Diffuse Large B Cell Lymphoma
Definition
B lineage lymphoma composed of large cells with a diffuse pattern of growth
Alternate/Historical Names
Diffuse histiocytic lymphoma
Diffuse mixed lymphocytic and histioctyic lymphoma
Centroblastic lymphoma
Large cleaved follicular center cell lymphoma
Large noncleaved follicular center cell lymphoma
Diagnostic Criteria
Diffuse effacement of normal architecture
Rare patterns
Sinusoidal
Rosettes
Myxoid stroma
Large non-cohesive cells make up over 50% of population or are present in confluent foci
Usual appearance is large vesicular nuclei and prominent nucleoli
Rarely medium sized nuclei with same vesicular features
Nuclei may be uniform or pleomorphic
Cytoplasm usually moderate to abundant
May be clear to eosinophilic to basophilic
A small cell population may be present
If over 50% small atypical B cells, consider diffuse mixed B cell lymphoma
If over 90% small T cells or histiocytes, consider T cell/ histiocyte rich B cell lymphoma
Small cells may occasionally be plasmacytoid
May be monotypic or polytypic
B cell phenotype required
40% present in extranodal sites
Most frequently in GI tract
May involve any site
Rare cytologic features
Spindle cell morphology
Signet ring cells
Cytoplasmic granules
May arise secondary to other types of B cell lymphoma
De novo
Secondary to transformation of low grade B cell lymphoma
In setting of immunodeficiency
Following variants are not considered distinct clinico-pathologic entities and are described on separate pages, still within the overall heading of diffuse large B cell lymphoma
Following are considered distinct entities and are described as separate diseases
Yasodha Natkunam MD PhD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342
Original posting:: September 30, 2007
Variant: ALK Positive Large B Cell Lymphoma
Amongst lymphomas, ALK is nearly restricted to primary systemic large cell lymphoma (T lineage)
A rare set of large B cell lymphomas express ALK
Large cells with immunoblastic features
Round nuclei with single large nucleolus
Binucleate cells common
One case reported with mixture of large and small cells
Basophilic cytoplasm, frequently with paranuclear hof
Frequently sinusoidal
B lineage based on immunoglobulin expression
IgA 5/7 cases
Light chain restriction 6/7
Based on stains or in situ hybridization
B lineage markers negative (CD20, CD79a)
ALK membrane positive, cytoplasm +/-
Rare cases with clathrin-ALK t(2;17) reported
t(2;5) not identified
EMA positive 7/7
CD30 negative 0/7
CD45RB weak to moderate positive
T lineage negative (CD3, CD43, CD45RO)
CD68 negative
CD57 positive 5/7
Aggressive course in 6/7 reported cases
Note that these are distinct from anaplastic variant of large B cell lymphoma, which is ALK negative
Variant: Anaplastic Variant of Diffuse Large B Cell Lymphoma
Previously included in Anaplastic Large Cell Lymphoma (ALCL)
ALCL is now restricted to T lineage (by phenotype or genotype) lymphomas
May share several featuares of ALCL
Very large cells with markedly pleomorphic nuclei
May resemble Reed-Sternberg cell
Sinusoidal pattern of growth
CD30 expression variable
EMA 7/22 positive
Distinguishing features from ALCL
B lineage
Lack of ALK staining
Age median 54 years more like large B cell lymphoma than ALCL
Behavior same as diffuse large B cell lymphoma
Note that these are distinct from ALK positive large B cell lymphoma
Variant: Immunoblastic Large B Cell Lymphoma
Abundant amphophilic cytoplasm and prominent central nucleolus
Currently thought to have same behavior as usual diffuse large B cell lymphoma
Originally thought to have high grade behavior
May be confused with plasmablastic lymphoma, especially in the setting of an oral cavity mass in an HIV+ patient
Variant: Microvillous Large B Cell Lymphoma
Alternate names
Anemone cell lymphoma
Villiform cell lymphoma
Porcupine cell lymphoma
Filiform cell lymphoma
Numerous microvilli seen by electron microscopyNo desmosomes as seen in carcinoma or mesothelioma
No distinctive histologic pattern
Some are sinusoidal or have fibrillar matrix
Rosettes seen in some lymphomas are composed of long cytoplasmic processes
Could be considered related to this variant
Same clinical behavior as usual diffuse large B cell lymphoma
Variant: T Cell Rich B Cell Lymphoma / Histiocyte Rich B Cell Lymphoma
Can be considered as a spectrum
Large atypical cells make up less than 10% of population
May have any features of usual large B cell lymphoma
May resemble Reed-Sternberg cells
B lineage
Neoplastic cells may be missed on flow analysis
CD30 0-8%
CD15 0-15%
EMA 0-60%
Reactive T cells predominante
Small to medium sized
Nuclei may be round or irregular
No increase in CD57 positive cells
Histiocytes may be numerous
May be associated with conventional large B cell lymphoma pattern
May be concurrent or metachronous
Same behavior as conventional diffuse large B cell lymphoma, stage for stage
Over half present as stage III or IV
Supplemental studies
Immunohistology and Flow
B lineage (CD20 or CD79a) positive
Immunoglobulin variably demonstrable
More frequent in immunoblastic variant
CD5
10%
bcl2
30-50%
CD10
25-50%
CD43
variable
CD30
variable
Ki67
usually >40%
T cell / histiocyte rich variant
Large cells may be missed on flow
CD30 0-8%
CD15 0-15%
EMA 0-60%
No increase in CD57+ small cell population
Genetic Study
Gene expression profiling has demonstrated subtypes:
Germinal center B-like DLBCL
Activated B-like DLBCL
Burkitt-like including c-myc
Some DLBCL with this signature show better response to aggressive chemotherapy targeting Burkitt lymphoma rather than standard DLBCL therapy
No reliable immunologic panel exists to make these distinctions
Differential Diagnosis
Non-neoplastic processes
Blastic lymphomas
Other B lineage lymphomas
Other lymphomas
Reactive immunoblastic processes may simulate DLBCL
Most common causes are mononucleosis, other viruses, vaccination and drug reaction
Any of the following favor a reactive process
History or clincal evidence of any of the above causes
Age under 20 years
Polymorphous infiltrate with immunoblastic large cells
Partial node involvement
Mixed B and T phenotype of large cells
Light chain polytypia in large cells
CD30 may be seen in both neoplastic and reactive processes
EBV is rare in DLBCL except in immunosuppressed patients
Its presence suggests mononucleosis or other reactive conditions
Immunoglobulin gene rearrangement study may be neccesary in difficult cases
Kikuchi lymphadenitis may simulate DLBCL
Patchy pale foci composed of histocytes and karyorrhectic debris
Atypical activated large lymphocytes predominantly peripheral
Most large cells T lineage
Plasmacytoid dendritic cells (plasmacytoid monocytes) may be present
No sheets of large B cells on CD20 stain
Extracapsular extension rare
Burkitt Lymphoma
Diffuse Large B Cell Lymphoma
Starry sky macrophages present
Starry sky pattern infrequent
Fine chromatin
Vesicular chromatin
Multiple small nucleoli
Few, prominent nucleoli
Uniform cells
Heterogeneous cells
Ki67 nearly 100%
Ki67 moderately high
Translocation involving myc gene
15% of cases have myc translocation
Generally only a problem if cytologic detail is obscured by processing related artifacts
Lymphoblastic Lymphoma, B or T
DLBCL
Median age 17-20 years
Median age 60 years
90% T lineage, 10% B lineage
B lineage
Starry sky macrophages present
Starry sky pattern infrequent
Fine chromatin
Vesicular chromatin
None or small nucleoli
May have prominent nucleoli
Uniform cells
Heterogeneous cells
Generally only a problem in suboptimally processed specimens
Diffuse Mixed Lymphoma
DLBCL
50-75% of cells are small atypical B cells
Over 50% large atypical B cells
No confluent foci of large cells
Confluent foci of large cells
In T cell rich B cell lymphoma, the background small cells are T lineage
Diffuse Large B Cell Lymphoma
Paraimmunoblastic SLL/CLL
Nuclear shape variable
Nuclei round, uniform
Nucleoli frequently multiple
Nucleoli single
Cytoplasm may be basophilic
Cytoplasm pale
Node capsule frequently destroyed
Node capsule preserved even if overrun
CD5 rare
CD5 80%
Plasmablastic Lymphoma
Immunoblastic DLBCL
Typically oral cavity mass in HIV+ patient
Wide variety of presentations, including HIV
LCA negative or minimal +
LCA >90%
CD20 minimal to negative, CD79a positive
Both CD20 and CD79a >90%
Ki67 >95%
Ki67 moderately high, variable
EBV in situ 50%
EBV in situ rare in de novo cases; frequent in immunodeficiency cases
CD138 positive
CD138 negative
Amphophilic cytoplasm and pleomorphic nuclei with prominent nucleoli may cause difficulty with distinction of plasmablastic lymphoma from immunoblastic large B cell lymphoma
Both may partially replace the node and be negative or minimally reactive for CD20 and CD45RB
Diffuse Large B Cell Lymphoma
True Histiocytic Lymphoma
Variable cytoplasm
Abundant cytoplasm with erythrophagocytosis
Most over 30 years of age
Most under 30 years
CD20, CD79a positive
CD20, CD79a negative
CD68, CD15, CD163, Lysozyme, CD138 negative or rare
CD138+ or at least two of: CD68, CD15, CD163, Lysozyme
Classical Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma
CD45RB, CD20 and CD79a 10-20%
CD45RB, CD20 and CD79a >90%
CD15 80%
CD15 5%
CD30 90%
CD30 30%
Light chains polytypic or negative
Light chains monotypic or negative
Reed-Sternberg cells are frequently positive for both kappa and lambda, apparently due to nonspecific uptake of serum immunoglobulin
Lymphocyte Predominant Hodgkin Lymphoma
Diffuse Large B Cell Lymphoma, T Cell Rich B Cell Variant
Background small cells B lineage
Background small cells T lineage
CD57+ small cells increased
No increase in CD57+ small cells
CD57+ rosettes around large cells
No CD57+ rosettes
Large cells EMA 50%
Large cells EMA negative
One report questions this clear distinction describing a subset of TCRBCL that had bcl6 positive large cells with increased numbers of CD57+ small cells and rosette formation (EMA not tested). In this same report, some LPHL cases showed 50% of small cells to be T lineage. (Kraus et al.)
Some consider cases reported as diffuse LPHL to fall in the spectrum of TCRBCL as the background population in diffuse LPHL is enriched for T cells
Primary Systemic Anaplastic Large Cell Lymphoma
Anaplastic Variant Large B Cell Lymphoma
ALK Positive Large B Cell Lymphoma
Marked anaplasia
Marked anaplasia
Monomorphic with round nuclei
Frequently sinusoidal
Frequently sinusoidal
Frequently sinusoidal
CD30 >90%
CD30 variable
CD30 negative
EMA 60%
EMA 33%
EMA positive
T lineage
B lineage
B lineage
ALK immunohistology 60-85% positive
ALK immunohistology negative
ALK immunohistology 100% positive
Majority of ALK positive cases show ALK translocation such as t(2;5) or t(1:2)
Lack ALK translocation
Rare cases reported with clathrin-ALK t(2:17) gene rearrangement
ALCL may lack T markers and require genetic analysis to determine lineage
Clinical
Approximately 30% of lymphomas
Median age 60 years
40% present in extranodal sites
Most commonly in GI tract
May involve any site
Grading/Staging/Report
Diffuse large B cell lymphomas not currently graded
Previously, the immunoblastic variant was considered high grade
Subsequent studies have shown no difference in prognosis
Adverse prognostic factors reported include
High prolferation rate measured by Ki67 staining
bcl2 expression
p53 overexpression
Ann Arbor Staging System
Stage I
I if involvement of a single lymph node region
IE if involvement of a single extralymphatic organ or site
Stage II
II if two or more lymph node regions on same side of diaphragm
IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
Stage III
III if Involvement of lymph node regions on both sides of the diphragm
IIIS if spleen involved
IIIE if extralymphatic site involved
Stage IV
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
Systemic Symptoms in 6 months preceding admission
Fever, night sweats, 10% weight loss
A = absent
B = present
Extranodal sites are also designated
M+ = marrow
L+ = lung
H+ = liver
P+ = pleura
O+ = bone
D+ = skin and subcutaneous tissue
Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.
The pathology report should contain the following information:
Diagnosis in the World Health Organization (WHO) classification
Equivalent diagnosis in other classifications used by relevant clinicians
Results of supplementary studies if performed
Relationship to other specimens from the same patient
Information relevant to staging if available
Classification/Lists
Types and variants of large B cell lymphoma
Bibliography
Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
Jaffe ES, Harris NL Stein H, Vardiman JW eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503-11.
Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P, Rigal-Huguet F, al Saati T, Cerretti DP, Morris SW, Mason DY. A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood. 1997 Mar 1;89(5):1483-90.
Haralambieva E, Pulford KA, Lamant L, Pileri S, Roncador G, Gatter KC, Delsol G, Mason DY. Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas.
Br J Haematol. 2000 Jun;109(3):584-91.
Hammer RD, Vnencak-Jones CL, Manning SS, Glick AD, Kinney MC. Microvillous lymphomas are B-cell neoplasms that frequently express CD56. Mod Pathol. 1998 Mar;11(3):239-46.
Greer JP, Macon WR, Lamar RE, Wolff SN, Stein RS, Flexner JM, Collins RD, Cousar JB. T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients. J Clin Oncol. 1995 Jul;13(7):1742-50.