What to know about the B-cell neoplasms Steven H. Swerdlow, M.D.

Transcription

1 What to know about the B-cell neoplasms Steven H. Swerdlow, M.D. Bullet points and key words The 2008 Revised WHO monograph on Tumours of the haematopoietic and lymphoid tissues includes many changes among the B-cell neoplasms that range from trivial to significant. Review of the changes since 2001 in the B-cell arena include the addition of new entities and subtypes, the recognition of specific gray zone areas and areas of uncertainty, new criteria for some old entities, several subtypes of lymphoma where age is among the defining features and the description of clonal lymphoid proliferations that fulfill the criteria for a lymphoma but which may not be overt malignancies. A selection of changes will be described in more detail such as the new criteria for chronic lymphocytic leukemia, in situ lymphomas, EBV+ diffuse large B-cell lymphoma of the elderly and the unclassifiable types of splenic and large B-cell lymphomas. Key words: WHO classification, B-cell lymphomas, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, splenic lymphoma. Introduction The revised 2008 WHO classification and monograph contains a moderate number of changes among the B-cell neoplasms, not all of which we will have time to discuss today. 1 The number of possible diagnoses listed in the actual classification has more than doubled since the 2001 edition and the number of pages increased by about one third (depending a bit on how you count things). 2 This discussion will begin with a look at the types of practical and philosophical changes made in the B-cell arena followed by a whirlwind tour of the B-cell neoplasms, looking at some of the specific changes. It should be recognized that due to significant time constraints, neither the verbal nor written discussion will be all inclusive. All direct quotations are from WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues published by IARC in 2008 and the individual chapters are not referenced. Nevertheless, one owes a major debt of gratitude to all of the authors who made it possible to give this presentation today. Similarly very limited references are cited, mostly ones that either are very recent or are from international groups that helped define our new criteria. Types of changes practical & philosophical The most obvious and expected type of change in the classification is of course the presence of new entities, provisional entities, subtypes & other categories carved out of what we thought was an all inclusive classification.

2 2 This means, of course, that the criteria for even some well-established common entities have been altered even though their name is not always altered. Therefore one needs to be careful. While it may be easy to look at the list and see what s new or different, it is not inherently obvious from the listing that anything should have changed, for example, in terms of the criteria for the chronic lymphocytic leukemia but it has! It is one thing not knowing about a new provisional entity that you might never see in your entire professional career but it is more dangerous to use an old term in a fashion that is no longer considered correct. There are organizational changes including the elimination of a category of neoplasms of uncertain malignant potential that impacts the B-cell neoplasms list. Lymphomatoid granulomatosis has moved to the mature B neoplasm listings and polymorphic PTLD moved into a separate classification of the PTLD (similar but not identical to what was in the 2001 chapter). In part, in an attempt to eliminate redundancy, there are some new names for old entities. B-cell has been deleted from nodal and extranodal marginal zone lymphomas and precursor deleted from B- and T- lymphoblastic leukemia/lymphoma. ALK+ DLBCL lost the diffuse part of its name since this type of lymphoma is never follicular. The concept that criteria for entities are based on many factors from genotypic findings to clinical findings has been even further expanded to take into account age in some situations. There are both some pediatric types of lymphoma as well as one provisional subtype of lymphoma that is recognized, in part, because it occurs in elderly patients (see below). Another significant set of changes relates to the recognition of more grayzones and greater degrees of acceptable uncertainty than in the past. While some I suppose might accuse the editors of becoming too wimpy, in fact the gray zones and areas of uncertainty have become well-established in the literature and there was a strong desire, one, not to be dogmatic in the absence of definitive data and, two, to keep well-defined entities as clean as possible still recognizing sometimes very significant variation within a given entity. The point is that, for example, there are some B-cell neoplasms where, no matter how good you are, you cannot and should not put the case into one of the better defined entities. For this reason there are three new categories (not entities) of different types of unclassifiable B-cell lymphomas that we will discuss (Splenic leukemia/lymphoma, unclassifiable; B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL); B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma). There is also recognition of more uncertainties within even some very well-established entities. For example, there are new stricter criteria for chronic lymphocytic leukemia (CLL) but with recognition that we don t really know best way to consider some of the cases that don t quite make it. The difficulty sometimes in distinguishing lymphoplasmacytic lymphoma from other B-cell lymphomas with plasmacytic differentiation is acknowledged with the explicit statement that some small B-cell

3 3 lymphomas with plasmacytic differentiation must be called just that and a differential diagnosis provided. Another issue that rears it s ugly (or perhaps to some beautiful) head within a number of small B-cell lymphomas is the issue of dealing with more subtle lymphoid neoplasms that might not be truly malignant. With more and more phenotypic studies being performed perhaps in circumstances where in the past they wouldn t have been or wouldn t have been so extensive, we are now recognizing more cases that seem to fit our criteria for a lymphoma and yet perhaps are not a truly overt neoplasm. As we will discuss this is an issue with CLL, follicular lymphoma (FL) and even with some mantle cell lymphomas (MCL). The 2008 monograph also brings up to date some observations that are incorrect in the 2001 monograph. For example in the 2001 monograph it is stated that Translocation t(9;14)(p13;q32) & rearrangement of the PAX-5 gene is reported in up to 50% of [lymphoplasmacytic lymphomas], as well as in other lymphomas with plasmacytoid differentiation However, we now recognize that PAX5 translocations are rarely if ever found in LPL but that 6q21 deletions in found in >50% of at least the bone marrow based cases. While in the 2001 monograph ALK+ DLBCL was described as expressing full-length ALK and the explanation for upregulation of ALK was unknown, it is now recognized that ALK+ large B-cell lymphoma DOES have ALK translocations and does express an ALK fusion protein (perhaps also with full length ALK). Finally, our model and description of B-cell development, which remains a critical component in our understanding of the B-cell lymphomas as emphasized by the functional lymphoma classifications of the early 1970 s, has been updated (and is now in color!). It also is helpful in understanding some of the newer ancillary studies that are performed and that are of prognostic importance in some circumstances. B-cell neoplasms our whirlwind tour B lymphoblastic leukaemia/lymphoma has gone from being one entity to being divided up in a fashion analogous to the acute myeloid leukemias, as shown below. This is covered in Dr. Arber s discussion. B lymphoblastic leukaemia/lymphoma, NOS B lymphoblastic leukaemia/lymphoma with recurrent cytogenetic abnormalities B lymphoblastic leukaemia/lymphoma with t(9:22) (q34;q11.2); BCR/ABL B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged B lymphoblastic leukaemia/lymphoma with t(12;21) (p13;q22); TEL/AML1(ETV6-RUNX1) B lymphoblastic leukaemia/lymphoma with hyperdiploidy

4 4 B lymphoblastic leukaemia/lymphoma with hypodiploidy (Hypodiploid ALL) B lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32)(il3-igh) B lymphoblastic leukaemia/lymphoma with t(1;19)(q23;p13.3); E2A- PBX1;TCF3/PBX1) Mature B-cell neoplasms Chronic lymphocytic leukaemia/small lymphocytic lymphoma B-cell prolymphocytic leukaemia Splenic marginal zone lymphoma Hairy cell leukaemia Splenic lymphoma/leukaemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy cell leukaemia-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 lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Paediatric nodal marginal zone lymphoma Follicular lymphoma Paediatric follicular lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS T-cell/histiocyte rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV+ DLBCL of the elderly DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8- associated multicentric Castleman disease Primary effusion lymphoma 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 Selected specific B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) There are new criteria for CLL. In addition, this is one of the B-cell neoplasms with recognition of a related more benign-appearing clonal B-cell proliferation and one where uncertainties as to the best criteria for recognition of an overt malignancy are acknowledged. Specifically, now In the absence of extramedullary tissue involvement, there must be 5x10 9 /L monoclonal lymphocytes with a CLL phenotype in the [peripheral blood]. The chapter discusses the International Workshop on CLL report that requires the lymphocytosis be present for at least three months and allows for the diagnosis of CLL with lower counts if patients have cytopenias or disease-related symptoms. 3 The category of monoclonal B lymphocytosis is recognized and

5 5 defined as the presence of a monoclonal peripheral blood lymphocyte population either with the phenotype of CLL or sometimes of non-cll-type B-cells. In some patients this comprises a very small population which all would agree should not be considered an overt neoplasm, but in others it can be associated with a lymphocytosis (but not large enough to fulfill the new criteria for CLL). This is an area of active investigation 4, as will be discussed, but for the time-being, some uncertainties are acknowledged. Specifically, it is stated Whether MBL is a predisposing condition or even a precursor of overt CLL has to be elucidated. Furthermore, Whether patients who would have fulfilled the criteria in the past for CLL but who fulfill the criteria only for monoclonal B lymphocytosis (MBL) are better considered to have low stage CLL or MBL remains to be determined. Some may prefer to still consider many of these cases more like CLL. The introduction of an unclassifiable category: Splenic B-cell lymphoma/leukaemia, unclassifiable Splenic B-cell lymphoma/leukaemia, unclassifiable includes 2 rare provisional entities, whose relationship to SMZL, to each other and to splenic lymphoma with villous lymphocytes remains to be better defined -- Splenic diffuse red pulp small B-cell lymphoma and Hairy cell leukemia variant. Splenic B-cell lymphoma/leukaemia, unclassifiable is to be used as is for other splenic small B-cell lymphomas not fulfilling the criteria for either of the above, or for any of the other better defined small B-cell lymphomas. Splenic diffuse red pulp small B-cell lymphoma is basically what the name says with diffuse splenic involvement by a small B-cell lymphoma that is composed of often plasmacytoid-appearing cells that do not fulfill the criteria for one of the other small B-cell lymphomas. It involves bone marrow sinuses (with or without interstitial and nodular infiltration) as well as the peripheral blood, often with villous cytology. It is another indolent but incurable lymphoma with responses following splenectomy. This provisional entity is considered synonymous with the less specific splenic lymphoma with villous lymphocytes and the recently described splenic red pulp lymphoma with numerous basophilic villous lymphocytes. 5 There is at least some degree of overlap with HCL-variant and perhaps they are a part of the same entity. These cases, however, absolutely must be distinguished from the sinusoidal large B-cell lymphomas involving spleen and bone marrow. The only change to Hairy cell leukemia variant(hcl-v) is that it moved chapters due to the belief that HCL-v should not be considered a type of HCL. It was felt that there was too little known about this, splenic diffuse red pulp small B-cell lymphoma, and other splenic small B-cell lymphomas to anoint it with another name or to combine it with something else at this time. Clarification of lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinemia and new criteria for plasma cell myeloma

6 6 The criteria for LPL are basically the same as before but it is acknowledged that some small B-cell lymphomas with plasmacytic differentiation need to be diagnosed as such and a differential diagnosis provided. As noted above, PAX5 translocations do NOT characterize this lymphoma. Consistent with the second international workshop of WM 6, WM is now defined as LPL with bone marrow involvement and an IgM monoclonal gammopathy of any concentration. This means that patients with an IgM paraprotein but without LPL are NOT diagnosed as WM and that the level of IgM paraprotein is diagnostically irrelevant. We will not have time to discuss plasma cell myeloma (please see the monograph). Nodal marginal zone lymphoma The major change here (other than loss of B-cell from its name) is that pediatric cases are to be separately designated because compared to adult cases, they are more often localized and have an excellent prognosis. Their histopathology and phenotype are similar to adult cases, but they more often have progressively transformed germinal center-like follicles sometimes with moth-eaten edges. Follicular lymphoma One of the longest discussions concerning revisions to the 2001 WHO classification and criteria for the lymphoid neoplasms related to the unpleasant but necessary topic of grading follicular lymphomas. The 2001 monograph, of course, adopted the counting method and stressed the presence of three grades although grade 3 cases could be subdivided based on the presence (3A) or absence (3B) of admixed centrocytes. The 2008 monograph retains the same basic criteria; however, the emphasis has changed. It is considered very acceptable to diagnose grade 1 or grade 2 FL as grade 1-2 (low grade). Distinction of grade 3A from 3B FL, however, is now emphasized since many grade 3B cases are felt to share more similarities with DLBCL than with other FL. This area is quite complex and beyond our discussion here today. There is also renewed emphasis on recognizing any diffuse areas with grade 3 cytology as DLBCL! Several follicular lymphoma variants are now recognized as listed below: Pediatric follicular lymphoma that, compared to adult-type FL, is more often localized, BCL2 protein negative, lacks a t(14;18) BCL2/IGH@ translocation and is more often grade 3 with large expansile follicles but does well. One must beware as cases of florid follicular hyperplasia particularly in young males with clonal CD10+ B-cell populations are reported. Furthermore children can get adult-type FL as well. Primary intestinal follicular lymphoma is often duodenal. Those cases are like other FL except that they are usually localized and do well sometimes even without treatment.

7 7 Other extranodal follicular lymphomas are described but remember that primary cutaneous FL are included in the separate category of primary cutaneous follicle center lymphoma. Intrafollicular neoplasia/ in situ follicular lymphoma was another area of extensive discussion regarding its name and significance (as you see it is listed with essentially two names). Lymph nodes, or other sites with follicular lymphoid proliferations, demonstrate an intact architecture but there scattered germinal centers with variably dense populations of BCL2+ CD10+ (monoclonal) centrocytes. The problem is that, while some cases seem to not progress and develop more overt FL, other cases have overt FL either at the same time or subsequently. The belief is that at least some of these cases lack the genotypic abnormalities required for an overt FL and that some of these are the tissue equivalent of the well know circulating cells with t(14;18) seen in normal individuals. Primary cutaneous follicle center lymphoma This is now considered a distinct entity, adopted from the 2005 WHO-EORTC classification. 7 Remember it refers only to primary cutaneous cases and is not used to refer to secondary FL in the skin. It is a very indolent entity with cutaneous but not usually extracutaneous recurrences. Remember also that it may be follicular or even entirely diffuse and that the number of centroblasts does not matter as long as there is not a diffuse sheet of centroblasts. In the latter situation one would then have a type of large B-cell lymphoma. Mantle cell lymphoma Whereas the basic criteria for mantle cell lymphoma (MCL) remain the same, it is now recognized that MCL has a broader clinical spectrum than perhaps initially appreciated including cases with a more indolent behavior. Cases with peripheral blood and marrow with or without splenic involvement are reported to do better occasionally even without therapy. These indolent cases appear to have fewer secondary chromosomal abnormalities compared to more conventional MCL and often have mutated IGH@ genes. Cases of in situ MCL with relatively subtle involvement mostly restricted to the mantle zones or even just the inner mantle zones are also described but one must be careful because, like with FL, some of these cases are associated with more overt disease. Others may do well for years without anti-neoplastic therapy. At the other end of the spectrum are the aggressive variants of MCL that have been minimally renamed. The blastoid variant resembles lymphoblastic lymphomas and the pleomorphic variant resembles DLBCL. Aside from these variants it is also noted that Although MCL is not graded, evaluation of the proliferation fraction either by counting mitotic figures or estimating the proportion of Ki-67+ nuclei is important because of its prognostic impact. Unfortunately,

8 8 there are no agreed upon cut-offs and Ki-67 staining/interpretation is not the most reproducible but a high proliferation fraction in MCL is a very important pathologic prognostic feature. High mitotic counts are reported as > mitoses/15 hpf or >50/mm 2 and high Ki-67 proportions reported to be >40 or 60%. Other studies report an adverse prognosis for patients with MCL that have an even lower proportion of Ki-67+ cells (>10, 20, 30%). This highlights the problem of being dogmatic about what defines a high Ki-67 in this setting. Diffuse large B-cell lymphoma: variants, subgroups and subtypes/entities The 2008 classification and monograph includes a long list with some new entities/subtypes and some changes of emphasis including (again) the recognition that we are only imperfect human beings and can t always make completely definitive classifications. DLBCL, not otherwise specified (NOS) includes three of the four former morphologic variants (centroblastic, immunoblastic, anaplastic) plus rare morphologic variants. Molecular and immunohistochemical subgroups are listed and discussed but without a requirement that they be recognized. In other words, it is still not considered a requirement to determine if a DLBCL, NOS is of germinal center or non-germinal center/activated B-cell type. DLBCL subtypes T-cell/histiocyte rich large B-cell lymphoma Although defined in a fashion similar to before, it has been reported that cases with histiocytes are more like the real thing (a more aggressive lymphoma) but one may need to do a CD68 stain to see the histiocytes. Primary DLBCL of the CNS is recognized as a distinct subtype now. Primary cutaneous DLBCL, leg type is another category adopted from the WHO-EORTC classification. These primary cutaneous lymphomas are not restricted to the leg, are aggressive and must be distinguished from diffuse primary cutaneous follicle center lymphomas that can have numerous large centrocytes. EBV+ DLBCL of the elderly is a new provisional subtype of DLBCL defined as an EBV+ clonal B-cell lymphoid proliferation that occurs in patients >50 years old, and without any known immunodeficiency or prior lymphoma. The belief, however, is that this is related to senescence of the immune system and is therefore an immunodeficiency-related lymphoma. It is considered a very aggressive lymphoma although some describe more clinical variation. It should be recognized that in spite of the definition, similar cases may occur rarely in younger individuals. The possibility of an underlying immunodeficiency must be very strongly considered in these circumstances. In addition, if a more specific type of EBV+ lymphoproliferative disorder can be diagnosed it should be this is a diagnosis only to consider in cases that otherwise would be a DLBCL, NOS. Cases of lymphomatoid granulomatosis, infectious mononucleosis (even if a clone can be demonstrated) and other

9 9 specific B-cell lymphomas that may be EBV+ such as plasmablastic lymphoma, primary effusion lymphoma or DLBCL associated with chronic inflammation should be diagnosed as such even if occurring in individuals over the age of 50. Other lymphomas of large B-cells Many of the other types of large B-cell lymphoma should already be familiar to those used to the 2001 classification. Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inflammation (formerly pyothorax lymphomas now includes cases associated with joint prostheses, etc. These are usually EBV positive.) Lymphomatoid granulomatosis (moved to lymphoma category but no changes) ALK-positive large B-cell lymphoma (Same lymphoma as before but, now separately listed and, as noted above, it has been demonstrated that these cases do have ALK translocations.) Plasmablastic lymphoma (This category is listed separately now and includes both the oral cavity type and other cases with more overt plasmacytic differentiation.) Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease Primary effusion lymphoma (& its solid variants) Borderline cases We will conclude with a brief discussion of a major change in the current monograph with the recognition of some gray zone cases that can be diagnosed as such. These unclassifiable categories represent diagnoses that can be used; however, they do not represent actual entities and remain an area of active investigation. B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt Lymphoma (BL) These cases tend to resemble BL both from a morphologic and phenotypic point of view but have one or more features that preclude that diagnosis. A complete discussion is beyond what we can cover today and, as with the rest of the topics being covered, the reader is referred to the WHO monograph. This category includes at least the vast majority of the double hit BCL2 & MYC translocated cases. These latter cases are extremely aggressive and should be identified.

10 10 Related to this topic the diagnosis of atypical BL is gone, although it is certainly still recognized that BL do show some morphologic variation and that the type of cytologic variation that used to qualify a case as atypical BL does not qualify the case for this gray zone diagnosis. We will not have time to review the complex topic of how to diagnose BL, except to state that the 2008 monograph makes the point that the diagnosis of BL is based on a combination of several diagnostic techniques without a gold standard. B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma (HL) These cases tend to look like either DLBCL but have a phenotype more like classical HL or vice versa. Other cases have an indeterminate histopathology as well as an indeterminate antigenic profile. Mediastinal tumors often in young males with a CD20 strongly positive, CD15 positive phenotype are the best characterized and most typical type of cases that are included in this category. Often the differential diagnosis is mediastinal large B-cell lymphoma versus HL. It is of interest that these two entities show some molecular and cytogenetic similarities. Summary I have attempted to share with you some of the conceptual and practical changes in the 2008 WHO classification & bluebook regarding the B-cell lymphomas. As you have seen there are some trivial changes, some more important practical changes related to acquisition of new data and further analysis of older data and some evolution of our concepts about B-cell neoplasia. While these changes may feel burdensome, they prove that our field remains vibrant. As President Kennedy said, Change is the law of life. And those who look only to the past or present are certain to miss the future. References 1. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; Jaffe ES, Harris NL, Stein H, Vardiman JW eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. In: Kleihues P, Sobin LH eds. World Health Organization Classification of Tumours. Lyon: IARC Press; Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111: Rawstron AC, Bennett FL, O'Connor SJ, Kwok M, Fenton JA, Plummer M, de Tute R, Owen RG, Richards SJ, Jack AS, Hillmen P. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359: Traverse-Glehen A, Baseggio L, Bauchu EC, Morel D, Gazzo S, Ffrench M, Verney A, Rolland D, Thieblemont C, Magaud JP, Salles G, Coiffier B, Berger F, Felman P. Splenic red pulp

11 lymphoma with numerous basophilic villous lymphocytes: a distinct clinicopathologic and molecular entity? Blood. 2008;111: Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA. Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003;30: Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:

12 What to know about the B-cell neoplasms Steven H. Swerdlow, M.D.

13 Plan Types of changes in the B-cell arena philosophical and practical Whirlwind tour of the B-cell neoplasms, looking at some of the specific changes. Can t be all inclusive

14 Fear s founded Potential diagnoses listed in classification Precursor B-cell neoplasms Mature B-cell neoplasms B-cell neoplasms, pages B-cell neoplasms, pages Numbers not exact

15 Types of changes practical & philosophical New entities/provisional entities, subtypes & other categories carved out of what we thought was an all inclusive classification Therefore, means the criteria for even some well-known entities have been altered even though their name is not always altered. Be careful. Its one thing not knowing about a new provisional entity but its more dangerous to use an old term in a fashion that is no longer considered correct.

16 Organizational changes Elimination of a category of neoplasms of uncertain malignant potential that impacts the B-cell neoplasms list LYG moved to the mature B neoplasm listings & polymorphic PTLD moved into a separate classification of the PTLD (similar but not identical to what was in the 2001 chapter).

17 2005 WHO-EORTC consensus classification of cutaneous lymphomas

18 New names for old entities (to eliminate redundancy) B-cell deleted from nodal and extranodal marginal zone lymphomas Precursor deleted from B- and T- lymphoblastic leukemia/lymphoma

19 Concept that criteria for entities are based on many factors from genes to clinical findings even further expanded to take into account age in some situations from pediatric lymphomas to one of the elderly.

20 The graying of the WHO Not referring to the editors! Greater recognition of gray zones areas of uncertainty & attempt to keep entities clean Some B-cell neoplasms where no matter how good you are you cannot and should not put the case into one of the better defined entities 3 new categories (not entities) of specific types of unclassifiable B-cell lymphomas Splenic leukemia/lymphoma, unclassifiable B-cell lymphoma, unclassifiable with features intermediate between DLBCL and BL B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical HL

21 Also recognition of more uncertainties within entities Chronic lymphocytic leukemia (new stricter criteria for CLL but with recognition that we don t really know best way to consider some of the cases that don t quite make it ). Lymphoplasmacytic lymphoma (explicitly states that some small B-cell lymphomas with plasmacytic differentiation must be called just that and a differential diagnosis provided).

22 Dealing with more subtle lymphoid neoplasms With more and more phenotypic studies being performed perhaps in circumstances where in the past they wouldn t have been or wouldn t have been so extensive, recognizing more cases that seem to fit our criteria for a lymphoma and yet perhaps are not a truly overt neoplasm CLL, FL, MCL.

23 Some things that were wrong are now brought up to date 2001: Translocation t(9;14)(p13;q32) & rearrangement of the PAX-5 gene is reported in up to 50% of [lymphoplasmacytic lymphomas], as well as in other lymphomas with plasmacytoid differentiation 2008: PAX5 translocations are rarely if ever found in LPL, find 6q21 deletions in >50% of at least the bone marrow based cases. 2001: ALK+ DLBCL -- expression of full-length ALK, explanation for upregulation of ALK unknown 2008: ALK+ large B-cell lymphoma DOES have ALK translocations & does express an ALK fusion protein.

24 Updated description of lymphoid development which is critical in understanding some of the concepts behind the classification & some of the ancillary studies we talk about.

25 B-cell development 2001 simpler and in black and white 2008 more complex and in color (see the monograph)

26 B-cell neoplasms our whirlwind tour

27 B lymphoblastic leukaemia/lymphoma B lymphoblastic leukaemia/lymphoma, NOS B lymphoblastic leukaemia/lymphoma with recurrent cytogenetic abnormalities B lymphoblastic leukaemia/lymphoma with t(9:22) (q34;q11.2); BCR/ABL B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged B lymphoblastic leukaemia/lymphoma with t(12;21) (p13;q22); TEL/AML1(ETV6-RUNX1) B lymphoblastic leukaemia/lymphoma with hyperdiploidy B lymphoblastic leukaemia/lymphoma with hypodiploidy (Hypodiploid ALL) B lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32)(il3-igh) B lymphoblastic leukaemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1;TCF3/PBX1)

28 Mature B-cell neoplasms Chronic lymphocytic leukaemia/small lymphocytic lymphoma B-cell prolymphocytic leukaemia Splenic marginal zone lymphoma Hairy cell leukaemia Splenic lymphoma/leukaemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy cell leukaemia-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 lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Paediatric nodal marginal zone lymphoma Follicular lymphoma Paediatric follicular lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS T-cell/histiocyte rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV+ DLBCL of the elderly DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8- associated multicentric Castleman disease Primary effusion lymphoma 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

29 CLL/SLL new criteria, a B-cell lymphoma with recognition of a related more benignappearing clonal B-cell proliferation, & uncertainties as to the best criteria for recognition of an overt malignancy acknowledged. In the absence of extramedullary tissue involvement, there must be 5x10 9 /L monoclonal lymphocytes with a CLL phenotype in the PB. International Workshop on CLL report requires lymphocytosis present 3 mo. & allows for dx with lower counts if patients have cytopenias or disease-related symptoms.

30 Monoclonal B lymphocytosis Monoclonal peripheral blood lymphocyte populations either with the phenotype of CLL or sometimes non-cll B-cells. In some very small population, but in others can be associated with a lymphocytosis (but not large enough to fulfill the new criteria for CLL).

31 Uncertainties acknowledged Whether MBL is a predisposing condition or even a precursor of overt CLL has to be elucidated. Whether patients who would have fulfilled the criteria in the past for CLL but who fulfill the criteria only for monoclonal B lymphocytosis (MBL) are better considered to have low stage CLL or MBL remains to be determined. Some may prefer to still consider many of these cases more like CLL.

32 CLL-phenotype monoclonal B-cell lymphocytosis NEJM, August 7, 2008 Level of monoclonal CLL-like B-cell lymphocytosis makes a difference in terms of progression to more overt CLL even when its less than 5x10 9 /L!

33 Splenic lymphomas

34 Somewhat more variability also recognized by WHO in SMZL -- some cases have mostly or exclusively monophasic WP nodules

35 The introduction of an unclassifiable category Splenic B-cell lymphoma/leukaemia, unclassifiable

36 Splenic B-cell B lymphoma/leukaemia, unclassifiable Includes 2 rare provisional entities, whose relationship to SMZL, to each other & to SLVL remains to be better defined Splenic diffuse red pulp small B-cell B lymphoma Hairy cell leukemia variant SBCL/L, U to be used as is for other splenic small B-cell B lymphomas not fulfilling the criteria for either of the above, or for any of the other better defined small B-cell B lymphomas.

37 Splenic diffuse red pulp small B-cell B lymphoma The name says it all. (almost) Involves BM sinusoids (±( interstitial & nodular) and PB, often with villous cytology. Another indolent but incurable ML with responses following splenectomy.

38 Relationship to other splenic B-cell neoplasms Considered synonymous with the less specific splenic lymphoma with villous lymphocytes & the recently described splenic red pulp lymphoma with numerous basophilic villous lymphocytes (Blood, 111:2253, 2008). Some degree of overlap with HCL- variant (more to follow). To be distinguished from sinusoidal large B-cell B lymphomas involving spleen and BM.

39 Hairy cell leukemia variant No changes here except it moved chapters due to the belief that HCL-v should not be considered a type of HCL. Too little known about this, SDRPSBCL, and other splenic small B-cell lymphomas to anoint it with another name or to combine it with something else.

40 Clarification of LPL & Waldenstrom macroglobulinemia & new criteria for plasma cell myeloma LPL criteria basically the same as before but it is acknowledged that some small B-cell lymphomas with plasmacytic differentiation need to be diagnosed as such & a ddx provided. PAX5 translocations do NOT characterize this lymphoma WM is defined as LPL with bone marrow involvement and an IgM monoclonal gammopathy of any concentration. IgM paraprotein without LPL is NOT WM Level of IgM paraprotein is irrelevant Plasma cell myeloma -- read the book

41 Nodal marginal zone lymphoma pediatric cases are to be separately designated Compared to adult cases, more often localized & have an excellent prognosis. Histology/phenotype similar to adult cases, but more often have PTGC-like follicles sometimes with moth-eaten edges.

42 Follicular lymphoma -- grading One of the longest ongoing discussions 2001 Grades 1, 2, 3(a & b) Based on # centroblasts/high power field 2008 criteria same but emphasis different Grade 1-2 (includes grades 1 & 2) = low grade FL Grade 3a (includes centrocytes) Grade 3b (all centroblasts) many cases with more similarities to DLBCL than the other FL

43 Renewed emphasis on recognizing any diffuse areas with grade 3 cytology as DLBCL!

44 Follicular lymphoma variants Pediatric follicular lymphoma compared to adult type, more often localized, BCL2-, no t(14;18), more often grade 3 with large expansile follicles but do well. Beware cases reported particularly in young males of florid follicular hyperplasia with clonal CD10+ B-cell populations! Primary intestinal follicular lymphoma often duodenal with those like other FL but usually localized and do well even without treatment. Other extranodal follicular lymphomas brief paragraph but remember primary cutaneous FL are included in primary cutaneous follicle center lymphoma.

45 Follicular lymphoma variants Pediatric follicular lymphoma compared to adult type, more often localized, BCL2-, no t(14;18), more often grade 3 with large expansile follicles but do well. Beware cases reported particularly in young males of florid follicular hyperplasia with clonal CD10+ B-cell populations!

46 Other FL variants Primary intestinal follicular lymphoma often duodenal with those like other FL but usually localized and do well even without treatment. Other extranodal follicular lymphomas brief paragraph but remember primary cutaneous FL are included in primary cutaneous follicle center lymphoma.

47 Intrafollicular neoplasia/ in situ follicular lymphoma (big discussions about name with no definitive agreement) Lymph nodes with an intact architecture but scattered germinal centers with variably dense populations of BCL2+ CD10+ (monoclonal) centrocytes. Problem is that while some cases seem to not progress & develop more overt FL, other cases have overt FL either at the same time or subsequently. Belief is that at least some of these cases lack the genotypic abnormalities required for an overt FL & that some of these are the tissue equivalent of the well know circulating cells with t(14;18) seen in normal individuals.

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50 Ki-67 CD10 BCL2

51 Primary cutaneous follicle center lymphoma Distinct entity now (from 2005 WHO- EORTC classification) primary cases only. Very indolent with cutaneous but not usually extracutaneous recurrences Growth pattern and number of centroblasts don t matter as long as not a diffuse sheet of centroblasts (then a type of large B-cell lymphoma).

52 Mantle cell lymphoma more indolent variants recognized Cases with PB, BM ± splenic involvement are reported to do better occasionally even without therapy. Appear to have fewer secondary chromosomal abnormalities compared to more conventional MCL. Cases of in situ MCL also described but be careful because, like with FL, some are associated with more overt disease.

53 At the other end. The aggressive variants that need to be recognized minimally renamed Blastoid variant resembles lymphoblastic lymphomas Pleomorphic variant resembles DLBCL. Although MCL is not graded, evaluation of the proliferation fraction either by counting mitotic figures or estimating the % of Ki- 67+ nuclei is important because of its prognostic impact.

54 No agreed upon cut-offs and Ki-67 staining/interpretation is not the most reproducible but a high proliferative fraction in MCL is a very important pathologic prognostic feature High mitotic count -- > mitoses/15 hpf or >50/mm 2 High Ki >40 or 60% (some studies >10, 20 or 30%).

55 Diffuse large B-cell lymphoma: variants, subgroups and subtypes/entities A long list with some new entities/subtypes and some changes of emphasis including (again) the recognition that we are only imperfect human beings and can t always make completely definitive classifications.

56 Large B-cell lymphomas DLBCL, not otherwise specified Includes 3 of the 4 former morphologic variants (CBic, IBic, Anaplastic) plus rare morphologic variants Molecular & immunohistochemical subgroups are listed and discussed but without a requirement that they be recognized.

57 DLBCL subtypes T-cell/histiocyte rich large B-cell lymphoma (cases with histiocytes might be more like the real thing but need to do CD68 stain to see them sometimes). Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type (from the WHO-EORTC classification) -- aggressive & to be distinguished from diffuse PCFCL. EBV+ DLBCL of the elderly - provisional

58 EBV+ DLBCL of the elderly Guess what defines elderly. Hint also called senile.

59 EBV+ DLBCL of the elderly An EBV+ clonal B-cell lymphoid proliferation that occurs in patients >50 years old, and without any known immunodeficiency or prior lymphoma. The belief, however, is that this is related to senescence of the immune system and is therefore an immunodeficiency-related lymphoma. A very aggressive lymphoma

60 Exceptions to criteria already discussed May occur rarely in younger individuals but possibility of an underlying immunodeficiency must be very strongly considered. The following are excluded: LYG, infectious mononucleosis, & other specific B-cell lymphomas that may be EBV+ such as plasmablastic lymphoma, PEL, DLBCL associated with chronic inflammation.

61 Other lymphomas of large B-cells Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inflammation (formerly pyothorax lymphomas now joint prostheses, etc) Lymphomatoid granulomatosis (moved to lymphoma category but no changes) ALK-positive large B-cell lymphoma new information. Plasmablastic lymphoma (includes both the oral cavity type & others with more overt plasmacytic differentiation) Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease Primary effusion lymphoma (& its solid variants)

62 Borderline cases B-cell lymphoma, unclassifiable with features intermediate between DLBCL and BL Tend to look/mark a lot like BL but have one or more features that would preclude that diagnosis Includes the double hit BCL2 & MYC translocated cases very aggressive Atypical Burkitt lymphoma is gone still recognized that BL do show some morphologic variation Diagnosis of BL is based on a combination of several diagnostic techniques without a gold standard.

63 Borderline lesions B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical HL Tend to look like one & mark like the other or have indeterminate antigenic profiles Mediastinal CD20+ CD15+ cases often in young males are the best characterized/most typical. Often ddx is mediastinal large B-cell lymphoma vs HL (which do show some molecular and cytogenetic similarities)

64 Summary Some of the conceptual & practical changes in the 2008 WHO classification & bluebook regarding the B-cell B lymphomas Some trivial changes, some more important practical changes related to acquisition of new data & further analysis of older data and some evolution of our concepts about B-cell B neoplasia We can t t be afraid of change.

65 Learn from the great masters! Change is the law of life. And those who look only to the past or present are certain to miss the future. John F. Kennedy