21/07/2017 1 Falko Fend Institute of Pathology and Neuropathology Reference centrefor haematopathology University Hospital Tübingen Potential Application of New Technologies to Lymphoproliferative Diseases in GIT – With Special Reference to Marginal Zone Lymphoma 2 Tissue - and microenvironment-specific manifestations of NHL FL in BM nodal MCL CLL MALT-Ly. stomach Despite highly efficient recirculation, extranodal lymphomas stay organ- confined for prolonged time Extranodal NHL usually derived from locally antigen-experienced cells Secondary MALT Intestinal T-NHLs CTCL Extensive dissemination Limited dissemination Adhesion molecules and chemokine receptors govern lymhpocyte migration Modified from Pals S T et al. Blood 2007;110:3102-3111 Mucosa BM Naive B/T-cells show broad recirculation Antigen contact and interaction with accessory cells lead to reprogramming Lymph node The prototype: MALT lymphoma extranodal marginal zone B-cell lymphoma Indolent B-cell lymphoma usually arising in acquired MALT, in a background of local chronic inflammation due to infection or autoimmune disease May remain localized for prolonged time, late dissemination and relapses, often at other MALT sites (frequently different clones) 4 Stomach: H. pylori Thyroid: Hashimoto thyreoiditis Salivary gland:Sjögren syndrome, Lung: Achromobacter xylosoxidans (?)* Skin: Borrelia burgdorferi Ocular adnexae: Chlamydia psittaci Regional differencesin associationwith infectious agent Pathogenetic role in part unconfirmed * Adam et al, BJH 2014 Gastric MALT lymphoma and Helicobacter Initially 90% H.p. positivity, eradication leads to regression in 60-80% (including 50-66% H.p.+ DLBCL of early stage) Both host and bacterial virulence, factors as well as nutrients play a role Indirect stimulation of tumor growth through variety of H.p. and T-cell mediated factors Translocation of H.p. virulence factor cagA into B-cells leads to direct activation of oncogenic signalling pathways and associates with response to eradication Morgner et al, JCO 2001; Chen et al, JCO 2001; Chen JNCI 2005; Adam et al, BJH 2014; Raderer et al, Ann Hematol 2015; Kuo et al, Blood 2012, 2017; Govi et al, Blood 2011 Blaseret al, JCI 2004 Pathogenesis of gastric MALT lymphoma 6 Zucca et al, Clin Cancer Res 2014
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Haem - Fend GI NHL Belfast 2017 · Fend et al, J Hematop 2012; Uppsala workshop Therapy n Complete regression Stable lesions Nodal dissem. Follow-up Watch&wait 24 7 17 2 55 (6-137)
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21/07/2017
1
Falko FendInstitute of Pathology and Neuropathology
Reference centre for haematopathologyUniversity Hospital Tübingen
Potential Application of New Technologies to Lymphoproliferative Diseases in GIT – With Special Reference to Marginal Zone Lymphoma
2
Tissue - and microenvironment-specific manifestations of NHL
FL in BM
nodal MCL
CLL
MALT-Ly.stomach
Despite highly efficientrecirculation, extranodal lymphomas stay organ-confined for prolonged
time
Extranodal NHL usuallyderived from locallyantigen-experienced
cells
Secondary MALT
Intestinal T-NHLs
CTCL
Extensive dissemination Limited dissemination
Adhesion molecules and chemokine receptors govern lymhpocyte migration
Modified from Pals S T et al. Blood 2007;110:3102-3111
MucosaBM
Naive B/T-cells show broadrecirculation
Antigen contact andinteraction with accessorycells lead to reprogramming
Lymph node
The prototype: MALT lymphomaextranodal marginal zone B-cell lymphoma
Indolent B-cell lymphoma usually arising in acquired MALT, in a background of local chronic inflammation due to infection orautoimmune disease
May remain localized for prolonged time, late dissemination and relapses, often at other MALT sites (frequently different clones)
4
Stomach: H. pylori
Thyroid: Hashimoto thyreoiditis
Salivary gland:Sjögrensyndrome,
Lung: Achromobacterxylosoxidans (?)*
Skin: Borrelia burgdorferi
Ocular adnexae: Chlamydiapsittaci
Regional differences in associationwith infectious agent
Pathogenetic role in partunconfirmed* Adam et al, BJH 2014
Gastric MALT lymphoma and Helicobacter
Initially 90% H.p. positivity, eradication leads to regression in 60-80% (including 50-66% H.p.+ DLBCL of early stage)
Both host and bacterial virulence, factors as well as nutrients play a role
Indirect stimulation of tumor growththrough variety of H.p. and T-cellmediated factors
Translocation of H.p. virulencefactor cagA into B-cells leads todirect activation of oncogenicsignalling pathways and associateswith response to eradication
Morgner et al, JCO 2001; Chen et al, JCO 2001; Chen JNCI 2005; Adam et al, BJH 2014; Raderer et al, Ann Hematol 2015; Kuo et al, Blood 2012, 2017; Govi et al, Blood 2011
Lymphoid follicles surrounded by marginal zone cells that infiltrate diffusely in lamina propria and into epithelium in small groups
5 MALT lymphoma Presence of dense infiltrate of marginal zone cells in lamina propria with prominent lymphoepitheliallesions
17
*modified from WotherspoonA et al, Lancet 1993
Is there a role for molecular primarydiagnosis?
Detection of B-cell clonality in biopsiesHigh rates of clonality initially reported (15-79%) in H.p. gastritis(especially in FFPE), associated with progression to MALT lymphoma
standard BIOMED-2 protocols and duplicates to avoid „pseudoclonal“ products show >90% clonality in MALT lymphoma, a subset (22%) ofclonal Wotherspoon 3/4 cases and lack of clonality in gastritis
Clonality = malignancy, but clonality very useful in appropriate settinguse all samples in case of multiple biopsies
Nakamura S et al, Am J Pathol 1998; Zucca et al, NEJM 1998; Hummel et al, Gut 2006
2 5 0 2 7 5 3 0 0
. A 0 3 _ 1 7 0 5 3 1 1 5 L 5
z e ( n t )
260
276.70
280 300
9 0 1 0 0 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0
C 4 0 2 - 1 7 6 0 n g I g H - C . B 0 4 _ 1 7 0 5 3 1 1 5 L 2
S i z e ( n t )
90 100 120
137.65
140
FR2 FR3
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Molecular follow-up after H.p. eradication
Frequently prolonged persistence of residual infiltrates or clonalplasma cells
clonal B-cell rearrangement can be used as specific marker, but persistence not associated with recurrent disease
Histology with immunhistochemistry remains gold standard fordiagnosing recurrence
Fend et al, Leukemia 1994
The future of clonality deteminationNext generation sequencing – NGS
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
20%FR1
10%FR1
5% FR1 2% FR1 1% FR1 0.1%FR1
20%FR2
10%FR2
5% FR2 2% FR2 1% FR2 0.1%FR2
Granta Seq.
react. Clonotype 1
react. Clonotype 2
react. Clonotype 3
react. Clonotype 4
react. Clonotype 5
react. Clonotype 6
react. Clonotype 7
react. Clonotype 8
react. Clonotype 9
Granta dilution series
Exact identification and quantification of clonal sequenceHigh sensitivity for follow-upIn B-NHL somatic hypermutation
What else is there besides gastric MALT lymphoma?
30-50% of extranodal NHL are in the GI tract
75-85% of all GI-NHL in the stomach
What to look out for: Other primary extranodal lymphoma entities
Premalignant/benign lymphoproliferations of GI tract
Indolent T-cell lymphoproliferative disorder of GI-tract25% of nodal NHL show GI involvement at primary DX
Strict criteria for diagnosis of primary GI lymphoma!
Complete phenotyping mandatory in primary diagnosis
Lympho-epithelial lesions can occur in other NHL
Cyclin D1
Lymphomatous polyposis
Distribution of subtypes among primary GI lymphomas
Koch et al.: Primary gastrointestinal Non-Hodgkin‘s lymphoma. German Multicenter Study JCO 19:3861-3873 (2001)
Primary intestinal/duodenal FL
• 63 patients, all stage IE• Uncharacteristic symptoms• Multiple warty polyps along descending part of duodenum• Limited to mucosa/submucosa in 19 of 20 cases• No ulcerations, no obstructive lesions• No involvement of stomach (n=61) and colorectum (n=39)
• Grade 1 in 60, Grade 2 in 3 cases• Typical immunophenotype (bcl-2+, bcl-6+, CD10+, low Ki-67,..)• t(14;18) by cytogenetics in 4/4 cases, no additional aberrations
Schmatz AI et al., J Clin Oncol 2011, 29:1445
Follicular lymphoma of the Duodenum
CD10(+)
Bcl-2(+)
Bcl-6(+)
H&E
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Schmatz AI et al., J Clin Oncol 2011, 29:1445Fend et al, J Hematop 2012; Uppsala workshop
Roberti et al, Nat Comm 2016; Nairismagi et al, Leukemia 2016; Kucuk et al, Nat Comm 2015;
Moffitt et al, J Exp Med 2017
Roberti et al, Nat Comm 2016
Molecular profiling defines MEITL as specific entityHigh frequency (92%) of SETD2 inactivation and subsequent
H3K36 trimethylation
High frequency of STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations
Distinct, though in part overlapping genetic profile from EATL
39 Roberti et al, Nat Comm 2016
Summary
Clonality determination for the moment remains the most important molecular test for diagnosing GI tract lymphomas
NGS technologies and targeted mutational analysis help to better characterize/define entities and will play a bigger role for DD, prognostic assessment and follow-up
Analysis of cell-free DNA will be useful for monitoring patients with aggressive lymphoma, role in indolent tumors (e.g. MALT lymphomas) currently unclear