal sites. The neoplastic
`cells may mimic Hodgkin/Reed-Sternberg cells and exhibit
`marked pleomorphism, with a broader range in morphology
`than typically seen in CHL. Necrosis and an inflammatory
`background are common. EBV+ DLBCL of the elderly
`should be distinguished from reactive hyperplasia associ-
`ated with EBV, also encountered in the elderly, which
`usually has a benign outcome with spontaneous regression
`in most patients.31,32
`
`Aggressive B-cell Lymphomas and
`Borderline Malignancies
`In the past 20 years there has been a greater appreciation of
`morphologic and immunophenotypic overlap between CHL
`and some large B-cell lymphomas, usually primary medias-
`tinal large B-cell lymphoma (PMBL) and mediastinal
`nodular sclerosis classical Hodgkin lymphoma
`(NSCHL).33,34 The use of gene expression profiling further
`confirmed a biological relationship.35,36 Prior case reports
`had identified cases of PMBL followed by CHL or vice
`versa, or other cases in which both lymphomas were
`composite in the same tumor mass.37 Notably, both neo-
`plasms occur in young adults and involve the mediastinum.
`In most biopsies one or the other diagnosis can be made,
`but in some cases the lymphoma exhibits transitional
`features that defy traditional diagnostic boxes; these tumors
`have been termed “grey zone” lymphomas. The 2008 WHO
`classification recognizes a provisional category of B-cell
`neoplasms with features intermediate between DLBCL and
`classical Hodgkin lymphoma.37,38 These tumors occur
`predominantly in young men and appear to be more
`aggressive than either PMBL or NSCHL.39 There are other
`diagnostic settings in which the diagnosis between DLBCL
`and CHL is challenging. For example, some EBV-associated
`B-cell lymphomas may exhibit features that closely
`resemble or mimic CHL.40 The borderline category should
`be used sparingly, but is appropriate in those cases in which
`a distinction between CHL and DLBCL is not possible.
`
`The WHO classification of 2008 recognizes a group of
`high-grade B-cell lymphomas that are not readily classified
`as either Burkitt lymphoma (BL) or DLBCL. This provi-
`sional category is termed: B-cell lymphoma, unclassifiable,
`with features intermediate between DLBCL and BL. These
`rare lymphomas, which occur predominantly in adults, have
`a germinal center phenotype that resembles BL but exhibit
`atypical cytological features for BL.41 Also included are
`cases with translocations of both MYC and BCL2 (“double
`hit”). While gene expression profiling may show similari-
`ties with classical BL,42,43 other data, including a very
`aggressive clinical course, support segregation from BL.44
`
`The 2008 WHO classification eliminated the variant
`category of “atypical BL,” which had been included in the
`2001 classification.45 Thus, a case with the typical BL
`phenotype (CD20+, BCL6+, CD10+, BCL2–) and genotype
`(so-called MYC-simple or MYC/IG in the absence of other
`major cytogenetic anomalies) may be classified as BL, even
`if there is some cytological variability in the morphology of
`the neoplastic cells. Likewise, cases of otherwise typical
`DLBCL with a very high growth fraction should not be
`included in this “intermediate” group.46 It should be noted
`that a MYC translocation does not mandate a diagnosis of
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`either BL or the borderline category, and that a MYC
`translocation may be found in cases of otherwise typical
`DLBCL.43,42 Thus, the final diagnosis rests on integration of
`morphologic, immunophenotypic and molecular data.
`
`Other changes in the classification of aggressive B-cell
`lymphomas recognize the importance of site or clinical
`factors in defining variants of DLBCL. I have already noted
`the subtype, EBV+ DLBCL of the elderly.47 DLBCL
`associated with chronic inflammation is another EBV+
`DLBCL arising in a specialized clinical setting, most often
`in association with long-standing pyothorax,48 but also in
`other instances of prolonged chronic inflammation, such as
`chronic osteomyelitis, or reaction to metallic implants in a
`joint or bone.49 Other site-specific categories are primary
`DLBCL of the central nervous system (CNS),50 and primary
`cutaneous DLBCL, leg-type.51 Interestingly, the “leg-type”
`of primary cutaneous DLBCL exhibits an activated B-cell
`(ABC) gene expression profile in most cases.52 One might
`expect that in the future biological and genetic parameters
`might drive the subclassification of DLBCL, rather than
`clinical features. However, clinical features remain impor-
`tant in clinical management.50 In addition, primary CNS
`DLBCL has a distinctive gene expression signature that
`may continue to justify it as a separate entity.53,54
`
`After separation of the specific new subtypes of DLBCL, we
`are still left with a large group of DLBCL for which
`pathological features are lacking to further stratify them for
`predicting prognosis or response to therapy. These are
`designated as DLBCL, not otherwise specified (NOS) in the
`WHO classification. Stratification according to gene
`expression profiling as germinal center B-cell (GCB) versus
`activated B-cell (ABC) types has proven prognostic value.55
`However, the GBC and ABC subtypes were not formally
`incorporated into the classification based on (1) the lack of
`availability of gene expression profiling as a routine
`diagnostic test and (2) the imperfect correlation of immuno-
`histochemical surrogate markers with genomic studies.
`Moreover, these designations do not as yet direct therapy,
`although recent studies suggest that ABC versus GCB
`lymphomas will exhibit differential sensitivity to certain
`drugs.56 Further development of targeted therapies and
`recognition of additional markers of clinical behavior will
`likely result in additional modifications to this category in
`the future.57,58
`
`Several aggressive B-cell lymphomas have an
`immunoprofile resembling the plasma cell stage of differen-
`tiation. These include plasmablastic lymphoma, ALK+ large
`B-cell lymphoma, and the HHV-8–associated malignancies,
`primary effusion lymphoma, and large B-cell lymphoma
`associated with multicentric Castleman’s disease. Most
`
`cases of plasmablastic lymphoma are associated with EBV
`and arise in setting of immunodeficiency, usually secondary
`to HIV infection, but also advanced age.59
`
`Follicular Lymphoma—How Many Grades?
`How Many Entities?
`The grading of FL was the subject of spirited discussion,
`both among the authors and the participants in the Clinical
`Advisory Committee. FL has traditionally been graded
`according to the proportion of centroblasts and stratified
`into three Grades, 1-3. However, most studies have shown
`poor interobserver and intraobserver reproducibility.
`Moreover, the clinical significance of the separation of
`Grades 1 and 2 has been questioned, with minimal differ-
`ences seen in long term outcome. Thus, the 2008 WHO
`classification lumps cases with few centroblasts as “FL
`Grade 1-2 (low grade)” and does not require or recommend
`further separation.
`
`FL Grade 3 is divided into Grades 3A and 3B, based on the
`absence of centrocytes in the latter category. Several studies
`have identified biological differences between these two
`subtypes, with most cases of FL Grade 3B being more
`closely related to DLBCL at the molecular level.60-63
`However, in clinical practice the separation of Grades 3A
`and 3B can be challenging and thus far imperfectly
`segregates the two variants. Diffuse areas in any Grade 3 FL
`should be designated as DLBCL (with FL) and are more
`commonly observed in Grade 3B.62 Further studies are
`likely to lead to more precise delineation of the Grade 3
`cases truly belonging within FL and those representing an
`intrafollicular variant of the GCB type of DLBCL.
`
`Pediatric and intestinal FL have already been mentioned as
`distinctive variants, with pediatric FL lacking an associa-
`tion with the t(14;18). Primary cutaneous follicle center
`lymphoma (PCFCL) is now segregated as a distinct disease
`entity, whereas it was considered a variant of FL in the 2001
`edition. Notably, PCFCL may contain a high proportion of
`large B-cells including large centrocytes and centroblasts.51
`Evidence of the t(14;18) is uncommon and most cases are
`BCL2 negative. Dissemination beyond the skin is rare, and
`the prognosis is usually excellent.
`
`Peripheral T-cell Lymphomas—Challenges
`Remain
`PTCL, NOS, remains a “wastebasket” category, analogous
`to DLBCL, NOS. Most cases lack distinct genetic or
`biological alterations, and prognostic models have largely
`relied on clinical features or generic factors, such as
`proliferation.64,65 Nevertheless, progress has been made in
`the understanding of a number of PTCL entities.
`Angioimmunoblastic T-cell lymphoma has been shown to
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`bear to close relationship to the TFH cell of the germinal
`center, and the follicular variant of PTCL, NOS shares a
`similar phenotype, although interestingly differs geneti-
`cally and clinically.66-68 The majority of nodal PTCL appear
`related to effector T-cells.
`
`The WHO classification of 2008 has applied more stringent
`criteria to the diagnosis of enteropathy-associated T-cell
`lymphoma (EATL), and the change in the diagnostic term
`from enteropathy-type T-cell lymphoma reflects these
`changes in criteria. It is appreciated that a variety of PTCL
`can present with intestinal disease, and not all of these are
`associated with celiac disease. For example, intestinal
`involvement can be seen at presentation, or with progres-
`sion, in extranodal NK/T-cell lymphoma and some gamma
`delta T-cell lymphomas. To make the diagnosis of EATL,
`one should have evidence of celiac disease, either at the
`genetic level, with the appropriate HLA-phenotype, or
`histologically, in the adjacent uninvolved small bowel
`mucosa. A variant of EATL was introduced into the
`classification, termed the monomorphic variant of EATL or
`Type II. These cases have some distinctive immuno-
`phenotypic and genotypic features. The tumor cells are
`CD8+, CD56+, and MYC amplifications have been shown in
`a subset of cases.69,70 The monomorphic variant occurs in
`the setting of celiac disease, but also occurs sporadically.
`
`Anaplastic large cell lymphoma (ALCL), ALK-positive is
`considered a distinct disease, which must be distinguished
`from the provisional entity of ALCL, ALK-negative. More
`serious debate revolved around the decision to segregate
`the ALK– ALCL cases from PTCL, NOS. Recent clinical
`studies appear to support this resolution, as the former has a
`better prognosis and evidence of a plateau, at least in a
`proportion of patients.71 Stringent morphologic and
`immunophenotypic criteria are required for the diagnosis of
`ALK– ALCL as CD30 may be expressed in a variety of
`PTCL subtypes, and CD15 may be negative in CHL.
`
`Three new variants of primary cutaneous PTCL were
`introduced: primary cutaneous gamma delta T-cell lym-
`phoma, and the provisional entities of primary cutaneous
`CD4+ small/medium T-cell lymphoma and primary cutane-
`ous aggressive epidermotropic CD8+ cytotoxic T-cell
`lymphoma. Cutaneous gamma delta T-cell lymphomas have
`a diverse histological and clinical spectrum and may
`display a panniculitis-like pattern.72 However, this disease
`has a much poorer prognosis than subcutaneous panniculi-
`tis-like T-cell lymphoma,73 which is defined as a lymphoma
`exclusively of alpha-beta phenotype in the 2008 WHO.74
`
`Conclusion
`The 2008 WHO classification is the continuation of a
`successful international collaboration among pathologists,
`biologists and clinicians interested in the hematological
`malignancies. The 2001 classification was rapidly adopted
`for clinical trials and successfully served as a common
`language for scientists comparing genetic and functional
`data. The modifications made in the 2008 classification are
`the result of this successful partnership, but are only a
`stepping stone to the future. It is evident that many areas
`will still be the subject of intense investigation, including
`the admittedly heterogeneous groups of DLBCL, NOS and
`PTCL, NOS. The inclusion of borderline categories is an
`intermediate step, and further modifications in these areas
`are expected.
`
`Disclosures
`Conflict-of-interest disclosure: The author declares no
`competing financial interests.
`Off-label drug use: None disclosed.
`
`Correspondence
`Elaine S. Jaffe, MD, Center for Cancer Research, National
`Cancer Institute, National Institutes of Health, Bethesda, MD
`20892; Phone: 301-496-0184; e-mail: elainejaffe@nih.gov
`
`3.
`
`References
`1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classifi-
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