Malignant

lymphoma

inthe

dog犬的惡性淋巴瘤Erik

Teske,

PhD,

Dip

ECVIM

CAUtrecht

UniversityCanine

Malignant

Lymphoma犬惡性淋巴瘤Annual

Incidence

Rate:

30

100/100.000

dogsNo

sex

predilectionIn

Golden

Retrievers

(both

♀,

♂)

castrated

dogs

higher

risk

onlymphoma

Breed

predisposition:

several

(Scottish

terrier!)

Age

>

?year,

peak

6-7

years

Weight:

Especially

large

dogs.

Related

with

breed?

Within

breedno

influence

年

沒有

在金毛為：30-100/100.000個(gè)狗偏好（包括♀，♂）絕育的患淋巴瘤的風(fēng)險(xiǎn)較高品種傾向：一些（蘇格蘭梗?。?gt;半歲， 期6

7歲重量：尤其是大型犬。與相關(guān)品種？在品種內(nèi)無影響Pathogenesis

病理學(xué)

Viral

infection

??????

Genetic

predisposition

Pesticides:

Risk ≈

1.5xhigher

Dogswith

atopicdermatitis:

12x

higherrisk

on

cutaneous

lymphoma

?????

Oxidative

stress?？？？？？？遺傳易感性

殺蟲劑：風(fēng)險(xiǎn)≈高1.5倍

犬異位性皮炎

皮膚淋巴瘤的風(fēng)險(xiǎn)

高

12倍?????氧化應(yīng)激？Breeds

at

higher

risk高風(fēng)險(xiǎn)品種

Scottish

terrier!蘇格蘭梗

Large

size

breeds:大尺寸的品種：BerneseMountain

Dogs

伯恩山犬Retrievers尋回犬Bouvier布維爾Rott

羅威那Doberman杜賓

Smaller

size

breeds

usually

less

often(Geographic

differences)較小尺寸的品種通常WHO

classification

caninemalignant

lymphomaGene

alized全身性Alimentar

消化道Thymic胸腺Skin皮膚Leukemic

(t

ue)白血病性（真性O(shè)

he (including

s

tary

enal)其他

包括單獨(dú)腎性）Primary

Cutaneous

Lymphomas性皮膚淋巴瘤

Epitheliotropic

(T

cell

origin)Most

common

in

the

dogRare

in

the

catTropism

of T

cells

for

epidermis

and

adnexalepithelium

Non

epitheliotropic

(usually

B

cell

origin)親上皮細(xì)胞的（T

細(xì)胞來源）

在狗最常見

貓罕見

T細(xì)胞趨向?yàn)楸砥ず蜕掀じ綄倨鞣怯H上皮細(xì)胞的（通常是B細(xì)胞來源）Plaques/Patches

斑塊Volume

21,

Issue

3,Hypopigmentation

and

erythema色素減少和紅腫Volume

21,

Issue

3,Erosion

and

haemorrhageof the

oral

mucosa

andmuco-cutaneous

junction糜爛和口腔黏膜及粘膜皮膚交界處Extensive

alopecia廣泛性脫毛Volume

21,

Issue

3,Clinical

Symptoms

I癥狀I(lǐng)Lymphadenopathy

(痛ess)淋巴腺病

無Dyspnea

呼吸Lymph

node/thymus淋Liquothorax水胸/胸腺

Abdominal

enlargement腹部變大Liver,spleen肝脾Ascites腹水

Tenesmus里急后重Clinical

Symptoms

II癥狀I(lǐng)I

Fat

e

Weight

loss

Fever

Vomiting,

diarrhea

Polyuria/polydipsia

虛弱

體重下降

發(fā)熱

拉稀

多尿多飲AnemiaCoagulopathyNeural

signs/blindnessSkin

lesions貧血凝血問題神經(jīng)癥狀/失明皮膚病灶Diagnosis

II

Hematologic

abnormalities

Leukocy ymphocyte

count:

notspecific!

Presence

of

pathological

lymphocytes

Biochemistry

Hypercalcemia

(10-30%)

Monoclonal

gammapathy

(rare!)血液異常沒有特性！白細(xì)胞/淋巴細(xì)胞計(jì)數(shù)病理淋巴細(xì)胞的存在生物化學(xué)

高鈣血癥（10

30％）單克隆丙種球蛋白病（罕見?。〥iagnosis

II

II

Fine

needleaspiration

biopsy

+

Cytology

Ultrasound

X

ray

Endoscopy

Serum

markers?

(e.g

thymidine

kinase

1)

PARR

test

(PCR

Antigen

Receptors

Rearrangements)

(Histology)

細(xì)針穿刺活檢+細(xì)胞學(xué)

超聲

X

射線

內(nèi)窺鏡標(biāo)志物？ 如胸苷激酶1）PARR測試（PCR抗原受體重排）（組織學(xué)）Endoscopy

+

biopsy內(nèi)窺鏡采樣Labrador

retriever.

Male.

4

y.

Malignant

Lymphoma

Colon拉布拉多，公，4歲，惡性淋巴瘤，結(jié)腸When

diagnosis

uncertain

=>

extra

diagnostictool:Diagnosis

of canine

lymphoid

neoplasia

usingclonal

rearrangements

of antigen

receptor

genes:PARR

test當(dāng)不確定

=>額外的 工具：使用克隆重排抗原受體 犬淋巴腫瘤：>PARR測試Atleast

50

000

cells

needed至少要50000細(xì)胞PARRSensitivity:

66-91%;Good

correlation

withimmunophenoty

eBoth

on

formalin

and

aspiration

biopsiesSpecificity

90%:

False

positives

possibleCat:

sensitivity

B

cell:

60%,

T

cell:

89%靈敏度：66

91％;與免疫分型有良好的相關(guān)性福爾 和抽吸活檢都可以特異性90％：可能假陽性貓

B細(xì)胞

靈敏度：60％，T細(xì)胞：89％Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的

需要組織學(xué)Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的

需要組織學(xué)

免疫組化Diagnosis

cutaneous

lymphoma皮膚淋巴瘤的

需要組織學(xué)

免疫組化重排Histological

Classification

of

Lymphomas淋巴瘤的組織學(xué)分類干細(xì)胞前體細(xì)胞T免疫母細(xì)胞T相關(guān)漿細(xì)胞淋巴漿細(xì)胞樣細(xì)胞成中心母細(xì)胞中心細(xì)胞B免疫母細(xì)胞漿細(xì)胞Kiel-ClassificationLow

grade

malignant

lymphomasKiel

分類低程度惡性淋巴瘤centroblastic/centrocytic成中心母細(xì)胞/中心細(xì)胞LP-immunocytoma淋巴漿細(xì)胞樣-免疫細(xì)胞瘤monomorphic單型性polymorphic多型性centrocytoid中心細(xì)胞樣Immunoblastic免疫母細(xì)胞Kiel-ClassificationHigh

grade

malignantlymphomasKiel-分類高程度惡性淋巴瘤Centroblastic:中心細(xì)胞Importance

of histological

classification組織學(xué)分類重點(diǎn)Subdivision

in

low

grade

malignancy

vs

high

grademalignancy

is

importantKnowing

that

within

these

grades

different

morphologicalpictures

can

beseenThese

subclassifications

are

at

this

moment

less

importantMore

important

is

………=>細(xì)分惡性程度低VS高是非常重要的可以從細(xì)胞的不同形態(tài)知道惡性程度的高低這些細(xì)分類是在此刻不那么重要更重要的是.........

>Immunophenoty

of

CanineMalignant

Lymphomas犬惡性淋巴瘤的免疫表型Current

routine

immunophenoty現(xiàn)有的常見免疫表型

CD21/CD79a/PAX

5

for

B

cell

CD3

for

T

cell

(Kappa/Lambda:

95%

of B

cell

tumours

is

lambdapositive)

On

histology

orcytology

slides

or

with

flowcytometry

CD21/CD79A/

PAX-5用于B細(xì)胞

CD3用于T細(xì)胞

（κ/λ：95％的B細(xì)胞瘤是λ陽性）B-cell

marker

CD79aB細(xì)胞標(biāo)記CD79a?Immunophenoty on

smears涂片上的免疫表型Reactive

lymph

node反應(yīng)性淋B-celllymphomaB細(xì)胞淋巴瘤Flowcytometry流式細(xì)胞儀Combined

histology

andimmunophenotype

Some

80%of

canine

lymphomas

are

high

grade

and

20%

lowgrade

Two

third

of

canine

lymphomas

are

B

celland

one-third

TcelllymphomasOf

the

B

celllymphomas

85%is

high

grade

and

15%

low

gradeOf

the

T-cell

lympho 63%

is

highgra e

and

37%

low

grade

犬淋巴瘤的80％為高程度和20％低程度三分之二犬淋巴瘤是B細(xì)胞和三分之一T細(xì)胞淋巴瘤在B細(xì)胞淋巴瘤中85％是高程度和15％低程度

T細(xì)胞淋巴瘤中63％是高程度和37％低程度Summary

Immunophenotype總結(jié)免疫表型To

be

demonstrated

with

CD79a

and

CD3用與CD79A和CD3來表示Not

related

with

age與

無關(guān)Related

with

certain

breeds

(eg

boxer),h wever

geographydependent與一些品種（如拳師犬）相關(guān)，但有地理區(qū)別Related

with

certain

chromosome

abnormalities與某些

異常相關(guān)Hy ercalcemia

related

with

T-cell

lymphomaT細(xì)胞淋巴瘤有關(guān)Related

with

prognosis

相關(guān)預(yù)后REAL

Classification

(Revised

EuropeanAmerican

Lymphoma

Classification)Summary

classification分類總結(jié)

Identify

different

prognostic

groups

Important

for

future

treatments:Small

T

cell

lymphoma

less

aggressively

treated?Large

T-cell

lymphoma

treated

differently

from

Bcell

lymphomas?

確定不同預(yù)后組

對今后的治療方法有重要意義小T細(xì)胞淋巴瘤不用太積極的治療？大T細(xì)胞淋巴瘤治療與B細(xì)胞淋巴瘤不同？WHO

Clinical

Staging

System

(1980)WHO臨床分期系統(tǒng)Stage12345One

lymph

node

/

lymphoid

organ>1

lymph

nodes

in

1

region

(±tonsils)More

lymph

nodes

in re

than

1

regionLiver

and/or

spleenBlood

and

bone

marrow/other

organsWithout

systemic

signsWith

systemic

signs階段一個(gè)淋 或淋巴（±扁桃體）

在一個(gè)區(qū)域>1淋

多個(gè)地方及多個(gè)淋

肝臟和/或脾臟

血液和骨髓/其他無全身癥狀Routine

bone

marrow

aspirates

for

staging?進(jìn)行常規(guī)骨髓穿刺進(jìn)行分期Much

debated

備受爭議Stage

V

(leukemic/Bone

marrow

pos)have

worseprognosis

第五階段（白血病/骨髓POS）預(yù)后差Zandvliet

et

al,

Vet

J

2013:

Zandvliet等人

Leukemic

Peripheral

Blood:15%

外周性白血病Vet

J

2013:15％

Leukemic

Bone

Marrow:

33%

骨髓性白血病

33％Martini

et

al,

VCO

2013:

Martini等，VCO2013：

hrombocytopenia,leucocytosis/lymphocytosis:higher

risk

forleukemicbonemarrow血小板減少，白細(xì)胞增多/淋巴細(xì)胞增多：是骨髓白血病的風(fēng)險(xiǎn)較高

Peripheral

blood

not

always

pr

dictive

for

leukemic

bon

marrow外周血并不總是能

骨髓白血病Complete

staging完成分期Peripheral

lymph

nodesPeripheral

blood:

Hematology

bio

hemistryBone

marrowUltraso

abdomenX-ray

thorax外周淋外周血：血液學(xué)+生化骨髓超聲腹部X射線胸部Treatment

modalities

in

caninemalignant

lymphomaTreatment

of

multicentric

lymphomaISurgery

(Stage

I

disease?;

splenectomy?Hormonal3)

ChemotherapyMulticentric

lymphomaNo

treatment:median

survival

6weeks不治療：平均生存期6周Corticosteroids:糖皮質(zhì)激素：CR-rates

17

43%CR-率17

43％Remission

times:

1

2month

緩解時(shí)間：1

2個(gè)月Median

survival:

2-3

months

平均生存期：2

3個(gè)月Chemotherapy:化療-

CR

rates

75

85% CR率75

85％-

One-years

survival

rate:

45-50

一年生存率：45％50％-

Two

yea

s

su

vival

rate:

20

25%

兩年生存率20

25％Monotherapy

vsMulti-agent

Therapy單療法VS多項(xiàng)治療VCR,CTX,PRED7775VCR,CTX,PRED長春新堿，環(huán)磷酰胺，2070VCR,CTX,MTX,ASP5990VCR,CTX,DOX,PREDVCR,CTX,DOX,ASP,PREDVCR,CTX,DOX,ASP,PREDMost

standard

multicentric

protocols:被廣泛使用的多中心淋巴瘤治療方法

CHOP

based

(Cyclophosphamide,

doxorubicine,

vincristin

andprednisolon)tr ht

prot

colsExamples

MW-prot cols,

Hannover

andAlso

in

humans!Sometimes

with

L-asparaginaseIn

dogs

up

to

recently

no

different

protocols

for

B

vs

Tcell

lymphomaand

Lowvs

High

grade:

this

will

change!基于CHOP（環(huán)磷酰胺

多柔比星

長春新堿和 龍

）比如MW-流程 漢諾威和烏得勒支流程在人醫(yī)中也應(yīng)用有時(shí)用左旋門冬酰胺酶在狗直到近期B細(xì)胞和T細(xì)胞淋巴瘤和低VS高程度瘤沒有不同的治療方法

這將改變+300

mg/m2

p.o.環(huán)磷酰胺+Doxorubicin

30mg/m2

i.v.柔比星CHOP

protocolCHOP

療程時(shí)間（天）Toxicity毒性

Usually

well

tolerated

通常難受程度好al

experiences

個(gè)人經(jīng)驗(yàn)Only

30%

of

dogs

willvomit only

1/3

will

need

tr

atment

for

this只有30%狗會 ，只有1/3需要治療

Hardly

ever

hospitalization

neededAlopecia

only

ins ecial

breeds(curly

coated

breeds)僅在特殊品種會脫毛（卷毛品種）Sometimes

pe

ivascular

problems

seen

(few

cases

during

30

yea

s)有時(shí)血管周有問題（30年 數(shù)病例）Toxicity毒性

Usually

well

tolerated

通常難受程度好al

experiences

個(gè)人經(jīng)驗(yàn)Only

30%

of

dogs

willvomit only

1/3

will

need

tr

atment

for

this只有30%狗會 ，只有1/3需要治療

Hardly

ever

hospitalization

neededAlopecia

only

ins ecial

breeds(curly

coated

breeds)僅在特殊品種會脫毛（卷毛品種）Sometimes

pe

ivascular

problems

seen

(few

cases

during

30

yea

s)有時(shí)血管周有問題（30年 數(shù)病例）Prognostic

Criteria預(yù)后指標(biāo)StageHistol cal

GradeImmunophenotypePrilferation

markers

(AgNOR)Pretreatment

with

corti

ost

roids階段組織學(xué)分級免疫表型擴(kuò)散標(biāo)記（嗜銀蛋白）用皮質(zhì)類固醇預(yù)治療ProliferationsmarkerAgNORsLow

Grade-低程度and

High

GradeMalignant

Lymphoma高程度的惡性淋巴瘤Prognostic

Factor:預(yù)后因素：Hypercalcemia??高鈣血癥Prognostic

Factor:預(yù)后因素：Hypercalcemia??高鈣血癥T-celllymphomaT細(xì)胞淋巴瘤Dose

escalation:Short/intense

vs

continous

treatment:

Choose

drug

that

is

not

influenced

by

MDR,

e.g.L-asparaginaseCyclophosphamideIfosfamide

Do

not

pre-treat

dogs

with

orticosteroids

Maintenance

therapy

might

induce

MDR

Type

of

re-induction

depending

also

on

time

ofrelapse

(effectivity

1sttreatment)

Some

combination

protocols

are

probably

better

than

monodrug

treatments

選擇不被多藥耐藥影響的藥物，例如左旋門冬酰胺酶環(huán)磷酰胺異環(huán)磷酰胺不要預(yù)先使用皮質(zhì)類固醇維持治療可能導(dǎo)致多藥物耐受Whichcytostatic

drugs

to

choose

afterrelapse?復(fù)發(fā)后有什么細(xì)胞抑制藥物？Treatment

of

extranodal

lymphomasPrognosis

epitheliotropiccutaneous

lymphoma

Dog:

median

survival

time

epidermotropiclymphomas:

2.6

month

(2

24

months)

Cat:

median

survival

time:

10,5

months

(2,5

months4

years)

狗:趨上皮性淋巴瘤平均生存時(shí)間：2.6月(2-24個(gè)月)

貓:平均生存時(shí)間：10,5個(gè)月（2.5個(gè)月

4年)Treatment

canine

cutaneous

lymphomasLomustine

as

treatment

for

canine

cutaneous

lymphoma洛莫司汀治療皮膚淋巴瘤(Risbon

etal,JIVM

2006+

Williams

et

al,

JVIM

2006)

Lomustine

(60

70

mg/m2

every

other

3

weeks)

82

dogs:

21xComplete

and

45x

Partial

Responses

Median

response

duration:88-94

days

17/82

dogs

neede