欧兽-血液学录音课件-23.犬恶性淋巴瘤

Malignant

lymphoma

inthe

dog犬的恶性淋巴瘤Erik

Teske,

PhD,

Dip

ECVIM

CAUtrecht

UniversityCanine

Malignant

Lymphoma犬恶性淋巴瘤Annual

Incidence

Rate:

30

100/100.000

dogsNo

sex

predilectionIn

Golden

Retrievers

(both

♀,

♂)

castrated

dogs

higher

risk

onlymphoma

Breed

predisposition:

several

(Scottish

terrier!)

Age

>

½year,

peak

6-7

years

Weight:

Especially

large

dogs.

Related

with

breed?

Within

breedno

influence

年

没有

在金毛为：30-100/100.000个狗偏好（包括♀，♂）绝育的患淋巴瘤的风险较高品种倾向：一些（苏格兰梗！）>半岁， 期6

7岁重量：尤其是大型犬。与相关品种？在品种内无影响Pathogenesis

病理学

Viral

infection

??????

Genetic

predisposition

Pesticides:

Risk ≈

1.5xhigher

Dogswith

atopicdermatitis:

12x

higherrisk

on

cutaneous

lymphoma

?????

Oxidative

stress?？？？？？？遗传易感性

杀虫剂：风险≈高1.5倍

犬异位性皮炎

皮肤淋巴瘤的风险

高

12倍?????氧化应激？Breeds

at

higher

risk高风险品种

Scottish

terrier!苏格兰梗

Large

size

breeds:大尺寸的品种：BerneseMountain

Dogs

伯恩山犬Retrievers寻回犬Bouvier布维尔Rott

罗威那Doberman杜宾

Smaller

size

breeds

usually

less

often(Geographic

differences)较小尺寸的品种通常WHO

classification

caninemalignant

lymphomaGene

alized全身性Alimentar

消化道Thymic胸腺Skin皮肤Leukemic

(t

ue)白血病性（真性O

he (including

s

tary

enal)其他

包括单独肾性）Primary

Cutaneous

Lymphomas性皮肤淋巴瘤

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)亲上皮细胞的（T

细胞来源）

在狗最常见

猫罕见

T细胞趋向为表皮和上皮附属器非亲上皮细胞的（通常是B细胞来源）Plaques/Patches

斑块Volume

21,

Issue

3,Hypopigmentation

and

erythema色素减少和红肿Volume

21,

Issue

3,Erosion

and

haemorrhageof the

oral

mucosa

andmuco-cutaneous

junction糜烂和口腔黏膜及粘膜皮肤交界处Extensive

alopecia广泛性脱毛Volume

21,

Issue

3,Clinical

Symptoms

I症状ILymphadenopathy

(痛ess)淋巴腺病

无Dyspnea

呼吸Lymph

node/thymus淋Liquothorax水胸/胸腺

Abdominal

enlargement腹部变大Liver,spleen肝脾Ascites腹水

Tenesmus里急后重Clinical

Symptoms

II症状II

Fat

e

Weight

loss

Fever

Vomiting,

diarrhea

Polyuria/polydipsia

虚弱

体重下降

发热

拉稀

多尿多饮AnemiaCoagulopathyNeural

signs/blindnessSkin

lesions贫血凝血问题神经症状/失明皮肤病灶Diagnosis

II

Hematologic

abnormalities

Leukocy ymphocyte

count:

notspecific!

Presence

of

pathological

lymphocytes

Biochemistry

Hypercalcemia

(10-30%)

Monoclonal

gammapathy

(rare!)血液异常没有特性！白细胞/淋巴细胞计数病理淋巴细胞的存在生物化学

高钙血症（10

30％）单克隆丙种球蛋白病（罕见！）Diagnosis

II

II

Fine

needleaspiration

biopsy

+

Cytology

Ultrasound

X

ray

Endoscopy

Serum

markers?

(e.g

thymidine

kinase

1)

PARR

test

(PCR

Antigen

Receptors

Rearrangements)

(Histology)

细针穿刺活检+细胞学

超声

X

射线

内窥镜标志物？ 如胸苷激酶1）PARR测试（PCR抗原受体重排）（组织学）Endoscopy

+

biopsy内窥镜采样Labrador

retriever.

Male.

4

y.

Malignant

Lymphoma

Colon拉布拉多，公，4岁，恶性淋巴瘤，结肠When

diagnosis

uncertain

=>

extra

diagnostictool:Diagnosis

of canine

lymphoid

neoplasia

usingclonal

rearrangements

of antigen

receptor

genes:PARR

test当不确定

=>额外的 工具：使用克隆重排抗原受体 犬淋巴肿瘤：>PARR测试Atleast

50

000

cells

needed至少要50000细胞PARRSensitivity:

66-91%;Good

correlation

withimmunophenoty

eBoth

on

formalin

and

aspiration

biopsiesSpecificity

90%:

False

positives

possibleCat:

sensitivity

B

cell:

60%,

T

cell:

89%灵敏度：66

91％;与免疫分型有良好的相关性福尔 和抽吸活检都可以特异性90％：可能假阳性猫

B细胞

灵敏度：60％，T细胞：89％Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的

需要组织学Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的

需要组织学

免疫组化Diagnosis

cutaneous

lymphoma皮肤淋巴瘤的

需要组织学

免疫组化重排Histological

Classification

of

Lymphomas淋巴瘤的组织学分类干细胞前体细胞T免疫母细胞T相关浆细胞淋巴浆细胞样细胞成中心母细胞中心细胞B免疫母细胞浆细胞Kiel-ClassificationLow

grade

malignant

lymphomasKiel

分类低程度恶性淋巴瘤centroblastic/centrocytic成中心母细胞/中心细胞LP-immunocytoma淋巴浆细胞样-免疫细胞瘤monomorphic单型性polymorphic多型性centrocytoid中心细胞样Immunoblastic免疫母细胞Kiel-ClassificationHigh

grade

malignantlymphomasKiel-分类高程度恶性淋巴瘤Centroblastic:中心细胞Importance

of histological

classification组织学分类重点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

………=>细分恶性程度低VS高是非常重要的可以从细胞的不同形态知道恶性程度的高低这些细分类是在此刻不那么重要更重要的是.........

>Immunophenoty

of

CanineMalignant

Lymphomas犬恶性淋巴瘤的免疫表型Current

routine

immunophenoty现有的常见免疫表型

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细胞

CD3用于T细胞

（κ/λ：95％的B细胞瘤是λ阳性）B-cell

marker

CD79aB细胞标记CD79a►Immunophenoty on

smears涂片上的免疫表型Reactive

lymph

node反应性淋B-celllymphomaB细胞淋巴瘤Flowcytometry流式细胞仪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％为高程度和20％低程度三分之二犬淋巴瘤是B细胞和三分之一T细胞淋巴瘤在B细胞淋巴瘤中85％是高程度和15％低程度

T细胞淋巴瘤中63％是高程度和37％低程度Summary

Immunophenotype总结免疫表型To

be

demonstrated

with

CD79a

and

CD3用与CD79A和CD3来表示Not

related

with

age与

无关Related

with

certain

breeds

(eg

boxer),h wever

geographydependent与一些品种（如拳师犬）相关，但有地理区别Related

with

certain

chromosome

abnormalities与某些

异常相关Hy ercalcemia

related

with

T-cell

lymphomaT细胞淋巴瘤有关Related

with

prognosis

相关预后REAL

Classification

(Revised

EuropeanAmerican

Lymphoma

Classification)Summary

classification分类总结

Identify

different

prognostic

groups

Important

for

future

treatments:Small

T

cell

lymphoma

less

aggressively

treated?Large

T-cell

lymphoma

treated

differently

from

Bcell

lymphomas?

确定不同预后组

对今后的治疗方法有重要意义小T细胞淋巴瘤不用太积极的治疗？大T细胞淋巴瘤治疗与B细胞淋巴瘤不同？WHO

Clinical

Staging

System

(1980)WHO临床分期系统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阶段一个淋 或淋巴（±扁桃体）

在一个区域>1淋

多个地方及多个淋

肝脏和/或脾脏

血液和骨髓/其他无全身症状Routine

bone

marrow

aspirates

for

staging?进行常规骨髓穿刺进行分期Much

debated

备受争议Stage

V

(leukemic/Bone

marrow

pos)have

worseprognosis

第五阶段（白血病/骨髓POS）预后差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血小板减少，白细胞增多/淋巴细胞增多：是骨髓白血病的风险较高

Peripheral

blood

not

always

pr

dictive

for

leukemic

bon

marrow外周血并不总是能

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：血液学+生化骨髓超声腹部X射线胸部Treatment

modalities

in

caninemalignant

lymphomaTreatment

of

multicentric

lymphomaISurgery

(Stage

I

disease?;

splenectomy?Hormonal3)

ChemotherapyMulticentric

lymphomaNo

treatment:median

survival

6weeks不治疗：平均生存期6周Corticosteroids:糖皮质激素：CR-rates

17

43%CR-率17

43％Remission

times:

1

2month

缓解时间：1

2个月Median

survival:

2-3

months

平均生存期：2

3个月Chemotherapy:化疗-

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%

两年生存率20

25％Monotherapy

vsMulti-agent

Therapy单疗法VS多项治疗VCR,CTX,PRED7775VCR,CTX,PRED长春新碱，环磷酰胺，2070VCR,CTX,MTX,ASP5990VCR,CTX,DOX,PREDVCR,CTX,DOX,ASP,PREDVCR,CTX,DOX,ASP,PREDMost

standard

multicentric

protocols:被广泛使用的多中心淋巴瘤治疗方法

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（环磷酰胺

多柔比星

长春新碱和 龙

）比如MW-流程 汉诺威和乌得勒支流程在人医中也应用有时用左旋门冬酰胺酶在狗直到近期B细胞和T细胞淋巴瘤和低VS高程度瘤没有不同的治疗方法

这将改变+300

mg/m2

p.o.环磷酰胺+Doxorubicin

30mg/m2

i.v.柔比星CHOP

protocolCHOP

疗程时间（天）Toxicity毒性

Usually

well

tolerated

通常难受程度好al

experiences

个人经验Only

30%

of

dogs

willvomit only

1/3

will

need

tr

atment

for

this只有30%狗会 ，只有1/3需要治疗

Hardly

ever

hospitalization

neededAlopecia

only

ins ecial

breeds(curly

coated

breeds)仅在特殊品种会脱毛（卷毛品种）Sometimes

pe

ivascular

problems

seen

(few

cases

during

30

yea

s)有时血管周有问题（30年 数病例）Toxicity毒性

Usually

well

tolerated

通常难受程度好al

experiences

个人经验Only

30%

of

dogs

willvomit only

1/3

will

need

tr

atment

for

this只有30%狗会 ，只有1/3需要治疗

Hardly

ever

hospitalization

neededAlopecia

only

ins ecial

breeds(curly

coated

breeds)仅在特殊品种会脱毛（卷毛品种）Sometimes

pe

ivascular

problems

seen

(few

cases

during

30

yea

s)有时血管周有问题（30年 数病例）Prognostic

Criteria预后指标StageHistol cal

GradeImmunophenotypePrilferation

markers

(AgNOR)Pretreatment

with

corti

ost

roids阶段组织学分级免疫表型扩散标记（嗜银蛋白）用皮质类固醇预治疗ProliferationsmarkerAgNORsLow

Grade-低程度and

High

GradeMalignant

Lymphoma高程度的恶性淋巴瘤Prognostic

Factor:预后因素：Hypercalcemia??高钙血症Prognostic

Factor:预后因素：Hypercalcemia??高钙血症T-celllymphomaT细胞淋巴瘤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

选择不被多药耐药影响的药物，例如左旋门冬酰胺酶环磷酰胺异环磷酰胺不要预先使用皮质类固醇维持治疗可能导致多药物耐受Whichcytostatic

drugs

to

choose

afterrelapse?复发后有什么细胞抑制药物？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:趋上皮性淋巴瘤平均生存时间：2.6月(2-24个月)

猫:平均生存时间：10,5个月（2.5个月

4年)Treatment

canine

cutaneous

lymphomasLomustine

as

treatment

for

canine

cutaneous

lymphoma洛莫司汀治疗皮肤淋巴瘤(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