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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. NON-HODGKIN L. immature cells (precursors) mature cells B T. Distinction clinical - PowerPoint PPT Presentation
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Diagnostika lymfomůExtranodální lymfomy
Doc. MUDr. L. Boudová, Ph. D.
Contents
WHO Classification
2008
LymphomasClonal disorders of lymphoid cells at various stages of differentiation
HODGKIN L.
NON-HODGKIN L.immature cells (precursors)mature cellsBT
Note:Hodgkin lymphoma is also a (mature)B-cell lymphoma.
Distinctionclinicalhistological
Lymphoid malignanciesEpidemiology
90%: B; FL+ DLBCL – 60%
4% of all new cancers each yearIncidence increasing
per 100 000:34 lymphoid neoplasms
Lymphoma diagnosis
Sample
Lymph node
Bone marrow
Spleen, extranodal tissue
Cerebrospinal fluid
Lymphoma diagnosis
Histology, cytologyImmunohistochemistry Ag detected in tissue slidesMolecular biologyClonality, lineage – gene rearrangementsTranslocation detection, mutations
Flow cytometryClinicopathological correlation, esp. T-cell
lymphomas difficult to diagnose
Gene rearrangement (PCR, Southern blot)
Clonality and lineage B-cells: IgHT-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)
Lymphoma diagnosismolecular biology
B-cell lymphomaClonal disorders of B-cells at various stages of differentiationof immature cells - lymphoblastsB-acute lymphoblastic leukaemia - frequent, childrenB-lymphoblastic lymphoma - rareof mature B-cells
most common: diffuse large B-cell lymphoma, follicular; plasma cell myeloma
Mature B-cell lymphomasChronic lymphocytic leukemia/small lymphocytic
lymphoma; B-cell prolymphocytic leukemiaLymphoplasmacytic lymphomaHairy cell leukemiaPlasma cell myelomaMonoclonal gammopathy of unknown significanceSolitary plasmacytoma of boneExtraosseous plasmacytomaExtranodal marginal zone B-cell lymphoma=
MALT Nodal marginal zone B-cell lymphomaSplenic marginal zone lymphoma
Mature B-cell lymphomasFollicular 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 lymphomaoften 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, testisbone, soft tissue, salivary glands, Waldeyer ring, lung, kidney, liver, spleen, female genital tract
Diffuse large B-cell lymphoma
Primary OR secondary
Chronic lymphocytic leukemiaFollicular lymphomaMarginal zone B-cell lymphomaNodular 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 lymphomaDifferential diagnosis
TumorsHaematological: lymphomas – peripheral - B, T
precursors - B, Tmyeloid neoplasm
Non-haematological: carcinoma, sarcoma, GIST, melanoma, seminoma, glial tumors
Reactive disorders: infectious mononucleosis, Kikuchi
T-cell /histiocyte rich B-cell lymphoma
diffuse large B-cell lymphoma
neoplastic B-cells scarcemajority reactive T-cells, histiocytes
Small B-cells rare BUT areas with
increased numbers of small B-cells
associated NLPHL ?
CD20Diffuse/ vaguely nodular
T-cell /histiocyte rich B-cell lymphomaDifferential diagnosis
1. Hodgkin lymphoma
- classical
- NLPHL (nodular paragranuloma)
2. T-cell lymphoma
3. Reactive disorders – T/HRBCL interfollicular
Diffuse large B-cell lymphomaclinicopathological subtypes
• mediastinal
Mediastinal DLBCLThymus
Female, 30 ys
Anterior mediastinal mass
Superior vena cava syndrome
Clinicopathological differential diagnosis?
Mediastinal DLBCLCompartmentalising fibrosis
Polymorphic large cells, abundant pale cytoplasm CD20, CD23, CD30, CD45
Mediastinal DLBCL – differential diagnosisProblems1. small biopsies, crushed cells, small areas for IH2. background: small ly, eosinophils; RS cells3. clinicopathological features – med. mass, young woman
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
GRAY ZONE
Classical Hodgkin lymphoma
Nodular sclerosis
Borderline cases
BCLUWFIBDLBCLACHL
BCLUWFIBDLBCLACHLDLBCL vs. CHLmorphology, IHC
Garcia, Histopathology 2005
BCLUWFIBDLBCLACHLDLBCL vs. CHLmorphology, 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
BCLUWFIBDLBCLABLDLBCL 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 diagnosisDiagnosis 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 lymphomasType B
DLBCL, MALT
MCL, FL T
EATLSite Stomach Intestines (ileocaec., jejunum, duodenum)
Diffuse large B-cell lymphoma of the stomach
DLBCLHE CD20
MALT lymphoma versus DLBCL
Gastric DLBCL de novotransformation of a low-grade lymphoma
clonal progression in timeIndependent 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 lymphomaDifferent sitescommon featuresArchitectureCytologyImmunophenotypeextrafolik. 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 markerPositivity: CD20, CD79a; Ig light chains; Ig
heavy chains: IgM; CD43Negativity: CD5, CD10, bcl6, IgD, cyclin D1
CD21, CD10, Ki-67: residual lymphoid follicles
Differential diagnosis of MALT lymphomaHP gastritis Wotherspoon criteria
spectrum 0-5
other lymphomas: DLBCL, MCL, FL…
Integrated approachfavoring MALT lymphoma:dense lymphoid infiltrate prominent LELDutcher bodiesinfiltration of muscularis mucosaeatypia of lymphoid cellsB - cell monoclonality
B-cell monoclonality detection
Monoclonal IgH rearrangement
Polyclonal IgH rearrangement
Imunohistochemistry - Ig light chains
Molecular biology - PCR - 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 lymphomaRecurrent 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
M60 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 surgeryObstruction/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
Anaplastic T-cells, plasma cells, eosinophils
CD3
TCR gamma - PCR
TGGE
ABI PRISM
Testicular lymphomas
Lymfomy varlete• Primární x sekundární
• 1% všech NHL
• 2% nádorů varlete
! nejčastější nádor varlete
u mužů 50 let !
I. Dospělí:DLBCLMALT lymfom, folikulární lymfom T-lymfomyT/NK – lymfomy, nosní typplasmocytom
II. Děti: před pubertouSek. (5% systém.): Burkitt, DLBCL,
lymfoblastické nádory
Primární: folikulární lymfom
Infiltrace varleteparciální
celková
Zvětšeníunilaterálníbilat. současné
Intertubulární růst
DLBCL
Destrukce tubulů,difúzní růst
Cytologické rysy
Nejčastěji: dif. velkobuněčný B-lymfom - CB, IB - CD20+, CD79a+
•Stadium IE
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
Multifokální, periventrikulární or unifocal mass
MR
Perivask.
manžety
RETIKULIN
CD20
Predispozice
imunitnídeficity
AIDS
EBV-LMPEBV-LMP
Vzácné prezentace lymfomů v NS
• LokalizaceOko
Dura materMícha, extradurální expanzeLymphomatosis cerebriKraniální a periferní nervy
• Typ lymfomuT-lymfom, ALCLintravask. lymfomSLL, 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. HIV4. primary immune deficiencies5. senile EBV-related B-cell lymphomas
PTLDPosttransplantation
lymphoproliferative disease
Clinicopathological spectrum1. 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?
EBVPolyklonální lymfoidní proliferace
Klonální populace
Sekundární genetické změny
„IM“
Plazmocytární hyperplazie
Polymorfní PTLD Monomorfní PTLD HL
Reaktivní T-buňky
Klesající imunitní odpověď
Vliv EBV
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 lidíagresívní 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 regulaceprognóza 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 chorobyu primárních imunodeficiencí
rare• More than 60 PID• Heterogenous• Manifestattion highly variable• Ataxia teleangiectasia• Wiskott Aldrich sy• CVID• SCID• XLP…
Lymfoproliferativní chorobyu 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
Senile EBV+
lymphoproliferationsno other overt ID,
only the age…
Oyama AJSP 2003
EBV + senile lymphoproliferations
• Rare
• Asia
• over 50
• Various histological appearance
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