Boala Hodgkin

Definitie
Este o proliferare clonala a unor
celule limfoide.
Descrisa initial de Thomas Hodgkin in
1832 primul limfom descris
Linia celulara a ramas mult timp
subiect de dezbatere
Cercetari recente demonstreaza
originea in centrul germinal din
foliculii limfoizi secundari

 Mai frecventa in Europa si USA (mai

rara in Japonia).
Incidenta varstei de tip bimodal
varful major intre 20 si 29 ani si
varful minor la 60 ani.
Histologia cea mai frecventa este cu
Scleroza Nodulara (NS) in adultii
tineri (>75% dintre cazuri sunt < 40
ani)

Factori de risc
Status socioeconomic ridicat in copilarie si
rasa Caucasian in USA.
Agregare familiala frecventa risc crescut la
gemeni tineri
Legatura puternica cu infectia cu EBV : risc
crescut la tinerii cu infectie dovedita cu
mononucleoza infectioasa

Classificare (REAL, WHO)

1. HL cu predominenta nodulara limfocitara (NLPHL): 38%; contine
limfocite B mari atipice si histiocite (celule popcorn)
2. HL clasic: celule mari mononucleate (celule Hodgkin) sau binucleate /
multinucleate (Reed-Sternberg)

Patru tipuri histologice:

. Scleroza nodulara~80%;.
. Celularitate mixta ~17%;.
. Depletie limfocitara rar
. Predominenta limfocitara.

TABLOUL
CLINIC IN
BOALA
HODGKIN

Tablou clinic
Frecvent cu adenopatii supradiafragmatice
nedureroase, de consistenta ferma frecvent
localizate laterocervical
Diseminarea are loc prin contiguitate pe lantul
ganglionar.

Localizari frecvente: supraclavicular si axilar

Rara este afectat inelul Waldeyer.
Splenomegalie doar in ~30%
Hepatomegalie 5%.
Neobisnuit doar cu adenopatii abdominale fara
afectare splenica.

Hodgkins
lymphoma

 De obicei se asociaza afectarea

supradiafragmatica cu intraabdominala si rar
doar afectare regionala sau doar
subdiafragmatica
Adenopatiile voluminoase (bulky) mediastinal si
in hil pot produce simptome locale:
(ex. compresie bronsica sau de vena cava
superioara/VCS) sau extensie directa (ex. plaman,
pericard, pleura sau coaste). Pleurezie in 20%.

 Determinarea extranodala apare rar prin fluxul sanguin

(e.g. maduva osoasa (14%), plaman sau ficat).
Prezenta bolii generalizate este acompaniata cu
adenopatii generalizate si afectare splenica si semne
generale
2 ~33% au 1 simptome constitutionale B:
Scadere ponderala >10% in ultimele 6 luni,
febra
Transpiratii reci nocturne.

Se coreleaza cu boala extensiva si prognostic prost

Alte simptome specifice:

Prurit generalizat
durere ganglionara indusa de consumul de alcool

Sensibilitate la infectii cu tuberculoza, fungi,

protozoare si virusuri (germeni oportunisti)

Investigatii, diagnostic si
stadializare

Documentarea semnelor "Bdin istoric.

Examen clinic al determinarilor ganglionare.

Confirma diagnosticulprin biopsie ganglionara prin excizie

gg,
biopsieghidata prin CT
sauchiarlaparotomie,mediastinoscopie
saumediastinotomie

Stadializareaclinicsi imagistica

Stadializareapatologic necesit obiopsiede confirmare si

confirmareain site-urianormale.

Frotiul de sange periferic:

anemienormocromnormocitar,
leucocitozreactiv,
eozinofiliei/sau
usoaratrombocitozareactiv.

Radiografie toracica

CTpiept,abdomen si
pelvispentru a
definideterminarile oculte

PET-CT (tomografie cu
emisie de pozitroni) este
standardul

 Radiology
Chest X-ray, CT
scan
Abdominal
ultrasound
PET scan

Chest X-ray enlarged

mediastinum

CT scan -Mediastinal
lymphadenopathy

PET-scan metabolically active

mediastinal mass

 Biopsie osteomedulara pentru

aexcludedeterminareamedulara la
pacientiicustadiul III/IVboliisau
simptomeB(nu sunt esenialen faza
de IA/AIIbolii);
BMpoate
prezentacaracteristicireactive
Scintigrafieosoasa,RMN
Biopsiainalte site-urisuspectede
exemplu,hepaticesauosoase.

Clasificarea Ann Arbor

Stage I afectarea unui singur ganglion sau grup ganglionar
Stage II afectarea a cel putin 2 ganglion/grupuri ganglionare
de aceeasi parte a diafragmului
Stage III afectarea de ambele parti ale diafragmului
III1 splina, hil splenic, gg celiac sau portal;
III2 + gg para-aortici, iliaic sau mesenterici

Stage IV afectarea a cel putin unei localizari extranodale (e.g.

BM, ficat sau alte localizari extranodale).

A fara semne constitutionale

B semne B
Additional subscripts applicable to any disease stage:
X bulky disease (widening of mediastinum by >33% or mass >10cm)
E involvement of a single extranodal site contiguous or proximal to known nodal site.
CS clinical stage
PS pathological stage

Tratament
Initial evaluarea stadiului si factorilor
de prognostic nefavorabil
Boala localizata, stadiul I-II
Boala avansata, stadiul III-IV

EVOLUTIE, PROGNOSTIC
Cu tratament - 40 90% din pacienti sunt in RC
pe termen lung
Factori de prognostic nefavorabil:
histologie CM si DL
varsta > 40
sex masculin
simptome B
VSH > 40 mm/h
stadiu III/IV
bulky disease

Prognostic favorabil:
stadiul I sau II
fara nici un factor de risc

Tinta: cura cu efecte secundare minime.

Tratamentul chimioterapie, e.g. ABVD 4 cicluri
+ radioterapie determinari de boala IFR (36
40Gy).
evolutie: ~90% failure-free survival (FFS) si >95%
OS la 5 ani
Alternative: iradiere limfoida subtotala (3640Gy)

Prognostic nefavorabil:
stafiul I sau II HL cu orice factor de risc

Scop:cura cuunele
reaciiadverseacceptabile.
Esentiala este chimioterapia
combinata, e.g. ABVD 6 cicluri +
radioterapie (3640Gy)
evolutie: >85% DFS si~90% OS la 5
ani.
Optiune terapeutica alternativa:
MOPP-ABVD 6 cicluri + radioterapie
a localizarilor afectate (3640Gy)

Boala Hodgkin avansata

Stadiul III-IV
Sunt identificati 7 factori de prognostic:

Hb <10.5g/dL.
Sex masculin.
Stadiul IV.
Varsta 45.
WBC >16 x109/L.
Lymfopenia <0.6 x 109/L sau <8% in formula leucocitara.
Albumina serica <40g/L.

Chimioterapie combinata
Introduceipacientntr-un studiuclinic
randomizat,multicentric,dac este posibil.

regimstandard pentru pacientiicuBHavansat(stadiul IIIsau

IV), care nu este nscrisntr-un studiuclinic.
6-8cicluri deABVDa fost echivalentul a12 cicluri deMOPPABVDregimalternativ(CR82%fa de83%)
ABVDare un riscmult mai micde infertilitatederegimuri
deMOPPi nu este asociat cu un risc crescutdeleucemie,
daranthraciclinelepotexacerbacomplicaii
cardiaceipulmonaresecundareiradierii mediastinale.
De multe oriprosttoleratde pacienivrstnicidin
cauzadozeicumulativede doxorubicin(insuficienta cardiaca)
ibleomicina (fibroza pulmonara).
6-8 cicluri BEACOPP standard si regim escaladat

Alternative:durate scurte dedozeterapeuticeintensificate,de

exemplu,StanfordVdoze micicumulativedealchilanti,
doxorubicin ibleomicinade peste 12sptmni, urmate
deradioterapiein zonele cu detereminare(5
cm);FFS89%,riscfoartesczutdeleucemie.

Radioterapie adjuvanta
Radioterapiaeste
administratafrecventla
bolimediastinalevoluminoasedup
terminarea chimioterapiei

Radioterapia la debut doar in boala

cu mase tumorale mari si compresie
importanta

Terapie de salvare

> 50%dintre pacienirecad dupa

radioterapieprimarainstadiul incipient,desi se stie ca
HLpoatefi vindecat princhimioterapieABVD.

n general, FFPdurabilai supravieuireaprelungitnusunt

realizate dechimioterapie conventionalepentru pacienii
curecderidup chimioterapiainiial.

Dozele mari dechimioterapie

(HDT),cutransplantautolog desnge perifericde
celulestem(SCT) audevenitabordareade
salvarestandard pentru majoritatea pacienilor cu
recderidupchimioterapie,cu rate de raspuns
complet(de pnla 80%),remisiunidurabilecomplete
dela 40-65%i de morbiditatei mortalitateredus.
HDTplusSCTautologpoateficea mai buna
optiunepentru pacientiicuboala refractara
latratamentul iniial,
deipacieniicuboalprogresivlaterapiaconventionalaa
u nc un prognosticnefavorabil.

LIMFOAMELE MALIGNE
NONHODGKINIENE

ORGANELE LIMFOIDE:
Centrale: - maduva hematogena
- timusul
Periferice: - ganglioni
- splina
- tesut limfoid atasat
mucoaselor ( MALT)

Ganglionul
limfatic

Limfoamele maligne - definitie

Grup heterogen de boli neoplazice cu
originea in celulele sistemului imun
- incidenta 2- 3 % cazuri noi / an

Clasificarile vechi ale limfoamelor

si schemele de tipizare
Grupul limfoamelor este divers. Distinctia intre
diferitele tipuri de limfoame se bazeaza pe
caracteristicile diferite ale celulelor tumorale. Au
fost folosite de-a lungul anilor diferite sisteme de
clasificare:
Rappaport: utilizat inainte de anii 1970, s-a bazat
numai pe aspectul microscopic
Kiel: utilizat in special in Europa, se bazeaza pe
aspectul microscopic si imunologic (in functie de
tipul de proteine produse de celula), a fost
updatat in 1992.
National Cancer Institute's Working Formulation
(IWF): introdus in 1982, IWF imparte limfoamele
in low-grade, intermediate-grade and high-

Revised European-American Classification of

Lymphoid Neoplasms (REAL): introdus in
1994, REAL descrie diferitele tipuri de
limfoame ca entitati cu fiecare tip clasificate
in functie de originea celulara, bazat pe
apectul
morfologic,
imunologic si
criteriile genetice

Tratamentul pacientilor cu limfom a fost

afectat de lipsa uniformitatii dintre aceste
sisteme de clasificare

Vechile clasificari ale

limfoamelor
Working formulation
Low-grade

A.small lymphocytic, consistent with

well chronic lymphocytic leukemia (SL)

B.follicular, predominantly small cleaved

cell (FSC)

C.follicular, mixed small cleaved and

large cell (FM)
Intermediate-grade

D. follicular, predominantly large cell

(FL)

E. diffuse, small cleaved cell (DSC)

F. diffuse mixed, small and large (DM) G.

diffuse, large cell cleaved or noncleaved
cell (DL)
High-grade

H. immunoblastic, large cell (IBL)

I. lymphoblastic, convoluted or
nonconvoluted cell (LL)

J. small noncleaved cell, Burkitt's or nonBurkitt's (SNC)

Rappaport classification

diffuse lymphocytic differentiated

(DLWD)

nodular lymphocytic poorly

differentiated (NLPD)
nodular mixed, lymphocytic and
histiocytic (NM)

nodular histiocytic (NH)

diffuse lymphocytic poorly differentiated
(DLDP)
diffuse mixed, lymphocyticand
histiocytic (DM)

diffuse histiocytic (DH)

diffuse lymphoblastic (DL)

diffuse undifferentiated, Burkitt's or nonBurkitt's (DU)

R.E.A.L. CLASIFICATION OF LYMPHOPROLIFERATIVE

DISORDERS
B-cell neoplasms
I. Precursor B-cell neoplasm: precursor Blymphoblastic leukaemia/lymphoma
II. Peripheral B-cell neoplasms
A. B-cell chronic lymphocytic
leukaemia/prolymphocytic leukaemia/small
lymphocytic lymphoma
B. Lymphoplasmacytoid lymphoma/immunocytoma
C. Mantle cell lymphoma
D. Follicle center cell lymphoma, follicular
1. Provisional cytologic grades: I (small
cell), II (mixed small and large cell), III (large
cell)
2. Provisional subtype: diffuse,
predominantly small cell type
E. Marginal zone B-cell lymphoma
1. Extranodal (MALT-type +/- monocytoid B
cells)
2. Provisional subtype: nodal (+/monocytoid B cells)
F. Provisional entity: splenic marginal zone
lymphoma (+/- villous
lymphocytes)
G. Hairy cell leukaemia
H. Plasmacytoma/plasma cell myeloma
I. Diffuse large B-cell lymphoma
1. Subtype: primary mediastinal (thymic) Bcell lymphoma
J. Burkitt's lymphoma
K. Provisional entity: high-grade B-cell
lymphoma, Burkitt-like

T-cell and putative NK-cell neoplasms

I. Precursor T-cell neoplasm: precursor T-lymphoblastic
lymphoma/leukaemia
II. Peripheral T-cell and NK-cell neoplasms
A. T-cell chronic lymphocytic leukaemia/prolymphocytic
leukaemia
B. Large granular lymphocyte leukaemia
1. T-cell type
2. NK-cell type
C. Mycosis fungoides/Sezary's syndrome
D. Peripheral T-cell lymphomas, unspecified
1. Provisional cytologic categories: medium-sized cell,
mixed medium and large cell, large cell, lymphoepithelioid cell
2. Provisional subtype: hepatosplenic gamma/delta T-cell
lymphoma
3. Provisional subtype: subcutaneous panniculitic T-cell
lymphoma
E. Angioimmunoblastic T-cell lymphoma
F. Angiocentric lymphoma
G. Intestinal T-cell lymphoma (+/- enteropathy associated)
H. Adult T-cell lymphoma/leukaemia
I. Anaplastic large cell lymphoma
1. CD30+ -cell type
2. T-cell type
3. Null-cell types
J. Provisional entity: anaplastic large cell lymphoma,
Hodgkin's-like
Hodgkin's disease
I. Lymphocyte predominance
II. Nodular sclerosis
III. Mixed cellularity
IV. Lymphocyte depletion
V. Provisional entity: lymphocyte-rich classical Hodgkin's
disease

Clasificarea WHO a limfoproliferarilor

cronice
B-Cell Neoplasms
I. Precursor B-cell neoplasm:
a. Precursor Blymphoblastic leukemia/lymphoma
II. Mature (peripheral) B-cell neoplasms

B-cell chronic lymphocytic leukemia /

small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma

Splenic marginal zone B-cell lymphoma (+/villous lymphocytes)

Nodal marginal zone lymphoma (+/- monocytoid

B-cells)

Extranodal marginal zone B-cell lymphoma of

mucosa-associated lymphoid tissue (MALT) type

Hairy cell leuekmia

Plasma cell myeloma/plasmacytoma

Follicular lymphoma, follicle center

Mantle cell lymphoma

Diffuse large cell B-cell lymphoma

Mediastinal large B-cell lymphoma

Intravascular large B-cell lymphoma

Primary effusion lymphoma

Burkitt's lymphoma/Burkitt's cell leukemia

B-cell proliferations of uncertain malignant

potential

Lymphomatoid granulomatosis

Post-transplant lymphoproliferative disorder

T-Cell and Natural Killer Cell Neoplasms

I. Precursor T cell neoplasm:
a.Precursor T-lymphoblastic lymphoma/leukemia
b. Blastic NK lymphoma (new)
II. Mature (peripheral) T cell and NK-cell neoplasms

T cell prolymphocytic leukemia

T-cell granular lymphocytic leukemia

Aggressive NK Cell leukemia

Adult T cell lymphoma/leukemia (HTLV1+)

Extranodal NK/T-cell lymphoma, nasal type (new)

Enteropathy-type T-cell lymphoma

Hepatosplenic gamma-delta T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Mycosis fungoides/Szary's syndrome

Primary Cutaneous Anaplastic large cell lymphoma

T/null cell

Peripheral T cell lymphoma, unspecified

Angioimmunoblastic T cell lymphoma

Primary Systemic Anaplastic large cell lymphoma ,

T/null cell

T-cell proliferation of uncertain malignant potential

Lymphomatoid papulosis
Hodgkin's Lymphoma (Hodgkin's Disease) (B Cell Origin)

Nodular lymphocyte predominance Hodgkin's

lymphoma

Classical Hodgkin's lymphoma

Nodular sclerosis Hodgkin's lymphoma
Lymphocyte-rich classical Hodgkin's lymphoma
Mixed cellularity Hodgkin's lymphoma
Lymphocyte depletion Hodgkin's lymphoma

Epidemiologie
Mai frecvente
la barbati
Mai frecvente
la adult,
incidenta
creste cu
varsta
Varsta medie
de diagnostic
este 45-55 ani

Factori predispozanti (1)

Imunodeficiente
Infectii cronice
Sex masculin
Varsta
Istoric familial de limfom
Istoric de cancer
Expunere medicamente:
imunosupresive, antiepileptice, MTX

Factori predispozanti (2)

Ocupationali:
Ierbicide, pesticide, solventi, adezivi

Alti factori:
Coloranti de par
Factori nutritionali
Transfuzii sanguine

Factorii infectiosi

Limfoamele maligne - clasificare

Criterii de clasificare histologica:
- tipul celular celula mica ( centrocit)
- celula mare ( centroblast)
- modelul infiltrarii nodular
- difuz
- analiza imunohistochimica
- analiza genetica

Clasificarea REAL / WHO ( OMS)

Revised European American Lymphoma Classification

Limfoame cu celule B :
Limfoame cu celule B precursoare
Leucemie / limfom limfoblastic
cu celule B
Limfoame cu celule B periferice
LLC, LLP, limfom cu limfocite
mici
Imunocitom / limfom
limfoplasmocitic, Boala
Waldenstrom
Limfom de centru folicular
Limfom de zona marginala
Leucemia cu celule paroase
Limfom cu celule de manta
Plasmocitom / mielom
Limfom difuz cu celule mari
Limfom Burkitt

Limfoame cu celule T :
Limfoame cu celule T precursoare
Leucemii / limfoame limfoblastice
cu celule T
Limfoame cu celule T periferice
LLC, LLP
LGL (leucemia cu limfocite
granulare mari)
Micosis fungoides / sindrom
Sezary
Limfoame cu celule T periferice,
nespecific
Limfom angioimunoblastic
Limfom angiocentric
Limfom de tip intestinal
Limfom / leucemie cu celule T ale
adultului ( HTLV +)
Limfom cu celule mari anaplazic

Clasificarea REAL / WHO ( OMS)

clasificarea clinica
LIMFOAME / LEUCEMII INDOLENTE (netratate Sv in ani)

Limfoame cu celule B :
LLC, LLP,
limfom cu limfocite mici
Imunocitom / limfom
limfoplasmocitic, Boala
Waldenstrom
Limfom de centru folicular
Limfom de zona marginala
Leucemia cu celule paroase

Limfoame cu celule T :
LLC,
LGL (leucemia cu limfocite
granulare mari)
Micosis fungoides / sindrom
Sezary

Clasificarea REAL / WHO ( OMS)

clasificarea clinica
LIMFOAME AGRESIVE (netratate Sv in luni)

LIMFOAME CU CELULE B
Limfom cu celule de manta
Plasmocitom / mielom
Limfom difuz cu celule mari

LIMFOAME CU CELULE T

Leucemia prolimfocitara
Limfoame cu celule T periferice,
nespecific
Limfom angioimunoblastic
Limfom angiocentric
Limfom de tip intestinal
Limfom cu celule mari anaplazic

Clasificarea REAL / WHO ( OMS)

clasificarea clinica
LIMFOAME FOARTE AGRESIVE (netratate Sv in saptamani)

LIMFOAME CU CELULE B

LIMFOAME CU CELULE T

Leucemie / limfom limfoblastic

cu celule B
Limfom Burkitt

Leucemii / limfom limfoblastic cu

celule T
Limfom / leucemie cu celule T ale
adultului ( HTLV +)

Limfoamele maligne tablou clinic

Semne generale (B):
- febra fara alta cauza
- pierdere in greutate
- transpiratii
Semne legate de infiltarea tumorala
- adenomegalie
- hepatomegalie / splenomegalie
- extraganglionara ( digestiv, respirator,
cutanat, SNC ..)

Aggressive NHL Burkitts lymphoma

Aggressive NHL parotid

involvement

Conjunctival infiltration in a case of indolent NHL

(MALT)

Cutaneous T-Cell
Lymphoma
Mycosis fungoides

Mycosis fungoides
cutaneous tumors

Mycosis fungoides: erythroderma and

descuamation

Extranodal NHL thyroid and orbital involvement

Limfoamele maligne diagnostic

BIOPSIE ganglionara / tesut implicat
- amprenta = Ex. citologic
- sectiuni in parafina
= Ex. histologic
= Ex. Imunohistochimic
- Ex. imunofenotipare / Ex. genetic

Limfom gastric

Limfoamele maligne protocol

stadializare
Anamneza / Ex. obiectiv
Rx. Torace / TAC Torace
Eco. Abd. / TAC Abdomen
Biopsie medulara
Analize laborator: Hemograma, VSH,
Fbg, LDH, EF, 2 microglobulina
Cazuri speciale : Ex ORL, EDS, RMN,
Scintigrafie osoasa,

Limfom mediastinal primitiv

Case 1. Westley C. Evans et al. J. Nucl. Med. Technol. 2011;39:190-194

(c) Copyright 2014 SNMMI; all rights reserved

Limfoamele maligne stadializare

(Clasificarea Ann Arbor)
Stadiul I un singur grup ganglionar
Stadiul II doua grupe ggl. de aceeasi parte a
diafragmului
Stadiul III grupe ggl. de ambele parti ale
diafragmului
Stadiul IV interesare viscerala
Substadii: A = fara semne generale
B = cu semne generale

International Prognostic Index IPI

Factor advers

Grup de risc

Numar de factori

Status de performanta
ECOG >2

Jos

0,1

LDH>normal

Jos-intermediar

Localizari extranodale

Inalt-intermediar

Stadiul III/IV

Inalt

4,5

Varsta > 60 ani

Limfoamele maligne - tratament

Limfoamele indolente:
- Leukeran
- cura CVP: Ciclofosfamida 400mg/m2/ zi Z1->5
Vincristin 1,4 mg/ m2 /zi Z1
Prednison 100 mg / zi Z1->5
- Fludarabina
- splenectomia
- radioterapia
- INTERFERON / CLADRIBIN / PENTOSTATIN =>HCL
- Anticorpi Monoclonali anti CD 20 ( RITUXIMAB)

Limfoamele maligne - tratament

Limfoamele agresive :
- Cura CHOP: Ciclofosfamida 750mg/m2/ zi Z1
Adriamicin 50 mg/m2/ zi Z1
Vincristin 1,4 mg/ m2 /zi Z1
Prednison 100 mg / zi Z1->5
- combinatii cu MTX, Cytosar
- radioterapia
- Anticorpi Monoclonali anti CD 20 ( RITUXIMAB)
- transplant medular

Limfoamele maligne - tratament

Limfoamele foarte agresive :
- Cura citostatice similare cu cele din LAL
- profilaxia SNC
- transplant medular