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Pathology Stephan Dirnhofer
Low-grade B-cell lymphoma
Patho-Basic 11. September 2018
• Definition
• LPL, MBL/CLL/SLL, MCL
• FL
Subtypes & variants
Diagnosis including Grading
Transformation
• Summary
Outline
Be aware - in Lymphoma
aggressive vs indolent
high grade versus low grade
large cell versus small cell
… does not mean the same!
• No grading in lymphoma
• Exception: Follicular Lymphoma (FL)
• «low grade lymphoma» does not exist
• synonymous with «cytic» or «small cell», but cave: MCL, etc
• Clinical approach: «indolent» vs «aggressive»
• Pathological approach: «small lymphoid B-cell neoplams»
• «High-grade B-cell lymphoma»: specific category in WHO2017
– NOS
– DH/TH
Definition
Lymphoplasmacytic lymphoma (LPL)/WM
• MYD88 L265P in >95% LPL
• MGUS, IgM in 50-80%
• PCM, MGUS, IgA & IgG negative
• Very rare in other SBCL (<5%)
• DLBCL: 10-30%, adverse prognosis
• Predictive biomarker
• Ibrutinib sensitive
2016
2012
2015
SLL/CLL: diffuse/pseudofollicular
CD23 CD5 CD3 CD20
SLL/CLL: Phenotype
• Definition
Monoclonal PB lymphocyte populations up to 5x109/L either with the
phenotype of CLL, atypical CLL (CD5+, bright CD20, some include
CD23-) or non-CLL (CD5-) in the absence of lymphomatous features.
MBL population has to be present for at least 3 months
• MBL, CLL‐type
Distinguish “low count” (<0.5) from “high count” MBL
• MBL, non CLL‐type
Related to (splenic) marginal zone lymphoma
Monoclonal B‐cell lymphocytosis (MBL)
Xochelli, Blood, 2014
Bruscaggin, BJH, 2014
WHO, 2017
• Same phenotype
• Similar genotype
• Distinguish “low count” (<0.5) from “high count” MBL
• “low count MBL”: limited, if any, risk of progression
• “high count” MBL: routine (yearly) follow up
• Eliminate CLL Dx if < 5x109/L & cytopenia without extramedullary disease
MBL, CLL-type and CLL
Giné, Haematologica, 2010
Bullan, JCO 2014
Mantle cell lymphoma (MCL): diffuse/nodular
CD20 CD3 CD5 Cyclin-D1
MCL: Phenotype/Genotype
In situ mantle cell neoplasia (ISMCN) Formerly: “In situ MCL”, MCLis
Rare (frequency <1%)
Low rate of progression
Avoid calling these lymphoma
Require clinical assessment
Not systematically diagnosed
Leukemic non-nodal MCL (15%)
PB, BM & spleen
No adenopathy
SOX11 -, IgH mutated
Clinically indolent (may transform to aggressive disease)
MCL, classical-type Lymph nodes & extranodal sites
SOX11 +, IgH unmutated
Mantle cell lymphoma (MCL)
Adam et al. Mod Pathol 2012
A lymphoma of germinal center B-cells (centrocytes &
centroblasts) with at least a partially follicular pattern
Follicular lymphoma: Definition
• Most common lymphoma worldwide (30%)
• Median age 55-59 yrs; male = female
• Generalized lymphadenopathy, Splenomegaly, BM
• Indolent clinical course, but: transformation & progression
• Follicular with diffuse areas
• Centroblast & centrocytes; FDC, reactive T-cells
• Grade 1 & 2 (low grade), 3A&B (high grade)
• Phenotype: CD19, CD20; CD10, BCL6, HGAL, LMO2; BCL2
• Genotype: IgH rearranged, t(14;18) and IgH/BCL2
FL - major features
• B-cell markers: CD19, CD20, PAX5, CD79A
• GC-markers: BCL6, CD10, Stathmin, HGAL, GCET1, LMO2
Phenotype of FL
Appl Immunhistochem Mol Morphol 2015
• Clonal IgH rearrangement
• Somatic hypermutation in variable regions (ongoing)
• Intraclonal variation
• t14;18 (IgH/BCL2): 90% (ambiguous protein
expression)
• BCL6 rearranged: 15%
• MYC rearranged: rare (2-4%)
• Recurrent mutations: KMT2D, CREBBP, EZH2, BCL2
Genotype of FL
Leich et al. Leukemia 2016
Miao et al. Human Pathol 2017
• In situ follicular neoplasia (ISFN)
• Duodenal-type FL
• Diffuse-appearing FL with del1p36
• Extranodal FL
• Pediatric-type FL
FL variants & related lymphomas
• Formerly: “in-situ Follicular lymphoma”, FLis
• Indolent clonal population
• High frequency (2-3% of “patients”)
• Low rate of progression
• Avoid calling these “lymphoma”
• Require clinical assessment
• Not systematically diagnosed
In situ follicular neoplasia (ISFN)
Xerri, Dirnhofer et al.
Virchow, 2016
Am J Surg Pathol 2016
• Variant of FL
• Different from generic GI-tract FL
• Low grade (G1)
• BCL2 positive (t14;18 positive)
• Excellent prognosis
• Avoid overtreatment
• Watch-and-wait strategy ?
Duodenal-type FL
Schmatz et al., JCO 2011
• Pediatric FL a provisional entity in 2008 monograph
• Promoted to definite entity
• Name change & refined criteria
• Can occur in (young) adults
• Large expansile follicles, Grade 3, high Ki-67
• BCL2 negative (t14;18 negative)
• Head & neck
• Excellent prognosis (only excision)
• DD: FL, Grade 3, conventional type
Pediatric-type FL
Quintanilla-Martinez et al.
Virchow, 2016
2016
FL with conventional morphology
50-70% express BCL2, often CD10 negative
No clinical impact
Diffuse variant of FL with deletion 1p36
Grade 1‐2
Large nodal mass in inguinal region, localized
Deletion 1p36
Good prognosis
Primary extranodal FL
Cutaneous
Pediatric-type FL
Promoted to definite entity
LBCL with IRF4-rearrangement
Provisional entity
Different subtypes of t(14;18) negative FL
Leich et al. Blood 2009
Leich et al. Leukemia 2016
Katzenberger et al. Blood 2009
Höller et al. Human Pathol 2012
Grading of FL
Jaffe E., Hematopatholoy 2017
WHO 2017
An excisional biopsy is
recommended for primary diagnosis.
DLBCL FL IIIb
FL IIIa FL II FL I
Grading of FL
Survival of patients with FL according to histological grade
Weisenburger et al. 2006; from: Jaffe et al, Hematopathology 2017
Transformation
• Occurs in many types of small B-cell lymphomas
• Most common in FL (2-3% per yr)
• Broad morphologic spectrum
• Mechanisms of transformation (in FL)
• Divergent evolution from common progenitor cell (CPC)
• Linear evolution
• High-level CNA
• Recurrent mutations in TP53,
MYC, CDKN2A, B2M …
Okosun et al, Nat Gen 2014
Schmidt et al, Leukemia 2014
Brunner et al, Leukemia 2014
Wagner-Johnston et al, Blood 2015
Casulo et al, Blood 2015
Agbay et al, Am J Surg Pathol 2016
Bouska et al, Leukemia 2017
Kridel et al, PLOS Medicine 2017
Kridel et al, Blood 2017 from: Pasqualucci et al, Cell 2014
tFL: Histotypes
• DLBCL, incl. DLBCL CD30+
• HGBCL, NOS (former BCL,u)
• HGBCL with double-hit (BCL2/MYC)
• Lymphoblastic Lymphoma (TdT+; CD34+)
• cHL
• Histiocytic Sarcoma
• DD: true composite lymphoma
2016
Thank you!
• Most common B-cell lymphoma
• Clinicopathological variants in updated WHO-classification
• Advanced stage, indolent course
• Grade 1 & 2; 3A & 3B
• Grading is mandatory (and prognostic), cave CNB
• Recurrent genetic alteration t14;18 (BCL/IgH) in 85%
• No clinical difference of t14;18-negative cases
• Transformation common (2-3%/yr)
• tFL: DLBCL, HGBCL-DH/TH, HGBCL-NOS, PBL, cHL, HS
“The Pathobiology of FL” - Summary
Am J Surg Pathol 2005
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