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Extranodal lymphomasFranco Cavalli

MD, FRCPScientific Director

Oncology Instituteof Southern Switzerland

CH-6500 Bellinzona

24. Ärzte-Fortbildungskurs in Klinischer OnkologieSt. Gallen, 20-22 Februar 2014

Frequency of Extranodal NHL in different countries

Israel 36% Lebanon 44% Jordan 30%, Kuwait 45% Thailand 58% Taiwan 55% Hong Kong 29%

Usa 24% of all NHLs Canada 27% Italy 48% The Netherlands 41% Denmark 37% Greece 46% Turkey 45%

scanty data from most developing countries

A general definition

“clinically dominant” extranodal component after routine staging procedures

No or only “minor” (< 25% of total tumor volume) nodal involvement

D’Amore et al. 1991

Primary Extranodal Lymphomas

Pathology• Most common

• Diffuse large B-cell lymphoma• Marginal zone lymphoma – MALT type

• Other histologies• Follicular lymphoma - @10-15% EN• NK/T-cell nasal type

• Rare• Enteropathy associated T-cell lymphoma

Extranodal lymphomas

GI tract: 19-63%Skin: 3-28%

Nasal/sinuses: 1-11%Orbit: 1-8%CNS: 1-10%

Bone: 1-16%

WaldeyersSalivary glandsTestisBreastCervixBladderMeningesLungKidney

Extranodal Lymphoma Survivalby histology and site in the IELSG series

Specific staging procedures for specific extranodal localizations

GI tract: endoscopy with multiple biopsies, EUS, ENT examination

Waldeyer’s ring: OGD with multiple biopsies

CNS: cranial (and spinal when appropriate) MRI, stereotaxic

biopsy, lumbar puncture with CSF examination, eye examination with slit-lamp

Nasal cavity, nasopharynx, paranasal sinus, orbit: CT scan or MRI of the head and neck

Testis: clinical and ultrasonographic scrotum examination,

lumbar puncture with CSF examination

Classification of primarygastrointestinal NHL

B-cell MALT type DLCL IPSID Mantle cell (Lymphomatous polyposis) Burkitt’s Other types corresponding to nodal equivalents

T-cell Enteropathy associated T-cell lymphoma (EATCL) Other types not associated with enteropathy

IELSG-4 study of gastric DLBCLCHOP vs CHOP+RT

IF-RT improved DFS but not OS

Martinelli et al. Leuk Lymphoma 2009

gastric body ulcer

multifocal “low-grade” marginal zoneB-cell lymphoma of MALT typewith plasmacytic differentiation.No histologic evidence of H. Pylori

• History of hiatal hernia & acid reflux (long-term dyspepsia)

• OGD (Oesophago-gastric-duodeno-scopy)

• Histologic examination of multiple gastric biopsies

56-yr old woman presenting with melena


• no clear evidence of B-symptoms• no relevant findings at the physical exam• normal routine laboratory exams

staging procedures?

any special investigation?

• Endoscopic Ultrasound (EUS): not done

• chest and abdomen CT scan:thickening of the gastric wall, no adenopathy, no hepatosplenomegaly

• bone marrow biopsy:hypercellular bone marrow with no evidence of lymphoma

• HIV serology: negative

• HCV serology: negative

• H. pylori serology and fecal Ag: negative

• FISH for t(11;18) not done


• wait and see?• surgery?• radiotherapy?• chemotherapy? (which one?)• monoclonal antobodies?• chemotherapy plus rituximab?• radioimmunotherapy?

H.pylori-negative gastric MALT lymphoma, Stage IE: How to treat?

What we did?

• “low dose” involved-field radiotherapy was proposed

according to: Tsang RW, et al. J Clin Oncol 2003


External beam irradiation to the stomach and regional nodes30.6 Gy total dose (1,8Gy x 17)

• Disappearance of GI symptoms • OGD: resolution of ulcer (mild residual erythema only)• Histological exam: complete remission of the MALT lymphoma


18 months after RT

• no symptoms• OGD: no evidence of mucosa lesions• Histology: plasmacyte infiltrates (lambda monoclonality) with

some mixed small lymphocytes (mainly reactive CD3+ cells very few CD20+ cells), indicating a possible/probable MALT lymphoma relapse. No large B-cells. No lymphoepithelial lesions.

• It was decided to wait and repeat OGD


• OGD: ulcer on the great gastric curvehiatal hernia

• endoscopic biopsy histology:

chronic gastritis and intestinal metaplasia, and residual MALT lymphoma withclearly reduced lymphoplasmocytic infiltrate [the residual lesion is constituted only by monoclonal (lambda) plasma cells.]No evidence of H. pylori

MALT lymphoma relapse


Immunochemotherapy was proposed (in a clinical trial)

after discussion with the patient…we

• re-introduced PPI treatment (omeprazole)• wait and see• repeat gastric biopsies after 3 months


IELSG-8 Study:Survival of primary intestinal DLBCL

Overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) of 87 patients with DLCL intestinal lymphoma.

Cortelazzo et al. British Journal of Haematology, 2002, 118, 218–228

The MALT concept

Acquired MALTwhere lymphoid tissue is not a natural component (e.g., Sjögren, Hashimoto, H. pylori-gastritis)

Native MALTnormally present in certain extranodal sites (e.g., Peyer’s patches)

MALT Lymphomafirst described in the stomach by Isaacson and Wright in 1983, but can arise from a wide variety of extranodal tissues (usually at acquired MALT sites)

WHO ClassificationMarginal Zone B-Cell Lymphomas

Nodal Marginal Zone Lymphoma ~ 2% of all NHLs

Extranodal Marginal Zone Lymphoma of mucosa-associated lymphoid-tissue (MALT Lymphoma) ~ 8% of all NHLs

Splenic Marginal Zone Lymphoma ~ 1% of all NHLs

Array-CGH identifes both common orsubtype-specific aberrations in MZL

MZLs share 3q and 18q gains NMZL are more similar to EMZL

than SMZL Extracopies of chr 3 and 18 are

the same as in DLBCL

EMZL and SMZL profiles show differences 3p, 6p and 18p gains in EMZL 6q losses in EMZL (A20/TNFAIP3) 7q, 8p, 14q and 17p losses in

SMZLA. Rinaldi et al., Blood in press

A20

MALT1API2t(11;18)up to 35 %

1. Deregulated MALT1

2. Deregulated Bcl-10

t(14;18)15- 20 % IgH promoter

t(1;14)very rare

MALT1

T- or B-cellAntigen receptor

Antigen

Bcl-10CARMA1

MALT1

IKK

p65/cRel

p50IKK

p65/cRel

p50

p65/cRel

p50

NF-kB onBcl-10

IgH promoter

Constitutive activation of NF-κB in MZL via recurrent translocations or A20 inactivation

3. A20 (TNFAIP3) inactivations

A20 deletions or mutations in up to 40 %

Novak et al. Blood 2009

A20 (TNFAIP3): a negative regulator of BCL10-mediated NF-kB activation

MALT lymphoma(Extranodal Marginal Zone B-Cell Lymphoma of MALT)

HISTOLOGICAL FEATURES AND PHENOTYPE

centrocyte-like cells (usually) lymphoepithelial lesions plasma cell differentiation scattered transformed blasts admixed non-neoplastic T-cell follicular colonisation sIg (usually IgM + and IgD - ) CD20, CD21, CD35 positive CD5, CD10, CD23 negative http://www.ncl.ac.uk/pathology/teaching/

Extranodal MALT Lymphoma

Lymphoma associated with:– Stomach » Chronic gastritis (H. pylori)– Orbit » Chlamydophila psittaci– alphaHCD » Campylobacter jejuni– Skin » Borrelia burgdorferi– Lung » Alcaligenaceae species– Salivary » Sjögren’s syndrome– Thyroid » Hashimoto’s thyroiditis

Frequency: 5 - 10% of all NHL70% - 90% present in stage I-II

Micro-organisms

Connective TissueDisease

From gastritis to MALT lymphoma

the B-cell clones that, later on, will give rise to the gastric MALT lymphoma, were detectable in H.Pylori -associated gastritis specimens taken several years before the lymphomadevelopment

Zucca et al, N Engl J Med 1998

H. pylori and MALT lymphomaa model of tumor progression

BB B

B

BBBB

BB B T

T

strain-specificstimulation

mucosal T-cell proliferation

H. pylori-dependentMALT lymphoma B-cell proliferation

contact-dependent B-cell stimulation

neutrophils activations with release of

genotoxic free radicals

antigen selectionautoimmunity

geneticalterations

T

additional genetic damages

B

T

T

diffuse large B-cell lymphoma

B BB

H. pylori chronic gastritis

H. pylori-independentMALT lymphoma

BB

Long-term outcome of gastric MALTlymphoma treated with antibiotics and PPI

A. Stathis et al. Ann Oncol. 20: 1086–1093; 2009

Helicobacter pylori eradication resulted in histological lymphoma remission in 76% of patientsLong-term clinical disease control was achieved in most cases

A watch and waitpolicy seems safe

in patients with minimal residual

disease or histological-only

local relapse

Non-gastric MALT lymphomas

Salivary Lung

Thyroid Liver

MALT lymphomas have been described at nearly all extranodal organs

(All microphotographs, courtesy of Prof. R. Gascoyne, Vancouver, Canada)

Non-gastric MALT lymphomasRegression with antibiotics

• Documented success - limited data in:– IPSID (C. jejuni): tetracycline/metronidazole– Skin (B. burgdorferi): doxycycline– Orbit (C. psittaci): doxycycline*

• Results highly variable in the literature• “Blind” treatment effective?

*100 mg bid for 3 weeks

Event-Free Survival

5-year EFS (95%CI):Chlorambucil , 52% (42%-60%)R-Chlorambucil, 70% (61%-77%)Rituximab, 51% (40%-61%)

Log-rank HR 95% C.I.R vs. Chl, P=0.957 0.99 (0.82-1.20)R-Chl vs. Chl, P=0.0005 0.52 (0.35-0.75)R-Chl vs. R, P= 0.0015 0.51 (0.33-0.78)

International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study

E. Zucca, 12-ICML, Hematol Oncol 2013. 31(suppl 1):97. Abs 007

testisbrain

IELSG surveys of primary testis and brain NHLpotentially curable diseases with a still very poor outcome

Zucca E, et al. J Clin Oncol 2003;21:20-27Ferreri AJ, et al. J Clin Oncol 2003;21:266-272

PCNSL Standard PracticeTherapeutic Strategy

Reni M. et al. Ann Oncol 1997

IELSG retrospective study of PCNSL

370 immunocompetent patients with PCNSL treated at 23 cancer centers from 5 countries:

CT followed by RT superior to RT alone

Best CT: HD MTX + HD ARA-C?

RT unnecessary in CR after HD MTX?

Significant outcome predictors:

Age >60 ys PS >1 elevated LDH high CSF protein level involvement of deep

regions of the brain

These 5 variables defined a prognostic score

Ferreri et al. Neurology 2002Ferreri et al. J Clin Oncol 2003

Subset of 75 cases treated with HD-MTX +/- WBRT

105 cases with complete data about allthe 5 prognostic variables

Ferreri et al. J Clin Oncol 2003

PCNSL survival according to theIELSG prognostic score

The IELSG-20 randomised phase 2 trial:HD Ara-C plus HD MTX vs HD MTX alone in PCNSL

Ferreri et al, Lancet 2009

MTX 3.5 g/m2 d1Ara-C 2 g/m2x2/d d2-3 (q 3 wks)

Stratification by IELSG score and intention to irradiate patients older than 60 (in CR)

versus

Randomisation

MTX 3.5 g/m2 d1(q 3 wks)

n = 40 n = 39

The IELSG-20 randomised phase 2 trial:HD Ara-C plus HD MTX vs HD MTX alone in PCNSL

HD MTX alone HD Ara-C plus HD MTX

CR 18% (95% CI 6–30) 46% (95% CI 31–61) p=0·006ORR 40% (95% CI 25–55) 69% (95% CI 55–83) p=0·009

Published online September 20, 2009 DOI:10.1016/S0140-6736(09)61416-1 Ferreri et al, Lancet 2009

Strata: IELSG score

®WBRT 36 Gy± boost 9 Gy

BCNU + Thiotepa + APBSCT

®

www.ielsg.org

4x HD MTX + HD Ara-C 4x HD MTX + HD Ara-C + Rituximab

4x HD MTX + HD Ara-C + Rituximab+ Thiotepa

Response assessment

CRPRSD

PD excess toxicity

failed SC harvest

WBRT 40 Gy± boost 9 Gy

IELSG-32 Randomised phase II study of primary CNS lymphoma

Strata: previous regimen and response

Testicular Lymphoma

Epidemiology

5% of all testicular malignancies

<2% of all non-Hodgkin’s lymphoma

Incidence: 0.17 to 0.26 per 100,000/yr , in Europe in the US the incidence increased from 0.06 per 100,000

in 1981-1985 to 0.09 2001-2005 (p=.025). highest incidence among whites (>80% of all cases)

85% of case in men older than 60 yr, the most common testis neoplasm after 60 yr

median OS 4.6 yr, CSS 55% at 5 yrs, 25-30% at 15 yrs.

Møller 1984; Shahab & Doll 1999; Zucca 2003; Gundrum 2009

IELSG-10 Study DesignProspective therapeutic clinical trial in testis DLBCL

RESTAGING

3x R-CHOP + intrathecal MTX (12 mg/wk on weeks 1 to 4)

RESTAGING

STAGE I

+ 3x R-CHOP(total 6 cycles)

+Scrotal RT25-30 Gy

STAGE II in CR


+Scrotal + IF RT

30-35 Gy

STAGE II in PR


if CRScrotal +

IF RT30-35 Gy

if PRScrotal +

IF RT35-45 Gy

5-year PFS 74% (95% CI 59-84%) 5-year OS 85% (95% CI 71-92%)

IELSG-10 study: final results

Median follow-up, 65 months43 patients are relapse free, 10 had relapse or progression: 2 nodal, 8 extranodal including 3 in the CNS. No contralateral-testis relapses occurred. 10 deaths: 6 from NHL, 2 AML, 1 heart failure, and 1 gastric cancer

Vitolo et al. JCO 2011

IELSG-10

IELSG-30 R-CHOP with intensive CNS prophylaxis and scrotal RT

weeks 1-156x R-CHOP 21(Rituximab on day 0 or day 1)

IT prophylaxis with 4x Depocyte(50 mg on day of cycles 2-5)

weeks 18-22Methotrexate 1.5 g/m2 q 14 days x2

from week 24Scrotal prophylactic radiotherapy

IELSG study of primary diffuse largeB-cell lymphoma of the breast

Ryan G et al. Ann Oncol 2008

n=204 median OS 8 yrs median PFS 5.5 yrs IPI, anthracycline regimens, and RT

significantly associated with longer OS (each P <0.03).

No benefit from mastectomy(as opposed to biopsy or lumpectomy)

At a median follow-up of 5.5 yrs, 37% progression rate, 16% in the

same or contralateral breast, 5% in the CNS, and 14% in other extranodal sites.

• Very fit young man (32 yro) • No relevant medical history • Dyspnoea during his regular training

The young army officer with dyspnoea

• A mediastinal mass was detected and biopsied


The histological diagnosis of primary mediastinal large B-cell lymphoma was made, with typical clear-cell appearance and interstitial fibrosis. Residual thymic cystic structures were also found, consistent with the origin from the thymus

18FDG PET-CT - Baseline

SUV max=16.7

18FDG PET-CT - Baseline

• Patient was enrolled in the IELSG-26 study

• 6 cycles of R-CHOP-14 +2R were given


18FDG PET-CT end-of-immunochemotherapy

Deauville score 3

MRU : SUVmax 2.3

MBP : SUVmax 2.1

Liver : SUVmax 2.7

is this a CR?


What would you do?

• Observation only?

• Radiotherapy?

• ASCT consolidation?

• According to local policy consolidation RT was given (36 Gy to the residual mediastinal lesion)

• A PET CT 3 months after RT showed a CR (Deauville score 2)

• At 4 years after RT he is still in CCR


Cazals-Hatem et al. 1996

PMBCL:a clinical entity or a subset of DLCL?

PMLCL (n=141) vs. DLCL (n=916)

Median age 37 yrs 54 yrsYoung women 59% 42 %Bulky 77% 7%High LDH 76% 51%BM+ 2% 17%CR rate 79% 68%3-yr OS 66% 61%

Statistically significant differences found in a large retrospective study of GELA:

CHOP 3rd generation HDS / ABMT

CR after CT 49% 51% 53%CR after CT+RT 61% 79% 75%10-year OS 44% 71% 77%Follow-up 52 mos 55 mos 36 mos

IELSG-9study of primary mediastinal DLBCL

Zinzani et al. Haematologica 2002

100%

80%

60%

40%

20%

P<0.0001 n =426O

vera

ll S

urvi

val

0 2 4 6 8 10 12 14 16 18 years

PMBL:the Vancouver experience

Savage et al. 2005

A Rosenwald, et al.J Exp Med 2003

KJ Savage, et al.Blood 2003

Gene expression of PMBCL identifies a clinicallyfavorable subgroup of DLCL (a separate entity?)

related to Hodgkin Lymphoma

The PMBCL molecular profile is resembling that of classical HL:over one third of the genes that were more highly expressed in PMBL than in other DLCLs were also characteristically expressed in HL

DLBCL PMBCL

STAT1

TRAF1

c-REL

Overall Survival for DA-EPOCH ± R

Dunleavy et al, NEJM, 2013; 368:1408-16

Diagnosis of PMLBCL

Registration

Baseline PET-CT

R-chemoimmunotherapy

Positive PET-CT Negative PET-CT

Off-protocol treatment(investigator’s choice)

Randomisation

Mediastinal IFRT (30 Gy) Observation

Restaging PET-CT

Web-based central review of PET-CT

IELSG-37 Study design

• history of «sideropenia»• coeliac disease diagnosed 1 year ago• Since then on gluten-free diet with rapidly recovered iron

level

~6 months ago: • unexplained fever lasting for weeks with no benefit from

empiric antibiotic treatment• haematemesis• CT scan: cystic lesion (ascess?) of the small intestine and

some small (<2cm) mesenteric LNs• the lesion was surgically removed

39 year old woman with coeliac disease

• histological diagnosis of EATL, type I(CD20-,CD5-, CD3+, CD7+ TIA1+, CD30+/-)

• confirmed by expert pathology review


• How to treat?


How to treat?

• CHOEP was started• After 3 cycles a CT scan showed a minimal increase

(around 2 cm) of some of the abdominal LNs

• A 4th cycle was given


39-yr old woman with coeliac disease

• How to treat?

After the 4th cycle restaging CT scan showed a furtherincrease of the nodes (up to 2.7 cm) and a clearthickening of the small intestine wall

• Histological report of EATL, type I (with CD30 now diffusely and strongly +ve) in both the small intestine and in the two resected enlarged regional LNs


What would you do now?


Survival of patients with intestinal B-cell lymphoma (IBCL) and intestinal T-cell lymphoma (ITCL) In a Multicenter Prospective Study From the German Study Group on Intestinal NHL

Daum S et al. JCO 2003;21:2740-2746

©2003 by American Society of Clinical Oncology

md, frcp scientific director - oncoconferences.ch · nasal cavity, nasopharynx, paranasal sinus,...

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