Ahmad Alduaij, MD FCAP Consultant Pathologist Pathology & Laboratory Medicine Institute

Update of WHO

Classifications of Tumors of the Lymphoid Tissues

Disclosure

It is required that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/ partner have, or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest.

Complete disclosure information is maintained and has been reviewed by the CME Advisory Committee

2

Learning Objectives

1. Overview of previous and current hematopoietic and lymphoid tumors classifications

2. Touching on new and controversial entities and clarification of current diagnostic criteria

3. New ancillary studies (eg, immunohistochemical markers and genetic signatures) helpful in working up a diagnosis

4. Highlights probable changes/ additions in the next edition of the “BLUE BOOK” tumor classification

Introduction

How did we get here

• “Consistent with the trends we see in the larger world where governments and major corporations adhere to international standards, we have moved from multiple competing classifications to just one generally acceptable classification”

• While some bemoan the complexity of our modern classification and long for earlier times, one should realize that this field has actually never been simple

Courtesy of Dr. Steven Swerdlow, U. Pittsburgh

Milestones 1960s-1980s

• Rappaport H. Tumors of the hematopoietic system. Washington, D.C.: Armed Forces Institute of Pathology; 1966. 442 p.

• Lukes RJ, Collins RD. Immunologic characterization of human malignant lymphomas. Cancer. 1974;34(4 Suppl):suppl:1488-503.

• Gerard-Marchant R, Hamlin I, Lennert K, Rilke F, Stansfeld AG, van Unnik JAM. Classification of non-Hodgkin's Lymphomas. Lancet. 1974;2:406-8.

• Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33:451-8.

• Anonymous. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112-35.

• Lennert K, Collins RD, Lukes RJ. Concordance of the Kiel and Lukes-Collins classifications of non-Hodgkin's lymphomas. Histopathology. 1983;7:549-59.

6

Tumours of the hematopoietic and lymphoid tissues

•Gall and Mallory classification •Rappaport classification •Kiel classification •Working Formulation •French-American-British (FAB) system • Lukes-Collins classification •Revised European-American classification of

Lymphoid neoplasms (REAL)

7

Classifications

The REAL Classification:

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361-92.

The “WHO ERA” 3rd and 4th editions:

• Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

• Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

8

Principles and Rationale of the WHO Classification 2001 (3rd ed.) and 2008 (4th ed.)

• Developed jointly by the Society for Hematopathology (SH) and the European Association for Haematopathology (EAHP).

• The work of a large number of hematopathologists along with the advice and consent of clinicians.

• The WHO classification emphasized the identification of distinct clinicopathologic entities, rather than just being a "cell of origin" classification.

• The concept was that one should incorporate key available information including morphology, immunophenotype, molecular and cytogenetic findings and clinical features.

• Referred to as “integrated approach” to disease definition.

9

Small B-cell lymphoproliferative disorders

Monoclonal B-cell (MBC) Lymphocytosis

• B-cells ≤ 5 x 10⁹/L

• Monoclonal:

• K:L < 0.3:1 or > 3:1

• Do not fulfill CLL criteria: Absence of features/ symptoms of other lymphoproliferative disorder, cytopenia or autoimmune disease

• MBCL can be seen in up to 12% of adults with normal blood counts (CLL-type)

11

MBCL Subtypes:

CLL-like (70%)

- CD5+, CD20 (dim), Ig (dim)

Atypical CLL (15%)

- CD5+, CD20 (bright) or CD23-

Non-CLL (15%)

- Phenotype/ Genotype suggestive of splenic lymphoma:

-CD49d+/CD38-, CD10-, 20% CD5+ weak

- 80% develop lymphocytosis more than 4 X 10⁹/L

- BM involvement (sinusoidal)

- 72% aberrant karyotypes: del(7q) 15%, t(7q) 13%, i(17q)

- 17% progression with splenomegaly and other lymphoma (MZL)

12

Low count (<50/µl):

- Very low risk of progression

- No monitoring required

High count (500-5000/µl):

- High risk cytogenetic alterations (5-9%)

- Annual progression requiring treatment 1-2%

- Require clinical monitoring

Dagklis et al, Blood, 2009

Karube et al, Sem Cancer Biol 2014 Xochelli A et al, Blood, 2014

MBCL: nodal counterpart

• Atypical cells with CLL phenotype in otherwise reactive LN

• Absence of proliferation centers

• Normal size or slightly enlarged (˂ 1.5cm nodes)

• Some regressed

13 Gibson SE et al, Haematologica, 2011

Histologic progression in CLL (clinical significance of proliferation centers)

• Additional factors affecting CLL survival:

• Expanded/ confluent proliferation centers

• High proliferation (Ki67 ˃30%)

• Del(11q) 25%, del(17p) 16% and ?t(14q) 13%

• Survival intermediate between CLL and Richter transformation

• Histological criteria not standardized

14 M Ciccone et al, Leukemia, 2012

New markers in CLL/ SLL

LEF1 (Lymphoid Enhancer binding factor 1)

• Transcription factor, WNT/ β-catenin pathway

• Role in lymphopoiesis

• Normally expressed in some T and pro-B cells but not mature B cells.

• 100% expression in CLL, not in other small B-Cell LPD (total of 290 B-LPD)

• 38% in DLBCL

• 88% Neg for β-catenin expression

15

B Tandon et al, Modern Path, 2011

16

B Tandon et al, Modern Path, 2011

SLL

MCL

17

B Tandon et al, Modern Path, 2011

Tonsils

Richter’s

New markers in CLL

CD200

• A transmembrane type Ia glycoprotein

• Expressed in various cell types (B cells, activated T cells, thymocytes, endothelial cells and neurons) as well as CLL, HCL and FL

• Negative/ dim in MCL but positive in 24% indolent SOX11-Neg MCL

18 challagundla et al, AJCP, 2014

New markers in CLL

CD49d

• Integrin family (α subunit), surface molecule

• Promotes microenvironment-mediated proliferation of CLL leukemic cells

• Prognostic value independent of CD38/ ZAP70

• Predictive value for B-Cell receptor targeted therapies?

19

Bulian et al, A Soci C Onc, 2014

Role of MYD88 mutation: Lymphoma with plasmacytic differentiation

˃90% Waldenstrom M/ LPL

˃50% IgM MGUS

70% LBCL (CNS & Testis)

29% DLBCL-ABC

7-9% MALT

0-10% SMZL

0-24% nMZL

3% CLL

20

• Crucial adaptor protein in IL-1,

IL-8 and TLRs signaling

pathway

• L265P, most common

mutation, detectable in FFPE

tissue

• Useful information in the

differential diagnosis

• Interpret with caution

Landgren & Tageja, Leukemia, 2014

Early & In-Situ Follicular Lymphoma

“in Situ” FL

• Incidental finding

• Low incidence of

progression (˂5%)

• Need to exclude

systemic lymphoma

Partial involvement by FL

• 50% progress to

overt FL 21

Adam et al, Am J Surg Pathol, 2005

Jegalian et al, Blood, 2010

FLIS PFL

Architecture intact Altered architecture

Follicle size normal Follicle size often expanded

Involved follicles widely scattered Involved follicles grouped together

in LN

Intact cuff with sharp edge to GC Blurred edge to GC and

attenuated cuff

Very strong expression of BCL2

and CD10

BCL2 and CD10 more variable in

intensity

Almost pure centrocytes Centrocytes with few centroblasts

Atypical cells confined to GC Atypical cells (CD10+/BCL2+ B

cells), may be found outside the

GC

Table Diagnostic features of FLIS and PFL

22

Mamessier et al, Haematol, 2014

IRF4 rearrangement (MUM1)

• Interferon regulatory factor 4 (IRF4) is a transcription factor protein encoded by the IRF4 gene located at 6p25-p23

• Presentation: Waldeyer’s ring, head and neck nodal and bowel

• Most commonly in children/ young adults

• Germinal center phenotype (CD10/bcl6)

• Bcl2 expression but no t(14;18)

• Strong IRF4 expression and IRF4 translocation

• Distinct entity within both DLBCL (most) and FL 3b (some)

• Treatment is often required but good prognosis

23 Liu et al, Am J Surg Pathol, 2013 Salaverria et al, Blood, 2014

Mantle cell lymphoma Indolent Variants

• In situ MCL, Mantle zone pattern, low proliferation index (SOX11+/-)

• Non-nodal subtype of MCL

• Leukemic disease/ splenomegaly

• SOX11-

• May transform into blastoid MCL (TP53 mutation)

24

Jares et al, J Clin Inv, 2012

Large/ Aggressive B-cell lymphoproliferative disorders

WHO 4th ed Diffuse Large B-cell Lymphomas (DLBCL)

• Diffuse large B-cell lymphoma, not otherwise specified

• DLBCL associated with chronic inflammation

• Lymphomatoid granulomatosis

• Primary mediastinal (thymic) large B-cell Lymphoma

• Intravascular large B-cell lymphoma

• ALK+ DLBCL

• Plasmablastic lymphoma

• Primary effusion lymphoma

• Large B-cell lymphoma arising in HHV8-associated multicentric Castleman Disease

26

DLBCL: Clinical Advisory Committee

• Classification should have a greater emphasis on the importance of cell of origin (COO)

• Many clinical trials are based on COO

• GCB and ABC/ non-GCB

• IHC algorithms should be used and stated in the diagnosis

• Move to mRNA gene expression based platforms soon

• Now COO is important for prognosis and probably will be important for treatment choices in the future

• Clinical subtypes (CNS, leg-type) are typically non-GCB/ABC type

• Clinical types are important and take precedence over COO

• Again, COO should be stated if known

27

Double hit Lymphoma (DHL) Clinical Advisory Committee

• Consensus that DHL is defined as translocation of MYC and BCL2 or BCL6

• Cases may have different morphology:

• B-cell lymphoma, unclassifiable with features intermediate between BL and DLBCL, (60-67%), BCL-U

• DLBCL (31-35%)

• Lymphoblastic lymphoma (20%)

• FL (2%)

• DLBCL morphology predicts better outcome (OS = 3 yrs Vs. 4 mon (p˂0.00001))

• FISH for BCL2 and MYC in all cases is preferred by clinicians

• May not be a practical recommendation

• Two steps might be a better approach (IHC:MYC, BCL-2 and Ki67)

• Controversy is where DHL should be classified (DLBCL or BCL-U)

• Clinicians prefer a new category for both DLBCL and BCL-U with DH

28 Johnson et al, Blood 2009 Snuderl et al, Am J Surg Pathol, 2010 Cook et al, AJSP 2014

DLBCL with MYC and BCL2 Co-expression (IHC)

• 20-30% of DLBCL are MYC+ BCL2+ by IHC (double expression)

• Not all have MYC/BCL2 rearrangement

• IHC for MYC and BCL2 (cutoff 40%)

• Worse prognosis than non double expression cases

• Not as bad as genetic “double hit”, figure1

29 Snuderl et al, Am J Surg Pathol, 2010

30 Cook et al, Am J Pathol 2014

MYC IHC

DHL and BCL-U: WHO update, current thinking

WHO 4th ed:

• B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCL-U)

• Cases morphologically resembling BL but that don’t “fit” (morphology, immunophenotype, genetics [DH])

• Includes but not limited to DH cases; does not include DLBCL-DH

WHO 4th ed Update:

• High grade B-cell lymphoma, NOS

• High grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (“double hit”)

• Specify whether DLBCL or BCL-U morphology

• If FISH or Cytogenetic is pending, sign out as “B-cell lymphoma with high grade features, pending genetic studies”

• Cases of FL or LBL with DH are not included in this category

• High grade B-cell lymphoma, NOS

• Cases with BCL-U morphology or other high grade features and no DH

31

Burkitt Lymphoma: ID3 mutation (new tumor suppressor gene)

• Inhibitor of DNA binding-3 (ID-3) protein regulate normal cellular development.

• Mutations in ID3 (alone) seem unlikely to have a clear oncogenic role in most cancers.

• MYC deregulation along with inactivating ID3 mutations might have a role by significantly amplifying the actions of these oncogenes in BL.

• Wild-type ID3 in BL decrease cell proliferation (?potential therapeutic approach)

32

Schmitz R et al, Nature, 2012

Leucci et al, J Pathol, 2008

MYC Negative Burkitt lymphoma • Rare • Younger than 40 • More frequently with nodal presentation

• Morphologically and phenotypically similar to BL

• All high grade morphology

• Complex karyotype • 11q aberrations may be seen. Figure

33

MYC Negative Burkitt lymphoma • Rare • Younger than 40 • More frequently with nodal presentation

• Morphologically and phenotypically similar to BL

• All high grade morphology

• Complex karyotype • 11q aberrations may be seen. Figure

34

CHL-DLBCL Gray Zone Lymphoma

WHO 4th ed:

• Chapter acknowledged that non-mediastinal cases can occur, but their features were not described in details

WHO 4th ed Update:

• Studies (Eberle et al, Modern path, 2011): 33 cases

• Patients with mediastinal disease were significantly younger, M>F

• Genetic: aberrations (2p16.1, 9p24.1 and 8q24) were observed (33%, 55%, 27%)

• Genetic aberrations were seen more with mediastinal involvement (Similar survival)

• About half resemble CHL and other are of a DLBCL

• Two subtypes now distinguished: mediastinal Vs. non-mediastinal

• ?No change in name

35

Nodular Lymphocytic Predominant Hodgkin Lymphoma (NLPHL), variants

Histopathologic NLPHL variants according to Fan et al.:

Pattern A: B cell–rich nodular, tumor cell–rich case with high numbers of LP cells in the nodules

Pattern B:Serpiginous/interconnected

Pattern C: Nodular with prominent extranodular LP cells

Pattern D: T cell–rich nodular pattern

Pattern E: Diffuse T cell/histiocyte–rich B-cell lymphoma–like pattern

Pattern F: Diffuse B-cell rich, moth-eaten, pattern.

36 Hartmann et al, Blood, 2013

Fan et al, Am J Surg Pathol, 2003 CD20

Nodular Lymphocytic Predominant Hodgkin Lymphoma (NLPHL), variants

Histopathologic NLPHL variants according to Fan et al.:

Pattern A: B cell–rich nodular, tumor cell–rich case with high numbers of LP cells in the nodules

Pattern B:Serpiginous/interconnected

Pattern C: Nodular with prominent extranodular LP cells

Pattern D: T cell–rich nodular pattern

Pattern E: Diffuse T cell/histiocyte–rich B-cell lymphoma–like pattern

Pattern F: Diffuse B-cell rich, moth-eaten, pattern.

37 Hartmann et al, Blood, 2013

Fan et al, Am J Surg Pathol, 2003 CD20

Patterns A&B = 75%

Patterns C-F = 25%

Variant patterns

associated with:

- High stage (p=0.0012)

- IPS score (p=0.0005)

- Early relapse (p=0.0009)

- But not worse overall

survival (p=0.1751)

“Diffuse” NLPHL Vs. THRLBCL

• Distinction may be difficult:

• Some make a diagnosis of relapsed NLPHL with diffuse pattern

• Others make diagnosis of progression to THRLBCL

Clinical Advisory Committee:

• Distinction is clinically important (NLPHL with diffuse areas has worse prognosis but not as bad as de novo THRLBCL)

• NLPHL with histological progression or diffuse areas should not be classified as THRLBCL

WHO 2008 ?Updates:

• Diagnosis of THRLBCL should be restricted to primary/ de novo cases

• Occurrence or relapse of NLPHL with a partially or entirely diffuse pattern should be called either diffuse LPHL or “NLPHL, THRLBCL-like”

• Careful search for focal NLPHL important in de novo cases of THRLBCL (One nodule of NLPHL rules out THRLBCL)

38

Plasma Cell Neoplasms WHO 4th ed Update

• IMWG genetic testing recommendations (2009):

• Recommend that at a minimum baseline genetic information should be obtained in all PCM cases.

39

Leukemia 2009

Plasma Cell Neoplasms WHO 4th ed Update

• New provisional category: “PC neoplasm with associated paraneoplastic syndrome”

• TEMPI (telangiectasias, elevated erythropoietin/ erythrocytosis, monoclonal gammopathy (IgG MGUS), perinephric fluid collections, intrapulmonary shunting)

• Dramatic responses to Bortezomib

40

Sykes, NEJM 2011

T/ NK Cell Lymphoproliferative Disorders

Primary cutaneous CD4 positive small/ medium T-cell Lymphoma

• Was provisional in 2008

• Vast majority of patients have an isolated single lesion

• 75% head and neck area

• Follicular helper T cells derived neoplasm, may express markers (PD1, CXCL13 and BCL6)

• TCR gene rearrangement (monoclonal)

• Excellent prognosis following simple excision

• Only patient with multiple lesions had an aggressive clinical course

42 Rodriguez Pinilla et al, Am J Surg Pathol, 2009 Garcia-Herrera et al, J Clin Onc, 2008

Grogg et al, Mod Pathol, 2008

Primary cutaneous CD4 positive small/ medium T-cell Lymphoma

• Was provisional in 2008

• Vast majority of patients have an isolated single lesion

• 75% head and neck area

• Follicular helper T cells derived neoplasm, may express markers (PD1, CXCL13 and BCL6)

• TCR gene rearrangement (monoclonal)

• Excellent prognosis following simple excision

• Only patient with multiple lesions had an aggressive clinical course

43 Rodriguez Pinilla et al, Am J Surg Pathol, 2009 Garcia-Herrera et al, J Clin Onc, 2008

Grogg et al, Mod Pathol, 2008

44

Rodriguez Pinilla et al, Am J Surg Pathol, 2009

Enteropathy associated T-cell lymphoma. Type I & II are distinct

EATL I:

• Northern European

• Celiac disease

• Medium –Large sized

• CD5-, CD8-/+, CD4-, CD103+

• Usually αβ

• Frequently +1q and +5q

EATL II:

• Asian and Hispanic

• Medium sized cells with clear cytoplasm, epitheliotropic

• CD56+, CD8+, CD4-, MAT kinase +

• Usually δγ

• 8q24(myc) amplifications

45

Tan SY, et al. Leukemia 2013

Enteropathy associated T-cell lymphoma. Type I & II are distinct

EATL I:

• Northern European

• Celiac disease

• Medium –Large sized

• CD5-, CD8-/+, CD4-, CD103+

• Usually αβ

• Frequently +1q and +5q

EATL II:

• Asian and Hispanic

• Medium sized cells with clear cytoplasm, epitheliotropic

• CD56+, CD8+, CD4-, MAT kinase +

• Usually δγ

• 8q24(myc) amplifications

46

Tan SY, et al. Leukemia 2013

T & NK cell lymphoma of the Gastrointestinal Tract

• EATL, classical (αβ)

• Monomorphic epitheliotropic intestinal T-cell lymphoma (γδ)

• Extranodal NK/T EBV+ (Mainly Asian)

• PTCL, NOS (α, γδ or TCR silent)

47

All Clinically Aggressive

Indolent GI T-cell OR NK cell LPD of low malignant potential

Features:

• Superficial infiltrate confined to mucosa. No invasion of the wall (non destructive)

• Very low proliferation rate.

• Bland infiltrate (may show atypia).

• Do not response to chemotherapy

• Most commonly affects colon and small bowel

48 Perry et al, blood, 2013 Mansoor et al, blood, 2011

49

Perry et al, blood, 2013 CD4 CD8

Indolent T-cell LPD of the GI tract

50

Petrella et al, Am J Surg Pathol, 2007

Indolent CD8+ lymphoid proliferation of the ear

• Dense monomorphous medium-sized,

non-epidermotropic clonal proliferation

• Treated with local radiotherapy or excision

• Local recurrence in some but no progression

• Also involves other acral cutaneous sites (face, nose, etc)

51

Petrella et al, Am J Surg Pathol, 2007

Indolent CD8+ lymphoid proliferation of the ear

• Dense monomorphous medium-sized,

non-epidermotropic clonal proliferation

• Treated with local radiotherapy or excision

• Local recurrence in some but no progression

• Also involves other acral cutaneous sites (face, nose, etc)

Hepatosplenic T-cell lymphoma γδ

• New recurrent mutations:

• STAT5B (33%); STAT3 (10%)

•Signal transducer and activator of transcription (STAT) factors 3&5:

• Implicated in lymphocyte development, survival and growth

•STAT5 activation has been linked to T-cell development and homeostasis, as well as to the initiation of γδ T-cell differentiation.

52

Nicolae et al, Leukemia, 2014

Signal transducer and activator of transcription (STAT) factors 3&5

Others:

• T-LGL (STAT3 (40%); STAT5B (2%))

• T-ALL (JAK1, JAK3, STAT5B (subset))

• T-PLL (STAT5B (36%))

• γδ TCL (STAT5B (33%); STAT3 (8%))

• EATL II (STAT5B (36%))

• NK TCL (STAT3 (6%); STAT5B(6%))

53

Nicolae et al, Leukemia, 2014

γδ

ALK negative ALCL

• No longer a provisional entity

• Should have very similar morphology and phenotype as ALK+ ALCL

• Patients older than ALK+

• Worse prognosis

• Required: cohesive growth pattern with hallmark-like cells. Strong and uniform CD30 expression

• Desirable: EMA+, cytotoxic+, sinusoidal growth, loss of “T-cell antigen”

54 Castellar et al, blood, 2014

CD30

55

Castellar et al, blood, 2014

ALCL,

ALK-:

DUSP22

& TP63 rearrangments

Breast implant associated anaplastic large cell lymphoma. Long term follow up in 60 patients

• 93% CR in patients with disease confined to the capsule

• 72% CR in patients with a mass, Figure

• No difference in OS or PFS in patients who had chemotherapy

• Recommend: implant removal with capsulectomy

56

Miranda et al, J Clin Oncol, 2013

WHO 2008

• 4th Edition is now over 7 years old and out of date

• Multiple meetings of editors (2012-2014)

• March 2014, Chicago: Clinical Advisory Committees (Lymphoid and Myeloid)

• December 2014, Chicago: Myeloid editor/advisors meeting

• March 2015, Boston: Editors/advisors meeting

• Mid April 2015: Authors invited to update chapters

• Update to 4th edition will be allowed

• Available both online and in print and eBook

• Anticipated in 2016 57

What to expect

• New significant information published over the last 7 years related to existing entities will be incorporated.

• ?New entities

• ?Shocking changes

• Classification should simply serve to:

• Codify practices

• Bring on a consensus about potentially controversial topics

• Provide a basis for guidelines.

58

Small B-cell LPD:

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2005;29(12):1661-4

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2014;142(6):837-44.

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15. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, Escaramis G, Jares P, Bea S, Gonzalez-Diaz M, Bassaganyas L, Baimann T, Juan M, Lopez-Guerra M, Colomer D, Tubio JM, Lopez C, Navarro A, Tornador C, Aymerich M,

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16. Richard P, Vassallo J, Malmary S, Missoury R, Delsol G, Brousset P, “insitu” mantle cel lymphoma: a report of two cases. J Clin Pathol 2006;59(9):995-6.

17. Salaverria I,Royo C, Varvajal-Cuenca A, Clot G, Navarro A, Valera A, Song JY, Woroniecka R, Rymkiewicz G, Klapper W, Hartmann EM, Sujobert P, Wlodarska I, Ferry JA, Gualard O, Ott G, Rosenwald A, Lopez-Guillermo A, Quintanilla-Martinez

L, Harris NL, Jaffe ES, Siebert R, Campo E, Bea S. CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. Blood. 2013;121(8):1394-402.

18. Tandon B, Peterson L, Gao J, Nelson B, Ma S, Rosen S, Chen YH. Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas. Mod Pathol.

2011;24(11):1433-43.

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20. Xi L, Arons E, Navarro W, Calvo KR, Stetler-Stevenson M, Raffeld M, Kreitman RJ, Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119(14):3330-2.

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References:

References Aggressive B-cell LPD: 1.Schmitz R, Young RM, Ceribelli M, et at. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012. 2. Love C, Sun Z, Jima D, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet 2012; 44:1321-5. 3. Salaverria I, Martin-Guerrero I, Wagener R, et al. Arecurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 2014;123:1187-98. 4. Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009;1142273-9. 5. Snuderl M, Kolman OK, Chen YB, et al. B-cell Lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol 2010;34:327-40. 6. Cook JR, Goldman B, Tubbs RR, et al. Clinical Significance of MYC Expression and/or High-grade Morphology in Non-Burkitt, Diffuse Aggressive B-cell Lymphomas: A SWOG S9704 Correlative Study. The American Journal of Surgical Pathology 2014;38:494-501.

7. Eberle FC, Salaverrial I, Steidl C, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol 2011;24:1586-97.

8. Fan Z, Natkunam Y, Bair E, Tibshirani , Warnke RA. Characterization of variant patterns of nodular lymphocyte predominant hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 2003;27:1346-56.

9. Hartmann S, Eichenauer DA, Plutschow A, et al. The prognostic impact of variant histology in nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood 2013;122:4246-52;quiz92.

10. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocyte predominant Hodgkin lymphoma as revealed by global gene expression analysis. The Journal of Experimental Medicine 200;205:2251-68.

11. Fonseca R, Bergsagel PL, Drach J, et at. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia2009;23:2210—21.

12. Sykes DB, Schroyens W, O'Connell C. The TEMPI Syndrome — A Novel Multisystem Disease. New England Journal of Medicine 2011;365:475—7.

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T and NK-cell LPD:

1. Nicola A, Xi L, Pittaluge S, et al. Frequent STAT5B mutations in gammadelta hepatosplenic T-cell lymphomas. Leukemia. 2014.

2. Perry AM, Warnke RA, Hu Q, et al. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood. 2013;122(22):3599-3606.

3. Mansoor A, Pittaluga S, Beck PL, Wilson WH, Ferry JA, Jaffe ES. NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. Blood. 2011;117(5):1447-1452.

4. Quintanilla-Martinez L, Ridaura C, Nagal F, et al. Hydroa vacciniforme-like lymphoma: a chronic EBV + lymphoproliferative disorder with risk to develop a systemic lymphoma. Blood. 2013. 5. Garcia-Herrera A, Colomo L, Camos M, et al. Primary cutaneous small/ medium CD4+T-cell lymphomas: a heterogeneous group of tumors with different clinicopathologic features and outcome. J Clin Oncol. 2008;26(20):3364-3371.

6. Rodriguez Pinilla SM, Roncador G, Rodriguez-Peralto JL, et al. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. The American journal of surgical pathology. 2009;33(1):81-90.

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