Prognostic Markers in B-cell Lymphomas Sergei Syrbu MD, PhD Department of Pathology...

Prognostic Markers in B-cell Lymphomas

Sergei Syrbu MD, PhDDepartment of Pathology

Hematopathology/Immunopathology

Disclosure

I have no actual or potential conflicts of interest in relation to the content of this presentation.

I will not be discussing off-label use of drugs or devices.

Prognostic Markers in B cell lymphomas

DLBCL• Clinical - International Prognostic Index (IPI) and Revised-IPI• Gene expression profiling

- Affymetrix U133 Plus on FT

- Gene expression in FFPE tissue (NanoString Lymph2CX)

- IHC algorithms for GCB and ABC phenotypes• Double hit lymphoma (DHL) and atypical “DHL”• IHC “DHS” (DPL) or MYC and BCL-2 double positive lymphoma • CD5+• Absolut Monocyte Count (AMC) and Absolute Lymphocyte Count (ALC) Prognostic Index

(AMLCPI)• Tumor associated macrophage polarization in DLBCL and Hodgkin lymphoma• Serum free light chains• BCL6 expression• P53+++/P21-• P21+• BCL2+

MCL - Ki67, P53, SOX11

FL - Serum cytokines and chemokines

Diffuse large B cell lymphoma

• Highly heterogeneous (clinically, immuno- phenotypically, morphologically, biologically) group of diseases

• Most common lymphoma in North America (30-40%)

• 24,000 new cases every year• Affects all ages and genders• ~40% of patients with DLBCL suffer relapses and

die of disease

Prognostic Markers in DLBCL

• Clinical - International Prognostic Index (IPI)- Age >60- Stage III or IV- Elevated LDH- Performance status 2 or higher- Two or more extranodal sitesDepending on IPI score the 5-year overall

survival ranges from 26% to 73%.IPI is also age-adjusted (<60 and >70)

OS of DLBCL patients

Gilles Salles et al. Blood 2011;117:7070-7078

©2011 by American Society of Hematology

Data are from patients with TMA availableaccording to the IPI for the 3 patient cohorts: r-CHOP 347 patients (panel 1a), c-CHOP 289 patients (panel 1b) and e-CHOP 878 patients (panel 1c).The log-rank P valuewas < .0001 for each cohort.

IPI

• One of the most clinical predictor of survival in DLBCL and can identify patients as Low (0,1), Low-Intermediate (2), High-Intermediate (3) and High Risk (4,5)

• Since Rituximab was introduce a revised IPI (R-IPI) was proposed, which stratifies patients into 3 groups – Very Good (0), Good (1,2) and Poor (3,4,5)

• The IPI does not capturer the biological spectrum of DLBCL!

DLBCL

Cell-of-origin - COO

Affymetrix on FT

Determining cell-of-origin subtypes of DLBCL using gene expression in FFPE tissue

(Lymph2Cx)

• NanoString technology was used to determine expression of 20 genes (15 target genes and 5 housekeeping) in FFPET-derived RNA

• >95% concordance of COO assignment by GEP• 7% were designated as “unclassified” • Turnaround time – 36 hrs

Scot et al. Blood 2014 123:1214-17

Patient outcomes according to COO in the independent validation cohort.

David W. Scott et al. Blood 2014;123:1214-1217


Lymph2Cx onFFPET

Affymetrix U133Plus on FT

Determining cell-of-origin subtypes of DLBCL using gene expression in FFPE tissue

(Lymph2Cx)

• NanoString technology was used to determine expression of 20 genes (15 target genes and 5 housekeeping) in FFPET-derived RNA

• >95% concordance of COO assignment by GEP• 7% were designated as “unclassified” • Turnaround time – 36 hrs

Scot et al. Blood 2014 123:1214-17

IHC Methods for Predicting Cell ofOrigin and Survival in Patients With DLBCL

Treated With Rituximab

• This study compares some of those algorithms and also proposes some modifications

• Paul N. Meyer et al. JCO 2011;29:200-207

Immunohistochemical algorithms examined in this study.

Meyer P N et al. JCO 2011;29:200-207

©2011 by American Society of Clinical Oncology

Overall survival of patients with diffuse large B-cell lymphoma according to immunophenotype by each algorithm.

Paul N. Meyer et al. JCO 2011;29:200-207©2011 by American Society of Clinical Oncology

Event-free survival of patients with diffuse large B-cell lymphoma according to immunophenotype by each algorithm.

Paul N. Meyer et al. JCO 2011;29:200-207


Conclusion• The Hans and Choi algorithms are useful to determine the cell of

origin of DLBCL and can separate patients into prognostic groups, with or without the use of BCL6.

• A new Tally algorithm showed the greatest concordance with microarray results .

• Although the Tally and Choi algorithms may be preferred, the pathologists should be allowed to choose the most appropriate algorithm for their practice.

• The immunohistochemical algorithms are sufficiently robust to allow cell of origin determination for future therapies based on cell of origin.

Like the IPI, COO subtyping doesn’t identify patients with highly aggressive DLBCL since these patients will be in both

subgroups!

R-CHOP is inadequate in many DLBCL subsets and high-risk groups

Subsets Freq PFS OS

ABC DLBCL 30-50% 2-yr 28% 2-yr 46%

DHL 5-7% 1-yr 33% <1 yr

DPL (MYC+BCL2) 34% 5-yr 27% 5-yr 30%

Elderly DLBCL >60 yr 50% 5-yr 50% 5-yr 58%

High IPI 45% 4-yr 53% 4-yr 55%

NCI CTPM: Recommendations of the DLBCL Subcommittee November 21, 214 Sonali Smith, Kristie Blum, David Maloney, Greg Nowakowski,Laurie Sehn, Michael Williams, Wyndham Wilson

Double hit lymphoma (DHL) and atypical DHL

• DHL - defined as an aggressive high-grade B-cell lymphoma with translocations involving both MYC and BCL2 or BCL6, BCL3, or CCND1 (MYC/BCL2 most common)

• Atypical DHL - abnormalities of MYC and BCL2 other than coexistent translocations:

1. MYC translocation + extra BCL2 copies2. t(14;18) + extra copies of MYC3. Extra copies of MYC and BCL2

• Represents 6–14% of patients

Double hit lymphoma (DHL) and atypical DHL (aDHL)

• CNS and bone marrow involvement are common • Most cases of DHL and aDHL have morphologic features of

DLBCL or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma

• The majority are of GCB-cell immunophenotype with a high proliferation rate

• There is no established standard therapy for DHL patients - median OS of <2 years

• Characterized by advanced stage disease, extranodal involvement, and high serum LDH levels.

Comparison of pathologic features of atypical and typical MYC/BCL2 DHL

Features Atypical MYC/BCL2 DHL MYC/BCL2 DHL

DLBCL 75% (30/40) 47% (36/76)

BCLU 18% (7/40) 46% (35/76)

Other 8% (3/40) 7% (5/76)

Immunophenotype

CD10* 72% (28/39) 99% (71/72)

BCL6 93% (25/27) 95% (36/38)

BCL2 (>50%) 94% (33/35) 90% (61/68)

MYC (>40%) 70% (14/20) 75% (9/12)

MYC/BCL2 Coexpress 55% (11/20) 67% (8/12)

Ki67 20–99% (≥70% in 28/32) 20–99% (≥70% in 60/69)

Complex karyotype 100% (5/5) 100% (27/27)

Li et al (2015). Modern Pathology 28:208-217

Double hit lymphoma: the MD Anderson Cancer Center clinical experience

British Journal of HaematologyVolume 166, Issue 6, pages 891-901, 18 JUN 2014 DOI: 10.1111/bjh.12982http://onlinelibrary.wiley.com/doi/10.1111/bjh.12982/full#bjh12982-fig-0001

http://onlinelibrary.wiley.com/doi/10.1111/bjh.2014.166.issue-6/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/bjh.12982/full#bjh12982-fig-0001

Double hit lymphoma: the MD Anderson Cancer Center clinical experience

British Journal of HaematologyVolume 166, Issue 6, pages 891-901, 18 JUN 2014 DOI: 10.1111/bjh.12982http://onlinelibrary.wiley.com/doi/10.1111/bjh.12982/full#bjh12982-fig-0003



Summary

• In DHL/aDHL only the PS≥2 and bone marrow involvement were independently associated with shorter EFS and OS

• Age, stage and # of extranodal sites have minimal impact on the outcome in DHL/aDHL

• Specific version of IPI – DHIPI, which includes only PS≥2 and bone marrow involvement (grading from 0-2)

• The outcome of DHL patients with current chemotherapeutic approaches is poor, and dismal for refractory or relapsed disease

Summary

• R-EPOCH, and frontline SCT should be further evaluated in larger studies with longer follow-up

• Therapy recommendations - R-EPOCH, with strong consideration for CNS targeting therapy especially when DHIPI ≥1, and strong consideration for frontline SCT in responding patients

• Further prospective research is needed to identify additional biological markers and to develop novel therapies

• The FISH for MYC, BCL-2 and BCL6 (?) probably should be performed on all CD10+ (GCB) DLBCL lymphomas, in particular with high MYC, BCL2 and Ki67

2

Clinical Significance of MYC Expression and/or "High-grade" Morphology in Non-Burkitt, Diffuse Aggressive B-cell Lymphomas: A SWOG S9704

Correlative Study

Cook et al. (2014) American Journal of Surgical Pathology. 38(4):494-501, April 2014.

© 2014 by Lippincott Williams & Wilkins. Published by Lippincott Williams & Wilkins, Inc. 2

TABLE 2

Clinical Significance of MYC Expression and/or "High-grade" Morphology in Non-Burkitt, Diffuse Aggressive B-cell Lymphomas: A SWOG S9704 Correlative Study.Cook, James; MD, PhD; Goldman, Bryan; Tubbs, Raymond; Rimsza, Lisa; Leblanc, Michael; Stiff, Patrick; Fisher, Richard

American Journal of Surgical Pathology. 38(4):494-501, April 2014.DOI: 10.1097/PAS.0000000000000147

TABLE 2 Clinical Features at Presentation Based on Presence or Absence of MYC Staining by IHC (P-values for All Comparisons >0.05)


TABLE 3



TABLE 3 Pathologic Features by Morphology


TABLE 4



TABLE 4 Pathologic Features of Cases With or Without MYC Staining by IHC

Clinical Significance of MYC Expression and/or "High-grade" Morphology in Non-Burkitt, Diffuse Aggressive B-cell

Lymphomas: A SWOG S9704 Correlative Study

• This study has confirmed the prognostic significance of MYC positivity by IHC in DLBCL and, for the first time, extends this observation to cases of BCLU

• BCLU was associated with increased incidence of MYC expression but no distinct clinicopathological features compare to DLBCL

• MYC+ cases were morphologically and phenotypically heterogeneous and had poor prognosis (PFS and OS)

• MYC IHC is suggested for use in routine clinical practice to assess prognosis in DLBCL

• Additional studies utilizing MYC IHC to risk-stratify therapies should also be considered.

Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated

with R-CHOP

• DHS-0: BCL2 <70% and MYC <40%• DHS-1: ether BCL2 or MYC ≥70% and ≥40• DHS-2: both BCL2 and MYC ≥70% and ≥40

• Tina Marie Green et al. JCO 2012;30:3460-3467

Tina Marie Green et al. JCO 2012;30:3460-3467


MYC BCL2

DHS 1

DHS 2

Overall survival (OS) and progression-free survival (PFS) after treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone in patients with diffuse large B-

cell lymphoma who were divided into groups on the basis of the double-hit s...

Tina Marie Green et al. JCO 2012;30:3460-3467


Double Hit Score (DHS)(Tina Marie Green et al. JCO 2012;30:3460-3467))

COO All patients(193)

DLBCLDHL+

DLBCLDHL-

DHS 0/1 DHS 2 DHS 2 without

DHL

GCB type 106 (56%) 10 (91%) * 95 (54%) 84 (65%) 20 (37%) 12 (27%)

ABC type 83 (44%) 1 (9%) 81 (46%) 46 (35%) 34 (63%) 33 (73%)*

Double Hit Score (DHS or DPS)(Tina Marie Green et al. JCO 2012;30:3460-3467)

DHS 0/1 DHS 2 P value

OS, 3 years 86% 43% P<0.001

PFS, 3 years 75% 39% P<0.001

• DHS system is useful in identifying DLBCL with a “double hit” biology, which is strongly associated with poor prognosis on R-CHOP therapy

• DHS-2 OS and PFS was independent of IPI score and COO

• DHS-2 w/o DHL is more common in ABC DLBCL

• Include cMYC and Bcl-2 IHC stains on all diffuse large B cell lymphomas

• For cMYC we prefer rabbit monoclonal antibody Clone Y69

• For Bcl-2 - Clone 124 (Dako) and/or Clone E17 (Epitomics)

CD5+ DLBCL

• Clinical presentation - elevated serum LDH level, advanced stage, frequent involvement of extranodal sites, presence of B symptoms, and presence of bulky mass, but a sex difference was not found

• Gene expression signature is similar in ABC-DLBCL and CD5+ DLBCL

• Cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive DLBCL

CD5+ DLBCL

• Common variant (centroblastic/monomorphic variant) - This variant was the most common -76%

• Giant cell rich variant - Giant cells with multiple nuclei intermixed with immunoblasts and centroblasts were observed in 11% of patients. Intravascular involvement is frequent in this variant.

• Polymorphic variant – 12% of patients • Immunoblastic variant: Only 1% of patients

Cytomorphologic features of four variants of de novo CD5+ DLBCL. The cells, varying from medium to large in size, are uniform, with a pale basophilic or amphophilic cytoplasm.

Motoko Yamaguchi et al. Haematologica 2008;93:1195-1202

©2008 by Ferrata Storti Foundation

Survival according to the histological features of de novo CD5+ diffuse large B-cell lymphoma (DLBCL).

Motoko Yamaguchi et al. Haematologica 2008;93:1195-1202

©2008 by Ferrata Storti Foundation

CD5+ DLBCL – differential Diagnosis

• CLL (Richter's Transformation to DLBCL): about 5–10% of CLL patientsmay lose or retain the CD5 molecule have a different molecular profile than de novo CD5+ BCL6 gene rearrangement is not seen in Richter's

• Mantle Cell lymphoma (MCL): Most cases of MCL over express cyclin D1 and have t (11; 14)

• Secondary CD5+ DLBCL (Non-Richter's): Rarely, CD5 can be acquired in patients with CD5- DLBCL, progression of CD5- low grade B cell lymphoma and CD5+ follicular lymphoma

CD5+ DLBCL – differential Diagnosis

• Intravascular B cell Lymphoma: CD5 expression is seen in about 40% casesNegative for CD29 and CD54Nonspecific clinical presentation

• Primary CNS lymphoma: 30% cases can express CD5 differentiation from de novo CD5+ DLBCL with CNS

involvement can be difficult Analyses on identifying expression of synaptophysin

and other CNS specific proteins are ongoing in CD5+ DLBCL

Progression-free (A) and overall (B) survival curves of patients with diffuse large B-cell lymphoma according to the presence or absence of CD5.

N. Niitsu et al. Ann Oncol 2010;21:2069-2074

© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Overall survival of patients in the chemotherapy group (n = 153) and in the R-chemotherapy group (n = 184).

K. Miyazaki et al. Ann Oncol 2011;22:1601-1607


Progression-free (A) and overall (B) survival curves of patients with CD5-positive diffuse large B-cell lymphoma according to whether they received rituximab combination

chemotherapy or chemotherapy alone.



(A) Overall survival (OS) curves of patients with germinal center B-cell type CD5-positive (CD5+) diffuse large B-cell lymphoma or nongerminal center B-cell type CD5+ diffuse large B-

cell lymphoma.



CD5+ DLBCL - Summary

• De novo CD5+ DLBCL is clinico-pathologically and genetically distinct from CD5-negative DLBCL and MCL lymphoma.

• Accounts for 5-10% of all DLBCL• Has an aggressive course and high IPI score at

presentation• GEP is similar to ABC type of DLBCL (83% are of ABC type)• Rituximab-based therapy improves PFS but does not

decrease CNS relapse rate or OS• CD5 stain should be performed on all cases of DLBCL

Summary on intrinsic biology of DLBCL

• Determine: COO CD5 on all DLBCL MYC, BCL2 and Ki67 on all lymphoma

regardless of morphology FISH for MYC, BCL2 and BCL6 on DLBCL

with high expression of MYC, BCL2, Ki67 and CD10


• Absolut Monocyte Count (AMC) and Absolute Lymphocyte Count (ALC) Prognostic Index:

Low - AMC <610/µl and ALC >1000/µlIntermediate – AMC ≥ 610/µl or ALC > 1000/µlHigh - AMC ≥610/µl and ALC ≤1000/µl

Absolut Monocyte Count (AMC) and Absolute Lymphocyte Count (ALC) Prognostic Index

• By univariate analysis, the AMC/ALC score was a predictor for OS and PFS.

• On multivariate analysis performed including the cell of origin (COO) and the International Prognostic Index, AMC/ALC score remained an independent predictor for OS and PFS.

• The AMC/ALC score was able to further stratify DLBCL clinical outcomes by COO

• The AMC/ALC score was independent of COO and added to its ability to identify patients with high-risk disease

• This prognostic score was independent of the IPI and added to its ability to identify high-risk patients

Kaplan–Meier estimates of progression-free (a, b) and overall (c, d) survival for the entire cohort of patients stratified by the AMC/ALC prognostic score (a, c) and the International Prognostic Index (b, d) are shown.

R A Wilcox et al. Leukemia (2011) 25, 1502–1509

Macrophage Polarizationimmunophenotype

• Classic activation – M1 phenotype CD68, CD80, CD86, HLA-DR, TNFα, IL-12, CCR7…

• Alternative activation – M2 and M2-likeCD68, CD163, CD206, IL10, CCL22 …

*CD68 – KP1 and PG-M1 clones

Staining of M2 TAM by CD163

Tumour associated macrophages in diffuse large B cell ‐ ‐lymphoma: a study of the Osaka Lymphoma Study Group (2-

year survival rate)

HistopathologyVolume 60, Issue 2, pages 313-319, 23 DEC 2011 DOI: 10.1111/j.1365-2559.2011.04096.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2559.2011.04096.x/full#f3

61%

91.9%82.1%

60%

http://onlinelibrary.wiley.com/doi/10.1111/his.2011.60.issue-2/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2559.2011.04096.x/full#f3

An increase of M2 macrophages predicts poor prognosis in

patients with diffuse large B-cell lymphoma treated with

rituximab, cyclophosphamide, doxorubicin, vincristine and

prednisoneNam et al. Leuk Lymphoma.

2014 55:2466-76

Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma

Virchows Archiv 2011; 459:361-366

http://link.springer.com/journal/428



Tumour associated macrophages in ‐lymphomas

• Tumor-associated macrophages (TAMs) play an important role in the tumor microenvironment.

• An increase in CD68 (+) cells was related to improved overall survival (OS). By contrast, an increased number of CD163 (+) cells and a higher ratio of CD163+/CD68+ cells were significantly associated with shorter OS and progression-free survival (PFS).

• In multivariate analysis, an increased ratio of CD163+/CD68+ cells was an independent predictor of shorter OS and PFS.

• These results suggest that M2 macrophages might have a lymphoma-promoting function in DLBCL and predict poor clinical outcome.

• Therapeutic approaches targeting M2 macrophages would be valuable for the management of DLBCL in the R era.

Elevated Serum Free Light Chains Are Associated With Event-Free and Overall Survival in Two Independent Cohorts of Patients With

Diffuse Large B-Cell Lymphoma

• 76 Patients North Central Cancer Treatment Group trial N0489

• 219 Patients UIHC/Mayo Clinic Specialize Program of Research Excellence Molecular Epidemiology Resource (MER)

- Abnormal ƙ/ƛ or elevated FLC in 32% and 14%- Elevate FLC was the strongest predictor of

outcome in multivariable models with the IPI components • Increased serum FLC is an independent adverse

prognostic factor for EFS and OS in DLBCL

(A) Event-free survival and (B) overall survival Kaplan-Meier survival curves by serum free light chain (FLC) in two cohorts (North Central Cancer Treatment Group trial N0489 and the

Specialized Program of Research Excellence Molecular Epidemiology Resource...

Maurer M J et al. JCO 2011;29:1620-1626


Free Light Chains

• Kappa and Lambda measurements were similar:Elevated FLC Abnormal κ:λ

NO489 (n=79) 34% 12% MER (n=219) 31% 15%• Patients with elevated FLC – inferior OS and EFS (P<.001)• The result remain significant for EFS and OS after adjusting for

IPI (in all IPI scores – independent of IPI!)• Abnormal κ:λ ratio was modestly associated with outcome

(P<.07) probably due to elevated FLC alone• Patients with normal range of κ and λ, the abnormal κ:λ ratio

was not associated with outcomes (P=0.99)

Outcome by type of free light chain (FLC) abnormality.

Maurer M J et al. JCO 2011;29:1620-1626


Elevated Monoclonal Free Light Chains Are a Serum Marker of ABC Type Diffuse Large B-Cell Lymphoma

Lambda Quantitative Free Light Chains 5.7 - 26.3 mg/L Kappa Quantitative Free Light Chains 3.3 - 19.4 mg/L Kappa/Lambda Free Light Chain Ratio 0.26 - 1.65

Elevated Monoclonal Free Light Chains Are a Serum Marker of ABC Type Diffuse Large B-Cell Lymphoma

• ~10% of DLBCL patients have elevated monoclonal sFLC with poor outcome

• The great majority of patients (10/11 or 91%) with elevated monoclonal sFLC have an ABC-type DLBCL by Tally algorithm

• Secretion of FLC by tumor suggests an activated B cell clone (characteristic for ABC type DLBCL)

• Following the sFLC may monitor response to therapy and progression


• BCL6 expression– BCL6+ better responded to CHOP than BCL6-– Therapy with R-CHOP benefitted BCL6- DLBCL but did

not changed the response for BCL6+ DLBCL P53+++/P21- as a surrogate for p53 mutation, inferior survival in GBC but not in ABC DLBCL P21+ - favorable independent marker in R-CHOP but not

CHOP treated patients BCL2+ - benefit for R-CHOP regimen for PFS and OS

- BCL2- show benefit in PFS but not in OS on R-CHOP

Points Aga, y ECOG LDH/ULN WBC, 109/L

0 <50 0-1 <0.67 <6.700

1 50-59 - 0.67-0.99 6.700-9.999

2 60-69 2-4 1.0-1.49 10.000-14.999

3 ≥70 - ≥1.5 ≥15.000

MIPI score = [0.03535 × age (years)] × age (years)]+ 0.6978 (if ECOG > 1)+ [1.367 × log10(LDH/ULN)] + [0.9393 × log10(WBC count)]

LR - <5.7; IR – 5.7-<6.2; HR - >6.2

Simplified MIPI

Biological MIPI = MIPI score + 0.02142 x Ki-67 (%)LR - <5.7; IR – 5.7-<6.5; HR - >6.5

MIPI score = [0.03535 × age (years)] × age (years)] + 0.6978 (if ECOG > 1) + [1.367 × log10(LDH/ULN)] + [0.9393 × log10(WBC count)]

Histopathology, cell proliferation indices and clinical outcome in 304 patients with MCL (European MCL Network)

Tiemann M at al. 2005 British J Haematology 131:29-38

Kaplan-Meier plot for overall survival of patients treated with CHOP (A) and R-CHOP (B) stratified in 3 groups according to the Ki-67 index of less than 10% (< 10), 10% to less than

30% (≥10), and 30% or more (≥30) Ki-67 positive cells.

Olaf Determann et al. Blood 2008;111:2385-2387


*

*

Klapper et al (2009). Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network. J Hematopathology 2:103-111

Residual GC

* Hot spots

> Proliferating T cells

SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study

British Journal of HaematologyVolume 166, Issue 1, pages 98-108, 29 MAR 2014 DOI: 10.1111/bjh.12854http://onlinelibrary.wiley.com/doi/10.1111/bjh.12854/full#bjh12854-fig-0002



MCL – Summary

• IHC – CD3, CD5, CD20, CD23, Cyclin D1, SOX11, MIB1 (Ki-67), TP53

• SOX11 – “low” and “high”• TP53 – negative, weak, intermediate (strong stain <30%),

strong (strong stain in >30%)• Ki-67 index:

– On primary diagnosis before treatment– Representative area which do not include GC, hot spots of

proliferation and proliferating T cells– 2 x 100 cells show high concordance with a gold standard (2 x

500)– For reporting use a cutoff of <30% or >30%

Follicular Lymphoma and FLIPI scoring system• FLIPI - Age >60 years, Stage III or IV disease, >4 lymph node groups involved, Serum

Hb <12 g/dL and Elevated serum LDH• The OS rate is 75% at 5 years, and ranges from 71% at 10 years for patients with a

FLIPI score between 0 to 1, and 36% for those with a FLIPI score of >3. • Median survival of all newly diagnosed patients is approximately 9 years. Although

the OS appears to have improved with advances in chemoimmunotherapy, the median event free survival (EFS) remains around 2 years for patients with advanced disease.

• FLIPI has several limitations. It focuses on clinical factors and does not take into account biological factors such as the tumor microenvironment and the host response

• When some patients with FL surviving <1 year and others >20 years, additional prognostic indicators are clearly needed to refine risk adapted therapy.

FLIPI score Risk category % of patients Median PFS (m)0 or 1 Good 36 842 Inter mediate 37 703 - 5 Poor 27 42

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in

follicular lymphoma

• Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL).

• 30 cytokines and chemokines were measured in pretreatment serum specimens from newly diagnosed FL patients (n = 209) and from 400 matched controls.

• Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy.

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in

follicular lymphoma• Six cytokines were associated with outcome in the Molecular

Epidemiology Resource (MER) after adjusting for the FL international prognostic index.

• In patients who were observed or treated with rituximab alone, increased serum IL-12 and interleukin 1 receptor antagonist (IL-1RA) (P = .005 and .02) were associated with a shorter event-free survival.

• In patients receiving chemotherapy, hepatocyte growth factor, IL-8, IL-1RA, and CXCL9 (P = .015, .048, .004, and .0005) predicted a shorter EFS.

• When the MER chemotherapy treated patients and SWOG (n=183) patients were combined in a meta-analysis, IL-2R, IL-1RA, and CXCL9 (P = .013, .042, and .0012) were associated with a poor EFS.

EFS by cytokine in all MER patients

Muhammad A. Mir et al. Blood 2015;125:992-998


EFS by cytokine in MER subgroups(A – observed or received rituximab; B-D – treated with

chemotherapy)

Muhammad A. Mir et al. Blood 2015;125:992-998


Conclusions• The IPI does not capturer the biologic spectrum of DLBCL• COO (by molecular or IHC) subtyping doesn’t identify

patients with highly aggressive DLBCL since these patients will be in both subgroups

• For COO by IHC choose most convenient algorithm • The FISH for MYC, BCL-2 and BCL6 should be performed

on all CD10+ (GCB) DLBCL lymphomas• BCLU (features of DLBCL and BL) with high MYC (>40%)

and Ki67 (>75%) should lead to FISH to exclude a DHL or aDHL.

• Report primary CD5+ DLBCL• MCL - for Ki67 reporting use a cutoff of <30% or >30%

DLBCL, centroblastic variant

DLBCL, anaplastic variant

DLBCL with clear cytoplasm

DLBCL, T-cell/histiocyte-rich type

DLBCL, Hodgkin-like (Lymph node)

DLBCL, multilobated variant

Intravascular large B cell lymphoma

– Involving the lumens of small vessels

– Widely disseminated at presentation and may present with skin lesions, neurologic symptoms

– Lack expression of CD29 and CD54

– Extremely aggressive clinical course

Kidney

Lung CD20

Plasmablastic lymphoma

Primary mediastinal large B-cell lymphoma

DLBCL, immunoblastic variant

MCL, common variant

MCL, interfollicular pattern

MCL, small cell/diffuse variant (SLL-like)

PinkHistiocytes

MCL, pleomorphic variant

MCL, blastoid variant

?

MCL CD23+

CD5 CD3

CD23 CD20

Cyclin D+ MCL CD5+/CD23+

MCL, nodal variant

CD3

CD20

20X

Bcl-6

CD10

CD5Bcl-2

60x

Cyclin D1

CD5- MCL, nodal variant

Prognostic Markers in B-cell Lymphomas Sergei Syrbu MD, PhD Department of Pathology...

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Transcript of Prognostic Markers in B-cell Lymphomas Sergei Syrbu MD, PhD Department of Pathology...