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Diagnostika lymfomů
Extranodální lymfomy
Doc. MUDr. L. Boudová, Ph. D.
Contents
WHO Classification
2008
Lymphomas
Clonal disorders of lymphoid cells at
various stages of differentiation
HODGKIN L.
Distinction
clinical
histological
NON-HODGKIN L.
immature cells (precursors)
mature cells
Note:
B
Hodgkin lymphoma is
also a (mature)B-cell
T
lymphoma.
Lymphoid malignancies
Epidemiology
90%: B; FL+ DLBCL – 60%
4% of all new cancers each year
Incidence increasing
per 100 000:
34 lymphoid neoplasms
Lymphoma diagnosis
Sample
Lymph node
Bone marrow
Spleen, extranodal tissue
Cerebrospinal fluid
Lymphoma diagnosis
Histology, cytology
Immunohistochemistry
Ag detected in tissue slides
Molecular biology
Clonality, lineage – gene rearrangements
Translocation detection, mutations
Flow cytometry
Clinicopathological correlation, esp. T-cell
lymphomas difficult to diagnose
Lymphoma diagnosis
molecular biology
Gene rearrangement (PCR, Southern blot)
Clonality and lineage
B-cells: IgH
T-cells: T-cell antigen receptor
Characteristic translocations
Mantle cell lymphoma t(11;14)
Follicular lymphoma, diffuse large B-cell l. t(14;18)
Anaplastic large cell lymphoma t(2;5)
Burkitt lymphoma t(8;14)
B-cell lymphoma
Clonal disorders of B-cells at various stages
of differentiation
of immature cells - lymphoblasts
B-acute lymphoblastic leukaemia - frequent,
children
B-lymphoblastic lymphoma - rare
of mature B-cells
most common: diffuse large B-cell lymphoma,
follicular; plasma cell myeloma
Mature B-cell lymphomas
Chronic lymphocytic leukemia/small lymphocytic
lymphoma; B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Hairy cell leukemia
Plasma cell myeloma
Monoclonal gammopathy of unknown significance
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell lymphoma=
MALT
Nodal marginal zone B-cell lymphoma
Splenic marginal zone lymphoma
Mature B-cell lymphomas
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukaemia
T-cell lymphoma
• Precursor T-cell lymphomas
- T-acute lymphoblastic leukaemia
- T-lymphoblastic lymphoma
– Mature T-and NK cell neoplasms
• uncommon –10% of all NHL
• Most frequent : peripheral T-cell lymphoma,
unspecified
• large cell anaplastic lymphoma
often difficult to diagnose
Most common T-cell lymphomas
• 1. Leukaemic/disseminated
adult T-cell leukaemia - HTLV 1
• 2. cutaneous - mycosis fungoides, Sezary
syndrome, primary cut. anaplast. lymphoma
• 3. other extranodal - extranod. NK/T - nasal,
enteropathy assoc.
• 4. nodal - peripheral T-cell lymphoma, NOS,
anaplastic large cell lymphoma
NK/T-cell lymphoma of nasal type
• EBV, angiocentric, destructive
• South America, Asia
Lethal midline granuloma
NK/T-cell l.
Wegener granulomatosis
Cocaine abuse
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma
aggresive, potentially curable
COMMON!
1/3 of all lymphomas of adults (med. 64 ys)
nodal OR extranodal (1/3)
GIT, skin, CNS, testis
bone, soft tissue, salivary glands,
Waldeyer ring, lung, kidney, liver,
spleen, female genital tract
Diffuse large B-cell lymphoma
Primary OR secondary
Chronic lymphocytic leukemia
Follicular lymphoma
Marginal zone B-cell lymphoma
Nodular lymphocyte predom. Hodgkin l.
Risk factor: immunodeficiency (often EBV+)
Diffuse large B-cell lymphoma
Morphologic variants
Centroblastic
Immunoblastic
Plasmablastic
DLBCL subtypes
T-cell/histiocyte rich
CNS
Skin- leg type
EBV positive - elderly
Special lymphomas of large B-cells
Mediastinal (thymic)
Intravascular
Chronic inflammation
Lymphomatoid granulomatosis
ALK positive plasmablastic
Arising in HHV8 Castleman dis.
Primary effusion
Diffuse large B-cell lymphoma, Giemsa
Diffuse large B-cell lymphoma
Differential diagnosis
Tumors
Haematological: lymphomas – peripheral - B, T
precursors - B, T
myeloid neoplasm
Non-haematological: carcinoma, sarcoma, GIST,
melanoma, seminoma, glial tumors
Reactive disorders: infectious mononucleosis,
Kikuchi
T-cell /histiocyte rich B-cell lymphoma
Diffuse/ vaguely nodular
CD20
diffuse large B-cell lymphoma
neoplastic B-cells scarce
majority reactive T-cells, histiocytes
Small B-cells rare BUT areas with
increased numbers of small B-cells
 associated NLPHL ?
T-cell /histiocyte rich B-cell
lymphoma
Differential diagnosis
1. Hodgkin lymphoma
- classical
- NLPHL (nodular paragranuloma)
2. T-cell lymphoma
3. Reactive disorders – T/HRBCL
interfollicular
Diffuse large B-cell lymphoma
clinicopathological subtypes
• mediastinal
Mediastinal DLBCL
Thymus
Female, 30 ys
Anterior mediastinal mass
Superior vena cava syndrome
Clinicopathological differential diagnosis?
Mediastinal DLBCL
Compartmentalising fibrosis
Polymorphic large cells, abundant pale cytoplasm
CD20, CD23, CD30, CD45
Mediastinal DLBCL – differential diagnosis
Problems
1. small biopsies, crushed cells, small areas for IH
2. background: small ly, eosinophils; RS cells
3. clinicopathological features – med. mass, young woman
GRAY ZONE
Traverse-Glehen : Mediastinal Gray Zone Lymphoma.
The Missing Link Between Classic Hodgkin Lymphoma
And
Mediastinal Large B-Cell Lymphoma.
Am J Surg Pathol, Nov. 2005, 29, 1411-1421
Classical Hodgkin lymphoma
Nodular sclerosis
Borderline cases
BCLUWFIBDLBCLACHL
BCLUWFIBDLBCLACHL
DLBCL vs. CHL
morphology, IHC
Garcia, Histopathology 2005
BCLUWFIBDLBCLACHL
DLBCL vs. CHL
morphology, IHC
Traverse-Glehen AJSP 2005
DLBCL
Differential diagnosis versus
Burkitt lymphoma
Burkitt lymphoma
1. endemic (Africa)
2. sporadic (young, rare)
3. immune deficiency-associated - HIV!
t(8;14)
starry sky
BCLUWFIBDLBCLABL
BCLUWFIBDLBCLABL
DLBCL versus Burkitt
morphology, IHC, genetics
Chuang
AJCP
Extranodal lymphomas
the primary tumor is extranodal (not nodal)
The biggest mass is extranodal at the time of the diagnosis
Diagnosis may be nmore difficult than in the LN – other tumours
may be more common in extranodal localizations
(carcinomas..) – think of the possibility of a lymphoma
Most common:
GIT, skin,
Waldeyer,CNS, testis, bone
soft tissue, salivary glands, lung, kidney, liver, spleen, female
genital tract
Histological types: DLBCL, MALT l.
Gastrointestinal lymphomas
most common extranodal lymphomas
50%
Klinické symptomy
často necharakteristické!
• pokročilé: tumor v břiše, srůsty
kliček, perforace
• lymfadenopatie
• hepatosplenomegalie
• KO: lymfocytóza,  LDH
• endoskopický nález
GI lymphomas
Type
B
DLBCL, MALT
MCL, FL
T
EATL
Site
 Stomach
 Intestines
(ileocaec., jejunum,
duodenum)
Diffuse large B-cell lymphoma of the stomach
DLBCL
HE
CD20
MALT lymphoma versus DLBCL
Gastric DLBCL
de novo
transformation of a low-grade lymphoma
clonal progression in time
Independent coexistence of 2 clones:
low /high grade component
DO NOT USE “HIGH-GRADE MALT LYMPHOMA“
MALT lymphoma

stomach, intestine (IPSID)
chronic antigenic stimulation
- Helicobacter pylori
Regulation: specific activated T-cells
Slow progression- 90%: stage IE, IIE
(bone marrow involvement: rare, 10%)
Helicobacter pylori
Chronic gastritis
Diseases associated with
Helicobacter pylori infection
• Chronic gastritis
• Peptic ulcer
• Gastric carcinoma
• Gastric MALT lymphoma
MALT lymphoma of the stomach
MALT lymphoma
Different sites
common features
Architecture
Cytology
Immunophenotype
extrafolik. infiltráty
folikulární kolonizace
lymfoepiteliální léze
monocytoidní, plazmat.
buňky
Macroscopy: often noncharacteristic
Microscopy: Wotherspoon criteria - spectrum
0
normal mucosa
1
chronic active gastritis
2
chronic active gastritis with lymphoid
follicles
3
suspicious lymphoid infiltrate,
probably reactive
4
suspicious lymphoid infiltrate,
probably lymphoma
5
MALT lymphoma
MALT lymphoma
Immunohistochemistry
No specific MALT lymphoma marker
Positivity: CD20, CD79a; Ig light chains; Ig
heavy chains: IgM; CD43
Negativity: CD5, CD10, bcl6, IgD, cyclin D1
CD21, CD10, Ki-67: residual lymphoid
follicles
Differential diagnosis of MALT lymphoma
HP gastritis
Wotherspoon criteria
spectrum 0-5
Integrated approach
favoring MALT lymphoma:
dense lymphoid infiltrate
prominent LEL
Dutcher bodies
infiltration of muscularis mucosae
atypia of lymphoid cells
B - cell monoclonality
other lymphomas: DLBCL, MCL, FL…
B-cell monoclonality detection
Imunohistochemistry -
Ig light chains
Molecular biology - PCR - IgH rearrangement
Polyclonal IgH rearrangement
Monoclonal IgH rearrangement
It is often not possible to establish
a clear diagnosis in a single biopsy.
repeat the biopsy; sampling
?
MALT lymphoma/gastritis?
Large cell component?
Correct diagnosis and treatment
Interdisciplinary communication
Repeated biopsies, specialized methods
MALT lymphoma after therapy
• Response: regression of lymphoid infiltrate and
LEL
• Gastric mucosa: atrophy, intestinal metaplasia,
empty, fibrotic, basal lymphoid aggregates
• Always assess Helicobacter pylori
• B-cell clonality assessment by PCR: not clear
Průkaz monoklonality
• Imunohistochemie
lehké řetězy Ig
• Molekulární genetika
PCR
přestavba genu IgH
CDR III
Gastric MALT lymphoma
Recurrent genetic abnormalities
• t(11;18)(q21;q21)/ API2-MALT1
usually the sole genetic abnormality, 25% of g. MALT
l., H. p. neg., no response to ATB
• t(14;18)(q32;q21)/ IgH-MALT1
non-gastric
• t(1;14)(p22;q32)/ IgH-BCL10; t(1;2)(p22;p12)
• Different strains of Helicobacter pylori
MALT l. in other sites
than the stomach
•
•
•
•
•
Eye – Chlamydia psittaci
Skin – Borrelia burgdorferi
IPSID – Campylobacter jejuni
Salivary, thyroid, lung, orbit, breast, skin
Localized; disseminated (30%, after a long
period)
• 5 y OAS: 90%
Multiple lymphomatous polyposis
Mantle cell lymphoma
Follicular lymphoma
MALT lymphoma
Mantle cell lymphoma
 Multiple lymphomatous
polyposis
 M60
 bad prognosis
 imunohistochemistry
 genetics
WHO
Mantle cell lymphoma - localisation
Lymph nodes, Waldeyer; bone marrow
Extranodal sites: GIT, skin, others
GIT: multiple lymphomatous polyposis
(MCL, FL, MALT l.)
Mantle cell lymphoma
CD5
Cyclin D1
MALT? MCL?
FISH t(11;14)(q13;q32)
Enteropathy-associated T-cell lymphoma
Proximal jejunum
Very rare x most common GI T-cell lymphoma
Acute abdomen (40%) – emergency surgery
Obstruction/perforation, peritonitis, sepsis, death
Non-acute: pain, weight loss, malabsorption
Age 60, M=F
Enteropathy-associated T-cell lymphoma
Striking association with celiac disease
Histology and immunomorphology
Anaplastic/pleomorphic (80%)
Celiac dis.+, enteropathy +, CD56Monomorphic (20%)
Celiac dis.-, enteropathy+/-, CD56+
Half of the patients die soon after the manifestation
Enteropathy-associated T-cell lymphoma
CD3
Anaplastic
T-cells, plasma cells,
eosinophils
TCR gamma - PCR
ABI PRISM
TGGE
Testicular lymphomas
Lymfomy varlete
• Primární x sekundární
• 1% všech NHL
• 2% nádorů varlete
! nejčastější nádor varlete
u mužů 50 let !
I. Dospělí:
DLBCL
MALT lymfom, folikulární lymfom
T-lymfomy
T/NK – lymfomy, nosní typ
plasmocytom
II. Děti: před pubertou
Sek. (5% systém.): Burkitt, DLBCL,
lymfoblastické nádory
Primární: folikulární lymfom
Infiltrace varlete
parciální
celková
Zvětšení
unilaterální
bilat. současné
DLBCL
Intertubulární růst
Destrukce tubulů,
difúzní růst
Cytologické rysy
•Stadium IE
Nejčastěji: dif. velkobuněčný B-lymfom
- CB, IB - CD20+, CD79a+
Lymfom varlete (DLBCL)
! nejčastější nádor varlete
u mužů 50 let !
primární diagnózy: 10%
chybné („seminom“)
• Většinou diagnostikován v KLIN. ST. IEA
• Prognóza nemocných není tak dobrá, jako
u odpovídající rizikové skupiny nodálního
DLBCL
• Pozdních relapsy: CNS, druhostranné
varle, zejména u nemocných nedostatečně
léčených v úvodu
The mysterious link
between
the brain
and
the testis
CNS lymphomas
Primární lymfomy CNS
• pouze v CNS
• mozek
• 1% intrakraniálních nádorů – 1% NHL
• imunodeficientní x imunokompetentní
MR
Multifokální, periventrikulární
or unifocal mass
Perivask.
manžety
CD20
RETIKULIN
EBV-LMP
Predispozice
imunitní
deficity
AIDS
Vzácné prezentace lymfomů v NS
• Lokalizace
Oko
Dura mater
Mícha, extradurální expanze
Lymphomatosis cerebri
Kraniální a periferní nervy
• Typ lymfomu
T-lymfom, ALCL
intravask. lymfom
SLL, MgZL, FL, PTLD
Závěr:
primární lymfom CNS
svébytná nádorová jednotka
histopatologická diagnóza
stereotaktická biopsie
Intravaskulární
B-lymfom
Intravaskulární
B-lymfom
Lymfoproliferace
u imunodeficitů
immunodeficiencies
• Associated tumors
• Skin, urogenital tract, lymphomas
Stavy se sníženou imunitou
1. iatrogenic immunosuppression after
transplantation
(posttransplantation lymphoproliferative disease,
PTLD)
2. autoimmune diseases (RA, SLE)
3. HIV
4. primary immune deficiencies
5. senile EBV-related B-cell lymphomas
PTLD
Posttransplantation
lymphoproliferative disease
Clinicopathological spectrum
1. Histol. Iniciální - časné
2. Polymorfní
3. Monomorfní
4. Hodgkinův lymfom, PTLD
podobná Hodgkinově lymfomu
Etiopatogeneze
• imunosuprese
• infekce EBV
• chronická antigenní stimulace štěpem
• další infekční agens?
Vliv EBV
Reaktivní T-buňky
„IM“
EBV
Polymorfní PTLD
Polyklonální
lymfoidní proliferace
Monomorfní PTLD
Klonální
populace
Plazmocytární
hyperplazie
Klesající imunitní odpověď
HL
Sekundární
genetické změny
PTLD – potransplantační
lymfoproliferace
Early – up to 1 year – EBV - strong role
Late – after 1 year
• Frekvence PTLD: 1-10%
- typ a stupeň imunosuprese,
- EBV status
• Lokalizace: často extranodální
• Nejvíce: 1. rok po transplantaci
PTLD časná x pozdní
• Mortalita: Tx solidních orgánů: 60%
kostní dřeně: 80%
• Reverzibilita: u některých PTLD
• Původ: příjemce (solidní) x dárce (BMT)
EBV
• Infectious mononucleosis
• Burkitt lymphoma
• Hodgkin lymphoma
• B-cell lymphomas in immunosuppressed
patients (HIV, transplantation)
• Nasopharyngeal carcinoma
HIV and lymphomas
• 1 st most frequent tumor: Kaposi sarcoma
• 2nd: lymphomas
• Lymphoma - AIDS defining illness
• 3% of patients with AIDS
Lymfomy u HIV pozitivních lidí
agresívní B-lymfomy, často extranodální;
heterogenní (GIT, CNS)
patogenetické faktory:
herpesviry: EBV (v 50%), Kaposi Sarcoma
Human Virus/HHV 8 (primary effusion
lymphoma)
chronická antigenní stimulace
genetické abnormality
poruchy cytokinové regulace
prognóza závisí na tíži imunodeficience
Lymphomas associated with HIV
Incidence increased: 60-200 x
(versus noninfected population)
Incidence decreases with HAART, ↑CD4
Hodgkin lymphoma: AIDS: risk 10 x higher
Lymfomy u HIV+
1. lymfomy postihující také imunokompetentní
pacienty
časté: Burkittův (klasický, plazmacytoidní, atypický)
DLBCL (často v CNS!)
vzácnější: extranodální B-lymfom z marginální zóny,
periferní T-lymfom, klasický Hodgkinův lymfom
2. lymfomy specifické pro HIV+ pacienty
primary effusion lymphoma, plazmoblastický lymfom
ústní dutiny
3. léze vyskytující se i u jiných imunodeficiencí polymorfní "PTLD"
Lymfoproliferativní choroby
u primárních imunodeficiencí
•
•
•
•
•
•
•
•
rare
More than 60 PID
Heterogenous
Manifestattion highly variable
Ataxia teleangiectasia
Wiskott Aldrich sy
CVID
SCID
XLP…
Lymfoproliferativní choroby
u primárních imunodeficiencí
hlavně u dětí, častěji u chlapců;
(x common variable immunodeficiency:
dospělí)
většinou extranodální (GIT, CNS)
většinou B-lymfoproliferace: fatální
infekční mononukleóza, DLBCL,
lymfomatoidní
granulomatóza,
Hodgkinův
lymfom;
T-lymfomy
/leukémie
Oyama AJSP 2003
Senile
EBV+
lymphoproliferations
no other overt ID,
only the age…
EBV + senile lymphoproliferations
•
•
•
•
Rare
Asia
over 50
Various histological appearance