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