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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
   T                also a (mature)B-cell
                      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            Site
EATL           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“          Polymorfní PTLD     Monomorfní PTLD     HL


         Polyklonální              Klonální       Sekundární
EBV      lymfoidní proliferace     populace       genetické změny


Plazmocytární
hyperplazie


                     Klesající imunitní odpověď
       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
                          Senile
                          EBV+
                  lymphoproliferations
                    no other overt ID,
                      only the age…




Oyama AJSP 2003
    EBV + senile lymphoproliferations

•   Rare
•   Asia
•   over 50
•   Various histological appearance

				
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