NonHodgkin Lymphoma

7/31/2019 NonHodgkin Lymphoma

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Non-Hodgkins

LymphomaA histopathologic andprognostic evaluation


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The non-Hodgkins lymphoma (NHL) classication systems

Classifying NHL

The non-Hodgkins lymphomas are a heterogeneous group of lymphoproliferative malignancies with

differing patterns of behavior and responses to treatment. NHL comprises many subtypes, each with

distinct epidemiology, etiology, and morphologic, immunophenotypic, and clinical features.1,2

The understanding and histopathologic diagnosis of NHL has improved with the use of advanced

technology. New pathologic entities have been described, and the understanding and treatment of

previously described pathologic subtypes have changed over the years. As a result, classication of the

lymphomas has undergone signicant reassessment over the past 40 years, and classication systems

are continually being rened and developed.2

In 1981, the IWF was introduced as a translational system to unify descriptive terminology and

facilitate comparisons across the different classication systems for lymphoma, including the

Rappaport and Kiel systems.3,4 Most clinical trials of lymphomas that were published in major

international journals in the 1980s and 1990s used the IWF either alone or in combination with

another classication system.3 The IWF classication system is important to understanding these

trials; however, this system is now viewed as having signicant deciencies.4

In 1994, the REAL classication dened lymphomas using a list of biologic entities dened by

clinicopathologic and immunogenetic features. The WHO/REAL classication system includes not only

lymphoid neoplasms, but also myeloid, histiocytic, and mast cell neoplasms.4 More recent updates

to this system also better reect our understanding of disease entities and their relationship to the

immune system.5

IWF=International Working Formulation; REAL=Revised European-American Lymphoma; WHO=World Health Organization.


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IWF classicationThe major categories in the IWF include low-, intermediate-, and high-grade lymphoma types, which

are based on the treated natural history and survival patterns. How each NHL is classied is shown in

Table 1.4

Table 1. IWF classication of lymphoproliferative diseases4

WHO/REAL classicationThe WHO/REAL system divided B-cell NHL into 3 clinically relevant categories, as shown in Table 2.4-6

Table 2. Simplied WHO/REAL classication of B-cell lymphomas4-6*

In 2008, WHO classications were reviewed and updated. Modications in this review reected clinical

and laboratory insights, which are helping to further dene borderline categories of the disease. 5

The 2008 WHO classication of NHL resulted in the following changes to the simplied classications

of B-cell lymphoma: Follicular lymphoma grades 1 and 2 are now grouped together as grade 1-2, and

B-cell is no longer used to describe nodal marginal zone lymphoma.5

*Includes WHO 2008 classication updates.

Low grade Intermediate grade High grade

H. Large cell, immunoblastic

I. Lymphoblastic

J. Small noncleaved cell Burkitts

or non-Burkitts

A. Small lymphocytic lymphoma (SLL),

chronic lymphocytic leukemia (CLL)

B. Follicular, predominantly small

cleaved cell

C. Follicular, mixed small cleaved and

large cell

D. Follicular, large cell

E. Diffuse, small cleaved cell

F. Diffuse, mixed small cleaved

and large cell

G. Diffuse, large cell

(cleaved and noncleaved)

Indolent lymphomas Aggressive lymphomas Highly aggressive lymphomas

Burkitts lymphoma

Lymphoblastic lymphoma

Diffuse large B-cell lymphoma (DLBCL)

Follicular lymphoma (grade 3)

Mantle cell lymphoma

CLL/SLL

Follicular lymphoma (grade 1-2)

Lymphoplasmacytic lymphoma

Splenic/nodal marginal zone lymphoma


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Formation of malignant B cells

Early B-cell development occurs in the bone marrow, where B-cell precursor cells undergo

immunoglobulin (Ig) heavy and light chain rearrangement and are equipped with a functional surface

antigen receptor. The descendants of these precursor cells, now called naive B cells, are found in

the bloodstream. Naive B cells undergo clonal expansion in germinal centers (GCs), which are foundin the cortex of lymph nodes.7 In the lymph node GC, the Ig genes are further modied by somatic

hypermutation, a process by which cells undergo rapid mutations and class-switch recombination.8

Tumors corresponding to almost all stages of B-cell development have been found in humans. Most

lymphoid tumors have gene rearrangements characteristic of the cell type from which they arose.9

Figure 1 shows the stages in B-cell development that give rise to CLL, follicular lymphoma, DLBCL,

Burkitts lymphoma, MALT lymphoma, and other B-cell lymphomas.

Figure 1. Cellular origin of B-cell lymphomas8


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Diagnosing lymphomas by immunophenotype

Immunophenotyping of lymphoid neoplasms is crucial in the morphologic evaluation of the tissue for

proper classication of disease. Some diseases have specic combinations of cell surface markers,

which can aid in identifying the immunophenotype and diagnosing the diseaseand thus in choosing

proper treatment. Two methods commonly used to identify the immunophenotype of lymphomas areow cytometry and immunohistochemistry.10

Flow cytometryFlow cytometry is an automated uorescence detection method used to characterize the

immunophenotype of cells. Cells are typically exposed to uorescently tagged antibodies that recognize

and bind to specic cell surface antigens and reect light at distinct wavelengths. This technique

allows researchers to identify cells by their immunophenotype and, importantly, to quantify each cell

population.10,11

ImmunohistochemistryImmunohistochemistry is a technique using microscopy to characterize the cells in a tissue sample.

It involves the use of labeled antibodies to detect and localize the expression of biomarkers.12 For

example, performing immunohistochemistry using labeled anti-CD20 antibodies identies a populationof B cells that express the CD20 antigen. The diagnosis of subtypes of B-cell lymphomas is often

conrmed by using immunohistochemistry to characterize the pattern of expression for several

biomarkers in a patients tissue sample.10,13 Follicular lymphoma, for example, has a characteristic

immunophenotype that includes CD20+, CD10+, bcl-2+, CD5, and cyclin D1 (Table 3).13


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Table 3. Immunohistochemistry prole of common lymphomas13*

*The expression patterns are based largely on a compilation of results in the WHO classication.Antigen is specic to the particular subtype of lymphoma and is not expressed in other lymphomas.

The National Comprehensive Cancer Network (NCCN) provides a decision tree labeled Use of

immunophenotyping in differential diagnosis of mature B-cell and T/NK-cell neoplasms.14 This

decision tree should be used in conjunction with clinical pathological correlation.

Low-grade B-cell NHL

Cyclin D1(bcl-1/

Antigen CD5 CD10 CD20 CD23 CD79a PRAD1) bcl-2 bcl-6 c-myc Tdt

Follicular lymphoma + + + +/ + /+

SLL + + + + +

MALT lymphoma + + +

Marginal zone lymphoma + + +

High-grade B-cell NHL

DLBCL /+ +/ + + +/ + /+

Mantle cell lymphoma + /+ + + + +

Burkitts lymphoma + + + + +

Lymphoblastic lymphoma +/ /+ /+ +/ +


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Cytogenetics in B cell malignancies

Detailed cytogenetic analysis enables the identication of chromosomal abnormalities in cancer

cells. Cytogenetic analyses of NHL have revealed several specic chromosomal abnormalities, such

as chromosomal translocations, associated with the onset of particular types of NHL. Chromosomal

abnormalities, along with immunophenotypic data, have helped dene and categorize NHL.15

Chromosomal translocationNonrandom chromosomal translocations are associated with lymphoid neoplasms and arise during

normal B-cell development. Cytogenetic analyses reveal that individual translocations show a high

degree of association with specic histologic subsets.15 Table 4 presents examples of the translocations

and genes involved in specic lymphoma subsets.15,16

Table 4. Most common chromosomal aberrations associated with NHL15,16

*In CLL, trisomy 12 and 17p deletion are also common chromosomal aberrations.

Lymphomas subset Most common aberration Gene

BCL2

BCL6

BCL1

BCL1

BCL10

c-myc

Follicular lymphoma

DLBCL

B-cell CLL/SLL

Mantle cell lymphoma

MALT lymphoma

Burkitts lymphoma

Apoptosis regulation

Transcription regulation

Cell-cycle regulation

Cell-cycle regulation

Apoptosis regulation

Cell proliferation and growth

t(14;18)

der(3)

13q del*

t(11;14)

t(1;14)

t(8;14)

Proto-oncogene normal function


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Determining prognosis across NHL subtypes

Prognostic indicatorsThe initial evaluation of NHL helps to establish the correct diagnosis and extent of disease. Prognostic

models have been developed for predicting outcome in patients on the basis of the patients clinical

characteristics before treatment. These models have been designed for the most common lymphomasand include the International Prognostic Index (IPI) for aggressive lymphoma and the Follicular

Lymphoma International Prognostic Index (FLIPI) for follicular lymphoma. Updates to both indices

have occurred in the past few years, but the updated versionsthe Revised International Prognostic

Index (R-IPI) and FLIPI2have yet to be universally adopted.

Five adverse prognostic risk factors for IPI17

1. Age >60 years

2. Ann Arbor stage III/IV

3. >1 extranodal site

4. Serum lactate dehydrogenase (LDH) level >normal

5. Eastern Cooperative Oncology Group (ECOG) performance status 2

One point is assigned to each of the previously listed characteristics present in a patient with

aggressive NHL. Scores range from 0 to 5.

Table 5. The International Prognostic Index (IPI) (1993)17

0-1Low

Low-intermediate

High-intermediate

2

3

35%

27%

22%

73%

51%

43%

87%

67%

High 4-5 16% 26% 44%

55%

Risk group IPI score Percentage of patients 5-year OS Complete response rate

OS=overall survival.


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Revised IPI (R-IPI) (2005)Because of the widespread use of chemoimmunotherapy in aggressive NHL, the accuracy of IPI

as a prognostic tool was re-examined and R-IPI was created. The R-IPI prediction of outcome is

often considered to be more clinically relevant because it categorizes patients into 3 more-distinct

prognostic groups. To determine R-IPI score, the original IPI risk factors are used and each factor

receives 1 point. Scores range from 0 to 5.18

Table 7. Prognostic index by risk group18

Very good

Good

0

1, 2

10%

45%

94%

80%

94%

Poor 3, 4, 5 45% 53% 55%

79%

Risk group No. of IPI factors Percentage of patients 4-year PFS 4-year OS

PFS=progression-free survival.

Age-adjusted International Prognostic Index (aaIPI)Because the prognoses for younger and older patients differ, an age-adjusted model, the aaIPI, is used

for patients with aggressive NHL who are 60 years. With this model, all of the prognostic risk factors

listed previously, with the exception of age and number of extranodal sites, are assigned one point.Scores range from 0 to 3.17


0Low

Low intermediate

High intermediate

1

2

22%

32%

32%

83%

69%

46%

92%

78%

57%

High 3 14% 32% 46%

Risk group IPI score Percentage of patients 5-year OS rate Complete response rate


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FLIPIThe FLIPI is a widely accepted prognostic index for patients with follicular lymphoma that was based

on a retrospective analysis of a robust patient population (N=4,167).19 Although FLIPI was based on

OS of the patients analyzed, it remains highly predictive of PFS as well.20 As a result, it continues tobe considered useful when interpreting clinical trials.

Five adverse prognostic risk factors for FLIPI19

1. Age 60 years

2. Ann Arbor stage III/IV

3. Hemoglobin level 4*

5. LDH level >normal

One point is assigned for each of the previously listed characteristics present in a patient with

follicular lymphoma. Scores range from 0 to 5.*The spleen is considered an extranodal site and not a nodal area.


0-1Low

Intermediate

High

2

3

36%

37%

27%

91%

78%

53%

71%

51%

36%

Risk group Number of risk factors Percentage of patients 5-year OS rate 10-year OS rate


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FLIPI vs FLIPI2: An overviewBecause FLIPI was based on a retrospective analysis that was formulated before the widespread use

of chemoimmunotherapy, the prospective F2 trial (N=1,093) was conducted. In the F2 trial, PFS was

chosen as the primary endpoint instead of OS due to the lengthy course of the disease.19,20

The analysis of the results became the basis for the new FLIPI2 model and inuenced the following

changes to the prognostic risk factors.

Table 9. FLIPI prognostic factor changes20

Although FLIPI2 data have been published, the relatively small size of the F2 trial and the fact that

these data are not mature have resulted in a slow uptake of this new prognostic tool. It remains to be

seen whether or not FLIPI2 will become more widely adopted.

*The spleen is considered an extranodal site and not a nodal area.ULN=upper limit of normal.

FLIPI2

Five adverse prognostic risk factors for FLIPI220

1. Age >60 years

2. Hemoglobin level ULN

4. LoDLIN >6 cm

5. Bone marrow involvement

One point is assigned for each risk factor present in the patient. Scores range from 0 to 5.


0Low

Intermediate

High

1-2

3-5

20%

53%

27%

91%

69%

51%

80%

51%

19%

Risk group Number of risk factors Percentage of patients 3-year PFS rate 5-year PFS rate

Ann Arbor stage III/IV

Number of nodal areas >4*

Serum LDH concentration >normal

Largest involved node (LoDLIN) >6 cm

Serum 2M >ULN

Bone marrow involvement

FLIPI (prognostic factors removed) FLIPI2 (prognostic factors added)


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past, the present and the future. Hematol Oncol. 2001;19:129-150. 5. Jaffe ES. The 2008 WHO classication of lymphomas:

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SA, Ascani S, Sabattini E, et al. Malignant lymphomas: the pathologists view point. Haematologica. 2000;85:1291-1321.

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Favera R, Harris NL, eds. Non-Hodgkins Lymphomas.Philadelphia, PA: Lippincott Williams & Wilkins; 2004:771-786. 8. Kppers

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Lippincott Williams & Wilkins; 2004:81-95. 11. Ross DD, Joneckis CC, Ordonez JV, et al. Estimation of cell survival by ow

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eds. Non-Hodgkins Lymphomas. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:59-67. 14. National ComprehensiveCancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkins Lymphomas. http://www.nccn.org/professionals/

physician_gls/PDF/nhl.pdf. V.1.2010. Accessed July 13, 2010. 15. Chaganti RS, Nanjangud G. Cytogenetics of lymphoma. In:

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Williams & Wilkins; 2004:809-824. 16. Dalla-Favera R, Pasqualucci L. Molecular genetics of lymphoma. In: Mauch PM, Armitage

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J Clin Oncol. 2009;27:4555-4562.

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NonHodgkin Lymphoma

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